|Year : 2018 | Volume
| Issue : 1 | Page : 12-18
A prospective randomised study on comparison of weekly versus 3 weekly cisplatin chemotherapy as an adjunct to radiotherapy in treatment of carcinoma of the uterine cervix
VL Anusha Konakalla1, Pranabandhu Das1, Jilla Swapna1, Amitabh Jena2, K Radhika3, B Sreenivasa Rao1, Jayasree Kuna1, KV Jagannathrao Naidu1, BV Subramanian1
1 Department of Radiation Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Surgical Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
3 Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
|Date of Web Publication||8-Jan-2019|
B V Subramanian
Associate Professor, Department of Radiation Oncology, Sri Venkateswara Institute of Medical Sciences, Tirupati - 517 507, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: The present study attempted to compare concurrent weekly and three weekly cisplatin with radiotherapy in locally advanced cervical cancer.
Methods: This prospective randomised study was conducted in 40 patients with locally advanced cervical cancer randomised into 2 arms. Arm A patients received external beam Radiotherapy (EBRT) to pelvis with concurrent weekly cisplatin at dose of 40 mg/m2 and arm B patients received EBRT to pelvis with concurrent cisplatin at dose of 75 mg/m2 three weekly followed by brachytherapy. Acute haematological, gastrointestinal (GI) and genitourinary toxicities and response rates were assessed.
Results: All the patient and disease characters were comparable in both arms. There was no significant difference in both arms in terms of upper GI toxicity (75% Vs 80%; P = 0.208), haematological (25% Vs 10%; P = 0.195) and nephrotoxicity (10% Vs 25%; P = 0.212). Compliance to chemoradiation was better in three weekly cisplatin arm but not statistically significant. After a median follow up of 12 months, tumor response rates in both arms were almost similar (85% Vs 90%; P = 0.128).
Conclusions: Our observations suggest that either concurrent weekly or three weekly cisplatin chemoradiation is equally effective in treatment of cervical cancer. However randomised trials with larger sample sizes and longer duration of follow up are required.
Keywords: 3 weekly cisplatin, concurrent chemoradiation, locally advanced cervical cancer
|How to cite this article:|
Anusha Konakalla V L, Das P, Swapna J, Jena A, Radhika K, Rao B S, Kuna J, Jagannathrao Naidu K V, Subramanian B V. A prospective randomised study on comparison of weekly versus 3 weekly cisplatin chemotherapy as an adjunct to radiotherapy in treatment of carcinoma of the uterine cervix. J Clin Sci Res 2018;7:12-8
|How to cite this URL:|
Anusha Konakalla V L, Das P, Swapna J, Jena A, Radhika K, Rao B S, Kuna J, Jagannathrao Naidu K V, Subramanian B V. A prospective randomised study on comparison of weekly versus 3 weekly cisplatin chemotherapy as an adjunct to radiotherapy in treatment of carcinoma of the uterine cervix. J Clin Sci Res [serial online] 2018 [cited 2019 Mar 22];7:12-8. Available from: http://www.jcsr.co.in/text.asp?2018/7/1/12/249626
| Introduction|| |
Uterine cervical cancer is the most common gynaecological malignancy worldwide and in India., Concurrent cisplatin-based chemoradiation (CRT) is the treatment of choice in locally advanced cervical cancer based on five randomised trials.,,,,, Most widely accepted CRT is weekly cisplatin at dose of 40 mg/m2. Several other trials,, used 3 weekly cisplatin 75–100 mg/m2 because of the ease of administration and better compliance which showed almost similar toxicity profile and clinical outcome compared to concurrent weekly cisplatin. This study was conducted to compare and evaluate the compliance, efficacy and toxicity profile of different dosing schedule of concurrent cisplatin, i.e., once in 3 weekly cisplatin (75 mg/m2) with weekly cisplatin (40 mg/m2).
| Material and Methods|| |
From March 2013 to August 2014, this prospective randomised study was carried out in histopathologically proven locally advanced carcinoma cervix patients. Forty patients were randomised by computer-generated random number tables to arm A (external beam radiotherapy (EBRT) + weekly cisplatin 40 mg/m2 followed by high-dose rate intracavitory brachytherapy (HDR ICBT) and arm B (EBRT + 3 weekly cisplatin 75 mg/m2 followed by HDR ICBT). The study was started after getting approval from the institutional ethics committee. Written informed consent was taken from the patients before the start of treatment.
The International Federation of Gynaecology and Obstetrics staging system was used to stage the patients. The study was conducted on patients meeting eligibility criteria: age ≤65 years, the Eastern Cooperative Oncology Group performance status 0–2, haematologic parameters ([haemoglobin (Hb) ≥10 g/dl, total white blood cell (WBC) count ≥4000/mm3 and platelets ≥100,000/mm3]) and renal function (calculated creatinine clearance ≥60 mL/min).
Radiotherapy was delivered by combination of EBRT and HDR ICBT. All patients were treated with Elekta Precise linear accelerator unit using 15 MV photons, EBRT. Patients were treated by four-field technique if the anteroposterior-posteroanterior (AP-PA) separation was >20 cm in the supine position. All patients were planned in the supine position. The superior border for the AP-PA field was kept at L4 to L5 interspace and inferior border at the inferior border of obturator foramen or lower depending on disease extension to the vagina to cover tumour with a margin of 2 cm. The lateral border was kept 2 cm from the lateral pelvic brim. For lateral fields, the superior and inferior borders were same as AP-PA field. The anterior border was kept just in front of the pubic symphysis, and the posterior border was set to cover the entire sacral hollow. Dose was delivered to the centre of field with isocentric technique.
Radiation was delivered by conventional fractionation to a total dose of 46–50 Gy at the rate of 2 Gy per fraction, 1 fraction per day and 5 fractions per week in 23–25 fractions over a period of 5–6 weeks.
HDR ICBT was performed using Varian GammaMedplus remote afterloading system with Ir192 isotope with a gap of 1 week in between subsequent fractions. The patient was assessed for ICBT fitness after completion of 15 fractions of EBRT. HDR brachytherapy was planned when the os was able to sound. Modified Fletcher suit applicator – central intrauterine tandem and paired ovoids or tandem and ring of different sizes were used according to individual patient's anatomy. Radiation was delivered by 600–800 cGy per fraction in 3–4 fractions to point A.
Cisplatin was given concurrently with EBRT once weekly (40 mg/m2) for a total of five cycles in arm A and once in 3 weeks (75 mg/m2) for a total of two cycles in arm B during the course of EBRT.
Pre-chemohydration was administered 500 ml of 0.9% saline (NS) over 1 h followed by prophylactic antiemetic medication with injection dexamethasone 16 mg intravenous (IV), injection palonosetron 0.25 mg IV and injection ranitidine 50 mg in 100 ml of 0.9% NS over half hour. Cisplatin 40 mg/m2 was given in 500 mL of 0.9% NS over 2 h in arm A patients. The total dose of cisplatin in arm B patients who received cisplatin 75 mg/m2 was calculated and given in 500 ml 0.9% NS over 2 h. It was followed by RT within 1 h after completion of the infusion.
Post-chemotherapy (CT) patients received 2 ampoules (300 mg) potassium chloride in 500 ml of 0.9% NS over 1 h followed by 2 ampoules of 50% w/v magnesium sulphate in 500 mL of 5% dextrose over 1 h. Post-chemohydration with 500 mL of 0.9% NS over 1 h was given.
In all the patients, peripheral venous blood samples were obtained after an overnight 8–12 h of fasting for blood investigations. For serum creatinine, 2 ml of whole blood was collected in a plain vial. For complete haemogram including erythrocyte sedimentation rate, 3 ml of whole blood was collected in a vial containing ethylenediaminetetraacetate as anticoagulant.
Serum creatinine was measured using autoanalyzer CX9 (Beckman Coulter, California, USA). The creatinine clearance was calculated using Cockcroft–Gault formula. Hb level, WBC count, differential WBC count and platelet count were measured using auto haematology analyser BC-5300 (Mindray, Shenzhen, China).
Serum sodium and serum potassium were measured using ion-selective electrode method using EPS 2000 electrolyte analyser. Serum calcium and serum magnesium were measured using timed endpoint method using autoanlayser CX9 (Beckman Coulter, California, USA).
All patients were examined weekly during their entire treatment course or earlier if the patient developed reactions. Acute haematological, gastrointestinal (GI) and genitourinary toxicities were assessed as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4 formulated by the NCI. Anti-emetics were given on the day of CT and for 2 days after CT. Any delay causing treatment interruption was noted, and appropriate gap corrections were done.
Dose-limiting toxicity was defined as Grade IV neutropenia, Grade IV thrombocytopenia, complicated Grade III haematologic toxicity (neutropenia with fever, thrombocytopenia with bleeding manifestation requiring platelet transfusion) and Grade III/IV non-haematological toxicity, other than nausea and vomiting.
Response assessment was done as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria. All responses were measured clinically. Responses to therapy were classified as complete, partial, stable or progressive.
All the patients were followed up for the first time, 6 weeks after completion of treatment. Patients were planned to follow-up every 1 month for first 3 months, every 3 monthly for 9 months then for every 4 months for 2 years. Follow-up procedures include general, systemic and pelvic examination, palpation of inguinal and supraclavicular nodes. Imaging studies, such as radiograph, computed tomography, ultrasonography and bone scan were done when required.
The information collected in pro forma was recorded in a master chart in MS Excel 2007 (Microsoft Corp, Redmond, WA). All the entries were double checked for any possible error.
Using this software, range, frequencies, percentages, means, standard deviations (SDs), Chi-square and 'P' values were calculated. All the descriptive statistical values were presented in the form of mean ± SD. Student independent 't' test was used to compare the means of different continuous variables. Pearson's Chi-square test was performed to assess the association among different categorical variables. P < 0.05 is taken to denote statistically significant relationship. Data analysis was performed with the help of computer using SPSS software version 20 ( IBM SPSS Statistics, Somers NY, USA).
| Results|| |
Patients (n = 120) with histopathologically diagnosed carcinoma of the cervix during the study period were screened for inclusion into the study. Of these, 60 were excluded from the study for several reasons: patients with early cervical cancer, metastatic disease at presentation, post-operative cases fit for adjuvant therapy, dual malignancies and recurrent cases. Sixty patients in locally advanced stages were eligible for concurrent CRT. Among these patients, 20 were not fit for CT due to several reasons such as old age, poor performance status, associated co-morbid conditions precluding administration of CT, pre-existing renal dysfunction and bilateral hydroureteronephrosis. The remaining of patients were recruited into the study, and were randomised into two arms with twenty patients each. Arm A patients received RT along with concurrent weekly cisplatin and arm B patients received RT along with concurrent 3 weekly cisplatin followed by HDR ICBT [Figure 1].
|Figure 1: Study plan *see text for details. CRT = Chemoradiation; FIGO = International Federation of Gynaecology and Obstetrics|
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All the patient and disease characteristics such as age, stage, size of tumour, uni or bilateral parametrial involvement were comparable in the both arms [Table 1].
Patients in the arm A received a mean dose of 50.5 mg per cycle, whereas patients in the arm B received a mean dose of 105.75 mg per cycle. The total cumulative dose in both the cycles was statistically similar with a mean of 230 mg in arm A versus 194 mg in arm B (P = 0.9) [Table 2]. Fourteen (70%) patients of arm A received five cycles of planned weekly cisplatin (40 mg/m2), five (25%) patients received four cycles and one (5%) patient received only 3 cycles. In arm B, 17 (85%) patients completely received planned two cycles of 3 weekly cisplatin (75 mg/m2) and three (15%) patients received only one cycle CT.
All patients were evaluated for different toxicities [Table 3] according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)version 4.0. There were no treatment-related deaths. No dose-limiting toxicities were recorded. Patterns of acute toxicities – haematological toxicity (anaemia, neutropenia and leucopenia), upper GI toxicity (nausea, vomiting), lower GI toxicity (diarrhoea) and nephrotoxicity and electrolyte imbalances were evaluated between two arms [Table 3].
The overall treatment time for both arms ranged from 35 to 62 days, with a mean of 46.85 days in arm A and 46.9 days in arm B. It was statistically similar in both arms [Table 4].
All the patients in the study were assessed for treatment response 6 weeks after the completion of treatment using RECIST criteria. Responses were assessed clinically; 17 (85%) patients of arm A, 19 (95%) patients of arm B had complete response and 3 patients of arm A and 1 of arm B had partial response (P = 0.195) after 6 weeks of completion of treatment [Table 5].
After a median follow-up of 12 months in arm A, 19 patients of arm A had complete response and 1 patient had progressive disease. After a median follow-up of 11.5 months in arm B, 1 patient in arm B lost to follow-up and 4 patients had progressive disease manifested as distant metastasis. Sites of progression are bone metastasis in two patients, two with supraclavicular lymph node recurrence.
Comparison of results of the present study with another study is shown in [Table 6].
|Table 6: Comparison of patient characteristics and toxicities of present study with Korean study|
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| Discussion|| |
In our country, most of the cervical cancers are being diagnosed in locally advanced or metastatic stages due to socioeconomic problems, illiteracy, lack of effective implementation of screening programmes, late presentation and irregular follow-up., After the NCI statement in 1992, concurrent CRT became the standard of choice for locally advanced carcinoma cervix.
CRT in all stages of carcinoma cervix either with platinum-based or non-platinum-based drugs improved 5-year overall survival (OS) by 6% and decreased the risk of death by 19%. There was no evidence to suggest that the benefit of CRT varied according to length of cycle and dose intensity of cisplatin but the benefit decreases with increasing stage of disease. Cisplatin in combination regimens did not gain popularity due to greater toxicities.,,
Weekly cisplatin provides radiosensitisation, by inhibiting potentially lethal and sublethal damage repair and smaller individual doses of cisplatin may lead to less CT-induced morbidity without compromising efficacy. Three weekly cisplatin is popular in head-and-neck cancers. It was assumed that tumour biology of squamous cell carcinoma of the cervix and head/neck is similar. High-dose CT may also help in preventing distant metastasis by neutralising occult micrometastasis apart from radiosensitisation.
In the present study, the planned RT treatment was completed in 100% of patients in both the arms. Scheduled five cycles of concurrent weekly cisplatin were completed by only of the 14 patients (70%) in arm A, and scheduled two cycles of concurrent 3 weekly cisplatin was completed by 17 (85%) patients in arm B. Most common reason for incomplete treatment was haematologic toxicity. One patient in arm B had treatment interruption. In a study comparing weekly versus triweekly cisplatin-based CRT, the two regimens were tolerated very well, with 86.3% and 92.5% completion of scheduled CT cycles for the weekly and triweekly arms, respectively. There was no statistically significant difference in compliance between the two arms (P > 0.05).
As per a study, 70% had incomplete treatment in the 3 weekly group and 15% in the weekly cisplatin group. This high rate of incomplete treatment was seen for the third cycle of CT. It was observed by patterns of care and survival study conducted by Indian Council Of Medical Research that better survival was seen in patients who received optimal RT and 150 mg or more of cisplatin and complications increase with increasing dose of cisplatin above 150 mg.
Acute toxicities, principally neutropenia and GI toxicities were more common with CRT but were transient. All patients were evaluated and graded for different toxicities according to NCI CTCAE.
There was no statistically significant difference between haematological toxicities in both arms (anaemia and leucopenia), and these toxicities were not described in Korean study. There was no statistically significant difference in neutropenia (25% vs. 10%, P = 0.195) in between the both arms. No Grade 3–4 toxicities were observed in this study. In a study, Grade 1–2 neutropenia was seen in 40% patients in both arms and Grade 3–4 neutropenia was seen in 39% patients in weekly cisplatin arm and 23% patients in 3 weekly cisplatin arm (P = 0.03). The lower percentage of neutropenia in this study may be due to less cumulative dose of cisplatin given to the patients/less number of cycles of cisplatin. Lee et al. compared weekly cisplatin and triweekly combination CT as concurrent adjuvant CRT in post-operative cases reported that the weekly cisplatin group showed the incidence of leucopenia in nearly 85% of the cases. Nearly 96% of the patients in triweekly group had leucopenia.
In this study, all patients had experienced nausea. Eight patients of arm A and six patients of arm B had Grade 1 vomiting. Five (25%) patients of arm A and 10 (50%) of arm B had Grade 2 vomiting (P = 0.208). Arm B patients had more vomiting than arm A patients, but there was no statistically significant difference. In one study, upper GI toxicity Grade 1–2 was seen in nearly 80% of the patients in both the weekly and 3 weekly arms [Table 6].
In the present study, 2 patients of arm A and 5 patients of arm B had Grade 1 nephrotoxicity (P = 0.212). More patients of arm B experienced nephrotoxicity. On comparison to Korean study, 8 (15.7%) patients of weekly cisplatin arm and 15 (28.3%) patients of 3 weekly cisplatin arm experienced Grade 1–2 nephrotoxicity which is comparable to this study.
Many analysis in squamous cell carcinoma of head and neck and cervix pointed that accelerated repopulation occurs after 4th week of the start of RT and this repopulation starts early in a fractionated RT. The mean duration of treatment should be below 8 weeks as suggested by the American Brachytherapy Society. Prolonged treatment time had an adverse effect on outcome because of accelerated repopulation of tumour. Any planned or unplanned interruptions or delays should be avoided.
The over all treatment period in this study for both arms ranged from 35 - 62 days, with a median of 46 days in arm A and 45 days in arm B. It was statistically similar in both arms. In the Korean study, treatment delay was observed in 2 patients in weekly arm and 1 patient in 3 weekly arm. The treatment delay was defined as delay of radiation period (56 days) by 1 week. In this study, 1 patient in each arm had treatment delay due to acute haematological and GI toxicity. Minor interruptions for 1–2 days resulted from acute treatment-related toxicities, the RT machine breakdown, patient and tumour-related factors and the gap between EBRT to first HDR ICBT and subsequent fractions of ICBT.
On assessment during the first follow-up, complete response was seen in 17 (85%) patients of arm A, 19 (95%) patients of arm B and three patients of arm A and 1 patient of arm B had partial response (P = 0.195). This study did not show any difference in terms of response between the two arms. According to Ryu et al., patients in the 3 weekly cisplatin arm fared better survival wise with 88.7% OS at 5 years versus 66.7% for the weekly cisplatin arm. The present study has fewer patients and short median follow-up of 12 months. Longer follow-up is required for survival comparison.
| Conclusion|| |
From the above findings, we can conclude that either concurrent weekly or 3 weekly cisplatin along with radiotherapy can be equally effective in the treatment of cervical cancer. However, further randomised trials with larger sample sizes and longer duration of follow-up are required to reach a consensus.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]