MOH Systemic Therapy Protocol 2011

ACKNOWLEDGEMENTS
We are grateful for positive feedback and constructive criticisms since the initial
protocol was prepared in 2004. This has been a great team effort with input from
oncologists and other specialists involved with cancer treatment, from both public and
private sectors around the country. There were also valuable contributions from the
pharmacists working as the secreteriat and also on chapters related to drug
reconstitution, extravasation and management of cytotoxic drug spillage.
The initial draft of the protocol was completed at the end of 2007. A revision of
the protocol was done in response to suggestions that the references and the
literature used in the second revision be updated before being distributed. I would
like to thank Assoc. Professor Dato‘ Dr Fuad Ismail and fellow members of the
working group who have put in a lot of work and effort into the initial draft and this
revision of the Protocol of Systemic Therapy.
I would also like to thank the Director-General of Health for his encouragement
towards the revision of the protocol of systemic therapy.
It is hoped that this revised protocol will be more useful and effective as a reference
for the practice of systemic therapy for adult patients with solid tumours.
Dr Gerard Lim Chin Chye

National Advisor for Radiotherapy and Oncology
Ministry of Health of Malaysia
Systemic Therapy of Cancer 2nd Edition Page 1 of 150

Ministry of Health and Ministry of Higher Education, Malaysia
FOREWORD
It is very commendable that the protocol for systemic therapy has been updated with
recent evidence from trials, and has been discussed among oncologists and other
specialists involved in the care of cancer patients in Malaysia. Although many new
drugs are now in the market, the choice of drugs used or the regimes employed must
be such that the greatest number of patients will benefit within a budget that is
sustainable. In this day and age of increasing health care costs, an endeavour such
as the judicious and practical revision of the protocol of systemic therapy would add
value to the treatment offered to cancer patients.
I support the multidisciplinary team approach to the care of cancer patients,

and the team work involved in this protocol revision augurs well for the future and
closer collaboration can only work out for the improved outcomes for the patients. I
am happy to note the roles of the different specialists and allied health staff in the
initiation, prescription, preparation, delivery and disposal of chemotherapy. It is
important that the most adequately trained staff be given the appropriate
responsibilities, as chemotherapy is a procedure that has considerable risk of side
effects which are often life threatening.
The oncologists and other specialists have worked very hard in adapting and
adopting the available evidence in the development of a standard treatment guideline
that is timely and relevant.
I would like thank Associate Prof. Dato‘ Dr Fuad Ismail who was given the task
to chair the committee for revision of this protocol, as well as the rest of the team,
including the pharmacists who have contributed to the success of this protocol. I
hope that the healthy cooperation and discussion between specialists in the various
fields and sectors in the preparation of this protocol revision will continue to grow and
flourish.
Once again congratulations to the team involved in preparing this protocol.
Y BHG TAN SRI DATO‘ SRI DR HAJI MOHD ISMAIL MERICAN

Director General of Health Malaysia

CONTENTS
PAGE
1. INTRODUCTION 4
2. OBJECTIVES 5
3. How to use this book 6
4. New Cancer Drugs in the Ministry of Health 8
CHEMOTHERAPY REGIMENS FOR SPECIFIC SITES

5. HEAD & NECK 10
6. NASOPHARYNX 12
7. BREAST
a. Chemotherapy 13
b. Hormone therapy 20
c. Targeted therapy 22
8. LUNG
a. Small cell lung cancer 23
b. Non-small cell lung cancer 26
9. GASTRO-INTESTINAL
a. Oesophagus 32
b. Stomach 34
c. GIST 36
d. Pancreas 37
e. Liver 39
f. Colorectal 40
10. GYNAECOLOGY
a. Ovary 44
b. Ovarian germ cell tumour 48
c. Uterus 50
d. Uterine sarcoma 51
e. Cervix 52
f. Gestational trophoblastic disease 55

11. GENITO-URINARY
a. Prostate 59
b. Bladder 61
c. Kidney 63
d. Testis 64
12. SARCOMAS
a. Soft tissue sarcoma 67
b. Osteosarcoma 69
13 BRAIN 70
14. PRACTICAL GUIDES

a. Pre-chemotherapy checks 72
b. ECOG performance status 73
c. Formulas 74
d. Management of emesis 75
e. Premedication 78
f. Hydration regimens 79
g. Common toxicity criteria 82
h. Dose modification guidelines 85
i. Neutropenic sepsis 86
j. Use of haematopoeitic colony-stimulating factors 88
k. Common toxicities guidelines 89
15. DRUG PREPARATION AND ADMINISTRATION

a. Administration of cytotoxic drugs 92
b. Management of extravasation 94
c. Management of cytotoxic Spill 97
d. Chemotherapy preparation and reconstitution 99
e. Cytotoxic reconstitution guidelines 100
16. APPENDIX
a. References 102
b. Glossary 148
c. List of contributors 149

1. INTRODUCTION
Systemic therapy for cancer has evolved from selected use of chemotherapy drugs in a
small number of patients to currently, a wide use in most cancers whether in the curative,
adjuvant or palliative settings. From a small number of drugs in common use, we have
seen an explosion of new chemotherapy drugs, new combinations and indications for
treatment. Along with development of chemotherapy drugs is the emergence of ‗targeted
therapies‘ with the promise of selectivity with less toxicities. These new agents are rapidly
being incorporated into routine practice overseas, in our private health care facilities
locally and to some extent in our government hospitals as well. It is therefore appropriate
to rename the new protocol as ―Systemic Therapy of Cancer‖
With the vast amount of scientific publications annually, we are in a situation of information
overload with potentially innumerable regimens ―appropriate‖ for every cancer type.
Unintentionally, we are subjected to selective reading of promotional materials and papers
which influence our practice in subtle ways. The contributors to this protocol have done
literature review and made recommendations for systemic therapy on the ―best evidence‖
available, suitable for our patients and appropriate for our health care system.
This protocol is intended for use as a guide for staff involved in systemic therapy for
cancer patients. The formatting has been for easy reference and not as a text debating
merits of different regimens. It is not meant to be comprehensive but for use in the clinic.
The user is reminded that variations of suggested regimens exist. In addition, modification
in dose and schedule may be required according to various factors such the patient, the
intent of therapy, availability of health care and also patient‘s own resources. Proper
scheduling and monitoring must be carried out to ensure the efficacy, and safety of the
treatment is optimised while side-effects are minimised. Adequate fully published
references are given and users are encouraged to look them up.
The first draft of this book was completed in 2008. It has been revised with additional
contributors and updated references. It is hoped that this book will be useful and used by
all concerned.
Assoc. Prof. (C) Dato‘ Dr. Fuad bin Ismail

Chairman
Systemic therapy of Cancer 2nd edition

2. OBJECTIVES
1. To ensure chemotherapy is administered safely to patients by following

procedures.
2. To ensure patient receive chemotherapy schedules in accordance with disease

types.
3. To ensure the safety of the staff handling cytotoxic drugs.
INITIATION OF CHEMOTHERAPY
The decision to initiate the chemotherapy treatment should be made by oncologists,

gynaecologic oncologists, haematologists, chest/respiratory physicians with special
interest in thoracic oncology or paediatric oncologists.
All patients should be treated according to established chemotherapy protocols and

variances from protocols should be monitored. The protocols shall be made available
at all government centres administering chemotherapy
RESPONSIBILITIES
Oncologists, Gynaecologic oncologists, Chest/Respiratory Physicians with special

interest in thoracic oncology, Haematologists and Paediatric Oncologists.
 Responsible for treatment decision, supervision and monitoring of the delivery of
chemotherapy.
Referring Consultants
 Responsible for coordinating and supervising delivery of chemotherapy and
managing of toxicity of treatment after discussion with the respective Oncologist /
Gynaecologist / Haematologist / Paediatric Oncologist.
Pharmacist
 To ensure the availability, preparation, delivery and safety of drugs and to
reconstitute the cytotoxic drugs according to guidelines.
 To monitor and manage pharmaceutical care issues of patients in the wards
Medical officers
 To coordinate, supervise and deliver the chemotherapy treatment.
Oncology nurses
 To ensure safe administration and disposal of chemotherapy. Nurses should
have post-basic training in oncology.

3. HOW TO USE THIS BOOK
This book is divided into various sections for each main tumour type.
There is a short narrative before each section with relevant references included. The
references are mostly randomised Phase III trials and are found in the appendix.
Readers are encouraged to read the references.
There are usually several choices of chemotherapy regimens for various tumour types.
Many are similar in efficacy. The choice of regimen may be individual or institutional
preference. It is not our intent to be rigid in treatment given the extensive choices
available. However we hope to keep a balance between efficacy, toxicity and
treatment cost.
The lay-out of the regimens is given in tables:
Cycle lengthd = Anti-emetice =

Drugsa Doseb (mg/m2) Routec Infusion timef Daysg
Key
a. - Drugs used in regimen
b. - Dose in milligram per square meter

 The figure refers to the individual dose, even if it is a bid or tds
dosing.
 The figure refers to dose of the day, such that the total per cycle
will be multiplied by the number of days of the infusion, eg for de
Gramont regime.
 In certain cases, absolute doses are given eg 30 mg
c. - Method of administration ie oral, intravenous, intra-muscular

 Unless familiar with the medication, all drugs should be given
intravenously
d. - Cycle length indicates duration of a chemotherapy cycle
 A 21 day cycle means Day 1 of Cycle 2 is on Day 22
e. - Recommended anti-emetic as per guidelines

f. - Time for infusion
 Bolus is generally given over 5 – 10 minutes
 24 hours indicated continuous infusion
 Some chemotherapy drugs are infusion time sensitive. Altering
infusion time would alter drug exposure and toxicity without
obvious increase in efficacy
g. - Which day(s) drug(s) should be given within the cycle duration.
Before chemotherapy is given, patients need assessment and pre-medication.

Subsequent cycles of treatment may need to be adjusted for toxicities. Please refer to
relevant sections:
 Pre-chemo checks
 Anti-emetic recommendations
 Toxicity grading
 Dose adjustment recommendations
Cisplatinum and Ifosfamide require fluid hydration as part of the chemotherapy

protocol. Please refer to ―Hydration regimes‖ section.
In combination chemotherapy, some drugs may be substituted by another eg cisplatin

and carboplatin. This is indicated by ‗or’ that is both drugs are not used together.
The indications for certain drugs may be very strict and all criteria must be fulfilled.
This is indicated by ‗AND‘ that is all individual criteria must be present. Please refer to
the MOH ―Blue Book‖ indications as a reference.
Preparation and administration of chemotherapy requires training on safe handling and

administration. Standard operating procedures are necessary as well as contingency
plans for accidents. Guidelines are given in the relevant sections.

4. NEW DRUGS IN MOH
Advancement in chemotherapy for adult solid tumour has been met by an exponential
rise in chemotherapy costs. The newer targeted therapies are even more costly. The
use of these drugs should be should be more accessible with this revision of the
consensus and protocol. Although it is nice to think that the ‗latest‘ therapies should be
used, in the real world, cost is and will always be an issue. By appropriate and
judicious use of new drugs, the most cost-effective treatment can be utilized and will
benefit a greater number of patients.
The new drugs currently in the MOH formulary include :
CHEMOTHERAPY
Capecitabine
Docetaxel
Gemcitabine
Irinotecan
Oxaliplatin
Paclitaxel
Vinorelbine
HORMONES
Anastrozole
Exemestane
Letrozole
TARGETED THERAPY
Imatinib
Trastuzumab
Due to toxicity and costs, the use of these drugs must be strictly within the ―Blue Book‘
approval with A* category, limited to oncologists.

5. HEAD & NECK
Head and Neck (H&N) cancers present a unique problem of optimising local control
due to severe morbidity of uncontrolled tumours which are unsightly, painful and cause
speech and alimentation difficulties. Surgery and radiotherapy as single modality or in
combination are curative therapies for H&N cancer. Chemotherapy may play a
supporting role as radiosensitisers, in the neoadjuvant, adjuvant and palliative settings.
Both adjuvant and neo-adjuvant chemotherapy has not been shown to be consistently
beneficial in a meta-analysis. Individual trials have been positive, some in subgroups
or showing improved DFS2-5. There is some suggestion of benefit in laryngeal
preservation6. Cisplatin combinations seem better than carboplatin in the neoadjuvant
setting7. Two recent trials have shown similar improvement in survival with docetaxel
and should be considered for neo-adjuvant therapy.
Concurrent chemo-radiotherapy (CCRT) with platinum agents has shown consistent

benefit across many trials, as definitive therapy, in the post-operative setting and with
alternative radiation schedules8-14. The result of CCRT also appeared better than
altered fractionation without chemotherapy15-17. Cisplatin was effective as single agent
or in combination, while carboplatin is best given with fluorouracil. Long term toxicity
appears acceptable with CCRT18. An earlier meta-analysis had already alluded to
advantage of CCRT1 and a second meta-analysis confirmed its superiority compared
to neo-adjuvant chemotherapy19. Results with other agents have been less
impressive20-22 except for radiation in combination with cetuximab23. However the
comparator arm in that trial was radiation alone. Although the median survival was
almost doubled, the graph was at a plateau and this may be less accurate than
absolute benefit / cure which was 10% at 3 years. This benefit had already been
shown with CCRT at a much lower cost19.
In the palliative setting, platinum combinations have higher response rates but there is
little effect on survival despite responses25. As treatment is for palliation, long inpatient
stay for infusional chemotherapy seems counter productive and shorter regimens may
be preferred although the evidence for this may not be from large controlled trials26.
Newer drugs in combination with cisplatin offer higher responses but with similar
survival27-29.
HEAD & NECK CHEMOTHERAPY
Concurrent Chemo-RT
Carbo-5FU
Cycle length (days) = 21 Anti-emetic = 3

Drugs Dose (mg/m2) Route Infusion time Days
Carboplatinum 70 IV 1 hour 1–4
5-Fluorouracil 600 IV 24 hours 1–4

Cisplatin-5FU

Cisplatinum 75 – 100 IV 2 hours 1
Single agent cisplatin

Cisplatinum 100 IV 2 hours 1
Neo-adjuvant
Cisplatin-5FU (as per concurrent regimen)

Docetaxel 75 IV 1 hour 1
Palliative
Cisplatin-5FU (as per concurrent regimen)
Single agent MTX

Methotrexate 40 IV Bolus 1
Carbo / 5-FU / FA

Folinic Acid 200 IV 2 hours 1–2
5-Fluorouracil 500 IV Bolus 1–2
Carboplatinum 300 IV 1 hour 2

6. NASOPHARYNX
Nasopharyngeal cancers (NPC) are different from other Head & Neck cancers in their
epidemiology, pathology and clinical behaviour. The choice of treatment is starkly
different with radiotherapy as primary modality and surgery reserved for salvage of
neck disease. Meta-analysis and individual trials had shown a consistent benefit of
CCRT in NPC, at least for local control and pooled for overall survival. The benefit in
the adjuvant and neo-adjuvant setting remains controversial with mostly negative trials
and no benefit was seen in meta-analysis1-10. Carboplatin seems equally efficacious
but its use is not encouraged unless cisplatin is contra-indicated11. Data for oxaliplatin
is intriguing but longer trial follow-up and more studies are needed before this drug can
be recommended12. For palliative chemotherapy, similar regimens as used in H&N
cancers can be used.
NPC CHEMOTHERAPY
Concurrent chemoradiotherapy
Single agent cisplatin

Weekly cisplatin / carboplatin

Cisplatinum 40 – 50 IV 1 hour 1
OR
Carboplatin* 100 IV 0.5 hours 1
*only if cisplatin contraindicated
Concurrent & adjuvant chemotherapy
Cisplatin concurrent with radiation and Cisplatin-5FU as adjuvant

Cisplatinum (concurrent) 100 IV 2 hours 1
then

7. BREAST
Breast cancer is recognised as a systemic condition even in early stage of the

disease, with a significant risk of distant micro-metastases. As a result, adjuvant
chemotherapy has an established role in eradicating these micro-metastases, thus
improving survival.
The pathology report for breast cancer should include :
 pT – Size of tumour
 pN – Status of nodal involvement
 G – Grade
 ER – estrogen receptor status
 PgR – progesterone receptor
 LVI – Lymphovascular invasion
 HER2 - HER2 Receptor status
By using these parameters, patients may be stratified into low, intermediate and high
risk factors64 (Table 1).
Table 1 : Stratification for low, intermediate and high risk St. Gallen 2007
MAJOR MINOR
RISK
Node pT Grade LVI ER HER2
Low Negative AND all minor T1 1 neg pos neg
Negative (+>1 minor) > T2 2 -3 pos neg pos
Intermediate
Positive (1-3) Any Any Any pos neg
Positive (1-3) Any Any Any neg pos
High
Positive > 4 Any Any Any Any Any
Modified from Persing, M., and Grosse R. Current St. Gallen Recommendations on Primary Therapy of Early
Breast Cancer. Breast Cancer. 2007; 2: 137-40
Pos = positive
Neg = negative
Adjuvant chemotherapy for breast cancer is a very complex issue. There are a myriad
of trials using various combinations, at varying doses and schedules showing
superiority in some way of one regimen over the other71. It is difficult to say which
regimen is optimal for a particular patient or group of patients given the complexity of
various strata of prognostic factors, and indirect comparisons as the ‗latest‘ regimens
have not been compared with each other.
The benefit of chemotherapy depends on the patient‘s risk of recurrence (Table 2).
The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis of
194 un-confounded randomised controlled trials of adjuvant chemotherapy and

hormonal therapy indicated that the use of anthracycline-based adjuvant
chemotherapy is associated with a 38% reduction in the annual breast cancer death
rate for women younger than 50 years of age. The increase in absolute overall survival
with anthracyclines is by 3% and without obvious detriment in other areas especially
cardiac mortality. Individual trials have also shown consistent benefit with
anthracylines3-8 with acceptable morbidity9. Addition of taxanes to epirubicin may
improve survival further although the results have been conflicting9-11,65,69. The
advantage of adjuvant chemotherapy in post-menopausal patients is smaller at 20%
relative improvement in OS for those between 50 and 69 years
Table 2 : Estimate of Benefit of Adjuvant Chemotherapy
Absolute survival Number needed to

Age Risk
difference treat (NNT)
<50 Low 4.6% 22
<50 Intermediate 8.7% 12
<50 High 15.1% 7
50-69 Low 2.4% 42

50-69 Intermediate 4.4% 23
50-69 High 7.4% 14
Adapted from EBCTCG Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and
15 year survival: an observation of RCT. Lancet 2005; 365: 1687-1717
Adjuvant chemotherapy
Indications : Intermediate and high-risk groups
RISK GROUP CHEMOTHERAPY REGIMEN No’s CYCLES
Low Not indicated Nil
1. CMF 6
Intermediate 2. FAC / FEC 6
3. AC 4
1. FAC / FEC
High 6
2. Taxane-based
The regimes should be individualised according to risk factors, co-morbidities and

patients‘ wishes.
All patients must be adequately counselled about the benefits and risks of adjuvant
chemotherapy.

Neo-adjuvant / primary chemotherapy
Indications:
1. Inoperable locally advanced breast cancer (LABC)
2. Operable but large breast cancer, to facilitate surgery
LABC are still treated for cure although a large proportion will develop distant
metastases. For these women, local disease control is important to avoid fungation,
bleeding and smell from uncontrolled breast/chest wall disease. The efficacy of
neoadjuvant chemotherapy is similar with adjuvant therapy and may allow for breast
conservation especially with moderate size tumours66,70. Neoadjuvant chemotherapy is
the treatment of choice for unresectable tumours12-19. Disease assessment must be
done at every cycle as the risk of resistance is higher with large volume disease and
early referral for resection should be considered in resistant tumours. Taxanes appear
to benefit those who have responded to anthracyclines18,67. The full complement of
treatment, sequentially from neo-adjuvant chemotherapy – surgery – radiotherapy is
preferred whenever possible.
Appropriate regimens:
1. FAC / FEC
2. CMF
3. AC
4. Taxane-based
All patients should be discussed for radiotherapy.
METASTATIC BREAST CANCER (MBC)
Treatment is palliative and patients should be counselled on further treatment and

chemotherapy individualised depending on disease and patient status.
For chemotherapy naive patients, any of the above regimens used in the adjuvant and
neo-adjuvant settings, may be used. Anthracylines-based regimens have higher
response rates and are preferred where there is predominant visceral disease. It is still
appropriate to use CMF regimen for selected patients.
Following progression after first-line chemotherapy, taxane-based chemotherapy may

be considered. Docetaxel is probably more active than paclitaxel in metastatic breast
cancer22-26. Taxanes can be used as single agent or in combination.

Chemotherapy for MBC
CHEMOTHERAPY STATUS SUGGESTED REGIMENS
1. FAC / FEC
Chemotherapy naïve 2. CMF
3. AC
1. FAC / FEC
Previous non-anthracycline chemotherapy
2. AC
Previous anthracycline chemotherapy Taxane-based
1. Capecitabine
Previous anthracycline & taxanes 2. Vinorelbine
3. Gemcitabine and platinum

BREAST CHEMOTHERAPY
Adjuvant1-32
CMF (Classic)

Cyclophosphamide 100 PO - 1 – 14
Methotrexate 40 IV Bolus 1&8
5-Fluorouracil 600 IV Bolus 1&8
CMF (Modified)

Cyclophosphamide 750 IV Bolus 1
5-Fluorouracil 600 IV Bolus 1
FAC

Doxorubicin 50 IV Bolus 1
FEC

5-Fluorouracil 500 – 600 IV Bolus 1
Epirubicin 60 – 75 IV Bolus 1
Cyclophosphamide 500 – 600 IV Bolus 1
AC (4 cycles only)


High dose FEC

Epirubicin 90 -100 IV Bolus 1
FEC (3) + Tax (3) 3 cycles of FEC followed by 3 cycles of Taxotere

Epirubicin 90 -100 IV Bolus 1
then
Docetaxel 75 – 100 IV 1 hour 1
4AC + 4T 4 cycles of AC followed by 4 cycles of Paclitaxel

Then
Paclitaxel 175 IV 3 hours 1
TAC

*The routine use of G-CSF with this regime is not recommend

METASTATIC BREAST CANCER
Single agent : paclitaxel, docetaxel or capecitabine
Cycle length (days) = 21 / 28 Anti-emetic = 2

2
Drugs Dose (mg/m ) Route Infusion time Days
or
Paclitaxel 80 IV 1 hour 1,8 & 15
Cycle length (days) = 21 / 28 Anti-emetic = 2

2
Drugs Dose (mg/m ) Route Infusion time Days
or
Docetaxel 35 IV 1 hour 1, 8 & 15

Capecitabine 1000 – 1250 PO Oral BID 1 – 14

Vinorelbine 20 – 30 IV Bolus 1, 8
Gem-cis/carbo

Gemcitabine 1000 IV Bolus 1, 8
and
Carboplatin or AUC 5 – 6 IV Bolus 1
Cisplatin 60 – 75 IV 2 hours 1

HORMONE THERAPY
Hormonal therapy is indicated in all patients with ER positive or PgR positive tumours
(including hormone uncertain). The EBCTG overview indicates survival benefit in both
pre and post-menopausal women with ER+ tumours. Tamoxifen is the treatment of
choice for pre-menopausal women as results with the use of ovarian ablation or LHRH
agonist have not shown addition benefit72.
For post-menopausal women hormone treatment options include tamoxifen and

aromatase inhibitors (AI). In the adjuvant setting,individual trial results and the NICE
review shows improved disease-free interval for women taking aromatase inhibitors
but even with longer follow-up, there is no obvious survival benefit41,43-45,47,49,50,53,71,73-
74
. Tamoxifen is still appropriate as initial hormone treatment for post-menopausal
women and a switch to an AI may be considered after 3 years of tamoxifen75-76.
Letrozole can be recommended for extended adjuvant therapy following standard
tamoxifen therapy52.
Available hormone therapies are :

 Tamoxifen
 Aromatase inhibitors
Note : Aromatase inhibitors are used ONLY for post-menopausal women
Adjuvant hormone therapy
Indicated in all women with breast cancers regardless of menopausal status. They
tumours must be either :
1. ER or PgR positive or
2 ER unknown
STATUS ADJUVANT HORMONE
Pre-menopausal Tamoxifen 20 mg daily for 5 years36
Post-menopausal Tamoxifen 20 mg daily for 5 years

Aromatase inhibitors (AI) can be considered :
 Contraindications to tamoxifen eg previous
thromboembolic disease, side-effects
 Switching therapy after 3 years of tamoxifen
Extended adjuvant :
Letrozole
 Only for node+ patients after 5 years of tamoxifen
 Duration : up to 5 years.

Primary hormone therapy
Indication :
1. Patients with locally advanced hormone receptor positive breast cancer who are
not fit for chemotherapy.
Type of hormone therapy
1. Tamoxifen
2. Aromatase inhibitors (only if tamoxifen is contraindicated)
Metastatic breast cancer (MBC)
Aromastase inhibitors have consistently shown improved responses in MBC. In the

metastatic setting, when hormonal treatment is indicated, the following sequence of
treatment is recommended.
LINE POST-MENOPAUSE PRE-MENOPAUSE
Aromatase inhibitor (AI)* Tamoxifen

 Anastrozole OR (if not on tamoxifen
 Letrozole OR previously)
First  Exemestane46
Aromatase inhibitor (AI)*
If Exemestane first line, use

 Anastrozole OR Letrozole
Ovarian ablation & AI
If Anastrozole / Letrozole first line, use
Second (surgical, radiation or
 Exemestane medical)
Tamoxifen
(if not on tamoxifen previously)
Tamoxifen
Third Medroxyprogesterone Acetate (MPA)
Megestrol Acetate
*Either anastrozole or letrozole should be used but not sequentially.

Patients who have been exposed to a hormonal agent in the adjuvant setting, should
not have the same therapy in the metastatic setting.

TARGETED THERAPY
Trastuzumab is indicated ONLY in women with HER2 over-expressed breast cancer
Indications for adjuvant Trastuzumab33,35
1. HER2 3+ by IHC and over-expressed by FISH (or similar test) AND

2. High risk of recurrence

Infusion
Drugs Dose (mg/kg) Route
time
Trastuzumab 8 (loading dose) IV 90 mins First infusion
Followed by
60 mins 3 weekly for
Trastuzumab 6 IV
(30 min) 1 year
Sequencing of systemic treatment
1. Adjuvant chemotherapy should be initiated within 6 weeks of surgery

2. Tamoxifen should be started after completion of chemotherapy
3. Tamoxifen can be given concurrently with radiotherapy
4. Trastuzumab in the adjuvant setting can be given together with radiotherapy
and hormonal therapy
SPECIAL GROUPS
1. Breast cancer in pregnancy
If chemotherapy is indicated, it can be given after 16 weeks of pregnancy.

The regimen most commonly used is the FAC/FEC regimen.
2. Breast cancer in the elderly (above 70 years old)
There is insufficient data to make recommendations on chemotherapy for those

over 70 years. Although there is a suggestion of benefit from the overview,
treatment should be individualised with consideration of comorbid conditions.
3. Male breast cancer
Treated as female breast cancer, stage for stage.

8. LUNG
SMALL CELL LUNG CANCER (SCLC)
CHEMOTHERAPY
Chemotherapy in both limited disease (LD) and extensive disease (ED) SCLC
improves symptom control and survival. However, in patients with ED, careful patient
selection is crucial to avoid unnecessary toxicities. Combination chemotherapy is
more effective than single agent or oral chemotherapy, and without a significant
increase in toxicities1-2. A meta-analysis has shown that cisplatinum-based
chemotherapy resulted in improved response rates and survival when compared with
anthracycline-based combinations3. Substitution of cisplatin with carboplatin does not
show significant difference in efficacy but is less toxic22. However as most studies
which showed survival advantage were with the use of cisplatin, carboplatin is
generally reserved for those unable to tolerate cisplatin. A randomised controlled
trial comparing cisplatin and etoposide with cyclophosphamide, epirubicin and
vincristine found an improvement in the median, 2-year and 5-year survival rates
survival in limited stage SCLC with the former chemotherapy regimen but no survival
benefit in extensive stage small cell lung cancer4. Alternating different regimens of
chemotherapy sequentially (e.g. EP and VAC) does not improve the outcome in LD16.
There are many new agents available but results with these newer agents have been
mixed and no specific advantage can be identified despite increasing cost 10-15.One
such agent of note is irinotecan in combination with cisplatin. Due to contradicting
evidence from 2 studies, irinotecan is not recommended for use in SCLC 11-12.
The role of maintenance treatment for SCLC is yet to be confirmed 23-24. Intensifying
chemotherapy with growth factors increases toxicity without obvious benefit overall5-9.
Data is limited on the use of second line chemotherapy. In most studies, subgroup
analysis shows that patients who responded well to first line chemotherapy are more
likely to respond to second line chemotherapy although overall response was poorer.
Single-agent topotecan is currently the only approved drug for the treatment of patients
with SCLC who have failed or relapsed after first-line chemotherapy25-26. Advanced
age, extensive pretreatment, prior platinum therapy, prior radiotherapy and renal
impairment are potential risk factors for increased myelosuppression during topotecan
therapy and appropriate dose reduction may be necessary. Oral topotecan has a 30%-
40% bioavailability and is an alternative. A combination of cyclophosphamide,
doxorubicin and vincristine may also be used following first-line treatment with EP.
In elderly patients with good performance status, the use of single agent etoposide is
inferior to combination therapy such as etoposide and cisplatin2. Substitution of
cisplatin with carboplatin may be advised as the AUC dosage takes into
consideration the declining renal function. A minimum of 2 cycles of standard
chemotherapy is adequate to elicit partial response in elderly patients with ED17.

In patients with LD SCLC, survival was improved with thoracic radiotherapy if given
with cycle 1 or 2 of chemotherapy18-19. Prophylactic cranial irradiation (PCI) has also
been shown in to improve survival in both LD and ED SCLC20, 21.
RECOMMENDATIONS
Chemotherapy Cisplatin and etoposide is recommended for first-line

treatment in limited stage SCLC
Cisplatin/carboplatin and etoposide should be

considered as first line treatment for extensive disease
SCLC.
Single agent etoposide is not recommended in SCLC.
Four to six cycles of chemotherapy is recommended.
Radiotherapy All patients with limited disease should be considered

for early thoracic radiotherapy within 30 days of starting
chemotherapy
Patients with limited and extensive disease who achieve

a response to chemotherapy could be considered for
prophylactic cranial irradiation.

SCLC CHEMOTHERAPY (Limited and Extensive disease)
EP
Etoposide (iv or oral) combined with either cisplatin or carboplatin

Etoposide or 100 IV 1 hour 1 -3
Etoposide 50 mg bid PO NA 1–7
AND
Cisplatin or 60 – 80 IV 2 hours 1
Carboplatin AUC 5 -6 IV 1 hour 1
VAC (when platinum is contraindicated or second line)

Vincristine 1.4 (max 2 mg) IV Bolus 1
Doxorubicin or 50 IV Bolus 1
Epirubicin 50 – 60 IV Bolus 1
Cyclophosphamide 750 – 1000 IV Bolus 1
Second line

Topotecan 1.5 IV Bolus 1–5
or
Topotecan 2.3 PO Bolus 1-5

NON-SMALL-CELL LUNG CANCER (NSCLC)
PALLIATIVE CHEMOTHERAPY
First Line Treatment
The NSCLC Collaborative Group meta-analysis evaluating the benefit of

chemotherapy in patients with stage IIIB-IV showed that cisplatin-based regimens
resulted in a 6 week improvement in median survival and 10% increase in one year
survival (15% to 25%) compared to best supportive care (BSC)1. In addition,
chemotherapy improves quality of life as compared to BSC2-3.
In a series of comparative studies, second generation chemotherapeutics

(ifosfamide, vinblastine, vindesine, mitomycin C) were compared with third generation
chemotherapeutics (paclitaxel, docetaxel, vinorelbine, gemcitabine)4-12. All these
agents were used as single agents or in combination with a platinum compound. There
was no significant difference in efficacy or survival rates. However, the use of third
generation chemotherapeutics gave lower incidences of grade 3 and 4 toxicities.
The 3rd generation agents have been compared against each other, in
combination with or without cisplatinum, as doublets or triplet therapy. There is
inconclusive evidence that a third generation agent is more effective than another in
improving median survival when combined with platinum 14-26. A meta-analysis of
gemcitabine and carboplatin with other platinum based regimens found a small
statistically significant improvement in survival with gemcitabine compared to older
combinations27. There is no concrete evidence that triplet regimens are superior to
doublet regimens8,19. However triplet regimens are frequently associated with
increased risk of toxicity.
In a recent meta-analysis, cisplatin based chemotherapy had better objective

response rates compared to carboplatin based regimens28. Subset analysis found
statistically significant survival with cisplatin based regimens in patients with non-
squamous histology and those treated with third generation agents. However
carboplatin is more convenient to administer and causes less emesis and
nephrotoxicity compared to cisplatin. Consequently, the decision to use either
carboplatin or cisplatin should be carefully considered bearing in mind the patient‘s co-
morbidity and fitness, as well as the specific toxicities of the third generation drug.
Patients with performance status (PS) 2 may be offered chemotherapy as it

improves their quality of life (QOL) but not survival2. Elderly patients (≥70) also benefit
from palliative single agent chemotherapy in terms of improvement in survival29-30.
Several RCTs showed that longer duration of chemotherapy beyond three to

four cycles offered no benefit in terms of QOL or survival31-35. Newer agents include
bevacizumab which improves DFS but result on OS is mixed 54-55. Simpler measures
such as palliative care seem to offer similar degree of benefit56.

RECOMMENDATIONS
Chemotherapy with a platinum-based doublet regimen should be considered in

patients with stage 3-4 NSCLC with PS 0-1.
The decision to use cisplatin or carboplatin should be carefully considered.
In the elderly (>70) or patients with PS 2, single agent chemotherapy may be

considered
The number of chemotherapy cycles should not exceed four unless the patient
is still responding after 4 cycles.
FIRST LINE THERAPY
Combination chemotherapy
EP

Etoposide 100 IV 1 hour 1–3
Cisplatin * 60 – 80 IV 2 hours 1
Gem-cis

Gemcitabine 1000 IV 0.5 hour 1&8
Paclitaxel-cisplatin


Docetaxel-cisplatin

Vinorelbine-cisplatin

Vinorelbine 25 IV Bolus 1&8
*Cisplatinum may be replaced by carboplatinum AUC 5-6
Single agent chemotherapy

Vinorelbine 25 – 30 IV Bolus 1&8

Gemcitabine 1000 – 1200 IV Bolus 1&8

Second Line Therapy
Patients who remain relatively fit (PS 0-1) at the time of progression may benefit from
second line chemotherapy. Docetaxel has been shown to improve time to progression,
survival and QOL33. The 3-weekly and weekly regimens have similar efficacy but the
weekly regimen is better tolerated34.
Second line chemotherapy with single agent docetaxel should be considered in

patients with PS 0-1.
Indications:
1. Good PS (WHO score of 0 or 1) AND

2. CR, PR or SD on 1st line chemotherapy
Recommended Regimens
Docetaxel 3 weekly

Docetaxel weekly

Docetaxel 35 IV 1 hour 1, 8 & 15

COMBINED MODALITY THERAPY
Neoadjuvant chemotherapy prior to curative surgery
This is used in patients who have resectable disease (stages I, II and IIIA).
There is conflicting evidence from three RCTs with regard to the benefits of
preoperative chemotherapy in resectable NSCLC. One large RCT showed no benefit
to chemotherapy in stage III disease but detected a survival advantage in stages I and
II in subset analysis35. The results of the recently published MRC LU22 trial did not
show a significant improvement in survival for the neoadjuvant chemotherapy
approach36
Preoperative chemotherapy is not recommended for patients with operable early

stage disease outside clinical trials.
Neoadjuvant chemoradiotherapy prior to curative surgery
There are no phase 3 randomized studies which address this issue.
There is no role for preoperative chemoradiation outside clinical trials.
Sequential chemoradiotherapy
The evidence indicates an improvement in overall survival with sequential platinum-

based chemotherapy and radical radiotherapy given at conventional fractionation. This
is based on trials involving stage III NSCLC in patients with good performance status
(PS 0-1)37-38. Careful attention should be given to radiotherapy planning as the risk of
radiation pneumonitis is increased compared to radiotherapy alone.
Patients with inoperable early stage disease due to medical reasons should not be
subjected to chemoradiation as their medical condition would also be a
contraindication for chemotherapy.
Platinum-based combination chemotherapy prior to conventional fractionation

radical radiotherapy should be considered for PS 0-1 patients
Concurrent chemoradiotherapy (CCRT)
There is conflicting evidence of a possible survival benefit with CCRT in patients with
locally advanced disease (stage 3) and good PS39-42. However, this is at the expense
of increased toxicity. A recent meta-analysis suggests a modest improvement in
survival but the trials were heterogeneous and the available data insufficient to
accurately define the size of the potential benefit43.
Patients with PS 0-1 may be considered for concurrent chemoradiotherapy.

However sequential therapy is advised as standard.

Adjuvant chemotherapy after surgery
After surgery, many patients develop regional or distant metastases. A large RCT
comparing adjuvant chemotherapy after surgery in stage 1 to 3 NSCLC demonstrated
a significant survival benefit of 4% at five years44. However, updated results from the
CALGB trial investigating adjuvant chemotherapy (paclitaxel and carboplatin) in stage
1B patients showed that the initial improvement in survival was no longer significant
with extended follow-up47. Results from the ANITA trial confirmed a survival benefit of
8.6% at 5 years for adjuvant chemotherapy in resected stage 1B to 3A NSCLC though
subgroup analysis indicated that the survival benefit was mainly seen in patients with
stage 2-3A disease46. However the dose of vinorelbine used in the trial is very high
and this regime needs to be used with caution. A meta-analysis of tegafur showed
improved survival in Stage 1 though not across all trials47-48.
Four cycles of adjuvant cisplatin-based chemotherapy should be considered for

resected stage 2-3 NSCLC.
Vinorelbine-cisplatin (x4)

Vinorelbine 30 IV Bolus 1,8,15,22
Cisplatin 100 IV 2 hours 1
Tegafur (x 1 year)

Tegafur 400 mg PO Daily cont
TARGETED THERAPY
Two anti-EGFR small molecules, gefitinib and erlotinib, appear active in NSCLC51-52.
In patients with stage IIIB and stage IV epidermal growth factor receptor (EGFR)
activating mutation-positive adenocarcinoma, first-line treatment with gefitinib results
in better progression-free survival compared to a platinum doublet58. As the overall
survival benefit is not seen, these agents cannot be recommended for use.
Although the overall survival benefit is not apparent, the quality of life for patients on
targeted therapy is better. Hence the use of these agents may be considered in the
subgroup of patients with EGFR mutations. Treatment with these agents must be
stopped on progression.

9. GASTRO-INTESTINAL TRACT
OESOPHAGUS
Stage I – III
CCRT can be considered in patient with patients with stage I – III carcinoma of
oesophagus or for surgically unfit patients.
An Intergroup randomized trial, Radiation Therapy Oncology Group (RTOG) 85-01,

of chemotherapy and radiation therapy versus radiation therapy alone resulted in an
improvement in 8 –year survival for the combined modality group1. These results
were also confirmed in a meta-analysis.
Adjuvant
Adjuvant radiotherapy can be considered for patients with positive margins.

Adjuvant chemotherapy not recommended.
Neo-adjuvant
Pre-operative chemotherapy (MRC OEO2) and pre-operative chemoradiation should

not be considered outside a clinical trial due to conflicting results in the trials with
most trials showing no difference in end-point or slight improvement in disease-free
survival.
Stage IV
The treatment options are RT alone, chemotherapy alone, palliative surgical

procedures or BSC. Choice of treatment depends on symptoms as well as patient
fitness.
Active agents include cisplatin, mitomycin, 5-fluorouracil which give response rates of
15-20%. The duration of response is usually short, typically 2-3 months with no
survival benefit.
Novel agent eg taxane and topoisomerase inhibitors may give a higher response
rates. They are still under clinical evaluation and should not be used outside clinical
trials.

OESOPHAGEAL CANCER CHEMOTHERAPY
Concurrent chemo-radiotherapy
Cisplatin-5FU

5-Fluorouracil 1000 IV continuous 1–4
Radiotherapy should start on Day 1, Cycle 1.
Palliative
ECF

Epirubicin 50 IV Bolus 1
5-Fluorouracil 200 IV Continuous 1 – 21
OR

5-Fluorouracil 600-750 IV Infusion 1–5
PF

5-Fluorouracil 750 – 1000 IV Bolus 1–5

STOMACH
Stage 1B – III
Adjuvant chemotherapy has not been shown to improve survival across many trials 1-6.
Adjuvant chemo-radiotherapy on the other hand can be considered. The Intergroup

trial (INT-0116) showed a significant 5 year survival benefit has been reported for
adjuvant combined modality therapy as compared to surgery alone 7. Median survival
was 36 months for the adjuvant chemoradiation group as compared to 27 months for
the surgery-alone arm.
Peri-operative chemotherapy can also be considered in patients with stage II-III

disease. A phase III trial (MAGIC) involving patients with stage II or higher
adenocarcinoma of the stomach or of the lower third of the oesophagus showed
improved 5 year overall survival for patients receiving peri-operative chemotherapy8.
Stage IV
Results from phase III trials suggested a survival benefit with chemotherapy9-14.
Chemotherapy agents with activity in carcinoma of stomach include 5FU, doxorubicin,
cisplatin, etoposide and mitomycin C. Response rates were 20 – 30% but the duration
of responses were short and with considerable toxicity. A recent meta-analysis
suggests the use of infusional ECF which is less toxic and more efficacious.
The results with irinotecan are inconclusive15. Although docetaxel regimen may be
efficacious, the improvement in survival is marginal16.

GASTRIC CANCER CHEMOTHERAPY
Concurrent chemo-radiotherapy (Neo-adj x 1 + CCRT x 2 + Adj x 2)
5FU-FA

Folinic acid 20 IV Bolus 1–5
Fluorouracil 425 IV Bolus 1–5
1 – 4 (Wk1)
Fluorouracil* *375 IV Bolus
1 – 3 (Wk5)
* dose during radiotherapy
Neoadjuvant
ECF200 (Neo-adj x3 + Adj x3)

5-Fluorouracil 200 IV Continuous 1 – 21
Palliative
ECF200
ECF

5-Fluorouracil 600 – 750 IV Infusion 1–5
Cisplatin-5FU

5-Fluorouracil 1000 IV Bolus 1–5

GASTROINTESTINAL STROMAL TUMOUR (GIST)
This is a rare mesenchymal tumour of the gastrointestinal tract. It has histological

characteristic of both neural and smooth muscle differentiation, and approximately
95% of GIST stain positively to cKit (CD117) protein which is involved in the tyrosine
kinase pathway.
Surgery is the main treatment modality for patients with respectable GIST. For
patients with unresectable, recurrent or metastatic GIST, surgery is usually not an
option. The response rates from systemic chemotherapy is modest ranging from 0-
27% with a median survival of 14-18 months1
Advanced GIST
Imatinib, a form of targeted therapy, has emerged as an effective treatment for

patients with advanced GIST. In this group of patients, the median survival has
improved from 14-18 months to 3 years2. The recommended dose of imatinib is
400mg daily. Trials comparing 400mg with higher doses have not shown significant
difference in overall survival3,5. Treatment should be continued until disease
progression4 and the drug should then be stopped. Dose escalation is not
recommended as the apparent benefit is marginal at much greater cost.
Adjuvant therapy
Recent clinical trials have demonstrated the efficacy of imatinib in the adjuvant
setting with large improvements in disease-free survival for patients receiving
therapy. The benefits appear greatest in those with higher risk especially with
tumours > 10cm. However all patients with recurrences appear to be salvaged
adequately with imatinib therapy and no survival benefit has been demonstrated.
Therefore adjuvant imanitib cannot be recommended6.
Indication for imatinib:
1. Histologically proven cKit (CD117) positive GIST AND

2. Unresectable, incomplete resection with macroscopic residual or metastatic
disease on imaging.
Recommended Regimen:
Tab Imatinib 400mg daily.

 Continuous treatment until disease progression. At disease progression,
treatment should be stopped
 Response assessment every 3 monthly to justify continuing the treatment.
o Consider using PET scan as baseline and for subsequent assessment
of metabolic response if CT assessment is inconclusive.

PANCREAS
Completely resected non-metastatic disease
Adjuvant chemotherapy with Mayo‘s regimen can be used in patients with good
performance status12.
Incompletely resected (macroscopic residual) non-metastatic disease
Concurrent chemo-radiotherapy with 5-FU can be considered2.
Locally advanced non-metastatic disease
Chemotherapy alone OR
Concurrent chemo-radiotherapy can be considered
Metastatic disease
Fluorouracil based chemotherapy has been used for many years as one of the
treatment in patient with metastatic disease. Response rates are low (<10%) with no
impact on survival.
Gemcitabine has been shown to have durable disease palliation in patients with
advanced or metastatic pancreatic cancer, refractory to fluorouracil (5-FU). A phase III
trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or
metastatic adenocarcinoma of the pancreas showed a significant improvement in
survival among patients treated with gemcitabine (1-year survival was 18% with
gemcitabine as compared to 2% with 5-FU)1.
Several other trials using gemcitabine combinations did not show an advantage over
single agent gemcitabine2-6,8-9,15. A combination of erlotinib and gemcitabine showed
statistical improved over single agent gemcitabine but the difference was too small to
be of clinical significance. A recent meta-analysis suggests an advantage for
combination therapy but the advantage is small10.
Single agent gemcitabine is still recommended for advanced pancreatic cancer.

PANCREATIC CANCER CHEMOTHERAPY
Adjuvant
Mayo (x 6)

Palliative
Single agent gemcitabine

Gemcitabine 1000 IV Bolus 1, 8, 15

LIVER
Hepatocellular carcinoma
There is no data to support adjuvant chemotherapy in resected hepatocellular

carcinoma.
Stage IV
Chemotherapeutic agents which have shown activity in hepatoma include adriamycin,

epirubicin and mitoxantrone. However responses are not durable and median survival
is short. Combination therapy has shown higher responses but this has not translated
into improved survival and with increased toxicity.
Single agent doxorubicin may be considered in patients who are fit. However this is to
be used with caution as patients may have impaired liver function and raised bilirubin.
Palliative
Single agent doxorubicin

Doxorubicin 50 – 60 IV Bolus 1
Targeted therapy.
The use of new targetted therapies including angiogenesis inhibitors, TKI and other
agents are in active research3. Sorafenib, a multi-kinase inhibitor has shown modest
efficacy in hepatoma with an improvement in median survival by 6 weeks2. Due to the
small incremental benefit and high cost, we do not recommend the use of this drug
routinely.

COLO-RECTAL CANCER (CRC)
5-Fluorouracil is the cornerstone of treatment in colorectal cancer, both in the adjuvant

and metastatic setting
The Mayo Clinic regimen is usually used as standard adjuvant therapy although
weekly 5-FU and de Gramont regimens have similar efficacy 1-4. Several meta-
analyses have confirmed improved survival in Dukes‘ C cancer with adjuvant
treatment but not in Dukes‘ B, although some discrepancies may be seen 5-11. For
Dukes‘ B patients, adjuvant chemotherapy may be considered for ‗high-risk cases‘ eg
perforation, large primary tumour and dense adhesions. Adjuvant chemotherapy with
radiotherapy has also been shown to be efficacious in rectal cancer when compared to
radiation alone12-13. Radiation is not recommended for colon cancers. Addition of
oxaliplatin with infustional chemotherapy has been shown to improve disease-free
survival in stage II & III disease and also overall survival in Stage III 16,37. No
improvement was seen with adjuvant irinotecan regime 38.Capecitabine offers similar
efficacy to the conventional adjuvant 5-FU chemotherapy and also in combination with
oxaliplatin 14-15,32.
Adjuvant chemotherapy is for 6 months.
Metastatic cancer
Palliative chemotherapy with fluorouracil based regimens confers survival advantage

and should be started early. There is suggestion for the use of surrogate markers
versus overall survival for impact of palliative chemotherapy16-17. This has not borne
out in a meta-analysis of infusional regimens which have higher response rates but
had no impact on survival18. Both oxaliplatin and irinotecan, in combination with
infusional fluorouracil, improves the overall survival for patients18-22. The sequence of
use of these drugs does not seem important23. Triplet chemotherapy could be given in
a start-stop fashion without any detriment39. Irinotecan should not be used as a single
agent23. Capecitabine has similar efficacy to fluorouracil with less use of resources25-
27
. However the impact of these new drugs may be less than anticipated28.Shorter use
of oxaliplatin may be as efficacious as longer duration of therapy32. Newer targeted
therapy has promising efficacy but its use cannot be advocated at present29-31.
Concurrent Chemo-radiotherapy (Rectal cancer)
CCRT is often used for locally advanced rectal cancers either pre-operatively or post-
operative adjuvant. Pre-operative CCRT is more efficacious than post-operative and
with less long term side-effects. The dose of fluorouracil used is lower than in adjuvant
therapy and thereafter patients usually go on to complete a total of 6 months of
chemotherapy although the benefit of further adjuvant chemotherapy may be
doubtful33-36.

COLORECTAL CHEMOTHERAPY
Adjuvant
de Gramont (x 12)

Folinic acid 100 – 200 IV 2 hours 1–2
Fluorouracil 600 IV 22 hours 1–2
MAYO / QUASAR (x 6)

Fluorouracil 370 – 425 IV Bolus 1–5
Weekly 5-FU/ FA (x 30 weeks)

Folinic acid 20 IV Bolus 1
Fluorouracil 370 – 425 IV Bolus 1
Single agent capecitabine (x8)

Capecitabine 1250 PO BID 1 – 14

FOLFOX-4 (Stage III only)

Folinic acid 200 IV 2 hours 1-2
Fluorouracil 400 IV Bolus 1-2
Fluorouracil 600 IV 22 hours 1–2
Oxaliplatin
85 – 100 IV 2 hours 1
(given with Folinic acid)
FOLFOX-6 (Stage III only)

Folinic acid 200 - 400 IV 2 hours 1-2
Fluorouracil 400 IV Bolus 1
Fluorouracil 2400 - 3000 IV 46 hours 1–2
Oxaliplatin
85 – 100 IV 2 hours 1
Concurrent Chemo-radiotherapy
5FU-FA

Fluorouracil 300 – 370 IV Bolus 1–5

Metastatic CRC
Any of the regimens in the adjuvant setting can be used. However response rate are
higher with oxaliplatin or irinotecan containing regimes with good palliation of
symptoms. These regimes are recommended as first line therapy especially in patients
where curative liver resection is considered.
FOLFOX- 4 or 6 (Refer to adjuvant section)
FOLFIRI

Folinic acid 200 IV 2 hours 1
Fluorouracil 400 IV Bolus 1
Fluorouracil 2400 – 3000 IV 46 hours 1–2
Irinotecan
180 IV 2 hours 1

10. GYNAECOLOGY
OVARY
Epithelial Ovarian Cancer (EOC)
Primary treatment for ovarian cancers is exploratory laparotomy and total abdominal
hysterectomy bilateral salphingo-oophorectomy, omentectomy with random peritoneal
biopsies. Peritoneal fluid should be taken for cytology as part of the staging procedure.
Pelvic lymphadenectomy and paraaortic sampling are recommended in patient with
apparent early stage ovarian cancer. In advanced stages, every attempt should be
made for optimal cytoreduction1-3 although disease biology also influences outcomes4.
Surgery should be performed by a Gynaecological Oncologist or by a gynaecologist
with special interest in Gynaecological Oncology. Fertility sparing surgery is indicated
in selected patients with selected type of ovarian carcinoma.
A. FIRST LINE CHEMOTHERAPY FOR EOC
Indications :
1. Stage 1 disease with high risk of recurrence :

a. Stage 1c
b. Stage 1b AND Grade 3 tumour or Clear cell histology5
2. Stage 2 and above
3. All Clear Cell Carcinoma
Chemotherapy regimen
Stage 1b – 2a.
Single agent carboplatin6-8,32-33.
Stage 2b & c, 3 and 4
Combination of Paclitaxel-carboplatin OR single agent Carboplatin
In advanced ovarian carcinoma, optimal cytoreduction is extremely important to

ensure improved survival and reduced risk of death. Combination of paclitaxel-
platinum has mostly shown to be more efficacious than non-taxane combination
although ICON-3 showed comparable results with carboplatin9-11. Higher taxane dose
is not indicated and triplet therapies are not more efficacious than doublets12-13. As
results with cisplatin and carboplatin combinations are equivalent, carboplatinum is
preferred for lower toxicity, better quality of life score and ease of drug
administration14-16. Six cycles of treatment should be given17.
Docetaxel-carboplatin may be used as an alternative regimen for first line

chemotherapy in patient who developed grade 3 neurotoxicity while on Paclitaxel18.

OVARIAN CANCER CHEMOTHERAPY
Carboplatin single agent

Carboplatin AUC 5 – 7 IV 1 hour 1
Paclitaxel – Carboplatin/cisplatin

Paclitaxel and 175 IV 3 hours 1
Carboplatin AUC 5 – 6 IV 1 hour 1
OR
OR
Paclitaxel and 135 IV 24 hour 1
CAP

Docetaxel-carboplatin

Carboplatin AUC 5 IV 1 hour 1

RECURRENT OVARIAN CANCER
Although first-line therapy in advanced ovarian cancer is associated with high

response rates, up to 80% of women will relapse.
Patient with recurrent ovarian cancer can be categorized into two groups:
a. Platinum sensitive group when disease free interval is more than 6 months
b. Platinum resistant group when disease free interval is less than 6 months
Chemotherapy for Platinum sensitive group
In platinum sensitive patient, combination platinum-based chemotherapy may be more

effective than single agent chemotherapy. Patients may be re-challenged with
platinum-based regimen similar to initial treatment19-23.
Secondary cytoreductive surgery can be considered for patients who have a low-grade
or focal recurrence after a long disease-free interval (> 6 months)23,24.
Chemotherapy for Platinum resistant group
Platinum-resistant patients should not be re-challenged with further platinum

chemotherapy25. The goal of therapy is palliation, and therefore side-effects of
therapy, quality of life, and convenience of administration should be considered before
deciding on chemotherapy.
Patients in this group should be thoroughly evaluated and counselled by an oncologist/

Gynaecological-Oncologist
General consideration
1. Patient with good performance status (WHO < 2),

2. Patient fully informed and counselled by Oncologist or Gynae-Oncologist
3. Chemotherapy must be delivered only by Oncologist or Gynae Oncologist
4. Patients who progress on two consecutive single-agent regimens without
evidence of clinical benefit are unlikely to benefit from additional
chemotherapy and may be offered best supportive care23.

Chemotherapy for Platinum-resistant EOC
Single agent paclitaxel

Single agent liposomal doxorubicin

Liposomal doxorubicin28 40 – 50 IV 1 hours 1
Oral Etoposide

Etoposide29 50 mg PO Daily 1 – 14
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy can be recommended for patients with large volume

abdominal / pelvic disease, intestinal obstruction, gross pleural effusion and unfit for
surgery.
Recommended regimen: Paclitaxel – Carboplatin/cisplatin

OVARIAN GERM CELL TUMOURS
Chemotherapy is the mainstay of treatment of patients with germ cell tumours (GCT).
These tumours are highly chemotherapy-sensitive and most patients are curable even
with advanced disease. Treatment must be delivered by a specialist who is familiar
with the management of such patients with approval by an oncologist. There are few
randomized trials of chemotherapy in these tumours and regimens are extrapolated
from results of testicular tumour trials.
Surgery is an adjunct to chemotherapy in GCT. As GCT affects younger women,

fertility preserving surgery is indicated in selected patients in stages I & II. Fertility
preserving surgery would include unilateral salphingo-oophorectomy, omentectomy,
lymphadenectomy and random peritoneal biopsy.
Indications for chemotherapy in stage 1 Germ Cell Tumour :

1. Stage 1c dysgerminoma or mixed germ cell tumour.
2. Grade 2 and 3 immature teratoma
3. Embryonal or endodermal sinus tumour
BEP regimens
In the BEP regimens, the cumulative dose of bleomycin should not exceed 300mg
3-Days BE500P

Bleomycin 30 mg IV Bolus 1, 8 & 15
Cisplatinum 50 IV 1 hour 1–2
3-Days BE360P

Bleomycin 15 mg IV Bolus 1–3
5 days BE500P


A total of 4 cycles of chemotherapy should be given1-3.
Baseline lung function test should be done prior to 1st cycle of chemotherapy.
Tumour markers (serum alpha feto-protein and/or beta HCG) are useful in the
monitoring of treatment. If there is poor response after two cycles of chemotherapy,
such patients must be referred to tertiary oncology centres for management.
As the tumour is highly curable and the risk of neutropenic sepsis is significant, it is
reasonable to use haemopoeitic growth factors (either G-CSF or GM-CSF)
prophylactically commencing 24-48 hours after chemotherapy for 3-5 doses of the
second cycle depending on the degree of neutropaenia 4. Dose reduction is not
advised for patients with germ cell tumours except in presence of severe non-
haematological toxicity.
N.B. Day 15 bleomycin should be given regardless of the blood count as it
would not add to the myelotoxicity
Second line chemotherapy
Patient with refractory / recurrent testicular GCT can still achieve long term remission
with salvage chemotherapy. Similar results are expected with ovarian GCT and fit
patient should be offered chemotherapy
Salvage Chemotherapy for GCT
VAC

Vincristine 1.5 IV Bolus 1 and 15
Actinomycin D 350 μ IV Bolus 1–5
Cyclophosphamide 150 IV 1 hour 1-5
TIP

Ifosfamide 1200 IV 4 hours 1–5
Cisplatin 20 IV 1 hour 1–5

UTERUS
Uterine cancer is the 3rd commonest gynaecological cancer in Malaysia. Uterine

cancer can be broadly divided into 2 groups:
1. Epithelial Uterine Cancer

2. Uterine Sarcoma
EPITHELIAL UTERINE CANCER
The majority of epithelial uterine cancers are the endometrioid histotype. The most
aggressive epithelial uterine cancers are clear cell carcinoma and uterine papillary
serous carcinoma (UPSC)1,2. Primary treatment of epithelial uterine cancer is
extrafascial hysterectomy and bilateral salpingo-oophorectomy and pelvic
lymphadenectomy ± Para-aortic lymph node sampling. Omentectomy is indicated in
clear cell and uterine papillary serous tumour.
Patients at high risk of pelvic recurrence are often treated with radiation to reduce risk
of pelvic recurrence. Despite the high risk of recurrence in more advanced stages,
clinical trials have not supported the use of adjuvant chemotherapy or hormones in the
adjuvant setting3-7. In recurrent or metastatic disease, palliative chemotherapy offers
some degree of response. Triplet therapy may be slightly more efficacious but single
agent treatment offers similar survival with less toxicity.
Indication for chemotherapy
a. Stage IV uterine cancer

b. Recurrent uterine cancer not amenable for surgery and radiotherapy.
Chemotherapy for Epithelial Uterine Cancer
Cisplatin-doxorubicin

Hormonal Therapy for Epithelial Uterine Cancer
Hormones are only indicated in advanced / metastatic diseases which strongly

express estrogen receptors.
a. Medroxyprogesterone Acetate PO 200 mg daily

b. Tamoxifen PO 20 mg daily

UTERINE SARCOMA
These are very rare tumours and as such there are few trials to address benefit of
chemotherapy in the adjuvant setting. In the metastatic setting, they should be treated
as sarcomas. Treatment will be as per institutional preference.
Surgery (TAHBSO + pelvic lymphadenectomy) is indicated from stage I – III. Palliative

surgery may be indicated in stage IV.
Adjuvant treatment is controversial.
Recommended regimens for advanced or metastatic setting:
For carcinosarcomas, ifosfamide is the most active single agent, and doxorubicin is
the most active for leiomyosarcomas.
Carcinosarcoma
Ifos-cisplatin

Ifosfamide 1.5g IV Bolus 1–5
Cisplatinum 20 IV 2 hours 1–5
Single agent ifosfamide

Ifosfamide 1.5g IV Bolus 1–5
Leiomyosarcoma


CERVIX
Cervical cancer is the commonest gynaecological cancer in Malaysia. Early cervical

cancer can be treated with either surgery or radiotherapy. Radiotherapy is the
treatment of choice for advanced cervical cancers.
Neoadjuvant and adjuvant chemotherapy
Neoadjuvant chemotherapy aims to reduce the tumour burden to facilitate surgery or

radiotherapy. However, evidence from large 52randomised trials does not indicate
benefits with respect to survival1-10. Two trials have shown that neo-adjuvant
chemotherapy prior to radiotherapy may be detrimental to patients leading to
decreased survival3,7. Hence, neo-adjuvant chemotherapy should be carried out only
within the context of a clinical trial.
In other tumour sites, adjuvant chemotherapy is often administered to eradicate

possible micrometastases. There are no large randomized trials addressing the
benefit of adjuvant chemotherapy in cervical cancer11. One trial did show survival
advantage but the experimental arm used chemo-RT and adjuvant chemotherapy12.
The trials on neo-adjuvant therapy also did not show a decrease in distance
metastases suggesting a lack of effectiveness of chemotherapy for
micrometastases2,3,5. Therefore adjuvant chemotherapy should be used within the
context of a trial.
Chemotherapy given concurrently with radiation may act synergistically to improve

the efficacy of radiotherapy, as well as having independent cell cytotoxicity. Recent
studies suggest that concurrent chemotherapy and radiotherapy in the radical
treatment of cancer of the cervix improves survival compared to radiotherapy alone 13-
19
. The improvement was seen in stages IB2 – IVA in both the radical and adjuvant
radiotherapy settings, with the relative risk of death being reduced by 30 – 40%. At
present, all patients with squamous carcinomas stages IB2 – IVA, should be
considered for concurrent chemo-radiotherapy unless contraindicated. These may
include patients with impaired renal function, inadequate blood counts and very old or
frail patients
Cisplatinum is the drug of choice for concurrent chemo-radiotherapy. Cisplatinum

combination has not shown any particular advantage over single agent cisplatinum
and results in greater toxicity. The role of carboplatinum, administered concurrently
with radiotherapy, is still undefined, and cannot be recommended except in unusual
circumstances20.

Palliative chemotherapy
There is a dearth of trials on palliative chemotherapy for cervical cancer. In general,

combination chemotherapy versus single agent cisplatinum has shown higher
responses without affecting survival21-25. Phase II studies have shown similar
response rates with median survival of 6 – 10 months26-29. Most studies were also
before the era of chemo-RT and therefore the results are more difficult to interpret.
Although paclitaxel shows high activity in Phase II, this has not borne out in Phase
III21,27. Long infusional regimens eg cis-5FU are inconvenient to patients and do not
seem to offer additional benefit. For this reason, single day chemotherapy may be
best for these group of patients with limited life expectancy. A four arm study using
platinum based regimes showed no difference in survival versus the standard
cisplatin-paclitaxel arm32. Higher doses of cisplatin do not influence survival30. A trial
with gemcitabine was stopped early because of inadequate activity31.
Single agent cisplatin or combinations can be recommended in the palliative

setting.
Cisplatinum-paclitaxel is a convenient regime and may be used as first line therapy.
CERVICAL CANCER CHEMOTHERAPY
Single agent cisplatinum

Cisplatinum 30 – 40 IV 1 hour 1
N.B. In practice, 50 mg total dose per week of cisplatinum could be used
Palliative chemotherapy
Single agent cisplatinum

Cisplatin 50 IV 1 hour 1
Cisplatin-5FU

Cisplatin 50-75 IV 1 hour 1
5 Fluorouracil 750-1000mg IV 24 hours 1–5

Cisplatin-MTX

Cisplatinum 50 IV 1 hour 1
Paclitaxel-cisplatin
*Carboplatin can be used if the patient is unable to tolerate cisplatin.

GESTATIONAL TROPHOBLASTIC DISEASE (GTT)
Indications for chemotherapy for GTT (following evacuation of hydatidiform mole) ;
a. A rise in hCG level of > 10% over three values recorded over 2 weeks.
b. A plateau in hCG level ( ± 10%) of four values recorded over 3 weeks
c. Detectable hCG levels at 6 months or more after evacuation.
d. Choriocarcinoma
FIGO staging of GTT
STAGE
I GTT confined to the uterine corpus.
II GTT extending to adnexa or vagina, but limited to the genital structures.
III GTT extending to the lungs, with or without genital tract involvement.
IV All other metastatic sites
Scoring system (modified WHO and FIGO 2000) for GTT
CRITERIA FOR SCORE 1-4
RISK FACTORS 0 1 2 4
Age (years) < 40 ≥ 40 - -

Antecedent
Hydatid Mole Abortion Term -
pregnancy
Interval months from
<4 4-6 7-12 >12
index pregnancy
Pre treatment BHCG
<103 103 - 104 >104 – 105 >105
(IU/L)
Site of metastases Spleen,
lung GIT Brain, Liver
including uterus Kidney
Number of
- 1–4 5–8 >8
metastases identified
Largest tumour mass,
- 3–4 ≥5 -
including Uterine (cm)
Previously
- - Single drug > 2 drugs
chemotherapy
The total score for a patient is obtained by adding the individual scores for each
prognostic factor.
Total score : < 6 = low risk

7 = high risk.

LOW RISK ( Total Score < 6 )
Methotrexate and Folinic Acid Rescue Regimen

2
50 mg/m
Methotrexate (MTX) IV or IM 1 hour 1,3,5 & 7
or 1 mg/kg
Folinic Acid (24 hours 6 – 12 mg
IM or oral Bolus 2,4,6 & 8
after each dose of MTX) or 0.1 mg/kg
Notes :
a. Chemotherapy is given till beta-Hcg levels come down to normal, and then 2
further courses are given.
b. There should be an interval of 7 days between the last day of folinic acid and
the first day of the next course
If patient failed to respond to single agent Methotrexate
a. In patient who was given a single high dose Methotrexate or Actinomycin

regimen, they can switch to 4 days course (as above) or Methotrexate
0.4mg/kg daily for 5 days regimen
Or
a. Single agent IV Actinomycin D 12mcg/kg daily for 5 days given every 2 weeks.
This regimen may also be used in patient with hepatic dysfunction.

HIGH RISK GTT (Total Score ≥ 7)
EMA-CO Regimen

(EMA)
Etoposide 100 IV 30 min 1,2
Actinomycin D 0.5 mg IV Bolus 1 ,2
Methotrexate 100 IV 1 hour 1
Methotrexate ** 200 IV 12 hours 1
Folinic Acid
15 mg IV or PO 12 hourly 2–3
(24 hrs post MTX x 4 doses)
(CO)
Vincristine 1.0 IV Bolus 8
Cyclophosphamide 600 IV 30 min 8
** MTX 200mg/m2, 12 hours infusion is commenced following 1 hour infusion
Note :
a. Cycles are repeated on Day 15 until beta HCG level return to normal. Then 2
further cycles are given.
b. Subcutaneous G-CSF may be administered in selected patients with significant

neutropenia. It must be started 24-48 hours after day 2 chemotherapy and the
last dose should be > 24 hours before vincristine and cyclophosphamide (CO).

RESISTANT GTT
BEP

2
Bleomycin 10 Units / m IV 24 hours 2–4
Note : On Day 1, give Etoposide prior to Cisplatin. On Day 2, Etoposide is given as

part of Cisplatin post-hydration. Bleomycin is given following Etoposide on Day 2-4.
EP-EMA

Cisplatin* 75 IV 12 hours 1
Etoposide 100 IV 1 hour 1, 8
Actinomycin D 500 ug IV Bolus 8
Folinic Acid 15 mg IV or PO 12 hourly 9 – 10
*Given in 1 litre of N/saline
Note: On Day 8, EMA regimen is given in standard dose but the second day of
Actinomycin D and Etoposide are omitted.
CHORIOCARCINOMA WITH BRAIN METASTASES
EMA-CO with high dose Methotrexate
For Brain metastases, the EMA-CO protocol is modified. The dose of MTX is
increased to 1000mg/m2. The MTX infusion is given over 24 hours. The urine must be
kept alkaline by administration of bicarbonate.

11. GENITO-URINARY
PROSTATE
Neo-Adjuvant and Adjuvant Hormonal Therapy
Androgen deprivation (AD) before radiotherapy or surgery has the potential to reduce
the size of the mass and eliminate tumour cells. Neo-adjuvant hormonal treatment
before radiotherapy can improve local control and disease-free survival with less
impact on overall survival1-5. This was confirmed in a meta-analysis which showed no
difference in overall survival. Short (3 months) AD is as effective as longer term3-4.
Other studies using adjuvant hormonal therapy for 2 or 3 years, when started
simultaneously with external radiation, improves local control, freedom from distant
metastases, relapse free survival and overall survival in patients with locally advanced
prostate cancer 7-18. Two recent meta-analyses indicate the survival advantage is
limited to those having radical radiotherapy but not with surgery6,26.
Patients most likely to benefit from AD :

1. Estimated life span of at least 10 years
2. Localised disease T1-2
 High Gleason score > 7 AND high PSA > 10 nmol/L
3. Locally advanced disease
 T3/4 tumours
 Node positive,
Note : These trials of neo-adjuvant and adjuvant androgen deprivation mainly used
conventional radiation dose levels of 65-70 Gray. Therefore the value in patients
treated with high dose conformal radiotherapy and IMRT remain unanswered.
Primary hormonal therapy
Prostate cancer typically affects elderly patients, some who are unfit for radical
treatment. Some of these patients are asymptomatic and have cancers detected on
screening. In this group of patients, hormone therapy is the preferred option. Although
early treatment may be of some benefit after many years, it is not without substantial
toxicity. Therefore patients need to be counselled, and deferred AD is an option with
treatment given for clinical or biochemical progression19-21.
Metastatic Disease
Prostate cancer is hormone sensitive and responds well to AD. The ‗gold standard‘ for
treatment is orchidectomy but medical therapy ie medical castration gives similar
results. There is minimal advantage of maximal androgen blockade, and this is seen
only after 5 years or more23-24. This improvement has to be balanced against the
increased side-effects with MAB. Furthermore in the overview, many of the trials with
survival at 5 years were small in the number of patients.

Hormone resistant prostate cancer
Hormone resistance occurs after AD therapy in prostate cancer and chemotherapy

should be considered. Docetaxel based chemotherapy regimens have been shown to
improve survival versus older chemotherapy24. Addition of extramustine chemotherapy
did not improve survival further25.
Hormone therapy of Prostate Cancer
Options :
1. Bilateral orchidectomy
2. LHRH agonist
a. Goserelin 3.6 mg S/C Monthly
b. Goserelin 10.8 mg S/C 3 monthly
c. Leuprorelin 3.75 mg I/M Monthly
3. Anti-androgens
 Flutamide PO 250 mg tds
 Bicalutamide PO 150 mg daily.
Starting LHRH agonist
LHRH agonist requires anti-androgen ‗cover‘ to prevent tumour flare when initially
started. Patients should start anti-androgens for at least 3 days prior to LHRH and
continued for 2-4 weeks.
PROSTATE CANCER CHEMOTHERAPY
Docetaxel-prednisolone

Prednisolone 10 mg (total) PO - 1 – 21
Mitoxantrone-prednisolone

Mitoxantrone 12 IV Bolus 1
Prednisolone 10 mg (total) PO - 1 – 21

BLADDER
Concurrent Chemoradiation
Results from various studies have shown that chemotherapy when given concurrently
with radiotherapy improves response rates and local control compared with
radiotherapy alone1-4. However these were small studies and CCRT cannot be
recommended.
Neo-Adjuvant Chemotherapy
Grossman et al randomized patients to radical cystectomy alone or 3 cycles of MVAC

chemotherapy before radical cystectomy. Median survival was prolonged in the
chemotherapy arm although the improvement in actuarial survival was statistically not
significant5. A large MRC/EORTC trial of neo-adjuvant MVAC or MVC pre-operatively
followed by either radical surgery or radiotherapy showed a non-significant
improvement in overall survival6. A recent meta-analysis however suggests benefit
from neo-adjuvant chemotherapy with 1/3 of patients recruited from the MRC/EORTC
trial7-8.
A recent meta-analysis suggests a benefit from adjuvant chemotherapy. However, the

number of patients across 6 trials was only 491 10. Three trials have compared different
adjuvant chemotherapy schedules but in the absence of stronger evidence, adjuvant
chemotherapy is not recommended11-13.
Metastatic disease
Transitional cell carcinoma of the bladder is quite chemosensitive and chemotherapy

may be useful in palliating metastatic cancer. MVAC is active but higher doses do not
improve results9. However this regimen is toxic and similar results with less toxicity
can be achieved with gemcitabine combination14-15. Where cisplatin is contraindicated,
it can be omitted from the ―CMV‖ regime and the 2 drug combination, MV can be used.

BLADDER CANCER CHEMOTHERAPY
MVAC

Methotrexate 30 IV Bolus 1,15 & 22
Vinblastine 3 IV Bolus 2,15 & 22
Adriamycin 30 IV Bolus 2
CMV

Methotrexate 30 IV Bolus 1, 8
Vinblastine 4 IV Bolus 1, 8
24 hours
Folinic acid 15 mg IV / PO Bolus QID
after MTX
Gem-Cis

Gemcitabine 1000 IV 30 min 1,8 & 15

KIDNEY
Metastatic renal carcinoma
Systemic treatments are only considered in the treatment of metastatic kidney cancer.
Interferon alfa is often used either alone or in combination. ―Positive‖ trials have used
very high dose usually 9 – 18 MIU 3 times a week but the relative benefit may be very
small. These regimens have considerable toxicities and careful patient selection is
needed. Combinations with other biological agent have not improved results except
with bevacizumab which confers a small 1-3. A relatively small trial of IFN with
chemotherapy has shown superior survival although the reference arm was
chemotherapy4. Radical nephrectomy in presence of metastatic disease has been
shown to improve survival in patients with resectable tumours5. Medroxyprogesterone
acetate has been used but has limited activity3, 6.
Adjuvant therapy
There is no indication for adjuvant therapy for renal carcinoma7-9.
Regimen for metastatic renal carcinoma

Drugs Dose Route Infusion time Days
M,W F
Interferon alfa 9 – 18 MIU SC Bolus
(3x /week)
Targeted therapies
Newer targeted therapies are emerging in the treatment of advanced renal cell
carcinoma. These include tyrosine kinase inhibitors, anti-angiogenic agents and
MTOR inhibitors10-14. Sunitinib has been shown to be superior to interferon in terms of
DFS as well as OS. However due to the high cost of these drugs, we are unable to
recommend their routine use in metastatic renal cancer.

TESTIS
TESTICULAR GERM CELL TUMOURS
Patients with testicular germ cell tumours (GCT) are typically young males between 15
– 30 years of age. GCTs are divided into seminomas and non-seminoma (NSGCT).
GCTs are highly curable even for those with extensive metastases. Patients with GCT
can be divided into prognostic groups1. Seminomas have good prognosis unless there
is presence of non-pulmonary metastases.
Prognostic-based staging system for metastatic germ cell cancer (IGCCCG)
NON-SEMINOMA
PROGNOSTIC GROUP CRITERIA
Good-prognosis All of the following criteria:
 55% of cases  Testis/retroperitoneal primary
 5-year survival 92%  No non-pulmonary visceral metastases
 AFP < 1,000 ng/ml
 hCG < 5,000 IU/l (1,000 ng/ml)
 LDH < 1.5 x ULN
Intermediate-prognosis All of the following criteria:

 30% of cases  Testis/retroperitoneal primary
 5-year survival 80%  No non-pulmonary visceral metastases
 AFP > 1,000 and < 10,000 ng/ml
 hCG > 5,000 and < 50,000 IU/l
 LDH > 1.5 and < 10 x ULN
Poor-prognosis Any of the following criteria

 15% of cases  Mediastinal primary
 5-year survival 48  Non-pulmonary visceral metastases
 AFP > 10,000 ng/ml
 hCG > 50,000 IU/l
SEMINOMA
PROGNOSTIC GROUP CRITERIA
Good-prognosis
 90% of cases
 No non-pulmonary visceral metastases
 5-year survival 86%
Intermediate-prognosis
 10% of cases  Non-pulmonary visceral metastases
 5-year survival 72%

BEP chemotherapy is considered standard for GCT. Due to toxicity of treatment in
the short and long term, there has been several trials addressing the following
issues:
 BEP vs Non-BEP regimens2-5
 Bleomycin versus none6-7
 Cisplatin vs carboplatin8-10
In summary, the results suggest non-BEP regimens gives similar results with
increasing toxicity, substitution of cisplatin with carboplatin or omiting bleomycin gives
inferior survival.
The BEP regimen can be given over 3 or 5 days. Although one trial showed superiority
of the 5 day regimen over a 3 day regimen, this trial used a lower dose of etoposide
and a larger trial with equivalent doses of etoposide showed no difference in the 3 vs 5
days regimens12-13. Higher doses of cisplatin is probably unneccessary11
For stage 1 seminomas, a single dose of carboplatin at AUC x 7 has equivalent results
to radiotherapy17.
Suggested chemotherapy for GCT
PROGNOSTIC GROUP CHEMOTHERAPY No’s CYCLES
Good BEP 3
Intermediate BEP 4
Poor BEP + EP 4+2
Relapsed GCT
Patients with recurrent disease can still have long term remission with
chemotherapy14-15. Therefore fit patients should be offered further chemotherapy.
Growth factors
Data does not support routine use of growth factors16. In the local setting, there was a
consensus for the routine use of growth factors as the rate of neutropenic sepsis is
reduced in this highly curable malignancy.

TESTICULAR GCT CHEMOTHERAPY
BEP
In the BEP regimens, the total cumulative dose of Bleomycin should not exceed
300mg. The total dose of etoposide should be 500 mg/m2.
3-Days BE500P

Cisplatinum 50 IV 2 hours 1–2
5 days BE500P

Salvage chemotherapy
TIP

Paclitaxel 175 – 225 IV 1 hour 1
Ifosfamide 1500 IV 1 hour 2–5
Carboplatin single agent (Stage 1 seminoma) – one cycle
Cycle length (days) = NA Anti-emetic = 4

Carboplatin AUC x 7 IV 1 hour 1

12. SARCOMA
SOFT TISSUE SARCOMA
The primary treatment in soft-tissue sarcoma is surgery. Radiotherapy is added to

improve local control rates. The definite role of chemotherapy is recommended in
small cell types of soft-tissue sarcomas (PNET, rhabdomyosarcoma, Ewings
sarcoma), high-risk group extremity sarcomas and metastatic sarcomas. The primary
endpoint in poor-prognosis situation is to eradicate gross and microscopic disease.
Doxorubicin and ifosfamide are the two most effective cytotoxic drugs used in soft-
tissue sarcomas.
The role of adjuvant chemotherapy in post surgical soft-tissue sarcoma is

controversial. The above notion is based on the past experience with small number of
patients, inhomogeneous group of soft-tissue sarcomas, sub-optimal doses and
combinations of chemotherapy. The use of modern chemotherapy improves response
rates and loco-regional control of the disease. An Italian study using epirubicin and
ifosfamide demonstrated significant improvement in disease free and overall survival
in favour of adjuvant chemotherapy1, but this was not seen in another trial using
CYVADIC regimen2. The sarcoma meta-analysis collaboration study showed a trend in
the improvement in survival but this was not significant3. The most common regimens
used in the adjuvant setting are single agent adriamycin, adriamycin-ifosfamide (AI)
and CYVADIC regimens.
Adjuvant chemotherapy is not recommended as routine but may be considered

in selected patients.
Unresectable and metastatic soft-tissue sarcomas
In advanced sarcomas, single agent doxorubicin is the treatment of choice. A large

EORTC trial showed equivalent results comparing with AI and CYVADIC4. Other trials
using other agents, higher drug doses & different combinations of chemotherapy, have
not shown improvement over doxorubicin5-12. Improved survival may be an inherent
characteristic of tumour growth rather than more intensive chemotherapy13. In
combination chemotherapy using MAID or AIM regimens impressive results were seen
in tumour responses but without impact on survival. Certain unfavourable histological
types eg leiomyosarcoma, clear cell sarcoma, alveolar soft-part sarcoma,
myxofibrosarcoma, dedifferentiated liposarcomas, malignant peripheral nerve sheath
tumour (MPNST), may benefit from these intensive regimens but the overall benefit is
uncertain.

SOFT TISSUE SARCOMA CHEMOTHERAPY

Doxorubicin 60 – 75 IV Bolus 1
Ifosfamide + Epirubicin

Ifosfamide 1800 IV 1 hour 1–5
Bolus
Mesna 360 IV 1–5
0,4, 8 hours
Epirubicin 60 IV 2 hours 1–2
G-CSF 300μg (total) SC Stat 8 – 15
Adria-ifos (AI)

Ifosfamide 5000 IV 24 hours 1
Bolus
Mesna 1000 IV 1–5
0,4, 8 hours
Doxorubicin 50 IV 2 hours 1
MAID

Doxorubicin 15 IV Continuous 1–4
Dacarbazine 250 IV Continuous 1–4
Ifosfamide 2500 IV Continuous 1–4
Bolus
Mesna 500 IV 1–5
0,4, 8 hours
Note: The above regimens should be used under the supervision of a trained clinical
oncologist and practised in a centre where blood products, haematopoietic growth factors and
infection control are readily available

OSTEOSARCOMA
Osteosarcoma is the commonest malignant sarcoma of the bone followed by Ewing‘s

sarcoma. The primary treatment is neo-adjuvant chemotherapy followed by interval
surgery and then post-operative chemotherapy. Selection of post-operative
chemotherapy is dependant on the histopathological response to neo-adjuvant
chemotherapy. The Enekkings‘ staging system is most-widely used in centres where
limb-salvage therapy is practised. The popular chemotherapy regimens (Memorial
Sloan Kettering Cancer Center T-10 and Institute Rizzoli Protocol) recommend high-
dose methotrexate, which is impractical in most centres in developing countries. One
of the chemotherapy regimen popularised by European Osteosarcoma Intergroup
(EOI) is simple and practical in clinical oncology set up2. This regimen utilises
conventional dose cisplatin plus doxorubicin every 3-weeks. Comparative trials
comparing complicated high-dose methotrexate regimens with EOI protocol have
shown similar outcomes as with more intensive regimens1.
The timing of surgery is important for optimal outcome. However a recent study
comparing neoadjuvant chemotherapy versus adjuvant chemotherapy after immediate
surgery did not show any difference in disease free, overall survival or amputation
rate5. The main endpoint of successful combination chemotherapy in osteosarcoma is
induction of maximum tumour necrosis. In case of sub-optimal tumour necrosis
(<90%), alternate chemotherapy is recommended involving ifosfamide and etoposide.
The EOI protocol could be used in the neoadjuvant, adjuvant and palliative settings.
European Osteosarcoma Intergroup (EOI) Protocol

Doxorubicin 25 IV Bolus 1–3
Salvage chemotherapy regimen
Ifos-etoposide

Ifosfamide 3000 IV 3 hours 1–4
Bolus
Mesna 600 IV 1–4
0,4, 8 hours
Note: The above regimen should be recommended under the supervision of a trained clinical
oncologist and practised in a centre where blood products, haematopoietic growth factors,
drug level monitoring and infection control are readily available

13. BRAIN
GLIOMA
Gliomas are the most aggressive and frequently diagnosed primary brain tumours.
Despite advances in surgical resection, radiation therapy and chemotherapy,
prognosis remains grim. The blood brain barrier limits the choice of cytotoxic drugs.
The role of chemotherapy in low-grade gliomas is controversial. Temozolamide

(TMZ) has shown activities in low-grade gliomas but with variable response rates.
Another study on the use of PCV regimen in low-grade oligodendroglioma showed
encouraging response rates4. However definite evidence of benefit is lacking in low
grade gliomas.
Adjuvant chemotherapy maybe considered for anaplastic astrocytoma and

glioblastoma multiforme. The most popular combination chemotherapy is PCV
regimen being considered as gold standard regimen in malignant gliomas1-2,5.The
most notable advancement in the management of glioblastoma has been concurrent
chemo-radiotherapy, followed by 6-months of adjuvant temozolamide (TMZ). This
study has shown statistically significant improvement in overall 2-year survival3.
Indication for Temozolamide :

1. Glioblastoma AND
2. Total / near total resection AND
3. ECOG / WHO PS 0 – 2 AND
4. Age < 60 years

BRAIN TUMOUR CHEMOTHERAPY
Adjuvant / Palliative
PCV

Procarbazine 60 PO Bolus 8 – 21
CCNU 110 PO Bolus 1
Vincristine 1.5 IV Bolus 8 & 29
Temozolamide

Temozolamide (TMZ) 150 – 200mg PO Oral 1–5
As temozolamide capsules are available in limited formulation, the daily dose may
differ to give an approximately correct dosing over the 5 days.
Single agent temozolamide
Cycle length (days) = 42* Anti-emetic = 3

Temozolamide (TMZ) 75 PO Oral RT days
*assuming a 6 week course of radical radiotherapy

14. PRACTICAL GUIDES
PRE-CHEMOTHERAPY CHECKS
1. Clinical assessment:
Assess the fitness of the patient
 Assess the toxicities of the chemotherapy
 Toxicities should be graded according to NCIC criteria
o (current version = Ver. 3 or use shortened version)
Laboratory assessment
2. Full blood count (FBC) should be checked prior to chemotherapy.

 Minimum baseline counts :
 White Cell Count > 3.0 x 109 /1
 (neutrophil count > 1.5 x 109/l)
 Platelets > 100 x 109/ 1
 Chemotherapy should not be given until counts recover fully.


3. Renal function
 Special attention to renal function should be given prior to the
administration of drugs such as cisplatinum and Ifosfamide.
 A baseline Creatinine Clearance should be done prior to the first dose
of cisplatinum administration. The Cockcroft and Gault formula gives
a good estimation of GFR. (refer Page 69)
 Creatinine Clearance should be more than 50 ml/minute.
 If less, get advice on alternative chemotherapy regimen.
 Serum creatinine should be not more than 150 micromol/L
4. Liver function test

 This should be checked with every cycle of chemotherapy but usually
it is not necessary to wait for results before administration except
where drugs are known to be metabolised in the liver eg doxorubicin
and raised bilirubin may increase toxicity.
5. Tumour markers
 Patients with non-seminomatous germ cell tumours MUST have serial
tumour markers, both AFP and BHCG.
 Ovarian cancers can be monitored with CA-125
 CEA monitoring is sometimes useful in the metastatic setting for colo-
rectal cancers
 CA19-9 maybe useful in pancreatic cancers.
*If any of these markers are not raised prior to therapy in advanced disease, then they are
probably useless for monitoring.

ECOG / WHO PERFORMANCE STATUS
The Performance Status (PS) of a patient is often a good indicator of likelihood of

benefit from chemotherapy. Several scales are used but the ECOG scale is practical
and easy to use.
BRIEF
GRADE ECOG DESCRIPTION
DESCRIPTION
Fully active, able to carry on all pre-disease

0 Normal
performance without restriction
Restricted in physically strenuous activity but

1 ambulatory and able to carry out work of a light Light work
or sedentary nature, eg light house or office work
Ambulatory and capable of all self-care but
2 unable to carry out any work activities. Up and Self-caring
about more than 50% of waking hours
Capable of only limited self-care, confined to bed

3 Non Self-caring
or chair more than 50% of waking hours
Completely disabled. Cannot carry on any self-

4 Moribund
care.
5 Dead Dead

IMPORTANT FORMULAS
Creatine clearance Cockcroft and Gault formula:
Calculated creatinine Clearance
Male = [ (140 – age in years) x weight (kg) ] x 1.23

serum creatinine (mmol/litre)
Female = [ (140 – age in years) x weight (kg ) x 1.05

serum creatinine (mmol/litre)
The result is given in micromol per litre.

Conversion from mg/dl is by multiplying results by 88.
Body surface area DuBois and DuBois formula :

(BSA)
BSA (m2) = (W 0.425 x H0.725) x 0.007184
W – patient‘s weight (kg)

H – patient‘s height (cm)
Alternative formula
BSA (m2) = ( W x H )1/2

60
Where:
 W – patient’s weight (kg)
 H – patient’s height (cm)
 60 – conversion/ correction factor
Body Mass Index Weight(kg) / Height(m)2

MANAGEMENT OF EMESIS
General Principles
 Patients should be counselled about nausea and vomiting that may result
following chemotherapy.
 Anti-emetics should be given routinely to all patients receiving moderate or
highly emetogenic chemotherapy.
 The intravenously route is preferred though oral anti-emetics can be as
effective.
There are 4 different types of chemotherapy induced nausea and vomiting (CINV).
Type of Role of
Description
CINV anti-emetics
1. Acute usually occurs minutes to hours after
chemotherapy is given and improves within 24
work best
hours. The vomiting is worst after 5-6 hours.
2. Delayed occurs more than 24 hours after chemotherapy. It

is commoner with cisplatin, carboplatin,
cyclophosphamide, and doxorubicin. For example,
cisplatin-related vomiting is at its worst 48 to 72 less useful
hours following chemotherapy and can last 6 – 7
days.
3. Anticipatory is learned from previous experiences with

vomiting. It occurs as a result of an unpleasant
experience with chemotherapy and as the person
is preparing for the next dose of chemotherapy. generally do
The person anticipates nausea and vomiting will not work.
occur as previously and vomits in the absence of
chemotherapy.
4. Refractory occurs after one, a few, or several chemotherapy

treatments even though the person is being
treated to prevent or control nausea and vomiting.
The anti-nausea and vomiting treatment is no
Do not work
longer effective. The person has become
―refractory‖ (no longer responding) to treatment to
prevent nausea and vomiting.
Breakthrough vomiting occurs despite treatment to prevent it. It requires additional

anti-nausea and vomiting treatment.
A guide to emetogenic potential of various chemotherapy drugs and appropriate anti-

emetics are given below (Table EM1).

Table EM1 : Emetogenic potential for selected antineoplastic agents
LEVEL Frequency DRUGS

of emesis (%)
Bevacizumab Hydroxyurea
Bleomycin Methotrexate < 50mg/m2
Busulfan Rituximab
1 <10
Chlorambucil Vinblastine
Fludarabine Vincristine
5-FU < 500mg/m2 Vinorelbine
Bortezomib Gemcitabine
Capecitabine Methotrexate
Cetuximab Mitomycin
Cytarabine < 1 gm/m2 Mitoxantrone
2 10 – 30
Docetaxel Paclitaxel
Etoposide Pemetrexed
5-FU 500-1000 mg/m2 Topotecan
Trastuzumab
Busulphan > 4mg/day Daunorubicin

Carboplatin Doxorubicin
Cisplatin < 50 mg/m2 Epirubicin < 90 mg/m2
Cyclo* < 1500 mg/m2 Idarubicin
3 30 – 90
Cyclo (oral) Ifosfamide
Cytarabine > 1 g/m2 Irinotecan
Dactinomycin Oxaliplatin
Procarbazine
AC / EC combination
Carmustine < 250 mg/m2
Cisplatinum > 50 mg/m2
4 > 90 Cyclo > 1500 mg/m2
Cytarabine > 1000 mg/m2
Dacarbazine
MTX > 1000 mg/m2
* cyclo = cyclophosphamide
For combination chemotherapy, addition of a drug of similar level, increases

emetogenic potential by one.

Table EM2 : Guidelines for anti-emetic prescription with chemotherapy
Emetogenic With chemotherapy Take home (oral)

Options
level D1 D2 – 3
5-HT3 A AND Dexamethasone Aprepitant D1 – 3

4
Dexamethasone +metoclopramide Lorazepam
5-HT3 A AND Dexamethasone

3 Aprepitant D1 – 3
Dexamethasone +metoclopramide
Dexamethasone and/or Dexamethasone

2 --
metoclopramide +metoclopramide
Nil or Nil or
1 --
Metoclopramide Metoclopramide
TABLE EM3 : Anti-emetics and dosages
DRUG DOSE ROUTE FREQUENCY
5-HT3 antagonist
1 mg IV
 Granisetron Daily
2 mg PO
8 mg IV
 Ondansetron Daily
24 mg PO
 Tropisetron 5 mg IV / PO Daily
12 mg IV Stat
Dexamethasone
8 mg PO daily
Metoclopramide 10 -20 mg IV or PO tds
Lorazepam 0.5 – 2 mg PO tds or qid
Prochlorperazine 10 mg PO or IV tds or qid
1 – 2 mg PO
Haloperidol tds or qid
1 – 3 mg IV
125 mg PO Day 1
Aprepitant
80 mg PO Day 2 & 3
Granisetron is the preferred choice for anti-emetics as it is as efficacious as other 5-

HT3A. The recommended dose is 0.15 mg/kg and usually only 1mg is needed. An
ampoule of 3mg can be used for 3 patients making it very cost effective.

Anticipatory Emesis Treatment
Lorazepam 0.5 - 2mg PO night before and morning of treatment.
Anti-emetics should be given iv.

All patients should be kept sedated before and during chemotherapy.
Breakthrough treatment for CINV
Continue with current anti-emetics AND add a new drug, either :
1. Prochlorperazine
2. Lorazepam
3. Haloperidol
If nausea and vomiting is controlled, continue on a scheduled basis and not ―as
required‖ (prn). If vomiting is still uncontrolled, use a higher level primary treatment for
control of nausea and vomiting.
PRE-MEDICATION
Intake
Medication Dose Route Days
action
1. Docetaxel (3 weekly)
Dexamethasone 8mg BID PO Day 0, 1, 2
2. Paclitaxel
Dexamethasone 20 mg stat IV Day 1
Chlorpheniramine 10 mg stat IV Day 1
Ranitidine 50 mg stat IV Day 1

HYDRATION REGIMENS
These fluid regimens are as a guide. Similar regimens should work too.
LOW DOSE CISPLATIN (20 mg/m2/day)

(2 litre IV fluid over 4 hours)
Solute Volume Time
1. Normal saline + 20mmol KCL 500 ml 1 hour
2. Mannitol 10% 500 ml 1 hour
3. Pre-med anti-emetics 15 min
4. Normal Saline + Cisplatin 500ml 1 hour
5. Normal Saline + 10 mmol MgSO4 500ml 1 hour
*There must be NO cardiovascular or renal disease.
Maintain oral fluid 1-1.5 litre during the subsequent hours.
This can be done as an outpatient treatment.
INTERMEDIATE DOSE CISPLATIN (40 – 80 mg/m2/day)

(3 litre IV fluid over 8 hours)
Solute Volume Time
1. Normal saline + 20mmol KCL 500 ml 1 hour
2. Mannitol 10% 500 ml 1 hour
3. Pre-med anti-emetics
4. Normal saline + cisplatin 500ml 2 hours
5. Normal saline + 10 mmol MgSO4 500ml 2 hours
6. Frusemide 20 mg
7. Normal saline 500 ml 1 hour
8. Normal saline 500 ml 1 hour
Maintain oral fluid 1-2 litre for 6 hours after I/V fluid
If urine output is less than 100ml/hour during chemotherapy, repeat IV mannitol 20%
100ml over 30 minutes
This can be done as an outpatient treatment.

HIGH DOSE CISPLATIN (80 – 120 mg/m2/day)
(4.5 litre IV fluids over 24 hours)
Solute Volume Time
1. Normal saline 500 ml 2 hours
2. Normal saline + 20mmol KCL 500ml 3 hours
4. Mannitol 10% 500ml 3 hours
5. Pre-med anti-emetics
6. Normal saline + ½ cisplatin 500ml 2 hours
7. Normal saline + ½ cisplatin 500ml 2 hours
8. Normal saline + 20mmol KCL 500ml 3 hours
10. Normal saline 500ml 3 hours
Advise oral fluid > 2 litres over next 24 hours after IV fluid is discontinued.
If urine output is less than 100ml/hour during chemotherapy, repeat IV mannitol 20%
100ml over 30 minutes

IFOSFAMIDE
Short Infusion Regimen
In the short infusion regimen, ifosfamide is given over 4 hours. The total amount of
Mesna given is the same as the total ifosfamide dose. Mesna is given in 3 divided
doses.
Assuming Ifosfamide dose is ―Y‖ mg, then the total dose of Mesna is also ―Y‖ mg
Solute Volume Infusion

TIME DRUG DOSE (mg)
(Normal Saline) time
1. 0 hour Mesna 1/3 x ―Y‖ 50 ml 15 minutes
2. 0–4 Ifosfamide ―Y‖ 1000 ml 4 hours
3. 4 hours Mesna 1/3 x ―Y‖ 50 ml 15 minutes
4. 4 – 8 hours ---- ----- 1000 ml 4 hours
5. 8 hours Mesna 1/3 x ―Y‖ 50 ml 15 minutes
Long Infusion Regimen (over 3 days)

Ifosfamide and mesna are infused concurrently.
Day1
TIME DRUG DOSE SOLUTE

(Normal Saline)
1. 0 hour Mesna 1 gm Bolus
2. 0 – 6 hour Ifosfamide 0.5 mg /m2 500 ml

Mesna 0.5 mg /m2 500 ml
Day 2 & 3 : Repeat Steps 2 – 5
Day 4
6. 0 – 6 hour Mesna 0.5 mg /m2 500 ml N/ saline

7. 6 – 12 hour Mesna 0.5 mg /m2 500 ml N/ saline

COMMON TOXICITY CRITERIA (Simplified CTC Ver 3.0)
General summary :
Grade 0 = No reaction / normal
Non-haematological toxicities
 Anything requiring medication is often Grade 2

 Reactions needing admission and / or support is usually > Grade 3
 Life-threatening reactions are invariably Grade 4 but not all Grade 4 are life
threatening
 Where unsure, mild, moderate and severe corresponds to Grades 1, 2 & 3
BLOOD /BONE MARROW
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Haemoglobin
<LLN – 10.0 8.0 – 10.0 6.5 – 8.0 <6.5
g / dL
Leukocytes
<LLN – 3000 2000 – 3000 1000 – 2000 <1000
mm3
Neutrophil
>1500 1000 – 1500 500 – 1000 <500
mm3
Platelets
<LLN -75 50 – 75 10 – 50 <10
000 / mm3
* LLN = Lower Limit of Normal
FEBRILE NEUTROPENIA
ANC < 1000 and Life threatening

- - present
fever >38.50C sepsis
CONSTITUTIONAL SYMPTOMS
Increased Difficulty in Severe or loss of Bedridden or

Fatigue fatigue performing some ability to perform disabling
Normal activity activities some activities
Fever, ANC>1000 38.0-39.00C 39.1- 400C >400C < 24 hrs >400C > 24 hrs
Weight gain/loss 5-10% 10 – 20% >20% -
LYMPHATICS
Moderate, req. Severe, limiting Severe, limiting

Lymphoedema Mild
compression function function,ulcer

NEUROLOGY
Adverse event Grade 1 Grade 2 Grade 3 Grade 4

Paresthesias or Interfering with Interfering with Permanent
Neuropathy Loss of Function Daily activities Sensory loss
Deep reflexes
GASTROINTESTINAL
Significantly
Requiring IV Requiring NGT
Anorexia Loss of appetite reduced oral
fluids or IV nutrition
intake.
Req. stool Requiring Enema or Obstruction/
Constipation softener/change Laxatives manual Toxic
of diet evacuation Megacolon
Dry mucosa, Brief fluid Sustained fluid Hemodynamic
Dehydration Skin turgor replacement <24 replacement Collapse, req.
diminished hrs Intensive care
>7 stools/day, Hemodynamic
Diarrhea, Increased 4-6 stools/day
incontinence, collapse, req.
no colostomy 1 - 3 stools/day nocturnal stool
dehydration Intensive care
Mild increase Moderate Severe increase Hemodynamic
Diarrhea with Loose,watery Increase, Interfering with collapse,req.
colostomy Colostomy o/p Normal activity normal Intensive care
activity
Complete
Esophagitis,
Mild dysphagia Requiring Requiring IV obstruction,
Odynophagia,
Can eat regular soft or Hydration or Perforation or
Dysphagia +/-
diet Liquid diet NGT feeding Ulceration with
Due to radiation
bleeding
Mouth dryness Mild Moderate - -
Patchy <1.5cm Confluent
Mucositis due to Erythema of Necrosis/deep
pseudomembran pseudomembran
radiation mucosa Ulcer+/-bleed
ous reaction ous reaction
Decreased oral Requiring IV
Nausea Able to eat -
intake fluids
Increased freq., As grade 1 but Req. IV Perforation,
Bld streaked Requiring fluids,transfusion Necrosis or
Proctitis stools ,rectal medication, or persistent Bleeding req.
discomfort ,no Anal fissure Discharge req. Surgical
medication rqd pads (mucus) intervention
Slightly thick Thick,ropy Acute gland
Salivary gland saliva, altered sticky necrosis
-
taste saliva,marked
altered taste
Markedly
Taste disturbance Slightly altered - -
Altered
> 6 in 24 hrs, Hemodynamic
Vomiting 1 in 24 hours 2-5 in 24 hrs
req. IV fluids collapse

DERMATOLOGY/SKIN
Adverse event Grade 1 Grade 2 Grade 3 Grade 4

Pronounced hair
Alopecia Mild hair loss - -
loss
Painful skin Painful skin
Hand-foot skin Skin changes,
changes, changes, -
reaction no pain
normal function intefere function
Severe/prolong
Pain, itchy , Pain/swelling
Injection site ulcer/necrosis -
erythema with phlebitis
or requiring op
Discoloration, Loss of nail or
Nail changes - -
Ridging/pitting painful nail bed
Pigmentation Localized Generalized - -
Moderate-brisk Confluent moist Necrosis or
erythema or desquamation ulceration of
Faint erythema,
Radiation dermatitis/ edema >1.5cm,not full thickness
Dry
or desquamation confined to skin dermis,+
desquamation
confined to skin fold, spontaneous
fold or creases pitting edema bleeding
PAIN
Pain due to radiation Mild ,not Pain/analgesics Interfering with Disabling

or bone pain interfering with interfering with daily activities
function function
PULMONARY
Severe ,poorly
Req. narcotics
Cough Mild controlled by -
Anti tussive
treatment
Pneumonitis or Radiographic Requiring
Req. steroid or Requiring
Pulmonary fibrosis changes, +/- Assisted
diuretics oxygen
mild symptoms ventilation
RENAL/GENITOURINARY
Dysuria Mild,req. no Symptoms Symptoms not

intervention relieved with Relieved with -
therapy therapy
Urinary frequency/ Nocturia Frequency > > hourly with
urgency frequency up to 2x normal but urgency or req. -
2x normal, < hourly catheter
Intermittent Persistent gross Necrosis,deep
Hematuria Microscopic
gross bleeding bleeding,clots ulcer,surgery

DOSE MODIFICATION GUIDELINES
The following is a guide and not meant to be taken as absolute rules.
Decisions on dose modification must be INDIVIDUALIZED and should have

consultant‘s approval.
General principles :
TOCIXITY ACTION
Haematological
Delay 1 week
 Inadequate FBC on day of treatment
Use same dose
Delay 1 more week
 Inadequate counts after 1 week delay
Dose reduce 75%
 Inadequate counts after 2 weeks Review regimen / plan
Non-haematological toxicity
Consider for dose reduction
 Grade 3
Use 75% of previous dose
MUST dose reduce
 Grade 4 Review regimen.
Use 50 – 75% of previous dose
Creatinine clearance (ml/min)
Cisplatin dose
 GFR > 60 100%
 GFR 40 – 60 50%
 GFR < 40 Omit
Neuropathy inc. ototoxicity

(Platinum, vinca alkaloids, taxane)
 Grade 2 Dose reduce to 75%
 Grade 3 – 4 Omit
Cystitis
(cyclophosphamide, ifosfamide)
 Grade 2 Increase fluid intake > 2L per day
 Grade 3 Add or increase mesna dose
GERM CELL TUMOUR
No dose reduction is recommended. All cases should be treated in consultation with

an oncologist.

MANAGEMENT OF NEUTROPENIC SEPSIS
Patients should be counselled about fever following chemotherapy and the need to
seek medical attention.
Definitions :
Fever : Single oral temperature of 38.3oC or temperature of

38.00C for >1 hour.
Neutropenia : neutrophil <500 cells/mm3, or <1000 cells/mm3 with a
predicted decrease to <500 cells/mm3.
Febrile neutropenia (FN) : presence of both fever and neutropenia.
Management
1. Admit patient
2. Septic work-up
Include blood cultures obtained immediately for bacteria and fungi.
 The yield of bacterial and fungal isolates is related to the culture systems
used and the volume of the blood sample
Little clinically useful information is gained from routine cultures from the nose,
oropharynx, urine and rectum, when lesions or disease processes are absent.
3. Start empirical antibiotics :

 Monotherapy - Cefepime or Ceftazidime
 Dual therapy - Cefepime or Ceftazidime + aminoglycoside
- Piperacillin with Tazobactam
- Imipenem – Cilastatin or Meropenem.
Combination antibiotics may be preferred in cases with severe neutropenia,
expected prolonged duration and complications such as sepsis,hypotension,
mucositis, and recurrent episodes of FN
The choice of antibiotics subsequently is guided by the culture and sensitivity
patterns as well as the prevailing resistance patterns.
Trough aminoglycoside levels (taken 0 – 6 hours pre-dose) should be
performed at least twice weekly. Level should be <1.0 for once daily dosing.
4. Reassessment
Frequent clinical assessment is important.
Daily FBC (full blood count) until resolution of neutropenia and fever settles.
5. G-CSFs should be considered in patients with FN with high-risk features :

 expected prolonged (>10 days) and profound (<0.1 x 109/L) neutropenia,
 age greater than 65 years,
 altered sensorium
 uncontrolled medical disease eg diabetis
 uncontrolled primary disease,
 focus of infection eg pneumonia,
 hypotension and multiorgan dysfunction (sepsis syndrome),
 possible hospital acquired infection
Usually GCSF can be stopped when WBC > 1000 cells/mm3
Following the occurrence of significant toxicity, the dose of subsequent cycles of
chemotherapy may need to be modified.

OUTPATIENT MANAGEMENT OF FEBRILE NEUTROPENIA
Intravenous antibiotic therapy is recommended for most patients with FN. However
patients with low risk can be treated with oral antibiotics even as out patient. However
they need careful selection and frequent assessment and must have access to
emergency care 24 hours.
 Absolute neutrophil count of >100 cells/mm3

 Absolute monocyte count of >100 cells/mm3
 Normal findings on a chest radiograph
 Nearly normal results of hepatic and renal function tests
 Duration of neutropenia of <7 days
 Resolution of neutropenia expected in <10 days
 No intravenous catheter–site infection
 Early evidence of bone marrow recovery
 Malignancy in remission
 Peak temperature of < 39.0_C
 No neurological or mental changes
 No appearance of illness
 No abdominal pain
 No comorbidity complications
Scoring index for identification of low-risk febrile neutropenic patients.
CHARACTERISTIC SCORE
1. Extent of illness
 No symptoms 5
 Mild symptoms 5
 Moderate symptoms 3
2. No hypotension 5
3. No chronic obstructive pulmonary disease 4
4. Solid tumor or no fungal infection 4
5. No dehydration 3
6. Outpatient at onset of fever 3
7. Age < 60 years 2
A score of > 21 indicates low risk of complication and the patient could be considered
for outpatient therapy with oral antibiotics. However unless you are familiar with
management of febrile neutropenia, this is not recommended.

USE OF HAEMATOPOETIC COLONY-STIMULATING FACTORS (CSF)
Indications for colony stimulating factors:
1. Secondary prophylaxis is recommended for patients who experienced febrile

neutropenia (FN) from a prior cycle of chemotherapy in which a reduction in the
dose may compromise disease free- or overall- survival.
However, if alternative but equal treatment that does not require CSF is
available, it should be used
2. Dose reduction or dose delay remains an appropriate option for palliative
situations e.g. metastatic pancreatic cancer.
3. Primary prophylaxis is recommended in situations where dose dense or dose
intense chemotherapy strategies have survival benefits, the use of CSFs is
supported when the risk of FN is 20% or higher i.e. in dose-dense strategies in
adjuvant node positive breast cancer, small cell lung cancer and aggressive
non Hodgkins lymphomas.
4. Primary prophylaxis may also be indicated in special situations even with
relatively less myelosuppressive regimens in patients with high risk factors for
FN. These include age>65 years, extensive bone and bone marrow
involvement, patients on combined chemo-radiation treatments ,poor nutritional
status, advanced stage of disease and medical co-morbidities including cardio-
respiratory, liver and renal impairments. In these situations primary prophylaxis
may be considered even with regimens with FN rates of less than 20%.
5. Therapeutic use of G-CSF in FN.
CSFs should not be routinely used for FN. CSFs may be considered as an
adjunct to antibiotics in patients with FN who are at increase risk from infection
associated complications. High risk features include expected prolonged
neutropenia(>10 days), profound neutropenia(< 0.1 x 10 power 9/L), age>65
years, pneumonia, hypotension and multi-organ dysfunction.
There is no proven role of routine use of CSFs in afebrile patients with
neutropenia
Administration of CSF
CSF should be given 24-72 hours after the administration of myelotoxic chemotherapy.
CSF should be continued until the absolute neutrophil count (ANC) > 1 x 109/L.
The recommended doses of CSF are :

 G-CSF = 5 μg/kg/d
 GM-CSF = 250 μg/m2/d.
Doses should be rounded to nearest vial size. The following doses can be used:
BODY WEIGHT DOSE OF GCSF (per day)

 < 40 kg 150 microgram*
 40 – 80 kg 300 microgram
 > 80 kg 450 microgram
*(half vial; stored other half in the fridge for use the next day)
Route : The preferred route is subcutaneous.

CHEMOTHERAPY TOXICITIES AND MANAGEMENT GUIDELINES
Toxicity Cytotoxic that may cause it
1 Alopecia Many especially anthracyclines, taxanes, etoposide
Counsel patient about hair loss following chemotherapy.

 Use a gentle shampoo and a soft brush.
 Avoid dyes, perms, bleaches and hair sprays.
 Protect scalp from sun exposure.
Patient may choose to wear a wig or scarf. Patient should be reassured

that the hair would grow back 2 – 3 months following chemotherapy.
2 Cardiotoxicity Anthracyclines
Others : Cyclophosphamide, Fluorouracil and trastuzumab
Cardiotoxicity is a well documented long term side-effect from

anthracyline use. The risk is dose dependant and increases with
cumulative life-time dose. The risk of clinical cardiomyopathy is less than
10% if the lifetime cumulative dose is less than the doses specified
Drug Maximum doses (mg/m2)

 Doxorubicin
- Bolus 400
- Concurrent radiation 400
- 24 hours infusion 550
 Daunorubicin 800
 Idarubicin 150
 Epirubicin 900
 Mitoxantrone 160
Management
Avoid Anthracyclines (eg adriamycin, epirubicin) in patients with cardiac

disease. Use with caution in patients with risk factors for coronary artery
disease such as hypertension, diabetes mellitus and obesity.
Investigations
 Baseline ECG and Chest X-ray.
 Full cardiac assessment for those with risk factors.
Cardiotoxic effects may be prevented by lowering the cumulative dose

or lowering the peak dose eg using different treatment schedule,
prolonging the infusion or using alternative anthracycline derivatives.
Monitor for symptoms of arrhythmia, ischemic cardiac events, CHF

symptoms and pericardial disease.

3 Diarrhea Irinotecan
Other cytotoxic drugs: Capecitabine, cisplatin, cytosine
arabinoside, cyclophosphamide, daunorubicin,
docetaxel, doxorubicin, 5-FU, MTX, oxaliplatin,
paclitaxel, topotecan
Irinotecan induced diarrhea
Start loperamide 4mg at the first sign of loose stool followed by 2mg
every 2 hours but not exceeding 48 hours
Diarrhoea starting within 24 hours

Due to ―Cholinergic syndrome‖
 Symptoms : sweating, hypersalivation, visual disturbances,
abdominal cramps, ―early‖ diarrhoea
Atropine (0.25mg SC) administered therapeutically
In subsequent courses, prophylactic atropine is indicated if the

cholinergic syndrome was severe in the previous cycle.
Diarrhoea after the first day
When diarrhoea occurs, patients must take loperamide or another anti-

diarrhoeal agent, eg diphenoxylate or dihydrocodeine tartrate every two
hours for at least 12 hours immediately, and up to 12 hours after the last
liquid stool.
Patients to drink large amounts of water, with electrolyte supplements
during diarrhoeal episode.
Prophylactic broad spectrum antibiotic if

 Diarrhea > 24 hours despite treatment , and
 Severe neutropenia.(NC <1000 cells/mm3)
A dose reduction is recommended for the next cycle.
Admit if :
 Diarrhea Grade 4
 Persisting diarrhoea > 48 hours despite anti-diarrhoeal and
antibiotic treatment.
 Fever.
 Vomiting and dehydration
If diarrhoea is resistant to appropriate treatment and is bloody,

pseudomembranous colitis (PMC) should be suspected.
Rectosigmoidoscopy and test for clostridium deficile is recommended.
Oral vancomycin is indicated if there is PMC.

4. Mucositis Anthracyclines, MTX, Alkylating agents, 5-FU
Possible therapeutic measures
 Sucking on Ice chips
 Gargles : Sodium bicarbonate, Chlorhexidine, Difflam, Thymol
 Nystatin syrup
5. Neurotoxicity Neuropathy
 Peripheral - Platinum, Vinca alkaloid, Taxanes
 Autonomic - Vinca alkaloids
Encephalopathy – Platinum, Ifosfamide, 5FU, IFN
Ototoxicity – Platinum
Options
 Amitriptylline 10- 25 mg nocte max = 150mg/day
 Carbamazepine 100 mg bd max = 1200mg/day
 Gabapentin 300 mg nocte max = 3600mg/day
Increase drug doses gradually every 3 – 7 days until therapeutic effect

or toxicity
6 Neutropenic See relevant section

sepsis
7 Pulmonary Bleomycin (if total dose >300 000iu USP /300 mg),
toxicity Busulphan, MTX, Mitomycin, Vinca alkaloids
Patients who have received extensive treatment with bleomycin may be

at risk of developing respiratory failure if a general anaesthetic is given
with high inspired oxygen concentrations. Basal lung crepitations or
sudden chest x ray changes are an indication to stop therapy.
8 Hand Foot Liposomal doxorubicin and daunorubicin, Capecitabine,

Syndrome MTX, 5FU (infusion), Epirubicin, 6-MP and ARA-C.
Presents as redness or a tingling sensation in hands and feet then

progresses to discomfort and swelling over a few days. Picking up
objects and walking would be a painful task. May lead to ulceration of
creases and desquamation of fingers, toes, palms and soles. Usually
self- limiting and will resolve in a few weeks.
 Advise patients to avoid sun exposure and hot baths/showers.

 Apply cold compression on affected areas for 20 minutes and then
removing for 20 minutes.
 Avoid tight fitting clothing and vigorous rubbing of skin, wear gloves.
 Frequent application of topical emollients and moisturizers.
9. Third space The presence of ascites, pleural effusion, oedema, etc

effects will increase the risk of methotrexate toxicity
Avoid use of methotrexate if there is ascites, oedema etc

15. DRUG PREPARATION AND ADMINISTRATION
ADMINISTRATION OF CYTOTOXIC DRUGS
Cytotoxic drugs should only be administered by personnel trained in safe practice and
aware of risks involved in cytotoxic administration
Pregnant women should avoid handling cytotoxic drugs or contaminated body waste.
Standard Operating Procedures (SOP) should be followed to prevent exposure to

particulates, aerosols, sprays and spills.
Important points:
1. Before Administration
 Follow supplier‘s recommended procedures for specific cytotoxic

drugs.
 Reconstitute drug with the correct amount of the appropriate
solvent to avoid concentrations of drugs which are too high.
 Should there be any need to dispel air or fluid from a syringe,
always place a sterile gauze at the needle tip to avoid the
formation of aerosol
 Wear appropriate Personal Protective Equipment
2. Cannula placement and iv line preparation
 Use the smallest branula compatible with iv fluid flow.

 Avoid :
 repeated puncture of the same vein,
 using a pre-existing peripheral site
 side of breast cancer / lymphoedematous arm
 Lightly secure branula with tape. DO NOT cover the site of the
injection
 Ensure iv access is free flowing
 Use plastic backed absorbent sheets / pads under the injection
site.
3. Pre- Chemotherapy administration
 Use injection trays to carry syringes to the patient‘s bedside

 Use Luer-lock fittings on needles, syringes and other equipment
 Prime iv tubing with non-cytotoxic fluids, below eye level.
 Inject a small volume of normal saline and draw a small amount of
blood to ensure the injection site is functioning properly
 Do Not transport patients while cytotoxic drug administration is in
progress.
 Do not eat or drink.

4. Chemotherapy administration
 Inject drugs slowly.

 If several drugs have to be given, administer vesicant agent
first followed by the other agents.
 All vesicant drugs should be given with a free flowing drip
 Look out for extravasation
 Check the needle is in place by intermittently drawing up
blood.
 Ask if the patient is having pain or burning sensation at the
puncture site
 Observe the injection site for blebbing
 When in doubt about the integrity of the vein or injection site at
any time – STOP THE INJECTION and TAKE THE NEEDLE
OUT.
 If there is extravasation inform medical staff. DO NOT
continue chemotherapy.
 If medical staff decides to continue chemotherapy, avoid a
site distal to the original vein
 After the chemotherapy drugs are injected, flush with saline.
5. After Administration
 Do Not recap needles.

 Do Not cut iv infusion sets or cytotoxic drug contaminated needles.
 Use disposable containers for transporting waste.
 Ensure sharps disposal containers are readily accessible and
additional disposal containers are available for cytotoxic waste.
 Dispose iv bags or flasks with the administration set still attached.
 After completion of procedures, remove Personal Protective
Equipment for either cleaning or disposal.
6. Disposal of cytotoxic contaminated body fluids:
 Protective clothing must be worn when disposing any body fluid.

Vomitus must be disposed of immediately. Avoid splashing.
 Mortuary staff to be informed if patient dies within 48 hours after
chemotherapy administration.
7. Oral Cytotoxics
 Do not break or grind tablets

 Do not use an automatic tablet counter

MANAGEMENT OF EXTRAVASATION
Extravasation is the leakage of intravenous fluid from the vein into the interstitial
tissues through a puncture in the vein or around the branula site
Vesicants are drugs that cause tissue necrosis, pain and tissue sloughing at the site
of extravasation. Irritants are drugs that can cause aching, tightness, phlebitis with or
without inflammation
Cytotoxic drugs which usually do not cause local problems after extravasation
 Bleomycin
 Cisplatinum (diluted)
 Cyclophosphamide
 Cytosine arabinoside (Cytarabine)
 Etoposide (diluted)
 Ifosfamide (diluted)
 MTX
VESICANT DRUGS IRRITANTS
Actinomycin D Carmustine (BCNU)

Daunorubicin Dacarbazine (DTIC)
Doxorubicin Etoposide (VP16)
Epirubicin Liposomal Doxorubicin
Idarubicin Mitoxantrone
Mitomycin C Paclitaxel
Mechlorethamine (Nitrogen mustard) Teniposide (VM -26)
Vinblastine Cisplatin*
Vincristine Fluorouracil*
Vindesine
Vinorelbine
* = only with concentrated solutions and large volume

ANTIDOTES
Most chemotherapy drugs do not have effective antidotes should extravasation

occur. The key to management is caution and prevention
The use of antidotes is to limit extent of damage and prevent progression.
No. Drug extravasated Antidote

1 Vinca alkaloids, Hyaluronidase injection 150u/ml around
epipodophyllotoxins extravasated site
Degrades hyaluronic acid and enhances absorption
of extravasated drug. FDA approved its use in
Vinorelbine, Vincristine and Vinblastine package
inserts
2 Dacarbazine, Sodium Thiosulphate injection

Mechlorethamine, Inactivates drug
Concentrated Cisplatin
(>0.4mg/ml)
3 Daunorubicin, Dimethylsulfonate topical solution

Doxorubicin, Commonly used solvent that penetrates tissues
Mitomycin well ; potent free radical scavenger that has
analgesic and anti-inflammatory effects. Mild
burning , skin scaling, unpleasant odour in breath
4 Anthracyclines eg Dexrazoxane injection reduces frequency, size and

doxorubicin, duration of wounds
epirubicin
Best treatment for extravasation is prevention

MANAGEMENT OF EXTRAVASATION
Stop the injection immediately,

1.
 do not remove the cannula yet.
Draw up to 3 to 5 ml of blood through the cannula to remove as much of

the chemotherapy drug as possible
2.
 If unable to aspirate residue drug from intravenous cannula, remove
cannula.
3. Use any antidote for the drug if available
The local toxic reaction to extravasation may be controlled by applying

warm or chilled compresses for 30 minutes intermittently.
4.
 Warm compress : etoposide, vinblastine, vincristine.
 Cold compress : all other drugs
Apply steroid creams twice a day until the erythema subsides.

 hydrocortisone 1% cream or betamethasone 1:10 or similar
5.
 Repeat compression four times a day, 15 minutes per application for 2
– 3 days.
Use occlusive light dressing and elevate the limb to prevent formation of
6.
haematoma.
Review the site regularly.

7.  Patient advised to seek medical attention immediately should there be
pain, swelling, blistering or ulceration.
Extensive necrotic damage may require surgery. Refer early when in

8.
doubt.

MANAGEMENT OF CYTOTOXIC SPILL
All Pharmacies, daycare and wards handling cytotoxics should be equipped with a ―Spill Kit‖
Contents of ―Spill Kit‖ (Example)
HKL PHARMACY SPILL KIT©
ITEM NO
1. Disposable gown 1
2. Disposable face mask N 95 1
3 Large gloves (latex) 1 pair
4 Large gloves (polyvinyl) 1 pair
5 Disposable shoe coveralls 1 pair
6 Eye goggles 1 pair
7 Disposable scoop 1
8 Disposable brush 1
9 Small dustpan 1
10 Waste plastic bag non tearable (blue) 1

Waste plastic bag (large, yellow) labelled
11 1
―Cytotoxic wastes , Handle with Care‖
12. Cytotoxic spill sign 1
13 Absorbent towels 12
14. Decon 90 solution 60 ml 1
15 Water for irrigation 200 ml 1
16. Cytotoxic incident report form 1
17. Small sharps container 1

PROCEDURE
1. When a cytotoxic spill occurs, get hold of a spill kit.

 Open the plastic bag containing the spill kit.
 Remove & display sign ―Cytotoxic spill. Caution! Proceed with care‖
2. Staff Protection : Wear following items
 Respirator mask and bouffant cap
 Gown. Tie to the back.
 Shoe coveralls
 Goggles unless you have glasses.
 Latex gloves and then the plastic gloves
3. Remove solid spill
 Brush the small pieces into the dustpan
 Discard the glass fragments/sharps into the small sharps container
 Put the sharps container , brush, and dustpan into the light blue plastic
bag
4. Liquid spills
 Use the absorbent towels or gauze pads to wipe up the spill. If in
powder form, wet the towels with water from the spill kit.
 Put towels with the spill into the light blue non-tearable plastic bag.
 Pour decontaminating liquid ―Decon 90‖ onto the affected surface
 Wipe with more pads.
 Pour water onto the affected area and wipe dry.
5. Completing procedure
 Remove plastic gloves and put into light blue plastic bag.
 Tie the light blue bag
 Put the light blue bag into the yellow plastic bag labelled ―Cytotoxic
waste. Handle with care‖
 Put the water for irrigation bottle, Decon 90 bottle into the same yellow
bag.
 Remove and dispose rubber gloves, shoe coveralls, cap, gown &
respirator mask, into the yellow plastic bag
 If cytotoxic spillage occurs onto the skin, wash with soap and plenty of
tap water. If the eyes are affected, wash with plenty of water (eye
wash sink if available) or normal saline and immediately see a doctor
 Tie up the yellow plastic bag and call Radicare or the cleansing
concession company to take away the cytotoxic wastes for
incineration
6. Reusable items
 Remove and clean with water goggles & cytotoxic spill sign.
 Put the spill sign and goggles into the outer packaging plastic bag of
spill kit.
7. Incident reporting
 Fill up the incident report form.
 Hand in the incident report form to Pharmacist
 Exchange old spill kit package with new spill kit.

CHEMOTHERAPY PREPARATION AND RECONSTITUTION
CYTOTOXIC DRUGS RECONSTITUTION (CDR)

The standard operating procedures (SOP) for CDR should include :
NO. ACTIVITIES
1. Equipment
 operational specifications for the use of cytotoxic drug reconstitution
facilities including cytotoxic drug safety cabinets.
 maintenance and certification of equipment and facilities.
2. Personnel
 Trained staff with certification
 Initial and ongoing validation (every 2 years) of operator
competence
3. Procedures
 Reconstitution procedures
 Routine cleaning and decontamination protocol.
 Spill management, emergency cleaning and decontamination
protocol.
4. Records
 Proper documentation and records.
 Maintenance of records of activities
5. Storage & disposal

 Proper storage of drugs and utensils
 Labeling and packaging for transport internally or externally.
 Proper disposal procedures
 Availability of drug safety information (―Product Monograph‖)
PERSONAL PROTECTIVE EQUIPMENT
Prior to selecting Personal Protective Equipment (PPE), the level of risk of exposure
should be assessed. The following PPE should be considered for use during
administration of cytotoxic drugs:
No ITEMS
1. Surgical mask
2. Long sleeved gown of impermeable material
3. Goggles (optional)
4. Latex gloves (powder free)
5. Bouffant cap (optional)

CYTOTOXIC DRUGS RECONSTITUTION GUIDELINE
Protect After reconstitution Vehicle for

Vehicle for
DRUG From infusion /
reconstitution Storage
Light Stability bolus
(2 – 80C)
Normal Saline
Actinomycin D Sterile water. X X 24 days
Dextrose 5%
Normal Saline Normal Saline

Bleomycin X X 7 days
Dextrose 5% Dextrose 5%
Dextrose 5%
*Carboplatin - X X 30 days
*Cis-platinum - X Room temp 9 days Normal Saline
Cyclophos- Normal Saline

Sterile water X X 28 days
phamide Dextrose 5%
Sterile water X Normal Saline

Dacarbazine X 96 hours
Normal Saline Dextrose 5%
7 days at
Doxorubicin Dextrose 5% room temp Normal Saline
X Room Temp
lyophilized Normal Saline 15 days at Dextrose 5%
2-80 C
Epirubicin Sterile water ----- X 28 days Normal Saline
4 days for
Lastet Normal Saline
*Etoposide - ----- Room Temp
48 hrs for Dextrose 5%
Fytosid
Normal Saline
*Fluorouracil - X Room temp. 9 days
Dextrose 5%
Gemcitabine Normal Saline ----- Room temp 7 days Normal Saline

Protect After reconstitution Vehicle for
Vehicle for
DRUG From infusion /
reconstitution Storage
Light Stability bolus
(2 – 80C)
Normal Saline
Ifosfamide Sterile water ----- X 42 days
Dextrose 5%
Normal Saline
Dextrose 5%
*Methotrexate Normal Saline X X 7 days
IT undiluted
Mitomycin-C Sterile water X Room temp 7 days Normal Saline
Sterile water Sterile water

Oxaliplatin X X 24 hrs
Dextrose 5% Dextrose 5%
Normal Saline
Dextrose 5%
Normal Saline
*Paclitaxel ----- Room temp. 48 hours Use glass
Dextrose 5%
syringe or
polypropylene
Solution
accompanied 28 days Normal Saline
Vinblastine X X
(bacteriostatic 7 days Dextrose 5%
NaCl inj.)
Normal Saline
*Vincristine - X X 21 days
Dextrose 5%
Vinorelbine Sterile water X Room temp 24 hours Normal Saline
X = Yes
Room Temp = 20 - 250C, Do not refrigerate.
* = Liquid
Notes:
1. Storage condition is listed according to the package insert of the current used
brand. There may be variations between brands.
2. If not prepared in clean room , use immediately
3. Even though the shelf-life of reconstituted solution might be more than a week
for certain drugs, normally a maximum of 7 days storage before use is not
exceeded

16. APPENDIX
REFERENCES
HEAD & NECK
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NASOPHARYNX
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carcinoma
The Cochrane Collaboration., The Cochrane Library 2006, Issue 4
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3 Chan ATC et al
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5. Lee AWM et al
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BREAST
1. Early Breast Cancer Trialists‘ Collaborative Group (EBCTCG)

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year survival: an overview of the randomised trials
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GASTRIC
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PANCREAS / HEPATOMA / GIST
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14. Yip D et al,
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HEPATOCELLULAR CARCINOMA
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GIST
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COLO-RECTAL
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2 Gershenson DM et al
Treatment of malignant germ cell tumours of the ovary with bleomycin, etoposide and
cisplatin
J Clin Onco: 1990; Vol.8: 715-720
3 William SD et al
Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: A
trial of the Gnecological Oncology Group
Gynecol Onco : 2004; 95: 496-499
4 Dimopoulos MA et al
Treatment of ovarian germ cell tumour with a 3 day bleomycin, etoposide and cisplatin
regimen: a prospective multicentered study
Gynel Onco 2004 :95 : 695-700
5 Dimopoulos MA et al
Favourable outcome of ovarian germ cell malignancies treated with cisplatin or carboplatin
based chemotherapy- a Hellenic Collaborative group study
Gynel Onco 1998 : 70 : 70-74
6 Slyaton RE et al
Vincristine, Dactinomycin and cyclophosphamide in the treatment of malignant germ cell
tumours of the ovary. Gynecological Oncology group study
Cancer 1985 : 56 : 243-8
7 Kondagunta G et al
Combination of paclitaxel, ifosfamide and cisplatin is an effective second line therapy for
patients with relapsed testicular germ cell tumour.
J Clin Oncol, 2005; 23; 6549-6555

UTERINE CANCER
1. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R.

Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma.
Am J Surg Pathol 1982;6(2):93–108
2. Slomovitz BM, Burke T. Eifel PJ et al .
Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases.
Gynecologic Oncology 91 (2003) 463–469)
3. von Minckwitz G et al
Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and
II endometrial cancer–a multicentre, open, controlled, prospectively randomised trial.
Eur J Cancer. 2002 Nov;38(17):2265-71
4. Maggi R et al
Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a
randomised trial.
Br J Cancer. 2006 Aug 7 ;95(3) :266-71.
5. Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, et al.
Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a
Gynecologic Oncology Group study
J Clin Oncol 2004;22:3902–8.
6. Thigpen JT et al
Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial
carcinoma: a dose-response study by the Gynecologic Oncology Group.
J Clin Oncol. 1999 Jun Vol17(6):1736-44.
7 Martin-Hirsch PL et al
Adjuvant progestagen therapy for the treatment of endometrial cancer: review and meta-
analyses of published randomised controlled trials
European Journal of Obstetrics & Gynecology and Reproductive Biology 65 (1996) 201-207
8. Harry J Robert N, Karl C
Phase III comparison of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs.
doxorubicin and cisplatin (AC) in women with advanced primary or recurrent metastatic
carcinoma of the uterine endometrium.
Gynecologic Oncology 100 (2006) 501 – 505
9. Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, et al.
Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in
advanced endometrial carcinoma: a Gynecologic Oncology Group study.
J Clin Oncol 2004 June 1 Vol.22(11) 2159– 66.
10. Aapro MS et al
Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a
randomised study (55872) by the EORTC Gynaecological Cancer Group.
Ann Oncol. 2003 Mar;14(3):441-8.
11. Fleming GF et al
Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel +
filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study.
Ann Oncol. 2004 Aug;15(8):1173-8.
12. Humber C, Tierney J, Symonds P, Collingwood M, Kirwan J, Williams C, Green J.
Chemotherapy for advanced, recurrent or metastatic endometrial carcinoma.
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003915.
13. Long HJ Third et al
Phase III comparison of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs.
doxorubicin and cisplatin (AC) in women with advanced primary or recurrent metastatic
carcinoma of the uterine endometrium.
Gynecol Oncol. 2006 Mar;100(3):501-5. Epub 2005 Sep 26.
14. J. Tate Thigpen et al

Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial
Carcinoma:A Gynecologic Oncology Group Study
J Clin Oncol 2004 Oct. 1 22 (19),

15. Marcus E. Randall et al
Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and
Cisplatin Chemotherapy in Advanced Endometrial Carcinoma:
A Gynecologic Oncology Group Study
J Clin Oncol 2006 Jan 1 Vol.24(1)

CERVIX
1. Kumar L et al.
Neoadjuvant chemotherapy in locally advanced cervical cancer: two randomised studies.
Aust NZ J Med, Vol. 26 1998 pp 387 – 390.
2. SundfØr K et al.
Radiotherapy and neoadjuvant chemotherapy for cervical carcinoma
Cancer Vol. 77, No. 11, June 1, 1996 pp2371-2378.
3. Tattersall MHN et al. .
Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in
locally advanced cervical cancer
J Clin Oncol, Vol. 13, No.2, (Feb) 1995 pp 444 – 451.
4. Sardi JE et al.
Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib
squamous carcinoma of the cervix: the final results.
Gynae. Onco., 67, 1997, pp 61 –69.
5. Chiara S et al .
Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in
FIGO Stage IIB III cervical carcinoma
Am J Clin Oncol (CCT) 17 (4), 1994 pp 294 – 297.
6. Chang TC, et al.
Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy
versus radiation therapy for bulky stage IB and IIA cervical cancer.
J Clin Oncol 2000 Apr ;18(8) :1740-7
7. Souhami L et al.
A randomized trial of chemotherapy followed by pelvic radiation therapy in Stage IIIB
carcinoma of the cervix.
J Clin Oncol, Vol. 9, No.6, (June) 1991 pp 970 – 977.
8 Symonds RP et al.
The Scottish and Manchester randomized trial of neo-adjuvant chemotherapy for advanced
cervical cancer.
Eur J Cancer 2000 May;36(8):994-1001
9 Herod J et al
Randomized, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin
(BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer
of the cervix.
Ann Oncol 2000 Sep;11(9):1175-81
10 Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration*,
Neoadjuvant chemotherapy for locally advanced cervical cancer: a systematic review and
meta-analysis of individual patient data from 21 randomised trials
European Journal of Cancer 39 (2003) 2470–2486
11. Tattersall MH et al.
A randomized trial of adjuvant chemotherapy after radical hysterectomy in stage Ib-Iia cervical
cancer patients with pelvic lymph node metastases.
Gynecol Oncol 1992 Aug;46(2):176-181
12. L.C. Wong et al
Chemoradiation and Adjuvant Chemotherapy in Cervical Cancer
J Clin Oncol , Vol 17, No 7 (July), 1999: pp 2055-2060
13. Keys HM. Et al.

N Eng J Med Vol. 340 No. 15 Apr. 15, 1999 pp 1154 –1161
Cisplatinum, radiation, and adjuvant hysterectomy compared with radiation and adjuvant
hysterectomy for bulky stage IB cervical carcinoma..
14. Morris M et al.

Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation
for high risk cervical cancer
N Eng J Med Vol. 340 No. 15 Apr. 15, 1999 pp 1137 – 1143

15. Peters WA et al.
Cis-platin, 5-Fluorouracil and radiation therapy are superior to radiation therapy as adjunctive
in high-risk, early stage carcinoma of the cervix : report of a phase III inter-group study.
J Clin Oncol Vol. 18, No. 8 (April), 2000 pp 1606 -1613
16. Rose PG, et al.
Concurrent cisplatin based radiotherapy and chemotherapy for locally advanced cervical
cancer.
N Eng J Med Vol. 340 No. 15 Apr. 15, 1999 pp 1144 –1153
17. Whitney CW et. Al
Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to
radiation therapy in Stage IIB – IVA carcinoma of the cervix with negative para-aortic lymph
nodes : a Gynaecology Oncology Group and Southwest Oncology Group study.
J Clin Oncol Vol. 17, No. 5 (May), 1999 pp 1339 -1348
18. R. Pearcey et al
Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in
Patients With Advanced Squamous Cell Cancer of the Cervix
J Clin Oncol Vol 20, No 4 (February 15), 2002: pp 966-972
19. John A Green,
Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the
uterine cervix: a systematic review and meta-analysis
THE Lancet • Vol 358 • September 8, 2001
20. RA, Rose PG, O‘Malley DM, et al.
Evaluation of concurrent and adjuvant carboplatin with radiation therapy for locally advanced
cervical cancer.
Gynecol Oncol 2004;94:121-124
21. Moore DH, Blessing JA, McQuellon RP, et al.
Phase III study of cisplatin with or without paclitaxel in stage IV, recurrent or persistent
squamous cell carcinoma of the cervix: A Gynecologic Oncology Group Study.
J Clin Oncol 2004;22:3113-3119.
22. Omura et al
Randomized trial of cisplatin versus cisplatin plus micolactol versus cisplatin plus ifosfamide in
advanced squamous carcinoma of the cervix : a Gynecologic Oncology Group study
J Clin Oncol 1997 Jan 15 (1) ;65 -171
23. Jeffrey D. Bloss, John
Randomized Trial of Cisplatin and Ifosfamide With or Without Bleomycin in Squamous
Carcinoma of the Cervix: A Gynecologic Oncology Group Study
J Clin Oncol 2002 April 1 ;Vol 20 (7) ;1832-1837
24. Harry J. Long
Randomized Phase III Trial of Cisplatin With or Without Topotecan in Carcinoma of the
Uterine Cervix: A Gynecologic Oncology Group Study
J Clin Oncol 2005 July 20 Vol. 23 (21)
25. Bradley J. Monk, Helen Q. Huang, David Cella, and Harry J. Long III
Quality of Life Outcomes From a Randomized Phase III Trial of Cisplatin With or Without
Topotecan in Advanced Carcinoma of the Cervix: A Gynecologic Oncology Group Study
J Clin Oncol 2005 July 20 Vol. 23 (21)
26. K. Serkies, J. Jassem & R. Dziadziuszko
Chemotherapy with mitomycin c, ifosfamide, and cisplatin for recurrent or persistent cervical
cancer
Int J Gynecol Cancer 2006, 16, 1152–1156
27. Choi Ch et al
Salvage chemotherapy with a combination of paclitaxel, ifosfamide, and cisplatin for the
patients with recurrent carcinoma of the uterine cervix
Int J Gynecol Cancer 2006, 16, 1157–1164
28. Daly M et al
A short and intensive single agent cisplatin regimen for recurrent carcinoma of the uterine
cervix
Int J Gynae Cancer 1995 5 pp 01 – 07

29 Harry J. Long III
Clinical results and quality of life analysis for the MVAC combination (methotrexate,
vinblastine, doxorubicin, and cisplatin) in carcinoma of the uterine cervix: A Gynecologic
Oncology Group study
Gynecologic Oncology 100 (2006) 537 – 543
30. Bonomi P, Blessing JA,Stehman FB et al.
J Clin Oncol 1985;3(8):1079-85)
Randomized trial of three dose schedules in squamous cell carcinoma of the cervix: A GOG
study.
31 Brewer CA et al
Cisplatin plus Gemcitabine in Previously Treated Carcinoma of Cervix: a phase II of the
Gynaecology Oncology Group
Gynel Onco 2006 : 100 : 385-388
32. Monk Bj et al
A Phase III trial of four cisplatin-containing regime doublet combinations in stage IVB,
recurrent, or persistent cervical carcinoma: a Gynaecologic Oncology Group study.
J Clin Oncol 2009 Oct 1; 27(28) 4649 - 4655

UTERINE SARCOMA
1 Sarcoma Meta-anaylsis Collaboration

Adjuvant chemotherapy for localized soft tissue sarcoma in adults
Cochrance Database Syst Review 2000
2 Sutton et al
A phase III trial of Ifostamide with or without cisplatin in Carcinosarcoma of the Uterus: A
Gynecologic Oncology Group Study
Gynel Oncol : 2000: 79 : 147-153
3 Giuntoli RN et al
Retrospective review of 208 patients with leiomyosarcoma of the uterus. Prognostic
indicators, surgical management and adjuvant therapy.
Gynel Oncol : 2003 ; 89: 460-469
GESTATIONAL TROPHOBLASTIC DISEASE
1 Foulman K et al
What is the best protocol of single agent methotrexate chemotherapy in non metastatic or
low risk metastatic gestational trophoblastic tumours? A review of the evidence
Gynecologic Oncology 2006 : 102: 103-110
2 Leiser AL et al
Evaluation and management of gestational trophoblastic disease
Commun Oncol 2006: 3: 152-156
3 John R et al
Secondary chemothereapy for high risk gestational trophoblastic neoplasia.
Gynecol Oncol : 2005: 97: 618-623
4 Staging classification and clinical practice guidelines for gynaecological cancers. A
collaborative between FIGO and Gynaecologic Cancer Society. Third edition 2006
5 Theodore C et al
Treatment of high risk gestational trophoblastic disease with chemotherapy combinations
containing cisplatin and etoposide.
Cancer : 1989 : 64 : 1824-1828
6 Chen LP et al
PEBA regimen (cisplatin, etoposide, bleomycin and adriamycin) in the treatment of drug
resistant choriocarcinoma.
Gynecol Oncol 1995: 56: 231-234
7 Surwit EA et al
Management of high risk gestational trophoblastic disease.
Journal of Reproductive Medicine :1987: 32(9) : 657-662
8 Benedet JL, Pecorelli S, Ngan HYS, Hacker NF.
Staging Classifications and Clinical Practise Guidelines for gynaecological Cancers.
A collaboration between FIGO and IGCS. Third Edition 2006.
9 Cole LA, Sutton JM.
Selecting an appropriate hCG test for managing gestational trophoblastic disease and
cancer.
J Reprod Med 2004;49:545–553
10 FIGO Oncology Committee Report.
FIGO staging for gestational trophoblastic neoplasia 2000. Int J Gynaecol Obstet
2002;77:285–287
11 John R. LurainT, Nejad B.
Secondary chemotherapy for high-risk gestational trophoblastic neoplasia.
Gynecologic Oncology 97 (2005) pp 618–623

SOFT TISSUE SARCOMA
1. Frustaci S, et al
Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles:
results of the Italian randomized cooperative trial.
J Clin Oncol. 2001 Mar 1;19(5):1238-47.
2. Bramwell V et al
Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma–reduced local recurrence
but no improvement in survival: a study of the European Organization for Research and
Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
J Clin Oncol. 1994 Jun;12(6):1137-49.
3 Sarcoma Meta-analysis Collaboration.
Adjuvant chemotherapy for soft-tissue sarcoma of adults: meta-analysis of individual data.
Lancet. 1997 Dec 6;350(9092):1647-54.
4. Santoro A et al
Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of
advanced soft tissue sarcomas: a randomized study of the European Organization for
Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
J Clin Oncol. 1995 Jul;13(7):1537-45.
5. Le Cesne A et al
Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide
versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-
macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the
European Organization for Research and Treatment of Cancer/Soft Tissue and Bone
Sarcoma Group.
J Clin Oncol. 2000 Jul;18(14):2676-84.
6. Lorigan P et al for European Organisation for Research and Treatment of Cancer Soft
Tissue and Bone Sarcoma Group Study.
J Clin Oncol. 2007 Jul 20;25(21):3144-50.
Phase III trial of two investigational schedules of ifosfamide compared with standard-dose
doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for
Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.
7 Nooij MA et al European Osteosarcoma Intergroup
Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone,
other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma
Intergroup Study
Eur J Cancer. 2005 Jan;41(2):225-30.
8. Nielsen OS et al
High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of
advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma
group.
Br J Cancer. 1998 Dec;78(12):1634-9.
9. Antman K et al
J Clin Oncol. 1993 Jul;11(7):1276-85.
An intergroup phase III randomized study of doxorubicin and dacarbazine with or without
ifosfamide and mesna in advanced soft tissue and bone sarcomas.
10. Edmonson JH et al
Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or
mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas.
J Clin Oncol. 1993 Jul;11(7):1269-75
11. Blum RH et al
Efficacy of ifosfamide in combination with doxorubicin for the treatment of metastatic soft-
tissue sarcoma. The Eastern Cooperative Oncology Group.
Cancer Chemother Pharmacol. 1993;31 Suppl 2:S238-40.
12. Judson I et al
Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus
doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the
EORTC Soft Tissue and Bone Sarcoma Group.
Eur J Cancer. 2001 May;37(7):870-7

13. Van Glabbeke M et al
Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an
analysis of 2,185 patients treated with anthracycline-containing first-line regimens–a
European Organization for Research and Treatment of Cancer Soft Tissue and Bone
Sarcoma Group Study.
J Clin Oncol. 1999 Jan;17(1):150-7.
OSTEOSARCOMA
1. Souhami RL et al
Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of
the European Osteosarcoma Intergroup.
Lancet. 1997 Sep 27;350(9082):911-7
2. Lewis IJ et al European Osteosarcoma Intergroup.
Improvement in histologic response but not survival in osteosarcoma patients treated with
intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma
Intergroup.
J Natl Cancer Inst. 2007 Jan 17;99(2):112-28.
3. Meyers PA, Gorlick R, Heller G, Casper E, Lane J, Huvos AG, Healey JH
Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the
Memorial Sloan-Kettering (T12) protocol.
J Clin Oncol. 1998 Jul;16(7):2452-8.
4. Bramwell VH et al. A comparison of two short intensive adjuvant chemotherapy regimens
in operable osteosarcoma of limbs in children and young adults: the first study of the
European Osteosarcoma Intergroup.
J Clin Oncol 1992;10:1579-1591
5. Goorin AM et al
Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy
for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651.
J Clin Oncol 2003 Apr 15;21(8):1574-80.

PROSTATE
1. D‘Amico AV et al
6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients
with clinically localized prostate cancer.
JAMA Vol. 292, No. 7, Aug. 18, 2004
2. Roach III M et al
Phase III trial comparing whole-pelvis versus prostate only radiotherapy and neoadjuvant
versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413
J Clin Oncol 2003 May 15 21 (10) pp 1904 – 1911
3 Denham J et al
Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer:
results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial
Lancet Oncol 2005; 6: 841–50
4 Crook J et al
Report of a multicenter Canadian Phase III randomized trial of 3 months vs 8 months
neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localised
prostate cancer.
IJROBP 2004 Vol 60 (1) pp 15 – 23
5 Klotz LH et al
Long-term follow-up of a randomized trial of 0 vs 3 months of neoadjuvant androgen ablation
before radical prostatectomy
J of Urol, Vol. 170, 791-794, Sept. 2003
6 Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant
hormone therapy for localised and locally advanced prostate cancer. Cochrane Database of
Systematic Reviews 2006, Issue 4. Art. No.: CD006019.
DOI:10.1002/14651858.CD006019.pub2.
7 Tyrrell CJ et al
Bicalutamide (‗Casodex‘) 150mg as adjuvant to radiotherapy in patients with localised or
locally advanced prostate cancer: Results from the randomised Early Prostate Cancer
Programme.
Radiotherapy & Oncol 76 (2005) pp 4 – 10
8 Bolla Bolla M, Collette L, Blank L, et al.
Long-term results with immediate androgen suppression and external irradiation in patients
with locally advanced prostate cancer (an EORTC study): a phase III 139randomized trial.
Lancet. 2002 Jul 13;360(9327):103-6
9 Pilepich MV et al.
Androgen suppression adjuvant to definitive radiotherapy in carcinomas of the prostate –
long-term results of Phase III RTOG 85-31.
Int J Radiat Oncol Biol Phys, 2005; 61 No 5:1285-1290)
10. Iversen P et al
Bicalutamide (150mg) versus placebo as immediate therapy alone or as adjuvant to therapy
with curative intent for early nonmetastatic prostate cancer : 5.3 years median follow-up
from the Scandinavian prostate Cancer Group Study number 6.
J of Urol Vol. 172, 1871-1876, Nov. 2004
11. Wirth MP et al
Bicalutamide 150mg in addition to standard care in patients with localised or locally
advanced prostate cancer. Results from the second analysis of the Early Prostate Cancer
Programme at median follow-up of 5.4 years.
J of Urol. Vol 172., 1865-1870, Nov. 2004
12. Wirth MP et al.
Prospective randomized trial comparing Flutamide as adjuvant treatment versus observation
after radical prostatectomy for locally advanced lymph node-negative prostate cancer
Eur Urol 45. 267-270, 2004
13. Pilepich M et al
Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation
adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate
IJROBP Vol.50. No 5 1242 – 1250 2001
14. Lawton CA et al

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31
evaluating the potential benefit of androgen suppression following standard radiation therapy
for unfavorable prognosis carcinoma of the prostate
IJROBP Vol 49, No. 4, pp 937-946, 2001
15. Hanks GE, et al.
Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal
cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation
Therapy Oncology Group Protocol 92-02.
J Clin Oncol 2003 Nov 1;21(21):3972-8
16. Horwitz E et al
Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. Short-
term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer
treated with radiation therapy
IJROBP Vol. 49, No. 4, pp. 947–956, 2001
17 Messing EM et al
Immediate versus deferred androgen deprivation treatment in patients with node-positive
prostate cancer after radical prostatectomy and pelvic lymphadenectomy
Lancet Oncol 2006: 7: 472–79
18 See W et al
Immediate treatment with Bicalutamide 150mg as adjuvant therapy significantly reduces the
risk of PSA progression in early prostate cancer
Eur Urology 2003 44, pp 512 – 518
19 Fritz h. Schroder
Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local
treatment of the primary tumor: results of European Organisation for the Research and
Treatment of Cancer 30846—a phase III study
The Journal of Urology vol. 172, 923–927, september 2004
20. Urs E. Studer
Immediate or Deferred Androgen Deprivation for Patients With Prostate Cancer Not Suitable
for Local Treatment With Curative Intent: European Organisation for Research and Treatment
of Cancer (EORTC) Trial 30891
J Clin Oncol 2006 Apr 20 24 (12) pp 1868 – 1876
21. Wilt T et al
Early versus deferred androgen suppression in the treatment of advanced prostatic cancer
Cochrane Database of Systematic Reviews2001, Issue 4
22. PCTCG
Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised
trials with 3283 deaths in 5710 patients
Lancet 355, 1482 -91, 2000
23 Schmitt B, Bennett C, Seidenfeld J, Samson D, Wilt T. Maximal androgen blockade for
advanced prostate cancer. Cochrane Database of Systematic Reviews 1999, Issue 2. Art.
No.: CD001526. DOI: 10.1002/14651858.CD001526.
24. Tannock IF et al
Docetaxel plus prednisolone or Mitoxantrone plus prednisolone for advanced prostate cancer
N Eng J Med 2004 Vol 351 (15) pp 1502 – 1512
25. Karim Fizazi et al
Addition of estramustine to chemotherapy and survival of patients with castration-refractory
prostate cancer: a meta-analysis of individual patient data
http://oncology.thelancet.com Published online October 16, 2007
26. Shelley Md et alAdjuvant hormone therapy for localised and locally advanced prostate
carcinoma: a systematic review and meta-analysis of randomised trials.
Cancer Treat Rev. 2009 Nov;35(7):540-6. Epub 2009 Jun 2
27. A. Heidenreich (Chairman) et al
European Association of Urology Guidelines on Prostate Cancer April 2010

BLADDER
1. Shipley WU, et al.

Treatment of invasive bladder cancer by cisplatin and irradiation in patients unsuited for
surgery: a high success rate in clinical stage II tumours in a National Bladder Cancer Group
trial.
JAMA 1987;258:931
2. Coppin CM, et al
Improved control of invasive bladder cancer by concurrent cisplatin and preoperative or
definitive radiation.
J Clin Oncol 1996;14(11);2901
3 Dunst J, et al.
Organ sparing treatment of advanced bladder cancer: a 10 year experience
Int J Radiat Oncol Biol Phys 1994;30:261
4 1) Rodel C, et al.
2) Invasive bladder cancer: organ preservation by radiochemotherapy.
3) Front Radiat Ther Oncol 2002;36:118
5 4) Grossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared to cystectomy
alone for locally advanced bladder cancer.
5) N Engl J Med 2003;349:859
6 International collaboration of trialists
Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive
bladder cancer: a randomised controlled trial
Lancet 1999; 354: 533–40
7 Neoadjuvant chemotherapy for invasive bladder cancer (Review)
Advanced Bladder Cancer Overview Collaboration
The Cochrane Collaboration
8 Neoadjuvant Chemotherapy in Invasive Bladder Cancer: Update of a Systematic Review and
Meta-Analysis of Individual Patient Data
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration
European Urology 48 (2005) 202–206
9 Sternberg CN et al
Randomized Phase III Trial of High–Dose-Intensity Methotrexate, Vinblastine, Doxorubicin, and
Cisplatin (MVAC) Chemotherapy and Recombinant Human Granulocyte Colony-Stimulating
Factor Versus Classic MVAC in Advanced Urothelial Tract Tumors: European Organization for
Research and Treatment of Cancer Protocol No. 30924
J Clin Oncol, Vol 19, No 10 (May 15), 2001: pp 2638-2646
10 Lehman et al
Adjuvant Chemotherapy in Invasive Bladder Cancer: A Systematic Review and Meta-Analysis
of Individual Patient Data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration
European Urology 48 (2005) 189–201
11 Lehman J et al
Adjuvant Cisplatin Plus Methotrexate Versus Methotrexate, Vinblastine, Epirubicin, and
Cisplatin in Locally Advanced Bladder Cancer: Results of a Randomized, Multicenter, Phase III
Trial (AUO-AB 05/95)
J Clin Oncol 2005 Aug 1 23 (22) pp 4963-4974
12. Adjuvant Cisplatin Plus Methotrexate Versus Methotrexate, Vinblastine, Epirubicin, and
Cisplatin in Locally Advanced Bladder Cancer: Results of a Randomized, Multicenter, Phase III
Trial (AUO-AB 05/95)
J Clin Oncol 2005 Aug 1 23 (22) pp 4963-4974
13 Milikan R et al
Integrated Therapy for Locally Advanced Bladder Cancer: Final Report of a Randomized Trial
of Cystectomy Plus Adjuvant M-VAC Versus Cystectomy With Both Preoperative and
Postoperative M-VAC
J Clin Oncol Vol 19, No 20 (October 15), 2001: pp 4005-4013

14. von der Maase H et al
Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in
Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational,
Multicenter, Phase III Study
J Clin Oncol 2000 Sep Vol 17 (17) pp 3068-3077
15 Von der Masse H et al
Long term survival results of a randomized trial comparing gemcitabine plus cisplatin, witth
methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.
6) J Clin Oncol 2005 July 20 23(21) pp 4602 – 4608

RENAL CANCER
1. Negrier S et al
Recombinant human interleukin-2, recombinant human interferon alfa-2a or both in
metastatic renal cell carcinoma
N Eng J Med 1998 338; pp 1272 – 1278
2. De Mulder PH et al
EORTC (30885) randomised phase III study with recombinant interferon alpha and
recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The
EORTC Genitourinary Group.
Br J Cancer. 1995 Feb;71(2):371-5
3 Medical Research Council Renal Cancer Collaborators
Interferon-α and survival in metastatic renal carcinoma : early results of a randomised
controlled trial
Lancer 1999 Vol 353 pp 14 – 17
4 Pyrhönen S et al
Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in
patients with advanced renal cell cancer.
J Clin Oncol. 1999 Sep;17(9):2859-67
5 Mickisch GHJ et al
Radical nephrectomy plus interferon-alfa based immunotherapy compared with interferon
alfa alone in metastatic renal cell carcinoma : a randomised trial
Lancet 2001 Vol. 358, pp 966 – 970
6 Kjaer M
The role of medroxyprogesterone acetate (MPA) in the treatment of renal adenocarcinoma
Cancer Treatment Review (1988) 15 pp 195 – 209
7 Pizzocaro G et al
Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a
multicentric randomized study.
J Clin Oncol. 2001 Jan 15;19(2):425-31
8 Messing EM et al
Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma:
an Eastern Cooperative Oncology Group/Intergroup trial.
J Clin Oncol. 2003 Apr 1;21(7):1214-22
9 Atzpodien J et al German Cooperative Renal Carcinoma Chemo-Immunotherapy Trials
Group (DGCIN)
Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in
renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of
the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).
Br J Cancer. 2005 Mar 14;92(5):843-6.
10. Motzer RJ et al
Sunitinib versus Interferon Alfa in Metastatic
Renal-Cell Carcinoma
N Engl J Med 2007;356:115-24.
11. Motzer RJ et al
Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients
With Metastatic Renal Cell Carcinoma
Published Ahead of Print on June 1, 2009 as 10.1200/JCO.2008.20.1293
12. Gore M et al
Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial
Lancet Oncol 2009; 10: 757–63
13. Escudier B et al
Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma
N Engl J Med 2007;356:125-34.
14. Oudard S et al
Everolimus (RAD001): an mTOR inhibitor for the treatment of metastatic renal cell carcinoma.
Expert Rev Anticancer Ther. 2009 Jun;9(6):705-17. Review.

TESTIS
1. International Germ Cell Cancer Collaborative Group.

International Germ Cell Consensus Classification: a prognostic factor-based staging system
for metastatic germ cell cancers.
J Clin Oncol 1997;15: 594 – 603 .
2. Kaye SB et al
Intensive induction sequential chemotherapy with BOP/VIP-B compared with treatment with
BEP/EP for poor prognosis metastatic Non-seminomatous germ cell tumour: a randomized
medical Research Coumcil/European Organisation for Research and Treatment of Cancer
study.
J Clin Oncol 1998 Feb 16(2) pp 692 – 701
3 Nichols CR et al
Randomized comparison of cisplatin and etoposide and either bleomycin of ifosfamide in
treatment of advanced disseminated germ cell tumours: an Eastern Cooperative Oncology
Group, Southwest Oncology Group and Cancer and Leukaemia Group B study
J Clin Oncol 1998 April 16(2) pp 1287 – 1293
4 de Wit R et al
Four cycles of BEP vs four cycles of VIP in patients with intermediate-prognosis metastatic
testicular non-seminoma: a randomized study of the EORTC Genitourinary Tract Cancer
Cooperative Group. European Organization for Research and Treatment of Cancer.
Br J Cancer. 1998 Sep;78(6):828-32.
5 Dearnaley DP et al
Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous
germ cell tumours: a prospective trial (MRC TE17).
Br J Cancer. 2005 Jun 20;92(12):2107-13.
6 de Wit R
Importance of bleomycin in combination chemotherapy for good-prognosis testicular
nonseminoma: a randomized study of the European Organization for Research and
Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.
J Clin Oncol. 1997 May;15(5):1837-43.
7 Culine S et al
Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-
cell tumors: a randomized trial of the Genito-Urinary Group of the French Federation of
Cancer Centers (GETUG T93BP).
Ann Oncol. 2007 May;18(5):917-24. Epub 2007
8 Bokemeyer C.
A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide
and bleomycin (CEB) for patients with ‗good-risk‘ metastatic non-seminomatous germ cell
tumors.
Ann Oncol. 1996 Dec;7(10):1015-21
9 Horwich A et al
Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide,
and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a
Multiinstitutional Medical Research Council/European Organization for Research and
Treatment of Cancer Trial.
J Clin Oncol. 1997 May;15(5):1844-52.
10 Bokemeyer C et al
Metastatic seminoma treated with either single agent carboplatin or cisplatin-based
combination chemotherapy: a pooled analysis of two randomised trials.
Br J Cancer. 2004 Aug 16;91(4):683-7.
11 Cushing B
Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either
high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant
germ cell tumors: a pediatric intergroup study–Pediatric Oncology Group
9049 and Children‘s Cancer Group 8882.
J Clin Oncol. 2004 Jul 1;22(13):2691-700.

12. Toner GC et al
Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours:
a randomised trial. Australian and New Zealand Germ Cell Trial Group.
Lancet. 2001 Mar 10;357(9258):739-45.
13 de Wit R et al
Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and
of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the
European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer
Cooperative Group and the Medical Research Council.
J Clin Oncol. 2001 Mar 15;19(6):1629-40.
14. Hartmann JT et al
Second line chemotherapy in patients with relapsed extragonanal nonseminomatous germ
cell tumours: resutls of an international multicenter analysis
J Clin Oncol 2001 Mar 15 19(6) pp 1641 – 1648
15 Kondagunta GV
Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for
patients with relapsed testicular germ cell tumors.
J Clin Oncol. 2005 Sep 20;23(27):6549-55
16. Fosså SD et al
Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ
cell malignancy. European Organization for Research and Treatment of Cancer, Genito-
Urinary Group, and the Medical Research Council Testicular Cancer Working Party,
Cambridge, United Kingdom.
J Clin Oncol. 1998 Feb;16(2):716-24.
17. Oliver RD et al
Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a
randomised trial
Lancet 2005; 366: 293–300

BRAIN
1. Levin VA, Silver P, Hannigan J et al.

Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and
vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report.
Int J Radiat Oncol Biol Phys. 1990 ;18(2):321-4
2. Kappale AC, PostamaTJ et al.
PVC chemotherapy for recurrent glioblastoma multiforme.
Neurology.2001;57[1];118-120.
3 Stupp R ,Mason WP et al .
Radiotherapy plus concomitant and adjuvant temozolamide for glioblastoma .
N Engl J Med .2005; 352;987-96.
4 NICE Guidelines:
Improving outcomes for peoples with brain and other CNS tumors.
June 2006
5 Brandes AA, Nicolardi L, Tosoni A et al.
Survival following adjuvant PCV or temozolomide for anaplastic astrocytoma.
Neuro-oncol. 2006 ; 8(3): 253–260

SUPPORTIVE CARE
1. Kris MG et al
American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006
J Clin Oncol 2006 June 20 24 (18)
2. Hughes W et al
2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer
CID 2002 15 march :34
3. Smith TJ et al
2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An
Evidence-Based Clinical Practice Guideline
J Clin Oncol 2006 July Vol 24 (19) 3187-3205.
4. European Journal of Cancer 42 (2006) 2433-2453
5. Hesketh PJ et al
The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy induced
nausea and vomiting – a multi-national, randomized, double-blind, placebo –controlled trial in
patients receiving high dose cisplatin – The aprepitant Protocol 052 study group
J Clin Oncol 2004 Nov 15 21 (22) pp 4112 – 4119
th
6. Drug information handbook 5 edition, 1997-1998;
Trissel Handbook of Injectable Drugs
7. Drug Safety 12 (4), 1995:245-255

GLOSSARY
5-FU 5-Fluorouracil
6-MP 6-Mercaptopurine
AD Androgen Deprivation
ADJ Adjuvant
AI Aromatase Inhibitor
ANC Absolute Neutrophil Count
ARA-C Cytosine Arabinoside
BID Twice a day
BSC Best Supportive Care
CCRT Concurrent Chemo-Radiotherapy
CDDP Cisplatinum
CDR Cytotoxic drug reconstitution
CRC Colo-Rectal Cancer
DFS Disease Free Survival
ED Extensive Disease SCLC
EOC Epithelial Ovarian Cancer
ER Estrogen receptor
FBC Full Blodd Count
FIAH Fluorescent In-Situ Hybridisation
FN Febrile Neutropenia
GCT Germ Cell Tumour
GI Gastro-Intestinal
GTT Gestational Trophoblastic Tumour
H&N Head & Neck
HER2 EGFR-2 / c-erb-B2
IFN Interferon
IHC Immunohistochemistry
IM IntraMuscular
IV IntraVenous
LD Limited disease SCLC
LLN Lower Limit of Normal
LVI Lympho-Vascular Invasion
MBC Metastatic Breast Cancer
MTX Methotrexate
NPC Nasopharyngeal cancer
NSCLC Non-Small Cell Lung Cancer
OS Overall Survival
PCI Prophylactic Cranial Irradiation
PET Positron Emission Tomography
PgR Progesterone Receptor
PO Per Oral
PS Performance Status
QID Four times a day
QOL Quality Of Life
RCT Randomised Controlled Trial
RT Radiotherapy
S/C Subcutaneous
SCLC Small Cell Lung Cancer
VCR Vincristine

LIST OF CONTRIBUTORS
Chairman / Editor : Fuad Ismail
NAME INSTITUTION SECTION
Clinical oncologists
 Ahmad Kamal Mohamed SDMC Genito-urinary
 Albert Lim Kok Hooi Gleneagles Breast
 Aloysius Raj Pantai Mutiara Lower GI
 Aminuddin Rahman HKL GU
 Anita Bustam PPUM Breast
 Azura Deniel HKL General
 C R Beena Devi Sarawak Gynae
 Biswa Mohan Biswal HUSM Sarcoma / Brain
 Chan Wee Han HKL Upper GI
 Chong Kwang Jeat MMC Head & Neck
 Deepak Rebenstisch HKL Sarcoma / Brain
 Fabian Lee HKL Gynae
 Foo Yoke Ching SJMC Upper GI
 Gerard Lim Chin Chye HKL General
 Jayendran Dharmaratnam MMC Lung
 Lau Fen Nee HKL Breast
 Marniza Saad PPUM Lung
 Mohd Azrif Ahmad Anuar PPUKM Lung
 Mohamad Roslan Haron HSI Upper GI
 Nik Muhd Aslan Abdullah PPUKM Colo-rectal
Gynae-oncologists
 Ghazali Ismail Kuantan Gynae
 Lim Keng Joo Johor Specialist Gynae
 Mohd Rushdan Md Noor Alor Setar Gynae
Medical Oncologists
 Christina Ng Van Tze Sunway Colo-rectal
 Joseph K Joseph Pantai Bangsar Supportive
Pharmacist
 Lim Yeok Siew Ampang Cytotoxics
Physician - Chest
 Abdul Razak Mutalib Penang Lung
 Liam Chong Kin PPUM Lung

NAME INSTITUTION SECTION
Surgeons - Breast
 Nor Aina Emran HKL Breast
 Nor Hisham Abdullah Putrajaya Breast
 Rohaizak Mohamed PPUKM Breast
 Yip Cheng Har PPUM Breast
Surgeons - colorectal
 Azmi Md Noor IIUM Colo-rectal
 Ismail Sagap PPUKM Colo-rectal
 Wan Khamizar Alor Setar Colo-rectal
Surgeon - Hepatobiliary
 Krishnan Raman Selayang Upper GI
Surgeons - Urology
 Chua Chong Beng Gleneagles GU
 Selvalingam Sothilingam HKL GU
HKL = Hospital Kuala Lumpur

HSI = Hospital Sultan Ismail, Johor
HUSM = Hospital Universiti Sains Malaysia
IIUM = International Islamic University Malaysia
MMC = Mahkota Medical Centre
PPUM = Pusat Perubatan Universiti Malaya
PPUKM = Pusat Perubatan Universiti Kebangsaan Malaysia
SDMC = Sime Darby Medical Centre Subang Jaya
Many of the contributors have helped with other sections of the book as well. We
would also like to acknowledge other contributors from both Ministry of Health and
Ministry of Higher Education, who have helped with this protocol.


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ACKNOWLEDGEMENTS

Dr Gerard Lim Chin Chye

Systemic Therapy of Cancer 2nd Edition Page 1 of 150

I support the multidisciplinary team approach to the care of cancer patients,

Once again congratulations to the team involved in preparing this protocol.

Y BHG TAN SRI DATO‘ SRI DR HAJI MOHD ISMAIL MERICAN

Systemic Therapy of Cancer 2nd Edition Page 2 of 150

CHEMOTHERAPY REGIMENS FOR SPECIFIC SITES

Systemic Therapy of Cancer 2nd Edition Page 3 of 150

14. PRACTICAL GUIDES

15. DRUG PREPARATION AND ADMINISTRATION

Systemic Therapy of Cancer 2nd Edition Page 4 of 150

Assoc. Prof. (C) Dato‘ Dr. Fuad bin Ismail

Systemic Therapy of Cancer 2nd Edition Page 5 of 150

1. To ensure chemotherapy is administered safely to patients by following

2. To ensure patient receive chemotherapy schedules in accordance with disease

3. To ensure the safety of the staff handling cytotoxic drugs.

The decision to initiate the chemotherapy treatment should be made by oncologists,

All patients should be treated according to established chemotherapy protocols and

Oncologists, Gynaecologic oncologists, Chest/Respiratory Physicians with special

Systemic Therapy of Cancer 2nd Edition Page 6 of 150

The lay-out of the regimens is given in tables:

Cycle lengthd = Anti-emetice =

a. - Drugs used in regimen

b. - Dose in milligram per square meter

c. - Method of administration ie oral, intravenous, intra-muscular

e. - Recommended anti-emetic as per guidelines

Systemic Therapy of Cancer 2nd Edition Page 7 of 150

g. - Which day(s) drug(s) should be given within the cycle duration.

Before chemotherapy is given, patients need assessment and pre-medication.

Cisplatinum and Ifosfamide require fluid hydration as part of the chemotherapy

In combination chemotherapy, some drugs may be substituted by another eg cisplatin

Preparation and administration of chemotherapy requires training on safe handling and

Systemic Therapy of Cancer 2nd Edition Page 8 of 150

The new drugs currently in the MOH formulary include :

Systemic Therapy of Cancer 2nd Edition Page 9 of 150

Concurrent chemo-radiotherapy (CCRT) with platinum agents has shown consistent

HEAD & NECK CHEMOTHERAPY

Cycle length (days) = 21 Anti-emetic = 3

Systemic Therapy of Cancer 2nd Edition Page 10 of 150

Cycle length (days) = 21 Anti-emetic = 4

Single agent cisplatin

Cycle length (days) = 21 Anti-emetic = 4

Cisplatin-5FU (as per concurrent regimen)

Cycle length (days) = 21 Anti-emetic = 4

Cisplatin-5FU (as per concurrent regimen)

Single agent MTX

Cycle length (days) = 7 Anti-emetic = 1

Cycle length (days) = 21 Anti-emetic = 3

Systemic Therapy of Cancer 2nd Edition Page 11 of 150

Single agent cisplatin

Cycle length (days) = 21 Anti-emetic = 4

Weekly cisplatin / carboplatin

Cycle length (days) = 7 Anti-emetic = 4

Concurrent & adjuvant chemotherapy

Cisplatin concurrent with radiation and Cisplatin-5FU as adjuvant

Cycle length (days) = 21 Anti-emetic = 4

Systemic Therapy of Cancer 2nd Edition Page 12 of 150

Breast cancer is recognised as a systemic condition even in early stage of the

The pathology report for breast cancer should include :

Systemic Therapy of Cancer 2nd Edition Page 13 of 150

Table 2 : Estimate of Benefit of Adjuvant Chemotherapy

Absolute survival Number needed to

50-69 Low 2.4% 42