|Year : 2016 | Volume
| Issue : 1 | Page : 56-59
Is neo-adjuvant chemotherapy a better option for management of cervical cancer patients of rural India?
GA Dastidar1, P Gupta2, B Basu3, A Basu4, JK Shah5, SL Seal6
1 Department of Radiotherapy, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Radiotherapy, Nil Ratan Sircar Medical College, Kolkata, West Bengal, India
3 Department of Radiotherapy, Bankura Sammilani Medical College, Bankura, West Bengal, India
4 Department of Anesthesiology, R. G. KAR Medical College, Kolkata, West Bengal, India
5 Department of General Surgery, Anandalok Hospital, Salt Lake City, Kolkata, West Bengal, India
6 Depaertment of Gynecology, Dr. Radha Gobinda Kar Medical College, Kolkata, West Bengal, India
|Date of Web Publication||28-Apr-2016|
G A Dastidar
Department of Radiotherapy, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Objectives: To explore alternate modality of treatment in patients of advanced cancer cervix by neo-adjuvant chemotherapy (NACT) followed by External Beam Radiotherapy (ERT) and Brachytherapy (BT). Short- (6 months) and long- (12 months) term follow-up data from these patients were compared with the retrospective data from an urban cancer centre, where standard protocol of concurrent chemo-radiotherapy is practiced. Materials and Methods: Two hundred patients of advanced cervical cancer, treated at our rural cancer centre between January 2007 and December 2007, were included in the study arm (Group A). These patients received three cycles of neo-adjuvant chemotherapy with Cisplatin, Bleomycin, and Vincristine before External-Beam Radiotherapy (EBT) followed by brachytherapy. Patients in the control arm (Group B) of an urban cancer centre, received EBT with weekly concomitant Cisplatin, followed by brachytherapy. Short- (6 months) and long- (12 months) term follow-up data from our patients were compared with the retrospective data from the urban cancer centre. Results and Analysis: Complete response rate was comparatively higher among patients of Group A, also correspondingly proportion of patients showing progressive disease and stable disease was lower among them. Local treatment failure was 87.5% among patients from Group A and 94.4% in Group B patients. Concomitant chemoradiation (CRT) was associated with more GI toxicities. Conclusion: Our result suggests NACT arm is as effective as CRT arm in respect of complete response with less pelvic failure and G.I toxicities. Further follow-up data are needed before arriving at a definite conclusion.
Keywords: Cancer cervix, chemo-radiation, concomitant, neo-adjuvant
|How to cite this article:|
Dastidar G A, Gupta P, Basu B, Basu A, Shah J K, Seal S L. Is neo-adjuvant chemotherapy a better option for management of cervical cancer patients of rural India?. Indian J Cancer 2016;53:56-9
|How to cite this URL:|
Dastidar G A, Gupta P, Basu B, Basu A, Shah J K, Seal S L. Is neo-adjuvant chemotherapy a better option for management of cervical cancer patients of rural India?. Indian J Cancer [serial online] 2016 [cited 2019 Aug 25];53:56-9. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/56/180826
| » Aims of the Study|| |
Cervical cancer is considered as the second most common cancer amongst women in India, but in rural India the incidence of cervical cancer far outnumbers any other cancer in adult women. In our rural based medical college hospital, of all women cancer patients, about 80% suffer from carcinoma cervix uteri stage IIB disease or above with poor personal hygiene. Although concomitant chemotherapy with external radiotherapy followed by brachytherapy is the standard protocol of management, we are unable to stick to such protocol due to unusual delay in starting radiation immediately after confirmation of diagnosis. Aim of this study is to observe the positive effect of neo-adjuvant chemotherapy in local control and prevention of distal metastasis in locally advanced cancer cervix. With the intent to arrest the disease progression and possible complete response and to improve disease free survival (DFS), we advocate neo-adjuvant chemotherapy (NACT) immediately after histopathological confirmation and base-line investigations. Retrospective analyses of short term (after 6 month) and long term (after 12 month) follow up of two different treatment modalities (NACT vs. concomitant chemoradiation (CRT)) were compared between rural cancer centre and urban cancer centre where concomitant chemo-radiotherapy (CT-RT) followed by brachytherapy was performed.
| » Materials and Method|| |
Two hundred women with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to stage IVA cancer cervix uteri treated with neo-adjuvant chemotherapy, in the Department of Radiotherapy in rural medical college from January 2007 to December 2007, were enrolled for the study and the treatment outcome was analyzed (Group A). This group was compared with 390 patients treated with concomitant chemo-radiation (Group B) at an urban medical college during the same period. Acceptance of the proposed protocol and signed informed consent was requested from all patients.
Inclusion criteria was as follows: No previous anticancer treatment, no past or coexistent malignant disease, squamous cell carcinoma of cervix uteri with locally advanced stage, adequate bone marrow reserve, normal renal and hepatic function, and no protocol deviation or default from scheduled follow up.
Criteria for “protocol deviation” in the study arm: a) Gap between two cycles of chemotherapy of more than 28 days, b) Gap of more than 5 days during external-beam radiotherapy, c) Overall treatment time of External-Beam Radiotherapy (EBT) more than 43 days, d) Gap between completion of EBT and start of high-dose-rate (HDR) brachytherapy of more than 5 weeks, e) Gap between two insertions of brachytherapy of more than 10 days.,
All women in Group A, i.e. patients treated at rural cancer centre, were treated by NACT regimen with Cisplatin 80 mg/m 2 as intravenous infusion, Bleomycin 30 mg as intravenous bolus, Vincristine 1.4 mg/m 2 as intravenous infusion on first day of every 21 days cycle for total three cycles. The objective response of NACT were assessed according to European Organisation for Research and Treatment of Cancer (EORTC) response evolution criteria i.e. Complete Response (CR) (disappearance of all measurable disease), Partial Response (PR) (>% reduction of lesion in the product of two maximal tumor diameters), Stable Disease (SD) (regression of < 50% or progression of > 25% of the tumor), Progressive Disease (PD) >% increase in tumor size and/or appearance of a new lesion).,
After neo-adjuvant chemotherapy, patients underwent EBT, followed by intracavitary high dose rate brachytherapy (ICRT). Whole pelvic dose of radiation was 50 Gy in 24 daily fractions over 5 weeks. This was followed by weekly insertions of ICRT with Manchester suit applicators done under spinal (saddle block) anesthesia and/or deep sedative analgesia for 3 consecutive weeks. Point A dose was equivalent to 7 Gy per insertion.
Objective response rate under this protocol of treatment was assessed 3 months after completion of brachytherapy as recovery from acute radiation reaction to vaginal mucosa is expected by this time. Results of these study arm patients were compared with similarly staged patients treated by CRT with Cisplatin intravenous infusion 40 mg/m 2 week ly for 5 consecutive weeks starting day 1 of EBT. Radiotherapy was given 15 minutes after completion of i.v. infusion of Cisplatin. Patients then underwent brachytherapy of three weekly insertions similar as that in the study arm.
| » Result Analysis|| |
Total 200 patients in NACT arm (Group A) and 390 patients in CRT arm (Group B) were analyzed. The clinico-pathological characteristics were well-balanced and there were no major differences in age distributions, body weight, bovine serum albumin (BSA), body mass index (BMI), performance status, hemoglobin level, tumor size, and gap between EBT and ICRT in both groups. Patients of well-differentiated carcinomas were equal in percentage in both arms while percentages of poorly differentiated carcinomas were more in the study arm. All stages in both arms were comparable except stage IVA, which was more in CRT arm [Table 1].
[Table 2],[Table 3],[Table 4] show complete response was better in the study arm for stage IIB and IIIB, whereas, in CRT group better result was observed for stage IIIA, however, differences were not statistically significant. Complete response was never observed in stage IVA in either arm. Progressive disease could be arrested in NACT arm, except for Stage IVA.
No statistical difference was found in relapse rate in the both arms [Table 5].
|Table 3: Comparative complete response in NACT and Concomitant CT-RT arm|
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There was no grade 3 and 4 toxicity in the gastro-intestinal tract, skin and genitor-urinary system in the NACT group of patients as per Radiation Therapy Oncology Group (RTOG) criteria. More blood transfusions were required in the CRT group. So, toxicity and treatment complication were noticed more in the CRT arm [Table 6].
|Table 6: Observed acute toxicity as per RTOG criteria (% of patients) in both arms|
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| » Discussion|| |
CT-RT is a “standard of care” for women with locally advanced carcinoma cervix. This was in response to a National Cancer Institute Alert based results of five randomized trials stating “strong consideration should be given to the incorporation of chemotherapy and radiotherapy for the treatment of cervical cancer”.
Subsequent systematic review and meta-analysis of nineteen randomized trials (published/unpublished summery data) of concomitant CT-RT vs. Radiotherapy, has showed a 29% reduction in the risk of death which has been translated into an overall survival of 12% at 5 years from CT-RT arm.
However, pelvic failures with or without a systemic component is a frequent problem for patients with locally advanced cervical cancer, in spite of encouraging results of concomitant CT-RT based on Cisplatin as observed by Patterson F.
Neo-adjuvant chemotherapy in the treatment of carcinoma cervix has mainly been attempted before definitive surgical management. A large number of studies were conducted and results were ambiguous. Compiling all these data, a large meta-analysis concluded that although there was a trend of improved overall survival with the use of neo-adjuvant therapy, it was still not clear enough to make any definite recommendation. They also concluded that neo-adjuvant chemotherapy followed by definitive surgical intervention might be a reasonable alternative to definitive chemo-radiation therapy.
Unfortunately, trials attempting neo-adjuvant chemotherapy before definitive chemo-radiation therapy are less in number, accruing far lesser number of patients and come with more conflicting results. Shueng et al., after a thorough review of literatures had concluded that neo-adjuvant chemotherapy before radiotherapy/chemo-radiotherapy would be experimental and did not recommend its routine use. They also thought that with the use of newer chemo-therapeutic agents the scenario might change. Leborgne et al., shared the same opinion that neo-adjuvant chemotherapy before radiotherapy should not be attempted. In fact, Souhami et al., found that use of neo-adjuvant chemotherapy adversely affected disease outcome and was associated with unacceptable toxicities.
Recently, newer chemotherapeutic agents e.g. Paclitaxel in combination with Cisplatin showed remarkable activity against cervical cancer. Also, trials using PVB (Cisplatin, Vincristine, and Bleomycin) came out with encouraging results. In one such trials, Tattersall et al., found that use of neo-adjuvant chemotherapy was not only associated with better tumor response but also less number of systemic relapses.
In spite of these conflicting evidences, we tried to explore the role of neo-adjuvant chemotherapy in locally advanced carcinoma cervix to suit the rural patients of India, with an object to achieve better treatment outcome.
Mandic A in his study has shown that in treatment of cervical cancer 97% complete response in NACT arm (n = 37) and 87% in CRT arm (n = 38). However, our study shows 35% response in NACT arm (n = 200) and 30% in CRT arm (n = 390), at least similar complete response rate in both arms with more number of patients in each arm. His study also reflected 3% of persistent/progressive disease in NACT arm and 13% in CRT arm, while our study shows 25% of stable/progressive disease in NACT arm and 32.3% in CRT arm, indicating more patients with stable/progressive disease in CRT arm, which is consistent with findings of Mandic A.,
In NACT arm, out of 50 (25%) of stable/progressive disease16 patients had relapsed and 14 (87.5%) had local recurrence and 2 (12.5%) of systemic disease. In CRT arm, 27 patients had relapsed and 25 (94.4%) had local recurrence and 2 (7.4%) had systemic disease, out of 127 (32.3%) of stable/progressive disease. Thus, we also noticed, like Patterson F, more pelvic failures in CRT arm based on Cisplatin chemotherapy.
NACT has been well tolerated; most common side effects were nausea/vomiting and alopecia. Moderate hematological toxicity has been observed but no episodes of neutropenic fever or episode of bleeding. [Table 6] shows the percentage of toxicities of 200 patients in NACT arm and 390 patients of CRT arm, which indicates more gastrointestinal (G.I.) toxicities and hematological toxicities in CRT arm. To have an overall survival analysis, we want to follow up these patients as no patient in any of the arm has died yet.
Sardi et al., using quick PVB (Cisplatin, Vincristine, and Bleomycin) reported longer overall survival in stage IB, IIB, and III B prior to either Surgery or Radiotherapy vs. Surgery or Radiotherapy only.
Poveda et al. has observed that NACT should be considered still investigational, and they also suggested that new drugs and new regimens may be explored in order to increase the rate of pathologic complete responses.
| » Conclusion|| |
Standard therapies given to patients with locally advanced cervical cancer does not have a major impact on the outcome of the disease on a stage by stage basis.
Our result suggests NACT arm is at least as effective as CRT arm in respect of complete response with less pelvic failure and less hematological and G.I. toxicities.
Considering the sufferings of rural cancer patients and impact of delay in the initiation of radiation-therapy on the course of the disease, we recommend trying this form of NACT treatment in all locally advanced cases of cancer cervix to arrest the progress of disease for quite a reasonable period. However, it is an interim analysis. Long term follow up of these patients enrolled in our study is needed to reach any definite conclusion regarding its effect on overall survival.
| » Acknowledgment|| |
We are grateful to Professor Asit Ranjan Deb, Head of Department of Radiotherapy, Midnapore Medical College, WB and Prof. Ajit Ranjan Bhattacharya Head of Department of Gynecology and Obstetrics R. G. Kar Medical College, for their valuable advices and to “Ethical Committee” of concerned Institutes for providing permission to carry out the work
| » References|| |
Nandakumar A, Ramnath T, Roselind FS. Two Year Report of the Population Based Cancer Registries 1999-2000. Ch. 2. National Cancer Registry Programme, Indian Council of Medical Research, April; 2005. p. 11.
Shueng PW, Hsu WL, Jen YM, Wu CJ, Liu HS. Neoadjuvant chemotherapy followed by radiotherapy should not be a standard approach for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 1998;40:889-96.
Nag S, Cardenes H, Chang S, Das IJ, Erickson B, Ibbott GS, et al
. Proposed guidelines for image-based intracavitary brachytherapy for cervical carcinoma: Report from image-guided brachytherapy working group. Int J Radiat Oncol Biol Phys 2004;60:1160-72.
Leborgne F, Leborgne JH, Doldán R, Zubizarreta E, Ortega B, Maisonneuve J, et al
. Induction chemotherapy and radiotherapy of advanced cancer of the cervix: A pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 1997;37:343-50.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al
. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Tierney J. Neoadjuvant Chemotherapy for Cervical Cancer Collaboration (NACCCMA): Neoadjuvant chemotherapy for locally advanced cervix cancer. Cochrane Database Syst Rev 2004:13.
Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, et al
. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358:781-6.
Pettersson F, editor. Annual Report on the Results of Treatment in Gynecological Cancer. Vol. 21. New York: FIGO; 1991.
Rydzewska L, Tierney J, Vale CL, Symonds PR. Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev 2010:CD007406.
Souhami L, Gil RA, Allan SE, Canary PC, Araújo CM, Pinto LH, et al
. A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. J Clin Oncol 1991;9:970-7.
Tattersall MH, Ramirez C, Coppleson M. A randomized trial comparing platinum-based chemotherapy followed by radiotherapy vs. radiotherapy alone in patients with locally advanced cervical cancer. Int J Gynecol Cancer 1992;2:244-51.
Mandic A. Neoadjuvant chemotherapy in treatment of cervical cancer-controversies. Arch Oncol 2005;13:89-90.
Sardi JE, Giaroli A, Sananes C, Ferreira M, Soderini A, Bermudez A, et al
. Long-term follow up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of cervix: The final results. Gynecol Oncol 1997;67:61-9.
Poveda A, Gonzalez-Martin A. Multimodality treatment in locoregional gynecological cancer: Cervical cancer treatment update. Ann Oncol 2008;19(Suppl 7):vii70-6.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]