Year : 2014 | Volume
: 10 | Issue : 2 | Page : 227--228
Concurrent chemoradiation for carcinoma of cervix: What lies beyond?
Ajeet Kumar Gandhi, Daya Nand Sharma, Goura Kishor Rath
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
Goura Kishor Rath
Room Number 238, Drbrairch, All India Institute of Medical Sciences, Ansari Nagar - 110 029, New Delhi
|How to cite this article:|
Gandhi AK, Sharma DN, Rath GK. Concurrent chemoradiation for carcinoma of cervix: What lies beyond?.J Can Res Ther 2014;10:227-228
|How to cite this URL:|
Gandhi AK, Sharma DN, Rath GK. Concurrent chemoradiation for carcinoma of cervix: What lies beyond?. J Can Res Ther [serial online] 2014 [cited 2020 Nov 24 ];10:227-228
Available from: https://www.cancerjournal.net/text.asp?2014/10/2/227/136537
Carcinoma of uterine cervix is the second most common malignancy among women in India as per the latest GLOBOCAN 2012 report.  Around 1.22 lakh new cases are diagnosed every year and more than 50% of the cases succumb to the disease  . With 60-80% of the cases presenting in locally advanced stage, , management of the carcinoma cervix remains challenging in Indian scenario.
The treatment of carcinoma cervix has witnessed major changes over the past few decades. From radium therapy alone in 1920s-1950s to combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) in 1950s-1970s and finally to concurrent chemoradiation (CCRT) in 1990s. Backed up with the results of five major randomized control trials, which showed an improvement in survival of around 10% with the use of CCRT, the National Cancer Institute (NCI) issued a clinical alert to establish CCRT as the standard treatment for carcinoma cervix. The alert led to rapid uptake of concurrent chemotherapy for carcinoma cervix patients treated with curative radiation. Barbera et al.,  showed in their study of 1039 patients that the use of CCRT surged from 9.4% to 67.4% abruptly after the NCI alert. Despite the increase in survival, we have reached a plateau in the last two decades. The five-year survival for locally advanced carcinoma cervix has remained static at 50-60% and this too comes at a cost of increased toxicities. Grade 3-4 hematological  toxicity is seen in >20-30% of patients and Grade 3-4 gastrointestinal (GI) toxicity  is also seen in >20% of the patients treated with CCRT. Presently, we are facing the dual challenge of increasing survival as well as reducing overwhelming toxicities of the treatment.
Several attempts have been made to modify or intensify existing CCRT protocols in an attempt to improve survival or decrease toxicity. Three weekly schedule of concurrent cisplatin versus weekly cisplatin,  concurrent intra-arterial infusion of platinum  and concurrent carboplatin with radiation  have all failed to yield any advantage. Phase III clinical trials , evaluating concurrent cisplatin plus 5-fluorouracil versus cisplatin alone showed that cisplatin weekly is less toxic and equally effective as compared to the combination regimen. Encouraging results have been seen with the concurrent use of nedaplatin (a synthetic analog of cisplatin) with radiotherapy. In a phase II multicentre trial  of 45 patients treated with concurrent nedaplatin, grade 4 hematological toxicity was seen in 6.7% of cases and grade 3 GI toxicity was seen in only 4.4% of patients. However, this drug needs to be compared in a phase III trial with standard weekly cisplatin. One approach which has shown improvement in survival in the last two decade was tested in a prospective, phase III, multicentre randomized trial. In this study by Dueρas-Gonzαlez et al. , 515 patients (stage IIB-IVA) were randomized to receive cisplatin 40 mg/m 2 and gemcitabine 125 mg/m 2 week ly for 6 weeks with concurrent EBRT followed by ICBT and then two adjuvant 21-day cycles of cisplatin, 50 mg/m 2 on day 1, plus gemcitabine, 1 gm/m 2 on days 1 and 8 versus standard treatment of weekly cisplatin and concurrent EBRT followed by ICBT. Concurrent gemcitabine plus cisplatin arm was superior for overall PFS (log-rank P = 0.0227; HR, 0.68; 95% CI, 0.49 to 0.95) as well as OS (log-rank P = 0.0224; HR, 0.68; 95%CI, 0.49 to 0.95). However, this came at the cost of overwhelming increase in toxicity including three treatment related deaths. Grade 3-4 hematological toxicity was predominant in experimental arm (71.9% versus 23.9%) as was grade 3-4 non-hematological toxicity (P = 0.002). One positive outcome of the study is that we have now at least an intervention (concurrent gemcitabine + cisplatin), which has shown improved survival as compared with conventional cisplatin based concurrent chemoradiation and we just need to tackle the increased toxicities.
Radiation technology over the period of time has also evolved and we have moved from 2-field to 4-field radiation treatment to conformal therapy in carcinoma cervix. Dosimetric studies have shown that intensity modulated radiation therapy (IMRT) can reduce bowel, rectal, bladder, and bone marrow dose and early clinical studies have demonstrated lower rates of GI, genitourinary, and hematologic toxicity compared with conventional techniques. The results have been also now validated by a prospective randomized trial by Gandhi et al. In this study, patients treated with IMRT had significantly lesser grade 3 acute gastrointestinal toxicity (4.5% versus 27.3%). A multicentric study  evaluating IMRT versus conventional concurrent chemoradiation is also currently recruiting and results are eagerly awaited. It now seems promising to combine the conformal delivery of radiation with IMRT to intensified regimen of gemcitabine plus cisplatin based concurrent chemoradiation for the best optimization of therapeutic ratio. This urgently needs to be tested in a phase III trial and would be definitely worthwhile.
In further quest for improving outcome, biological agents are being tested concurrently with radiation. Bevacizumab in combination with concurrent cisplatin and radiotherapy was evaluated in a phase II study by Schefter et al. and found to be feasible and safe with respect to protocol specified treatment related adverse effects. Nogueira-Rodrigues et al. in a phase I trial showed the feasibility of concurrent erlotinib combined with cisplatin and radiotherapy and defined the maximum tolerated dose of erlotinib as 150 mg daily with radiation. Moore et al. demonstrated the feasibility of combining concomitant cetuximab with cisplatin and radiotherapy. These studies are initial attempts with encouraging results in the concomitant molecular targeting for carcinoma cervix and more convincing results from phase II--III trials are needed before it comes into a routine practice.
The recent advances in intensified CCRT protocols, conformal delivery of radiation therapy and molecular targeting with concomitant radiation has opened avenues for newer areas of research and an urgent need for phase III clinical trials to test these hypothesis. The results are promising and in the near future, we are hopefully going to come out of the plateau of survival in the management of carcinoma cervix.
|1||Globocan 2012 Cancer statistics. Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx [Last accessed on 2014 May 10].|
|2||Shrivastava S, Mahantshetty U, Engineer R, Tongaonkar H, Kulkarni J, Dinshaw K. Treatment and outcome in cancer cervix patients treated between 1979 and 1994: A single institutional experience. J Cancer Res Ther 2013;9:672-9.|
|3||Azad SK, Choudhary V. Treatment results of radical radiotherapy of carcinoma uterine cervix using external beam radiotherapy and high dose rate intracavitary radiotherapy. J Can Res Ther 2010;6:482-6.|
|4||Barbera L, Paszat L, Thomas G, Covens A, Fyles A, Elit L, et al. The rapid uptake of concurrent chemotherapy for cervix cancer patients treated with curative radiation. Int J Radiat Oncol Biol Phys 2006;64:1389-94.|
|5||Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol 2003;68:217-26.|
|6||Einstein MH, Novetsky AP, Garg M, Hailpern SM, Huang GS, Glueck A, et al. Survival and toxicity differences between 5-day and weekly cisplatin in patients with locally advanced cervical cancer. Cancer 2007;109:48-53.|
|7||Onishi H, Yamaguchi M, Kuriyama K, Tsukamoto T, Ishigame K, Ichikawa T, et al. Effect of concurrent intra-arterial infusion of platinum drugs for patients with stage III or IV uterine cervical cancer treated with radical radiation therapy. Cancer J Sci Am 2000;6:40-5.|
|8||Cetina L, Garcia-Arias A, Uribe Mde J, Candelaria M, Rivera L, Oñate-Ocaña L, et al. Concurrent chemoradiation with carboplatin for elderly, diabetic and hypertensive patients with locally advanced cervical cancer. Eur J Gynaecol Oncol 2008;29:608-12.|
|9||Kim YS, Shin SS, Nam JH, Kim YT, Kim YM, Kim JH, et al. Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer. Gynecol Oncol 2008;108:195-200.|
|10||Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3 rd , Moore DH, et al. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: A gynecologic oncology group study. J Clin Oncol 2005;23:8289-95.|
|11||Yokoyama Y, Takano T, Nakahara K, Shoji T, Sato H, Yamada H, et al. A phase II multicenter trial of concurrent chemoradiotherapy with weekly nedaplatin in advanced uterine cervical carcinoma: Tohoku Gynecologic Cancer Unit Study. Oncol Rep 2008;19:1551-6.|
|12||Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 2011;29:1678-85.|
|13||Gandhi AK, Sharma DN, Rath GK, Julka PK, Subramani V, Sharma S, et al. Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: A prospective randomized study. Int J Radiat Oncol Biol Phys 2013;87:542-8.|
|14||Phase II/III clinical trial of Intensity modulated radiation therapy with concurrent cisplatin for stage I-IVA cervical carcinoma. Available from: http://clinicaltrials.gov/show/NCT01554397 [Last accessed on 2014 May 11].|
|15||Schefter TE, Winter K, Kwon JS, Stuhr K, Balaraj K, Yaremko BP, et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: Preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys 2012;83:1179-84.|
|16||Nogueira-Rodrigues A, do Carmo CC, Viegas C, Erlich F, Camisão C, Fontão K, et al. Phase I trial of erlotinib combined with cisplatin and radiotherapy for patients with locally advanced cervical squamous cell cancer. Clin Cancer Res 2008;14:6324-9.|
|17||Moore KN, Sill MW, Miller DS, McCourt C, De Geest K, Rose PG, et al. A phase I trial of tailored radiation therapy with concomitant cetuximab and cisplatin in the treatment of patients with cervical cancer: A gynecologic oncology group study. Gynecol Oncol 2012;127:456-61.|