Concomitant Chemoradiation in Advanced Stage Carcinoma Cervix (CRACx)

• ClinicalTrials.gov Identifier: NCT00193791
• Recruitment Status: Completed
• First Posted: September 19, 2005
• Last Update Posted: September 17, 2019
• Sponsor: Tata Memorial Hospital
• Information provided by (Responsible Party): Sk Shrivastava, Tata Memorial Hospital

Tracking Information

• First Submitted Date: September 13, 2005
• First Posted Date: September 19, 2005
• Last Update Posted Date: September 17, 2019
• Actual Study Start Date: July 7, 2003
• Actual Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 26, 2017): To compare the disease free survivals. [ Time Frame: December 2009 ]

Original Primary Outcome Measures (submitted: September 13, 2005)

• 1.To evaluate the single agent concomitant chemotherapy (Cisplatin) in Stage IIIB carcinoma cervix
• 2.To compare the disease free survivals.
• 3.To compare the normal tissue toxicities (Acute & Late) of standard radiation therapy with concomitant chemo-radiation.

Current Secondary Outcome Measures (submitted: March 26, 2017)

• To compare the overall survivals [ Time Frame: December 2010 ]
• To compare the distant metastasis rates [ Time Frame: December 2010 ]
• To compare the quality of life in both the groups [ Time Frame: December 2010 ]
• To compare the normal tissue toxicities (Acute & Late) of standard radiation therapy with concomitant chemo-radiation. [ Time Frame: June 2017 ]

Original Secondary Outcome Measures (submitted: September 13, 2005)

• 1. To compare the overall survivals
• 2. To compare the distant metastasis rates
• 3. To compare the quality of life in both the groups

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Concomitant Chemoradiation in Advanced Stage Carcinoma Cervix
• Official Title: Concomitant Chemo-radiation in Advanced Stage Carcinoma Cervix: A Phase III Randomized Trial
• Brief Summary: A study to evaluate the efficacy of concomitant chemoradiation as compared to radiotherapy alone. Concomitant chemoradiation is not a new treatment modality for carcinoma cervix. Studies have shown improvement in survivals with chemoradiation, but majority of the patients was in early stages. Since this treatment modality has not been tested adequately in advanced stages in our setting, the present study is being undertaken. The study arm of chemoradiation has the potential to improve the survivals by 10%, but is associated with additional 5% risk of toxicities, which are treatable. In the study arm, apart form the standard radiotherapy treatment, you will receive weekly chemotherapy injections (Cisplatin) during external radiation therapy. The study arm is associated with additional 5% acute hematological and gastrointestinal toxicities, which are treatable with medications, blood transfusions, modifications in the ongoing treatment etc.

Detailed Description

Carcinoma cervix is the commonest malignancy seen in Asian women and constitutes approximately 30% of all cancers (1). It is also the leading cause of cancer mortality in India. Nearly 50% of the patients present with advanced stages (FIGO Stage III/IV). The main stay of treatment has traditionally been radical radiation therapy and over decades the survival rates have achieved a plateau of 30 - 45% at 5 years. In developing countries the socioeconomic problems, illiteracy, late presentation and irregular follow-up have further compromised our survivals. Over the last decade there have been studies on the use of chemo-radiotherapy in carcinoma cervix. Over 19 randomized trials have been published addressing the issue of chemo-radiotherapy. However, heterogeneous data, poor randomization, inadequate number of patients, sub-optimal radiotherapy, non-uniform use of chemotherapeutic drugs, its sequencing and poor documentation have not yet provided the evidence to substantially alter the practice. Hence, meta-analysis of these trials was undertaken to further evaluate the role of chemo-radiotherapy in carcinoma cervix (2,3).

The first meta-analysis published by Cochrane Collaborative Group of 4580 randomized patients (19 randomized trials) suggested that chemo-radiation did show an absolute survival benefit improvement both in progression free and overall survivals by 16% and 12% respectively (p<0.0001). The survivals were significantly better with Cisplatin based concomitant chemo-radiation (p<0.0001). Incidentally, the distant metastasis rates were also significantly lower in chemo-radiation (p<0.0001). However, all these benefits were seen only in early stages. In addition, acute grade 3/4 hematological and gastro-intestinal toxicities were higher with chemo-radiation (additional 8% and 5% respectively). The data was insufficient to report on late toxicity (2).

The second meta-analysis of 9 randomized trials, recently published by the Canadian Group to evaluate only cisplatin based concomitant chemo-radiation confirms the improvement in overall survival (4year survival data) in advanced stages, bulky IB tumors (prior to surgery) and high risk early disease (post-surgery). Although acute grade 3/4 hematological and gastro-intestinal toxicities were higher in chemo-radiation, they were short-lived, with only 2 deaths and the remaining resolved with medical treatment. There was no significant increase in the late toxicity from the data available.

Both the Cochrane and Canadian meta-analysis have to a large extent tried to address the role of concomitant chemo-radiation, but Carcinoma Cervix Stage III accounted for only 30-35% and moreover evaluation with optimal radiation schedules and comparison of late toxicities still remains unanswered. What is more important is that the cisplatin is relatively inexpensive and is available worldwide. This means that cisplatin-based chemo-radiation is affordable in the developing countries where carcinoma cervix still forms the major cancer. However, the role of chemo-radiation in Carcinoma Cervix Stage IIIB in a developing countries including India still remains unexplored. We propose this randomized study to evaluate the role and benefit of chemo-radiation in-patients with cervical cancer.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Concomitant chemo-radiation versus radiation alone

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Cancer of Cervix

Intervention

Other: CT + RT

Injection Cisplatin 40mg/m2 weekly for 5 weeks during the entire course of external radiation therapy

Study Arms

• No Intervention: Radiation (RT) Alone
  Standard radical radiation therapy alone
• Experimental: CT + RT
  Injection Cisplatin 40mg/m2 weekly for 5 weeks during the entire course of external radiation therapy
  Intervention: Other: CT + RT

Publications *

• Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, Williams CJ. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001 Sep 8;358(9284):781-6. doi: 10.1016/S0140-6736(01)05965-7.
• Lukka H, Hirte H, Fyles A, Thomas G, Elit L, Johnston M, Fung MF, Browman G; Cancer Care Ontario Practice Guidelines Initiative Gynecology Disease Site Group. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer--a meta-analysis. Clin Oncol (R Coll Radiol). 2002 Jun;14(3):203-12. doi: 10.1053/clon.2002.0076.
• Shrivastava S, Mahantshetty U, Engineer R, Chopra S, Hawaldar R, Hande V, Kerkar RA, Maheshwari A, Shylasree TS, Ghosh J, Bajpai J, Gurram L, Gulia S, Gupta S; Gynecologic Disease Management Group. Cisplatin Chemoradiotherapy vs Radiotherapy in FIGO Stage IIIB Squamous Cell Carcinoma of the Uterine Cervix: A Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):506-513. doi: 10.1001/jamaoncol.2017.5179.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 13, 2005): 850
• Original Enrollment: Same as current
• Actual Study Completion Date: December 2017
• Actual Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically proven squamous carcinoma of cervix
• Performance index world health organization (WHO) grade 0 or 1
• Patients below 65 years of age
• FIGO Stage IIIB
• Normal ECG and Cardiovascular system
• Normal hematological parameters
• Normal renal and liver function tests

Exclusion Criteria:

• Co-morbid conditions like medical renal disease
• Medical or Psychological condition that would preclude treatment
• H/o Previous treatment / Pregnancy
• Patient unreliable for treatment completion and follow-up.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: India

Administrative Information

• NCT Number: NCT00193791
• Other Study ID Numbers: TMH/114/2003/CRACX TRIAL
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual patient data (IPD) related to patient characteristics, treatment and outcome variables.

• Current Responsible Party: Sk Shrivastava, Tata Memorial Hospital
• Original Responsible Party: Not Provided
• Current Study Sponsor: Tata Memorial Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Shyamkishore J Shrivastava, MD,DNB(RT); Professor & Head, Department of Radiation Oncology, Tata Memorial Hospital

• PRS Account: Tata Memorial Hospital
• Verification Date: September 2019