Effect of concurrent chemoradiation with cisplatin versus concurrent chemoradiation with carboplatin in locally advanced carcinoma cervix: A quasi-experimental study

Background: The standard approach for locally advanced cervical cancer is concurrent chemoradiation with platinum agents, preferably cisplatin. This study was aimed at comparing the treatment response and toxicity of carboplatin-based versus cisplatin-based concurrent chemoradiation in locally advanced carcinoma of the cervix.

In the case of locally advanced carcinoma cervix, the use of concurrent chemoradiation with carboplatin had a similar treatment response to cisplatin-based concurrent chemoradiation. Concurrent chemoradiation with carboplatin had less chance of anaemia, vomiting, and renal toxicity. Toxicities such as leucopenia, thrombocytopenia, nausea, hyponatremia, radiation-induced dermatitis, cystitis, proctitis, and diarrhea were similar between carboplatin and cisplatin-based concurrent chemoradiotherapy. 

Cervical carcinoma is the most common gynecological malignancy and is considered a major global health problem for women. It is the eighth most common cancer in the world, with an anticipated 6,04,127 cases and 3,41,831 deaths in 2020, according to the Global Cancer Observatory (GLOBOCAN) 2020 database. The incidences of cervical cancer are significantly higher in underdeveloped countries such as Sub-Saharan Africa and Southeast Asia [1]. In Bangladesh, according to the hospital cancer registry report (2018-2020), carcinoma cervix is the 2^nd most common malignancy among the female population of Bangladesh [2]. The three most prevalent histologies of cervical cancer are squamous cell carcinoma (SCC), adenocarcinoma (AC), and small cell neuroendocrine carcinoma. SCC accounts for approximately 80% and AC accounts for approximately 20% of all cervical cancers [3]. 

Asian countries exhibit a higher prevalence of locally advanced carcinoma cervix (LACC) [4]. According to a Bangladeshi study, the majority of these patients had stage IIB disease [5]. The treatment options for cervical cancer are composed of surgery, radiotherapy, and/or chemotherapy according to the stage and performance status of patients. Radiotherapy plays a vital role in the management of LACC. Both external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICRT) are used as radiotherapy. According to the National Comprehensive Cancer Network (NCCN) guideline, the recommended treatment choice for locally advanced carcinoma cervix is concurrent chemoradiation (CCRT), which includes pelvic external beam radiotherapy concurrent with platinum agents, preferably cisplatin, followed by intracavity brachytherapy [6]. Cisplatin-based CCRT is the preferred treatment option because of its established benefits in terms of overall survival and progression-free survival compared to radiotherapy alone [7, 8].

Cisplatin is a platinum complex that acts as DNA cross-linkers and reacts preferentially with N-7 guanine and blocks DNA replication, RNA transcription, and protein synthesis. Despite its proven benefit, cisplatin-induced toxicity such as nausea, vomiting, nephrotoxicity, and neurotoxicity are common, and a specific hydration policy is needed to be maintained during cisplatin administration. Carboplatin, on the other hand, is another platinum-based chemotherapy that has a similar mechanism of action as cisplatin. Compared to cisplatin, carboplatin rarely causes nephrotoxicity or severe nausea or vomiting; instead, its dose-limiting toxicity is myelosuppression, primarily thrombocytopenia [9]. In a Thai study, carboplatin showed equivalent outcomes to cisplatin in concurrent chemoradiation for locally advanced cervical cancer. Furthermore, carboplatin was associated with higher compliance and lower rates of anemia, neutropenia, and nephrotoxicity [10]. Therefore, carboplatin is often used instead of cisplatin in patients who are unable to tolerate cisplatin-related toxicity or the aggressive hydration that needs to be avoided. Since no previous study was carried out to compare the effectiveness of these two-platinum based anticancer drugs during concurrent chemoradiation of cervical cancer in our country's perspective, the present study may aid in optimising the concurrent chemoradiation schedule in cervical cancer in Bangladesh. The objective of the study was to compare the treatment response and toxicity of concurrent chemoradiation with carboplatin to concurrent chemoradiation with cisplatin in LACC.

Criteria for exclusion
Age below 20 and above 70 years old; other epithelial tumors of the cervix, including neuroendocrine tumors; patients with an Eastern Co-operative Oncology Group (ECOG) performance status of three or above; prior chemotherapy or pelvic radiation or surgery; uncontrolled concurrent medical condition; and pregnant or lactating patients were excluded.

The study was conducted from September 2022 to August 2023 at Bangabandhu Sheikh Mujib Medical University (BSMMU), Delta Hospital Limited, and Ahsania Mission Cancer and General Hospital in Dhaka, Bangladesh. At first, a total of 91 patients of LACC was assessed for eligibility. Seven patients were excluded as they did not meet selection criteria. Finally, following the application of inclusion and exclusion criteria, 84 patients were equally divided between two arms (42 patients in Arm A and 42 patients in Arm B) using purposive sampling (Figure 1). Two patients from each arm were either dropped or lost to follow up.  Finally, 40 participants in  each arm were analysed. 

Patients of Arm A were treated by concurrent chemoradiation (CCRT) with weekly cisplatin at a dose of 40 mg/m² intravenously. Patients of Arm B were treated by concurrent chemoradiation (CCRT) with weekly carboplatin intravenously at a dose of Area Under the Curve (AUC) equal to 2 using the Calvert formula. As a part of CCRT, all patients received pelvic radiotherapy to the primary tumor and pelvic lymph nodes at a total dose of 50 Gy in 25 fractions by the three-dimensional conformal radiation therapy technique.  After pelvic radiation with EBRT, all the patients of both arms were treated with ICRT. Three insertions (one insertion per week) of ICRT and 7 Gy for each insertion were given. 

In this study, outcome variables are treatment responses and acute toxicities. Patients of both arms were assessed weekly during CCRT, starting from the onset of radiotherapy. Response evaluation was done during and after treatment. The final responses were documented 3 months after completion of all therapy. To assess the tumor response to the radiotherapy treatment, Response Evaluation Criteria in Solid Tumors (RECIST) were followed [13]. According to RECIST criteria, if there is complete disappearance of all target lesions, it is mentioned as complete response (CR), if there is 30% or more reduction of size of all target lesions it is mentioned as partial response (PR), 20% or more increase size of target lesions is mentioned as progressive disease (PD) and finding in-between PR and PD is stated as stable disease (SD).  Acute and late hematological toxicities (both hematological and non-hematological), if present, were recorded using toxicity criteria of the radiation therapy oncology group [14]. To gather information, a data collection sheet was employed. 

According to the International Federation of Gynecology and Obstetrics (FIGO), LACC is defined as stages IIB–IVA, which is assessed by clinical examination, imaging and pathological findings.

The mean (standard deviation) of age of the 80 participants in both arms was 51.5 (9.1) years. In Arm A, the mean age was 52 (8.8) years, while in Arm B, the mean age was 50.9 (9.4) years. Nearly two-thirds of all participants (77.5%) had an ECOG performance status score of 0. The majority of the patients in both arms were at stage IIB, with 57.5% in Arm A and 52.5% in Arm B. The vast majority of the patients in both arms were diagnosed with squamous cell carcinoma: 92.5% and 90% for Arms A and B, respectively. Most of the patients in both arms had the histology of a moderately differentiated tumor (77.5% and 72.5% in Arms A and B, respectively) majority of the patients in both arms were diagnosed with squamous cell carcinoma: 92.5% and 90% for Arms A and B, respectively. Most of the patients in both arms had the histology of a moderately differentiated tumor (77.5% and 72.5% in Arms A and B, respectively) (Table 1).

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We would like to thank all of the medical and radiation oncologists at Delta Hospital Limited and Ahsania Mission Cancer and General Hospital, as well as the patients who took part in this study. 

Conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: SMAH, MAB, UKS, MR, NKS, MJU. Drafting the work or reviewing it critically for important intellectual content: SMAH, MAB, UKS, MR, NKS, MJU. Final approval of the version to be published: SMAH, MAB, UKS, MR, NKS, MJU. Accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: SMAH.