Ignite Creation Date:
2024-05-05 @ 11:46 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00128817
Status:
TERMINATED
Last Update Posted:
2013-01-23
First Post:
2005-08-09
Brief Title:
Concurrent Chemoradiation Versus Surgery With Adjuvant Therapy in Advanced Laryngopharyngeal Cancers
Sponsor:
Tata Memorial Hospital
Organization:
Tata Memorial Hospital
Study Overview
Official Title:
Phase III Randomized Clinical Trial to Compare Results of Concurrent Chemo-radiation With Surgery and Postoperative RadiotherapyChemoradiotherapy in Advanced Laryngeal and Hypopharyngeal Cancers
Status:
TERMINATED
Status Verified Date:
2013-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Slow Accrual
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 ie 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
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 ie 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
Detailed 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 13rd 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 radiationRT 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 10000 patients would have to undergo CT In OSullivan 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 23 patients had KPS 90 or more In RTOG trial the mucosal toxicity in concurrent CTRT 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 eg 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 CTRT 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 CTRT 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 CTRT with TLPORT 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 005 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 mgm2 over 20-30 minutes on days 1 22 and 43 In arm 2 Cisplatin CDDP100 mgm2 will be given to patients with multiple lymphnodal involvement extranodal spread positive resection margins perineural involvement or vascular embolization
Surgery Near totalTotal Laryngectomy with bilateral neck dissection with primary speech rehabilitation either by myo-mucosal shunt NTL or by primary tracheo-esophageal puncture
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 radiationRT 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 10000 patients would have to undergo CT In OSullivan 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 23 patients had KPS 90 or more In RTOG trial the mucosal toxicity in concurrent CTRT 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 eg 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 CTRT 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 CTRT 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 CTRT with TLPORT 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 005 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 mgm2 over 20-30 minutes on days 1 22 and 43 In arm 2 Cisplatin CDDP100 mgm2 will be given to patients with multiple lymphnodal involvement extranodal spread positive resection margins perineural involvement or vascular embolization
Surgery Near totalTotal Laryngectomy with bilateral neck dissection with primary speech rehabilitation either by myo-mucosal shunt NTL or by primary tracheo-esophageal puncture
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| DAECTCProjno 42004-2005 | None | None | None |