Concurrent Chemotherapy

and Radiotherapy for Organ

Preservation in Advanced
Laryngeal Cancer

RTOG 91-11 trial

Background
 In June 1991, VA trial results were published.

 Conclusion: IC and definitive RT can be effective

in preserving the larynx in a high percentage of
patients, without compromising overall survival.

 IC followed by RT became standard of care for

laryngeal preservation in advanced laryngeal
cancers.
Lacunae
 Non-inferiority trial. Only proved if the
newer treatment was comparable to
the then gold standard (TL).
 Primary end-point was overall
survival, not laryngectomy free
survival.
 The value of adding chemotherapy to
radiotherapy and the optimal timing of
chemotherapy were unknown.
Methods
 Patients with locally advanced cancer of
the larynx were randomly assigned to one
of three treatments:
1. induction cisplatin plus fluorouracil
followed by radiotherapy (IC+RT),
2. radiotherapy with concurrent
administration of cisplatin (CRT) , or
3. radiotherapy (RT) alone.

 The primary end point was preservation of

the larynx.
Patient selection
Inclusion:
 Biopsy-proven, previously untreated stage III or IV
squamous-cell carcinoma of the glottic or
supraglottic larynx.
 A Karnofsky performance score of at least 60.
 WBC count >3500/mm3
 platelet count of at least 100,000/mm3,
 Normal serum calcium level
 creatinine clearance of at least 50 ml / minute.

Exclusion:
 T1 primary tumor or with large-volume stage T4
disease
Pretreatment staging
 Laryngoscopy
 measurement of the tumor
 HRCT neck.
 CT chest and barium esophagography
or panendoscopy - To rule out
synchronous primary cancers
 Imaging was performed as clinically
indicated to rule out metastatic disease.
1st group – IC + RT
Similar to the treatment group in VA trial.

 Cisplatin 100 mg/m2 on day 1

 Fluorouracil 1000 mg/m2 every 24 hours
for 5 days
 Every three weeks for two courses and
Re-assess.
 Evaluation by indirect laryngoscopy and
CT imaging of the neck.
Induction CT+ RT

Complete/ partial 3rd cycle PF + RT

response Day 43
2 cycles of PF
Day 1, 22
Less than partial/ Laryngectomy +
progression RT
2nd group – concurrent CT + RT
 Cisplatin – 100 mg/m2 on days 1, 22,
and 43 of RT.
 The rationale for the second group was
based on the enhancement of radiation
effects on tumor cells by concurrent
treatment with cisplatin.
3rd group – RT alone
 Primary tumor and clinically positive
nodes – 70 Gy in 35 fractions over
seven weeks.

 Salvage surgery followed by adjuvant

RT were given 50-70 Gy depending on
margin status.
 Dose of radiation and radiotherapy
schedule were the same in all three
study groups.
Surgery
 N2, N3 – neck dissection eight weeks
after the completion of radiotherapy.

 Laryngectomy –
 proven persistent or recurrent carcinoma
after the completion of treatment (both
groups).
 inadequate response after two courses
of induction chemotherapy (Group 1).
Follow-up
 Examination of the head and neck and CT
imaging – 8 weeks.
 Direct laryngoscopy under GA if disease
suspected.
 Two questionnaires were used to evaluate
QOL:
1. Functional Assessment of Cancer Therapy
— Head and Neck Scale, version 2, 4
2. University of Washington Quality of Life
instrument
Study End Points
 Primary end point - preservation of the
larynx.
 Other end points
 overall survival
 disease-free survival
 local control
 locoregional control
 the time to distant metastasis
 laryngectomy-free survival.
 Toxic effects were graded according to the
National Cancer Institute Common Toxicity
Criteria, version 1.0, during induction
chemotherapy and according to the
Radiation Therapy Oncology Group toxicity
criteria during radiotherapy.
 All deaths occurring during treatment or
within 30 days after the completion of
treatment were considered to be possibly
treatment-related.
Statistical analysis
 Dunnett’s two-sided test was used to
adjust for multiple comparisons.
 The sample size was calculated with the
use of Bristol’s modification.
 The sample size was increased by 10
percent to account for patients deemed
ineligible or lost to follow-up.
 OS, DFS AND LFS using Kaplan–Meier
method with the log rank test.
Population stats
 August 1992 to May 2000
 547 patients
 21 - ineligible
 1 withdrew consent
 7 were excluded as outcome information
was not submitted
 518 patients were included in the
analysis
 Toxic effects
 Response to treatment and compliance
 Preservation of the larynx
 Speech and swallowing
 Survival outcomes
 Pattern of failure
 Distant metastasis
Toxicity profile

IC + RT CCRT RT

Grade 3 or 4 RT toxicity 24% 30% 36%

Total toxicity 81% 82% 61%

Deaths 3% 5% 3%
Response to treatment & compliance
IC + RT n = 173 CCRT n = 172 RT n = 173

Completed 134 – 3 doses 120 – 3 doses na

intended CT 40 – 2 doses
Completed RT 91 % 94 % 95 %

Complete 150 154 148

response
Group 1 168/173

Non-responders
Responders (144)
(24)

Complete response Partial response TL – 7 patients

Primary – 21% Primary – 64% RT - 11 Patients
Nodes – 23% Nodes – 34% (1 TL)

134 – 3rd cycle, 10 discontinued

Preservation of the larynx
IC + RT CCRT RT
Preserved 125/173 (72%) 145/172 (84%) 116/173 (67%)
larynx