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Year : 2018  |  Volume : 55  |  Issue : 2  |  Page : 123--124

Carcinoma cervix – No role for surgery in stages IB2-IIB?

Prasanth Ganesan 
 Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Correspondence Address:
Dr. Prasanth Ganesan
Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
India




How to cite this article:
Ganesan P. Carcinoma cervix – No role for surgery in stages IB2-IIB?.Indian J Cancer 2018;55:123-124


How to cite this URL:
Ganesan P. Carcinoma cervix – No role for surgery in stages IB2-IIB?. Indian J Cancer [serial online] 2018 [cited 2019 Jan 22 ];55:123-124
Available from: http://www.indianjcancer.com/text.asp?2018/55/2/123/249204


Full Text



Cancer of the uterine cervix continues to be among the commonest cancers affecting women in India and many other low- and middle-income countries. India alone is believed to contribute about one-quarter of the world's cervix cancer deaths.[1] Most patients present in advanced stages where surgery is not feasible, and concurrent chemotherapy has been established as standard therapy. For those with early disease (stages IA and IB1), primary surgery is the preferred option.[2] However, a significant proportion of women present in stages IB2 (>4 cm, confined to cervix), IIA (involving vagina upper one-third), and IIB (involvement of parametrium short of pelvic wall), where both surgery as well as radiation can be considered as definitive options.[2] The advantage of primary surgery is that it may have lesser adverse impact on the bladder, rectum, and sexual function, especially in the long term. Moreover, multiple studies have shown that when chemotherapy is added to surgery, it is superior to radiation alone in terms of disease control.[3] One of the drawbacks of surgery is that nearly half the patients need additional radiation (±chemotherapy) therapy (because of high-risk features). Thus, it was not known whether neoadjuvant chemotherapy (NACT) followed by surgery (NACT-S) would be superior to concurrent chemoradiation (CRT) in IB2–IIB cervical cancer. Only a randomized trial could answer this question and one such trial, conducted at the Tata Memorial Hospital in Mumbai, was recently reported by Gupta et al.[4]

In this study involving 633 women with stages IB2, IIA, and IIB cervical cancer, the investigators hypothesized that NACT (three cycles of paclitaxel and carboplatin) followed by radical hysterectomy would be superior to chemotherapy (weekly cisplatin for 5 weeks) concurrently administered with standard radiotherapy (40 Gray external beam followed by intracavitary application to a total of 80–90 Gray at point A). Patients in the NACT-S were allowed to switch to CRT in case of inoperability or progression during/after NACT. The 5-year disease-free survival (DFS) was better in the CRT arm (76% vs. 69%; P = 0.038); a superiority which persisted in multivariate analysis after adjusting for standard factors like age and stage. Though the short-term toxicities were similar, the long-term toxicities to the bladder, rectum, and sexual function – at least in the first 2 years – was lesser in the NACT-S arm. Vaginal toxicities with NACT-S was half of that seen with CRT (19% vs. 39%).

Though the trial established that CRT should be the standard of care for IB2–IIB carcinoma cervix, a few interesting subanalyses must be considered. One, CRT was not superior when DFS was recalculated after including death as an event (72% vs. 67%; P = 0.086) and overall survival was similar (75% at 5 years in both groups). Was this because of increased deaths due to “other causes” in CRT arm? Or were the relapses in the surgical arm predominantly local which could be salvaged with radiation? Two, post-hoc analyses did not show a superiority of CRT over NACT-S for stages IB2 and IIA and only stage IIB benefited from CRT. Could NACT-S be still considered as an option for stages IB2 and IIA? There are many centers in the country and in many parts of the world where there is limited access to radiation therapy. Can these places practice chemotherapy followed by surgery, at least for stages IB2 and stages IIA disease? This interpretation, however, must be tempered with the caveat that it was not part of the primary aim of this study but was derived after post-hoc analysis. Moreover, nearly half of the patients in the NACT-S arm ended up receiving additional radiation. This included about 21% patients in the neoadjuvant group who crossed over to CRT due to inoperability and an additional 23% who required postoperative therapy (CRT 13% and radiation 10%) due to high-risk features in the post-op specimen. Since quality of life was not part of the study, the exact patient-level impact of long-term toxicities, especially sexual function (median age was only 50 years), is difficult to judge from this study.

Despite the questions that remain, the authors of this paper must be complimented on the fantastic effort in completing such a large study. Awareness about clinical trials is low in India and patient consenting is a challenging process. Even in this trial, of the 1,078 potentially eligible patients, over 30% of the eligible population declined consent or were considered unreliable for follow up. There are multiple social and treatment adherence issues in treating patients from low socioeconomic strata who represent the majority of patients with cervical cancer in large governmental hospitals. Despite these, the investigators in this study achieved high rates of protocol adherence, as well as treatment completion.

The only other study (The multicenter, EORTC 559944) asking a similar question (comparing NACT-S with CRT in stages IB2–IIB carcinoma cervix) had a similar proportion of patients with stage IIB disease (56% vs. 57%) and same rates of operability after NACT (76% vs. 72%) in a preliminary analysis.[5] The long-term efficacy data from EORTC 559944 are expected only in 2019. Unless that trial shows a different result, at this point, the strong evidence from Gupta et al. suggests that CRT should be the therapy of choice for all women with stages IB2–IIB cervical cancer. Whether a select patient with IB2–IIA disease can be treated with NACT-S? This might include women with keen interest in preserving sexual function as well as hospitals without access to radiation services. Only a separate phase III trial including patients exclusively in stages IB2 and IIA can conclusively answer the specific question. Based on the results of this study; however, it is unlikely that the efficacy of surgical approach would be superior in terms of disease control to CRT. Hence, the trial would have to be powered for noninferiority with the assumption that toxicities may be lesser. This kind of a study would need very large number of patients and the logistics of conducting such a study would be quite formidable, if not impossible.

References

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2Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N, et al. Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv72-83.
3Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy for locally advanced cervical cancer: A systematic review and meta-analysis of individual patient data from 21 randomised trials. Eur J Cancer 2003;39:2470-86.
4Gupta S, Maheshwari A, Parab P, Mahantshetty U, Hawaldar R, Sastri Chopra S, et al. Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: A Randomized controlled trial. J Clin Oncol 2018;36:1548-55.
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