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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cancer of Cervix	Other: CT + RT	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 850 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Concomitant chemo-radiation versus radiation alone
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Concomitant Chemo-radiation in Advanced Stage Carcinoma Cervix: A Phase III Randomized Trial
• Actual Study Start Date: July 7, 2003
• Actual Primary Completion Date: May 2017
• Actual Study Completion Date: December 2017

Arms and Interventions

Arm	Intervention/treatment
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	Other: CT + RT; Injection Cisplatin 40mg/m2 weekly for 5 weeks during the entire course of external radiation therapy

Outcome Measures

Primary Outcome Measures :

1. To compare the disease free survivals. [ Time Frame: December 2009 ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

India

Tata Memorial Hospital

Mumbai, Maharastra, India, 400 012

Sponsors and Collaborators

Tata Memorial Hospital

Investigators

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

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sk Shrivastava, Professor and Head, Radiation Oncology, Tata Memorial Hospital
• ClinicalTrials.gov Identifier: NCT00193791
• Other Study ID Numbers: TMH/114/2003/CRACX TRIAL
• First Posted: September 19, 2005
• Last Update Posted: September 17, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

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

Keywords provided by Sk Shrivastava, Tata Memorial Hospital:

Carcinoma Cervix; FIGO Stage IIIB; Radiation therapy; Chemoradiation; Treatment related toxicities; Cervical Cancer; Cervix Cancer

Additional relevant MeSH terms:

Carcinoma; Uterine Cervical Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases