| CTRI Number |
CTRI/2025/02/080576 [Registered on: 14/02/2025] Trial Registered Prospectively |
| Last Modified On: |
31/01/2025 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug
Radiation Therapy |
| Study Design |
Randomized, Parallel Group Trial |
|
Public Title of Study
|
Comparison of "Chemoradiation" vs "Chemotherapy Followed by Surgery" for Patients with Locally Advanced Hypopharyngeal Cancers, on its Impact on Disease Free Survival |
|
Scientific Title of Study
|
Concurrent Chemoradiation versus Neoadjuvant Chemotherapy followed by Definitive Therapy for management of Locally Advanced Resectable Hypopharyngeal Squamous Cancers: A Phase III Randomized Controlled Trial. |
| Trial Acronym |
NIL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr Sarbani Ghosh Laskar |
| Designation |
Professor Radiation Oncologist |
| Affiliation |
Tata Memorial Hospital |
| Address |
Room number 1126,11th floor, Homi Bhabha Block, Tata Memorial Hospital, Parel, Mumbai.
Mumbai
MAHARASHTRA
400012
India |
| Phone |
9820834386 |
| Fax |
24146937 |
| Email |
sarbanilaskar@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Sarbani Ghosh Laskar |
| Designation |
Professor Radiation Oncologist |
| Affiliation |
Tata Memorial Hospital |
| Address |
Room number 1126,11th floor, Homi Bhabha Block, Tata Memorial Hospital, Parel, Mumbai.
Mumbai
MAHARASHTRA
400012
India |
| Phone |
9820834386 |
| Fax |
24146937 |
| Email |
sarbanilaskar@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Sarbani Ghosh Laskar |
| Designation |
Professor Radiation Oncologist |
| Affiliation |
Tata Memorial Hospital |
| Address |
Room number 1126,11th floor, Homi Bhabha Block, Tata Memorial Hospital, Parel, Mumbai.
Mumbai
MAHARASHTRA
400012
India |
| Phone |
9820834386 |
| Fax |
24146937 |
| Email |
sarbanilaskar@gmail.com |
|
|
Source of Monetary or Material Support
|
| Intramural Funding |
| Tata Memorial Hospital, Parel, Mumbai, 400012, India |
|
|
Primary Sponsor
|
| Name |
TMC Research Administrative Committee |
| Address |
3rd Floor Main Building, Tata Memorial Hospital, Parel, Mumbai 400012 |
| Type of Sponsor |
Research institution and hospital |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Sarbani Ghosh Laskar |
Tata Memorial Hospital |
OPD 205 206 HBB OPD 109 GJB Tata Memorial Hospital, Parel
Mumbai
MAHARASHTRA |
9820834386
-
sarbanilaskar@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee - 2, Tata Memorial Centre |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: C131||Malignant neoplasm of aryepiglottic fold, hypopharyngeal aspect, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Comparator Agent |
Concurrent Chemoradiation (CCRT) Arm |
Patients randomized to CCRT arm will be given chemoradiation as per protocol:
Protocol for radiotherapy – Intensity modulated radiotherapy (IMRT) will be used for
radiation.
1. For definitive RT, the primary tumor volume and the involved lymph nodes would receive a dose of 70Gy/ 35 fractions (#) equivalent. The uninvolved, regional lymph nodes that are at low risk of metastases will receive a dose of 50Gy/ 25 #, equivalent.
2. For adjuvant RT, a dose of 60Gy/30# will be delivered to the pre-op tumor bed, the remaining pharynx, uninvolved nodal regions in the neck and tracheostomy will receive 50Gy/ 25#, equivalent.
3. In all instances spinal cord will be shielded at 46 Gy equivalent. Other organs at risk (OARs) will be delineated as per standard guidelines
Protocol for Chemotherapy for CCRT – Concurrent cisplatin - 40 mg/m2, intravenous (weekly). |
| Intervention |
Neoadjuvant Chemotherapy (NACT) followed by Adjuvant Therapy Arm |
Patients randomized to NACT arm will be given 2 cycles of chemotherapy with DCF and then response assessment of disease will be done with PET-CECT and DLS after 2weeks of NACT. Response assessment will be done as per protocol using RECIST version 1.1 criteria.
1. Patients who show complete response will receive CCRT.
2. Patients who show partial response will receive one more cycle of NACT with DPF and if clinical progression is suspected PET CECT &/or DLS will be done after 2 weeks of NACT and a DLS. Those with partial and/or complete response will go on to receive CCRT.
3. Patients who show stable or progressive disease after 2 cycles of NACT will undergo surgery.
4. Extent of Surgery will depend on the characteristics of disease and will entail total laryngectomy with partial pharyngectomy or total laryngopharyngopharyngectomy, with appropriate reconstruction.
5. Adjuvant therapy following surgery:
-All patients who undergo surgery will be subjected to adjuvant radiation.
-Those with preoperative clinico-radiological evidence of Extra Capsular Spread as per the new AJCC 8TH Edition, will be subjected to adjuvant Chemoradiation.
-Adjuvant chemoradiation will also be given in the presence of histopathological characteristics like close/positive margins or ECS
5. A small percent of these patients may become inoperable while undergoing NACT due to disease progression. They will be offered CCRT if feasible and palliative therapy if CCRT is not possible.
6. Protocol for chemotherapy will be as follows:
-For NACT – A 3 drug regimen will be used on inpatient basis at following doses - Docetaxel - 75 mg /m2 + cisplatin 75 mg/m2 + 5 flourouracil 750 mg/m2 intravenous infusion over day 1-4, every 3 weeks for 2 cycles followed by evaluation. Patients may receive a 3rd cycle also if there is partial response after 2 cycles of NACT.
-For CCRT after NACT -cisplatin 40mg/m2 intravenous weekly, Docetaxel (15mg/m2 or carboplatin (AUC 2). |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
99.00 Year(s) |
| Gender |
Both |
| Details |
1. Age 18+ years
2. Hypopharynx squamous cell carcinoma proven by histology, stage III/IV M0, eligible for laryngo-pharyngectomy
3.Functional larynx- defined as patients who are:
a. not dependent on tracheostomy tube
b. not dependent on feeding tube in view of tumour related dysphagia
c. no history of recurrent pneumonia requiring hospitalization
4. Performance status ECOG 0-1
5. Neutrophils more than equal to 1.5 x 109/l, Platelets count more than equal to 100 x 109/l, haemoglobin more than equal to 10 g/dl
6. Total bilirubin less than equal to 1.5 x upper reference range
7. ASAT and ALAT less than equal to 2.5 x upper reference range, alkaline phosphatases less than equal to 5 x upper reference range
8. Serum creatinine greater than equal to 50 cc/min
9. Written informed consent
|
|
| ExclusionCriteria |
| Details |
1. Clinical/radiological evidence of gross cartilage erosion
2. History of any prior cancer directed treatment for this disease
3. Uncontrolled co-morbidities eg hypertension, diabetes mellitus, coronary artery disease, COPD, Tuberculosis.
4. Active infection with HIV, HCV, HBV
5. Severe sensorineural hearing loss
6. Pregnant women
7. Patients with dysfunctional larynx.
|
|
|
Method of Generating Random Sequence
|
Stratified randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| To evaluate if NACT followed by definitive therapy in stage III/IV M0 hypopharyngeal squamous cell cancers improves disease free survival compared to upfront definitive CCRT. |
Date of randomization (after accrual) to date of the first episode of disease recurrence or progression or death. |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| Overall Survival |
Date of randomization (after accrual) to date of death |
| Laryngectomy free survival |
Date of randomization (after accrual) to date of total laryngectomy or death |
| Functional larynx preservation |
Date of randomization to date of any death, local disease recurrence, total laryngectomy, tracheostomy and/or feeding tube placement after therapy (i.e. week 20), and tracheostomy and/or feeding tube persistence recorded after 24 months |
| QOL |
Baseline, 6 months, 12 months and at 24 months post-treatment completion between the 2 arms |
|
|
Target Sample Size
|
Total Sample Size="660"
Sample Size from India="660"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
01/03/2025 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="10"
Months="0"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Applicable |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
Aim: The aim of this study will be to examine whether neoadjuvant chemotherapy before definitive therapy
(surgery or CCRT) can improve disease free survival in locally advanced (Stage III & IV M0) hypopharyngeal
squamous cell cancers compared to standard definitive CCRT. - Management of Locally advanced hypopharyngeal squamous cell cancers has undergone a paradigm
shift over past few decades and organ preservation therapies are being preferred over ablative
surgeries without compromise on survival. The results of EORTC trial 24891 comparing a larynx preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell
carcinoma showed no compromise of disease control or survival and allowed more than half of the
survivors to retain their larynx. The organ preservation arm in this trial was neoadjuvant chemotherapy
followed by radiotherapy which was compared with the standard arm of surgery followed by adjuvant therapy. In this trial there was no concurrent chemoradiotherapy arm.
- Data from RTOG 91-11 trial for laryngeal squamous cell cancers treatment has shown superiority of
concurrent chemoradiation(CCRT) approach to radiation alone or to neoadjuvant chemotherapy
followed by radiotherapy approach. This result of laryngeal cancers management is extrapolated to
hypopharyngeal cancers today and we are using CCRT in cancers of hypopharynx for larngeal
preservation. This trial did not have a surgery arm.
- The hypopharyngeal cancers are biologically different from laryngeal cancers. They are usually poorly
differentiated. They present at a late stage and are usually high in disease volume. Early presentations
are unfortunately quite uncommon as most patients do not have symptoms until late, at which point
the prognosis is poor. Approximately 60-80 % of the patients reported in large series have stage III or
IV disease at presentation, and the 5-year overall survival rate is reported to be around 15% to
45%. In the review by Gourin and Terris, the important factors in the poor prognosis of
patients who present with a hypopharyngeal cancer are the high rates of regional and distant
metastasis. Nearly 60% to 80% of these patients have clinically positive regional lymph nodes, and
in approximately 40% of cases contralateral occult nodal metastases are present. The number of
patients who develop distant metastasis, is reported to be between 10% and 30% or even higher, and
this is an even more important prognostic factor. Distant metastatic spread has been reported to occur
in up to 60% of hypopharyngeal cancer cases, either at presentation or during follow-up. The
frequency of distant metastases is also among the highest of all head and neck cancers for this
primary site. Therefore, these cancers are much more aggressive as compared to laryngeal cancers.
The survival rates for stage III/IV laryngeal cancers is about 55%. Therefore the treatment
options for laryngeal cancers should not be extrapolated to hypopharyngeal cancers.
- The salvage surgery rates are poor and it entails more extensive and morbid procedures as compared
to laryngeal cancer.as well for these patients and in salvage settings the surgeries are known to be
much more morbid for this primary site. The percentage of patients who can be salvaged after
CCRT for this site is also very low.
According to NCCN guidelines today, the patients eligible for this trial can be offered any of the following
three modalities of treatment today: - CCRT
- NACT followed by CCRT or surgery depending on response to NACT
- Upfront surgery
- Majority of these patients are treated with concomitant CT+ RT based on data extrapolated from RTOG
91-11 and the MACH-NC data which demonstrated that concurrent chemotherapy with radiation
therapy produces best results.
- The problem with the above mentioned approach is that RTOG 91-11 dealt with only laryngeal cancers
and not hypopharyngeal cancers.
- In view of the more aggressive behavior of these cancers as compared to laryngeal cancers it is felt
that level I evidence is required for deciding on treatment option for this group of patients instead of
extrapolating data from RTOG 91-11 since that trial was for laryngeal cancers alone.
|