SURGERY I
SURGICAL ONCOLOGY
Dr. Cecilio Hipolito, Jr.
KEY POINTS FROM SCHWARTZ’S
1. Alterations critical for malignant cancer growth:
a. Self-sufficiency of growth signals
b. Insensitivity to growth-inhibitory signals
c. Evasion of apoptosis
d. Potential for limitless replication
e. Angiogenesis
f. Invasion and metastasis
2. Understanding cancer biology is essential to successfully
implement personalized cancer therapy
3. Modern cancer therapy is multidisciplinary
a. Surgeons + Medical oncologists + Radiation
oncologists + Reconstructive surgeons +
Pathologists + Radiologists + Primary care
physicians
PRINCIPLES OF SURGICAL ONCOLOGY
Cancer
 Propagating mass (tumor) of cells
 Propensity for unrestricted/unrestrained local growth
(invasiveness) capacity for subsequent reimplantation and
growth at a site distant from the primary mass (metastasis)
 Cell proliferation and transformation (dysplasia)
 All three characteristics must be present to be considered a
cancer
Carcinogenesis
Risk factors:
1. Oncogenic viruses (ex. HSV/HPV and cervical CA)
2. Chemicals (ex. Smoking and lung CA)
3. Chronic irritation (ex. Hyperkeratosis and oral cavity CA)
4. Genetic factors (ex. BRCA1 / BRCA2  Breast CA)
Note:
Most of the factors produce alteration in the DNA make-up of
a normal cell causing cancer later on. For cancer to occur, you
must have not only one of the factors, but at least 2.
A. Iniitiation:
- Single cell (clonegenic origin) undergoes complex
molecular and biochemical interactions resulting in
malignant transformation
- Interaction of cancer promoting genes (oncogenes) and
cancer protecting genes (suppressor genes)
 Overexpression of oncogenes plus the effects of
environmental factors
 Deletion / underexpression of suppressor genes
B. Promotion:
- Single cell accumulation
C. Progression:
- Benign  In situ  Metastatic
Cell Kinetics
 The cell cycle has implications in cancer treatment
 Cell cycle dysregulation
o Cancer cells has the ability to bypass quiescence leading
to proliferation
o Mutations in the cell cycle proteins, growth factors,
transcription factors will allow unregulated cell growth
 G0 phase (rest phase) – State of cells not in the active cell
cycle but capable of entering G1 upon stimulation
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Cell Cycle
A. Gap 1 phase (G1) – Preparation period from mitosis to start of
DNA synthesis
B. DNA synthesis (S) – Longest phase in cycle; main target for
cancer drugs
C. Gap 2 phase (G2) – Preparation period between DNA
synthesis to next mitotic phase
D. Mitotic phase (M) – Cell division seen morphologically
Intermitotic time
- Duration of 1 cell cycle (avg. 8 – 24 hrs)
- S phase (avg. 6-10 hrs)
- Cells rapidly proliferating will have shorter intermitotic time
Note:
In CA cells, the stage of terminal differentiation is deleted.
Most CA cells undergo G0 phase or the actively replicating
phase.
Contents of Cancerous Tissue
1. Actively proliferating cells (clonogenic stem cells) in periphery
2. Non-actively proliferating cells (G0) with “clonogenic” capacity
- Cell proliferation may have been inhibited by inadequacy
of nutrients or other homeostatic factors (e.g. oxygen
levels are low) due to the increased cell size
3. Cells in center that have lost clonogenic capacity
Tumor Growth
 Growth depends on neovascularization induced by Tumor
Angiogenesis Factor (TAF)
 These cells are found in the periphery, are well-oxygenated
and rapidly dividing
Clinical Implication:
- The best area to biopsy is active cells at the periphery
- A tumor on diagnostic imaging that is hypervascular is
probably cancerous.
 Centrally located cells subject to decrease in PO2 retain
clonogenic activity and can metastasize
 Expressed in terms of volume doubling time (DT)
o Range: Week to one year with median DT of 60 days
 Breast CA – 130 days
 Lung CA – 160 days
 Melanoma – 140 days
 Metastatic melanoma – 64 days
o If patient enters with microcalcifications (breast) and
mammography is done, the next schedule for her
mammography will be 5-6 months (130 days) after to
observe if the microcalcification has grown or reduced in
size.
 Small tumor – Close to 100% of cells proliferating (greater
rate of mitosis)
 As tumor enlarges, more cells drop out of proliferating cycle.
 Growth continues but at a decreased rate:
o Lack of nutrients / blood supply
o Immune system response
o Large tumors may have cells in G0 or G1
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 1.0 cm tumor (clinically detectable) contains 10 cells Therapeutic Implications
 Factors that affect the rate of growth: 1. Knowledge of stage, behavior, pattern of spread dictates
1. Inherent behavior (aggressiveness) of the tumor treatment.
(angiogenic factor, membrane characteristics, enzymes, - Carcinomas: Check corresponding lymph node basins
DNA factors) - Sarcomas: Check for distant metastases even if (-) nodes
2. Host defense mechanisms (host responses like T killer Table. Stages in metastasis
cells, fibrosis, etc.)
Early Metastasis Late Metastasis
Rarely curable when reaches Poor correlation of size and
a certain size survival
Good correlation between Correlated better with depth of
size and survival invasion
Potential for multi-site
Few metastatic sites
involvement
Local recurrence does not Large tumors may still be
influence survival curable even with extension
Resection of metastatic Success possible with
nodules no effect on survival metastasectomy

2. Tumors with propensity for local invasion need wider

resection margins (e.g. BCC)
- Locoregional treatment is indicated if:
 Dissemination likely in early stages (surgery +
chemotherapy)
Therapeutic Implications  Local control doubtful (surgery + radiation therapy)
1. Actively proliferating cells are most responsive to cytotoxic
treatment (chemotherapy/radiation treatment) Pre-op Planning
- Removal of primary tumor may increase growth rate in 1. Clinical Staging (TNM)
metastatic foci thus vulnerable to cytotoxic therapy - PE, imaging (CT, MRI, PET)
- Cytoreductive (debulking) surgery reduces tumor bulk & - Know indications for each imaging technique
may increase growth rate to allow cytotoxic treatment to  For lung CA, do not use MRI since MRI requires
work e.g. ovarian cancer scanning of non-moving object
2. Growth Rate  For breast mass, do not use CT scan, best will be
- Tumor aggressiveness – Function of the blood supply mammography and ultrasound (screening)
(includes angiogenic factor, membrane characteristics, 2. Pre-op Conference
enzymes, DNA factors) - With other specialists and relatives
- Host defense mechanisms (includes host responses like T - Planning multidisciplinary approach
killer cells, fibrosis, etc.) - Explaining extent of surgery
- Clinical Implication: - Explaining risks and outcome
 An immune-compromised patient may have faster 3. Pre-op Preparation
tumor growth - Medical risk evaluation
Fast Growing Ca Slow Growing Ca - Optimize patient condition
Intensive surveillance for the Long period of surveillance  Pulmonary physiotherapy
st
1 1 – 2 years necessary (>10 yrs)  Nutritional support
Short incubation (rapid Long incubation period (long  Bowel preparation
doubling time) doubling time)  Antibiotic prophylaxis
Early recurrence and Early recurrence uncommon, - Timing of surgery (ex. Post RT)
dissemination is common less invasive  The patient who underwent RT should undergo the
Rare late recurrence Late recurrence common operation 4 – 6 weeks after RT
Few deaths after 3 years post Patients continue to die of
resection cancer > 5 years Intra-op Conduct of Operation
Pancreatic and lung CA, Ewing 1. Determine stage during surgery
Well-differentiated thyroid CA,
sarcoma, Anaplastic thyroid
Basal cell CA, Chondroma
2. Histologic confirmation
CA 3. “En-bloc resection”
- Nodal dissection not picking
Cancer Metastasis - Avoid tumor spillage
 Tumor cells will detach, implant and grow (metastasis) - Do not cut the tumor, but cut the normal tissues containing
 Rule: Carcinoma first metastasizes to the lymphatics the tumor
(lymphogenous) while sarcoma invades the bloodstream 4. Attain tumor free margins by wide resection
(hematogenous)
 When lymphatic channel is entered, regional nodes filter it, Types of Cancer Operations
causing lymphadenopathy (nodal metastasis) 1. Curative resection
 Organ selectivity: Preference of cancer cells to implant in - Usually for Stage I to III patients
specific organs (ex. Metastasis to the lungs, liver, bone, - Resectable tumor w/adjacent lymph nodes
ovary, brain, and peritoneal cavity) - Cure can be attained by surgery (e.g. radical resection)
1. Epithelial / solid CA: Regional lymph nodes 2. Cytoreductive surgery
- Breast CA  Axillary lymph nodes - For Stage IV patients especially for ovarian carcinoma
- Lung CA  Thoracic lymph nodes - Decrease tumor load prior to adjuvant therapy
- Gastric CA  Celiac group of lymph nodes - Indicated if other effective therapies are available to
2. Sarcoma: 98% will metastasize hematogenously control residual disease
- Sarcoma in extremities  Lungs  Ovarian cancer – Resection of bowel with infiltration
- Sarcoma in abdomen  Liver to prevent perforation during chemotherapy

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3. Diagnostic surgery 3. Antibiotics
- e.g. Biopsy operation - i.e. Adriamycin, bleomycin
- Biopsy to confirm diagnosis or histology of cancer - Interferes with various points in sequence of DNA to RNA
4. Palliative surgery to protein formation
- e.g. Esophageal carcinoma, Stage IV stomach cancer - Interferes with DNA replication or inhibition of RNA
- Unresectable tumor but longevity can be increased synthesis
- Patient can be made comfortable - Cell cycle non-specific
5. Prophylactic surgery 4. Anti-microtubular agents
- Prevent future cancer from developing - Plant origin
 Prophylactic mastectomy for high risk for breast - Causes disorganization of mitotic spindles
cancer - Produce mitotic arrest of the cell in metaphase
 Total colectomy for multiple polyposis of colon - Cell cycle specific
a. Vinca alkaloids (e.g. vincristine, vimblastine): Inhibit
6. Metastasectomy assembly of microtubules
- e.g. Colon cancer that metastasized to liver b. Taxanes (e.g. paclitaxel, docetaxel): Inhibit
- Resection of metastatic nodules microtubular disassembly
Post-op Management First Order Kinetic Phenomenon
 Maintenance of records  First dose: A relatively constant proportion (NOT absolute
o Accurate record keeping number) of cells are killed
o Indicate clinical pathologic state  Second dose: Kills the SAME percentage of remaining cells
o Document surgical and adjuvant therapy  Subsequent dose: Eliminates CLOSE to 100% of cells
 Follow-up  Therapeutic Implication: Chemotherapy drugs are usually
o Detect recurrences given in several cycles
o Monitor treatment outcome  Side effects: Vomiting, alopecia, decreased immune
response, weakness/anorexia, anemia, organ-specific
PRINCIPLES OF CHEMOTHERAPY o Most chemotherapy drugs affect the liver, but also kidney
 Usually the primary modality of therapy in patients with and heart. i.e. Doxorubricin is cardiotoxic
documented distant metastatic disease
 Goal of therapy: Decrease the tumor burden thus prolonging Intermittent Therapy
survival  Rationale:
 Adjuvant chemotherapy – Chemotherapy administered to a o Allow recovery of immune system (starting at 2-3 weeks
patient who is at high risk for distant recurrence but has no after chemotherapy)
evidence of distant disease o At day 14, neutrophil levels are low
o Goal: Eradication of micrometastatic disease, with the o Immune system will start to recover at day 21.
intent of decreasing relapse rates and improving survival o Recovery is expected within 21 – 26 days.
rates o Allows recovery of DNA damage in normal cells which is
o 3 potential advantages of preoperative chemo: faster than cancer cells
 Preoperative regression of tumor can facilitate o Better effect than continuous therapy
resection that were initially inoperable  Combination of drugs has more effective tumor kill and less
 Treatment of micrometastases without the delay of complication.
post-op recovery  Criteria for objective response for clinically measurable
 Ability to assess a cancer’s response to treatment tumors
clinically, after a number of courses of chemo and Response Criterion
pathologically, after surgical resection Complete Complete disappearance
 Chemo destroys cells by the first-order kinetics, meaning that Partial ≥ 50% reduction in T size
with the administration of a drug a constant percentage if cells None < 50% reduction in T size
are killed, not a constant number of cells. Progression > 50% increase in total measurable disease
 Chemotherapeutic agents can be classified according to the
phase of the cell cycle they are effective in.  Complete clinical response: Tumor not palpable or seen using
imaging techniques (e.g. ultrasound) but can be seen in microscopy
 Cell-cycle phase-nonspecific agents (e.g. Ankylating agents)  Complete pathologic response: no traces of tumor even in
have a linear dose-response curve microscopy
 Cell-cycle phase-specific drugs have a plateau with respect to o Happens 20% of the time
cell killing ability, and cell kill will not increase with further
increases in drug dose. Cancer Treatment Strategies
1. Neoadjuvant Therapy
Goal: - Down stage tumor before surgery
- To kill cancer cells by interfering with its metabolic pathway - Prepares for curative resection
without serious damage to normal cells - Test response to cytotoxic therapy
Classification According to Mechanism of Action - Most popular strategy for breast cancer (breast
1. Alkylating agents conservation surgery)
- i.e. Cyclophosphamide 2. Adjuvant Therapy
- Binds to nucleic acids thereby altering the structure - Given after primary treatment or surgery
- Cell cycle non specific - Eradicate microscopic cancer cells not removed by
- Cross resistance with other alkylating agents primary treatment
2. Antimetabolites - Prevent distant metastasis/local recurrence
- i.e. 5-FU (for adenocarcinoma of GIT), methotrexate 3. Palliative Chemotherapy
- Structural analogues of nucleic acid precursors results in - Incurable disease but death not imminent
production of false intermediate metabolites - Can significantly prolong and improve quality of life
- S-phase specific agents - Patient must have good performance status

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 Targeted Therapy Factors Affecting Radiosensitivity
 Newest form of cytotoxic therapy 1. Oxygen tension
 Cancer-causing gene is known - Necrotic tumors (↓ O2 tension-resistant)
 e.g. HER2/neu, ER, PR in breast CA - Anemic patients (↓ O2 carrying hgb-resistant)
 Blocks the growth of cancer cells by interfering with specific 2. Fractionation
targeted molecules needed for carcinogenesis and tumor - Balance between T cell kill & normal cell recovery
growth
- Longer interval, less damage to normal cells
 Rather than by simply interfering with rapidly dividing cells
- Greater dose/fraction, the greater the effect
(traditional chemotherapy) - Greater mitotic activity, the shorter the interval
 More effective, less harmful, more expensive than
chemotherapy 3. Volume irradiated
- Larger volume, lower tissue tolerance
Types of targeted therapy
- Large tumor means more cells and poor oxygenation
1. Small molecules
- Gefitinib: Targets EGF receptor tyrosine kinase, for
lung cancer and some solid tumors 4. Tumor cell type
- Imatinib for CML, GIST - Lymphoreticular: Sensitivie
- Tamoxifen: Targets estrogen receptors of breast - Fibrosis: Resistant
cancer 5. Tumor bed
- Aromatase inhibitor: Newer drug for breast cancer
- Rich blood supply: Good response to management
that blocks production of estrogen
2. Monoclonal antibodies Combined Modality
- Trastuzumab: Targets HER2 / neu receptor of breast  RT works better Pre-op because there is higher oxygen
cancer tension and undamaged vascular supply.
PRINCIPLES OF RADIATION THERAPY 1. Pre-op RT
 Radiation deposition results in DNA damage manifested by - Intact blood supply
single and double-strand breaks in the sugar phosphate - Reduction of tumor size
backbone of the DNA molecule - Decreases recurrence
 Radiation damage is manifested primarily by the loss of - Limiting factor is ↑ complications
cellular reproductive integrity - Delay not more than 6 weeks
 Extent of DNA damage is dependent on several factors. The - Difficult salvage surgery
most important of these is cellular oxygen. 2. Post-op RT
o Hypoxic cells are significantly less radiosensitive that - For bulky or aggressive tumors
aerated cells - Positive margins
 Most radiation sensitive phases are G2 and M, while G1 and - Prevents recurrence
late S phases are less sensitive - Give early to prevent fibrosis
 Fractionation - Complications also increases (carotid blow out in radical
o Delivery of radiation in divided doses allows the surviving neck dissection)
G1 and S phase cells to progress to more sensitive
phases, a process referred to as re-assortment 3. Chemotherapy prior to RT
 Several chemicals can modify the effects of ionizing radiation - Sensitize tumor cells to RT effects
 These include: - Advanced H & N and breast cancer
o Hypoxic cell sensitizers such as metronidazole and Types of Radiation Therapy
misonidazole, which mimic oxygen and increase cell kill of 1. External
hypoxic cells. - X-ray
o Thiamidine analogues iododeoxyuridine and - Gamma beam
bromodeoxyuridine - Particle beam
 These molecules are incorporated in the DNA in place - IMRT (intensity modulated RT)
if thymidine and render the cells susceptible to
radiation damage 2. Interstitial radiation
 However, they are associated with considerable acute - Brachytherapy
toxicity - Recurrences after external RT
 Delivered in a homogenous dose to a well defined region that - Unresectable cancers
includes tumor and/or surrounding tissue at risk for subclinical 3. Intracavitary (Uterine. Cervix CA)
disease. - Insertion of radium packed tubes inside the cavity
 Local therapy
 Curative role of RT in some cancers: 4. Systemic RT
o Early stage SCC of the head and neck - I131 – Thyroid CA
o Cervix cancer - Phosphorus 32 – Bone metastasis
o Lymphoma
o Transitional cancer of the urinary bladder
 Affects cells by interfering with reproduction and mitosis
 Affects rapidly dividing cells
 Aims to effect maximal damage to cancer cells but allows
recovery of normal cells

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 ONGOING TRIALS IN CANCER THERAPY
1. Genetic and molecular medicine
- Human genome project
- Identifies tumor based on genetic constitution/signature
- Oncotype Assay 21, MammaPrint for breast CA
- Used in targeted therapy
2. Stem Cell Therapy
- For Stage IV cancers
3. Immunotherapy (e.g. dendritic cell therapy)
- Macrophage engulfs cancer cell and retains memory
(receptors) for the specific tumor cell
- Dendritic cell will go to lymph nodes and present to T
cytotoxic cells for them to identify and search cancer cells
in system
- e.g. for lymphoma patients, renal cell cancer
4. Nanotechnology in medicine
- Real time therapy
REFERENCES
1. Dr. Hipolito’s lecture (recording and powerpoint)
2. Schwartz Principles of Surgery
3. 2013B Transcription
QUESTIONS
1. What is the most like organ of metastasis for a sarcoma in the
abdomen?
2. What type of surgery is common for stage IV ovarian
carcinoma?
3. Name two chemotherapeutic agents that are cell cycle
specific.
4. What type of receptor is targeted by Gefitinib?
5. Radiation therapy alone can be curative for what cancers?
6. Why are anemic patients less responsive to RT?
REMARKS/ANSWERS
 Please refer to Schwartz for a clearer picture of the
Gompertzian curve
1. Liver
2. Cytoreductive
3. Vincristine, Vinblastine, Paclitaxel, Docetaxel
4. EGF tyrosine kinase receptor
5. Early SCC of head and neck, cervix CA, lymphoma,
transitional CA of urinary bladder
6. Less oxygen available to create free radicals that kill cancer
cells

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