Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00128817 |
| Other study ID # |
TMH/196/2004 |
| Secondary ID |
DAECTC/Projno 4/ |
| Status |
Terminated |
| Phase |
Phase 3
|
| First received |
August 9, 2005 |
| Last updated |
January 21, 2013 |
| Start date |
May 2005 |
| Est. completion date |
May 2015 |
Study information
| Verified date |
January 2013 |
| Source |
Tata Memorial Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
India: Department of Atomic Energy |
| Study type |
Interventional
|
Clinical Trial Summary
Surgery with post operative radiotherapy (PORT) had been the mainstay of treatment for
advanced laryngeal-pharyngeal cancers (ALHC) until the eighth decade of the past century.
Total laryngectomy with post-operative radiotherapy (TL + PORT) used to result in permanent
tracheostomy and loss of speech.
Early trials like the VA or European Organisation for Research and Treatment of Cancer
(EORTC) trials compared surgery with post-operative radiotherapy to induction chemotherapy
(ICT) and radiotherapy (RT). Subsequent attempts have been focused on the added benefit of
including concurrent chemotherapy. There is no randomized trial available in the literature
comparing concurrent chemoradiation with the standard treatment, i.e. surgery followed by
radiotherapy. However, most of the studies comparing neoadjuvant chemotherapy and
radiotherapy reported better locoregional control rates and better survival rates with
surgery followed by post-operative chemotherapy. Further, the advances in primary voice
rehabilitation have substantially improved the quality of life after laryngectomy. Thus,
there is a strong case for comparing the results of concurrent chemo-radiation with surgery
and post-operative radiotherapy in a randomized clinical trial. This trial will answer the
question - "whether we are saving voice at the cost of life".
The investigators propose to randomize 900 patients of laryngeal and hypopharyngeal cancers
in surgery with PORT and a concomitant chemoradiation arm and compare the survival and
locoregional control rates.
Description:
TL + PORT has traditionally been the gold standard in management of ALHC. However, this
results in permanent tracheostomy and a possible loss of speech. In case of partial
laryngectomy and even in case of TL, there are various options of voice rehabilitation but
the successes of all these procedures are highly variable. In 1980s several authors reported
interesting possibility of LP with ICT. The first randomized study (RCT) came from VA group
who randomized patients to receive either 2 cycles of ICT + RT Vs surgery +PORT. Patients
with more than PR received a 3rd cycle followed by definitive RT. There were more local
recurrences and fewer distant metastases in the ICT arm. Of the 166 ICT patients, nearly
1/3rd required salvage TL with ultimate LP in 66% surviving patients. These results proved
that ICT and definitive RT can be effective in LP without compromising overall survival.
European Organization for Research and Treatment of Cancer (EORTC) study randomly assigned
hypopharynx cancer patients to receive either immediate surgery with PORT (arm 1) or ICT.
Patients with a CR after 2 or 3 cycles of CT were treated there after by RT. Locoregional
failures occurred at approximately the same frequencies in both arms but there were fewer
distant failures in the ICT arm. The median survival was found to be similar in both arms
with LPR of 35% in the ICT arm. This study showed the feasibility of LP in patients with
cancer of the hypopharynx. A smaller trial from MSKCC15 reported 52% LPR and another
European RCT reported poorer survival in the CT arm with LPR of 20% only. The latter trial
had a smaller number of patients and imbalance in randomized groups (4 out of 5 stage IV
patients got randomized into CT arm) that could have flawed the outcome. The 3 RCTs
(excluding MSKCC trial) were compiled by MACH-NC to obtain a meta analysis that showed
similar disease free survival and a non significant trend of higher 6% survival in pooled
surgery arm which was counterbalanced by LPR of 58% in the pooled CT arm. Quality of life
measures performed as part of the VA study demonstrated that LP offers better speech, good
communication skills, lesser pain and depression compared to surgery.
In three arm study by RTOG (91-11), incidence of laryngectomy was 28% in induction (ICT)
chemotherapy arm, 16% in concomitant arm, and 31% in radiation(RT) alone arm. Following TL,
the incidence of major and minor complications ranged from 52% to 59% and did not differ
significantly among the 3 arms. Fistula was lowest in RT alone arm (15%) and highest in
concomitant arm (30%). Similar experience was reported from MSKCC with fistulas occurring in
39%, resulting in prolonged hospitalization. When compared with complication rates of
surgery in untreated patients, the complication rates following unsuccessful LP protocol is
significantly higher. In spite of higher morbidity, local-regional control is excellent for
this group of patients. In RTOG trial, local-regional control following SS was 74% for CT
arms and 90% for RT alone arm. At 24 months, the overall survival was equal in all arms.
The necessity of adding chemotherapy to radiotherapy itself is debatable. The MACH -NC
reported 4% improvement in overall survival at 2 and 5 yrs with CT. So to prevent death of
400 patients at 5 years, 10,000 patients would have to undergo CT. In O'Sullivan'
questionnaire based study, apart from extent of disease the other significant variables that
influenced treatment recommendation were physicians specialty and their geographical area of
practice. Most LP protocols are often accompanied by increased toxicity and are generally
achieved in good performance status patients unlike majority of head and neck cancer
patients. In VA trial, 77% patients had Karnofsky performance score (KPS) more than 80 and
in RTOG 91-11 trial, 2/3 patients had KPS 90 or more. In RTOG trial, the mucosal toxicity in
concurrent CT+RT arm was twice as much as the mucosal toxicity in other two arms. High grade
toxic effects occurred more when CT was added to RT but there was no significant difference
in rate of toxic effects between concurrent arm and ICT arm. Incidence of treatment
modification, treatment interruption and hospitalizations are higher (compared to RT alone)
when CT is administered concomitantly or during altered fractionation due to complications
such as mucositis, dysphagia, pain, desquamation etc. The indirect costs attributable to
non-surgical approaches e.g frequent expensive imagings, duration of treatment , duration of
recuperation, cost of chemotherapy drugs, enhanced need for supportive care, stringent
follow up and salvage surgery (in one third to half of the patients) may be more than the
costs for radical surgery. Careful monitoring of the conservatively treated patient is
mandatory to allow for early salvage of failures (in VA trial, induction CT arm had more
local recurrences and only 2% patients were lost to follow-up). Given the infirmity and poor
compliance of head and neck cancer patients such a stringent follow-up appears difficult (in
VA trial patients were followed up every month for 1st year).
Nearly 40-60% patients fail on LPP and predicting this failure before spares these patients
of unnecessary chemoradiation and its toxicities, trauma of recurrent disease and
complications of salvage surgery. Mutation of the p53 gene has been found to regulate cell
proliferation and chemosensitivity. LP is significantly higher in the group of patients
whose tumors over expressed p53 but it does not predict survival. A retrospective study
nested within the VA study reported that T stage, p53 over-expression and elevated
proliferating cell nuclear antigen index were independent predictors of successful LP .
Success of RT depends on killing all clonogenic cells that increases linearly with tumor
volume (TV). Lesions are classified as T3 or T4 despite a wide variation in TV if one were
to perform volumetric analysis for all. TV is one of the most precise and most relevant
predictors of RT outcome. This inverse relationship may be explained on the basis of hypoxia
due to central tumor necrosis that is detrimental for CT as well as RT. Cartilage invasion,
soft tissue extension, volume, extensive nodal involvement, pre epiglottic space invasion,
paraglottic space invasion and arytenoids infiltration are some of the radiological
parameters that can predict poor outcome to RT.
Recent studies show adjuvant concurrent chemoradiation to the emerging standard of care for
high risk tumors providing an estimated five year progression free survival benefit of 11%
in advanced stage III and IV tumors or even early stage tumors with extranodal spread,
positive resection margins, perineural involvement or vascular embolization. A similar study
by RTOG showed an estimated 10% improvement in two year locoregional control in high risk
tumors with multiple lymphnodal involvement, extranodal spread and positive resection
margins.
To sum up, CT+RT has the advantages of potential radiosensitization by chemotherapy induced
cell cycle redistribution, overcoming radio-resistance within the field of RT, targeting
different subpopulation of cells leading to more kill, reduction or delay in distant
metastases. Its disadvantages are increased expense, enhanced toxicity and need of good
interdisciplinary integration. What needs to be appreciated is the fact that CT+RT has never
been evaluated against the standard treatment of TL + PORT. Although the quality of life has
been reported to be better after laryngeal preservation, speech rehabilitation has improved
steadily over past decade. Time seems to be ripe now to compare LP with CT+RT with TL+PORT
and speech rehabilitation with locoregional control and quality of life as endpoint.
DETAILED STUDY PLAN:
Study type: Prospective randomized controlled trial with 900 patients (450 in each arm).
Trial size calculated for 392 events with expected improvement of base line survival of 42%
by 10% (alpha error of 0.05 and power of 80).
RANDOMIZATION
Arm 1: Radiation Therapy+ CDDP
Arm 2: Surgery + Post operative RT(+ CDDP for high risk cases)
Arms 1 and 2: Cisplatin (CDDP) 100 mg/m2 over 20-30 minutes on days 1, 22, and 43. In arm 2
Cisplatin (CDDP)100 mg/m2 will be given to patients with multiple lymphnodal involvement,
extranodal spread, positive resection margins, perineural involvement or vascular
embolization.
Surgery: Near total/Total Laryngectomy with bilateral neck dissection with primary speech
rehabilitation either by myo-mucosal shunt (NTL) or by primary tracheo-esophageal puncture.
