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ORIGINAL ARTICLE
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Concurrent chemotherapy with high-dose rate brachytherapy after treatment with chemoradiotherapy in cases of locally advanced carcinoma cervix: A study from rural area of Maharashtra, India


1 Department of Radiation Oncology, Rural Medical College, PIMS, Ahmednagar, Maharashtra, India
2 Department of Radiotherapy and Oncology, Rural Medical College, PIMS, Ahmednagar, Maharashtra, India
3 Department of Microbiology, Rural Medical College, PIMS, Ahmednagar, Maharashtra, India

Date of Submission22-Apr-2020
Date of Decision01-Jul-2020
Date of Acceptance10-Sep-2020
Date of Web Publication18-Aug-2021

Correspondence Address:
Vandana Shailendra Jain,
Department of Radiation Oncology, Rural Medical College, PIMS, Loni, Ahmednagar - 413 736, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_507_20

 > Abstract 


Aim: This study aims to evaluate the efficacy, feasibility, tolerability, and toxicity of concurrent chemotherapy and brachytherapy for locally advanced cervical carcinoma.
Materials and Methods: Forty patients of cervical carcinoma were included in this study. The study period ranges from October 2016 to September 2019. Patients were evaluated and treated as per the protocol: external beam radiotherapy (50 Gy in 25 fractions) and concurrent weekly chemotherapy with injection (Inj.) cisplatin (30 mg/m2) followed by high-dose rate brachytherapy (3 fractions of 7 Gy each) and concurrent chemotherapy Inj. cisplatin (30 mg/m2).
Results: Out of 40 patients enrolled in the study, 36 patients completed the treatment (17 Stage II and 19 Stage III). The incidence of Grade I and II skin toxicities were 78% and 10%, respectively. The incidence of genitourinary toxicities with respect to Grade I and II were 72% and 12%, respectively. There were Grade III hematological toxicities in two patients and the brachytherapy treatment was delayed for 4–6 days. The overall complete response was found in 28 (78%) patients, partial response in six (16.7%) patients, and progressive disease in two (5.6%) patients at 3 months of follow-up. On the last follow-up, 21 (58%) patients were disease-free and there was disease failure in seven patients (5 local recurrence and 2 with distant metastasis).
Conclusion: Brachytherapy with the addition of concurrent chemotherapy is effective and feasible with acceptable toxicity for advanced stages of carcinoma cervix. This study upholds an interesting approach that can be regarded as feasible and tolerable for cervical cancer patients.

Keywords: Brachytherapy, carcinoma cervix, concurrent chemotherapy



How to cite this URL:
Jain VS, Virkar M, Sarje MB, Waghmare CM, Patel S, Jain SM. Concurrent chemotherapy with high-dose rate brachytherapy after treatment with chemoradiotherapy in cases of locally advanced carcinoma cervix: A study from rural area of Maharashtra, India. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=324035




 > Introduction Top


In India, carcinoma cervix is the most common cancer among the rural population and in some metro cities.[1],[2] Worldwide, cervical cancer ranks as the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women as per the GLOBOCAN 2018.[3] Surgery or radiotherapy as a single modality gives good results in early stage (Stage I), and combined modality approach chemotherapy concurrently with radiotherapy is the treatment of choice in the management of advanced-stage carcinoma cervix disease.

According to the published literature, approximately half of the locally advanced disease fails in locoregional area.[4],[5] This is attributable to the presence of bulk of the primary lesion with its attendant increase in the hypoxic cells, poor geometry, impaired blood supply, and increase in growth fraction, thereby resulting in poor radiation response.[6] Standard treatment regimen for such cases has remained external beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy wherever possible.[7] Cure is interlinked with radiation dose escalation to improve local control, but limitations are the tolerance of the surrounding critical organs.[8],[9],[10],[11],[12] To achieve good local response, the radiation dose can be escalated to some extent, but the addition of concurrent chemotherapy to brachytherapy following concurrent chemoradiation is the new concept and has not been much evaluated.[13]

The purpose of this study was to evaluate the efficacy, feasibility, tolerability, and toxicity of concurrent chemotherapy and brachytherapy in locally advanced cervical carcinoma (LACC) patients who are already treated with concurrent chemoradiation to pelvis with the objective to quantify the disease response in terms of locoregional control and disease-free survival.


 > Materials and Methods Top


This descriptive longitudinal study was conducted in the department of radiation oncology in the institute situated in the rural area of Maharashtra, India, after taking the institutional ethics committee permission. The study was planned for 40 cases only; once this number was achieved, the routine department protocol for the carcinoma cervix treatment was continued. As per the study design, 40 patients of diagnosed carcinoma cervix (Stage II and III), who satisfied the inclusion criteria (“histopathologically proven, *carcinoma cervix cases of International Federation of Gynaecology and Obstetrics [FIGO] Stage II and III, *age below 70 years, and *normal hematological and biochemical functions) and were ready to give consent, were included in this study. The study period ranges from October 2016 to September 2019 including follow-up. Patients with prior treatment (surgery, chemotherapy, and radiotherapy) were excluded from the study. Patients were evaluated clinically by history, general, systemic, and local examination. Relevant hematological and radiological investigations were done. All patients were given treatment as per the protocol, EBRT by three-dimensional conformal radiotherapy, 200 cGy per fraction per day, 5 days in a week to a total dose of 5000 cGy over 5 weeks duration on Linear Accelerator (Varian DBX 6 MV) by Antero-Posterior/four field box technique along with concurrent weekly five courses of chemotherapy with injection (Inj.) cisplatin (30 mg/m2). After a week gap of completion of EBRT, the patients were planned for high-dose rate (HDR) intracavitary brachytherapy (ICRT), 3 fractions of 7 Gy each to point “A” at weekly interval and weekly concurrent chemotherapy with Inj. cisplatin (30 mg/m2) given 1 day before intracavitary application. As the procedure, planning and dose delivery all were done in brachytherapy room, and simultaneous administration of chemotherapy at the same time was not possible; thus, study planned for chemotherapy 1 day before ICRT.[6] The dose of Inj. cisplatin 30 mg/m2 was chosen so that the weekly dose of Inj. cisplatin will be 40–50 mg. As per the departmental protocol for carcinoma cervix cases, the dose of Inj. cisplatin on a weekly basis was kept below 50 mg, as more than 50 mg dose along with pelvic radiotherapy gives more gastrointestinal (GI) toxicities and more treatment interruptions. Complete hematological and biochemical evaluation was done before each chemotherapy. Blood transfusions were given as and when required to maintain the hemoglobin level at 10 g%. Inj. filgrastim support was given for low white blood cell counts when required.

After completion of the treatment, response evaluation was documented with clinical, hematological, and radiological evaluation at 6 weeks, 3rd, and 6th month and there after every 3–4 monthly follow-up till the last follow-up in September 2019. The prognostic outcome of each patient was assessed using the Response Assessment Criteria in Solid Tumors (RECIST) version 1.1 for the disease-free survival, locoregional control for the complete or partial response, and disease failure for locoregional recurrence/distant metastases. Acute toxicities were assessed weekly during EBRT, ICRT, and again on the first follow-up after 6 weeks. Late toxicities were assessed till the last follow-up. Acute and late toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and Radiation Therapy Oncology Group (RTOG) Toxicity criteria. During the treatment, patients were reviewed weekly for acute radiation as well as chemotherapy-induced toxicities.

All the data collected were compiled, and statistical analysis was done by simple statistical techniques using mean, standard deviation, median, range, and proportion/percentage.


 > Results Top


A total of forty patients were enrolled in the study with appropriate inclusion and exclusion criteria in the department of radiation oncology. Various parameters assessed are mentioned in [Table 1]. The median age of the patients was 54 years (range 36–69 years). The patients were assessed and staged as per the FIGO staging for cervical cancer. There were 19 patients from Stage II and 21 from Stage III. The most common histopathology was squamous cell carcinoma in 37 cases, followed by adenosquamous in two and adenocarcinoma in one. Median overall treatment time was 56 days (range 54–67 days). Thirty-six patients completed treatment (17 Stage II and 19 Stage III). Two patients defaulted treatment during EBRT, one patient did not report for ICRT, and one defaulted for the third fraction of ICRT (all four defaulted cases we called, two said inability to come due to family issues, and one reported after long gap, and one patient was not ready to come). Hemoglobin, complete blood count, and renal functions were assessed pretreatment, before each weekly chemotherapy, and before every brachytherapy application. Blood transfusions were given as and when required to maintain the hemoglobin level at 10 g%. After completion of treatment on the first follow-up after 6 weeks, 27 patients had complete disease response (13 Stage II and 14 Stage III), while three and four patients had residual disease from Stage II and III, respectively. Two patients were with progressive disease, one–one each from Stage II and III. One patient with partial response of Stage II had complete response on the second follow-up at 3 months. Both the progressive disease patients expired within 6 months of treatment completion. On the last follow-up (24–36 months), there were five local recurrences (two and three patients from Stage II and III, respectively) and two distant metastases (one patient with bone after 12 months and one with lung after 24 months) noted. The response to treatment on the first 6 months and till the last follow-up (24–36 months) is shown in [Table 2] and [Chart 1].
Table 1: Patient data

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Table 2: Treatment response till last follow-up (24-36 months): Total patients for evaluation = 36

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The patients were assessed for toxicities associated with treatment as per the CTCAE and RTOG toxicity grading every week. There were no significant acute and chronic upper and lower GI toxicities noted and the chemotherapy-induced nausea vomiting was manageable with antiemetics. The incidence of genitourinary toxicities with respect to Grade I and II was 72% and 12%, respectively. The incidence of Grade I and II skin toxicities was 78% and 10%, respectively. There were significant chronic lower GI toxicities in the form of proctitis in three patients (8%) managed with symptomatic treatment. One patient (3%) with progressive disease had severe hydronephrosis and managed by percutaneous nephrostomy. Details of acute and chronic toxicities are shown in [Table 3] and [Table 4]. There were significant hematological toxicities noted in two patients (total leukocyte count was below 2000/cc) and the ICRT treatment was delayed for 4–6 days and filgrastim support was given. Details of the hematological toxicities are shown in [Table 5].
Table 3: Acute toxicities (total cases 36)

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Table 4: Late toxicities

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Table 5: Hematological toxicities as per Common Terminology Criteria for Adverse Event grading (Version - 4.0)

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 > Discussion Top


External radiotherapy and ICRT are the standard treatment modalities in advanced stage of cervical carcinoma. In recent years, concurrent chemotherapy with external radiotherapy has improved the treatment outcome in advanced uterine cervical cancer and known as the standard choice of care.[14],[15] Cisplatin is considered as the most effective single agent as a systemic therapy in eradicating micro-metastasis and moreover as a radiosensitizer in uterine cervical carcinoma.[16],[17] Cisplatin, when simultaneously administered with radiotherapy, has radiosensitivity effect by the inhibition of DNA synthesis, inhibition of transcription elongation by DNA interstrand cross-links, and inhibition of repair of radiation-induced DNA damage and increases the sensitivity of hypoxic cells and cell death.[18],[19] Meta-analysis of five randomized trial report published in February 1999 shows that concurrent chemoradiation with cisplatin a dose of 40 mg/m2 on a weekly basis is standard of care in LACC. In our study, dose of cisplatin was 30 mg/m2 weekly which is little lower side because review of reports shows that only 67% of the patients could complete six cycles of planned chemotherapy due to acute toxicity of chemotherapy.[20] Punushapai et al. found in their study that concurrent chemoradiotherapy with weekly cisplatin 40 mg/m2 in locally advanced cervical cancer gives good treatment outcomes.[21] When reducing the cisplatin dose to 20 mg/m2, treatment responses were still comparable to the standard, but acute toxicity could be reduced. The 40 mg/m2 group showed unplanned interruptions in 13/70 (18.6%), which was significantly different from the 5/70 (7.1%) in the 20 mg/m2 group (P = 0.02), resulting in prolonged treatment time (P = 0.026). Complete responses were found in 69/70 (98.6%) and 68/70 (97.1%), respectively, with no significant difference. Acute toxicities in the first group was significantly higher when compared to the second group (P < 0.05) as follows: Grade 1–2 leukopenia (14.8% vs. 6.4%), Grade 1–2 neutropenia (9.3% vs. 2.6%), Grade 2 N/V (3.8% vs. 1%), Grade 2 diarrhea (2.4% vs. 0.7%), and Grade 1 sensory neuropathy (4.5% vs. 1.2%).[20] As per the American Brachytherapy Society Guidelines, total radiation dose (external + brachy) in early-stage cases was 80–85 Gy and in advanced-stage cases was 85–90 Gy of low dose-rate (LDR) equivalents.[14] About 40% of total tumor dose is delivered by ICRT in the cervical and parametrial region with dose to the rectum and bladder within limits, achieved by computerized accurate treatment planning. It is a logical concept to expect that the best time to apply chemotherapy during the course of radiotherapy will be during the brachytherapy insertions. There are two reasons for this assumption: The dose of radiation applied during one brachytherapy insertion is much higher than external radiation; due to that difference, we can expect that the effects of the combination of brachytherapy and chemotherapy are substantially greater than either of both, and the second reason is that the dose rate of brachytherapy is decreasing by inverse-square law and thus potentially results in less toxicity to surrounding normal tissues.[22]

There are limited data on the concurrent use of chemotherapy and ICRT in uterine cervical carcinoma. The pilot study in 1998 by Koumantakis et al. was done to cause downstaging of the tumor to render it operable with the hope to improve the prognosis for locally advanced carcinoma of cervix.[23] Thirty-six cases with Stage IIA/B-IIIA cervical cancers were treated with concurrent platinum chemotherapy (cisplatin or carboplatin) and medium-dose rate (MDR)-ICRT. The dose to the point “A” was 20–25 Gy of two applications at weekly interval with simultaneous continuous platinum infusion (Inj. cisplatin 50 mg/m2 and Inj. carboplatin 300 mg/m2). Radical hysterectomy and pelvic lymphadenectomy were performed in 31 patients after MDR-ICRT and concurrent chemotherapy; 83% had pathologic complete response. The most common acute effects were hematological toxicities as Grade 3, 4 thrombocytopenia in 2 cases and Grade 1, 2 anemia and leukopenia in three patients. Local abdominal pain and Grade 1, 2 cystitis were noted in six patients. There was no renal dysfunction. In aforementioned study, the patients had surgery by hysterectomy and lymphadenectomy in addition to radiotherapy compared to our study where cases were treated by radical radiotherapy with concurrent chemotherapy, and no surgery was performed. Another study was conducted by Vrdoljak et al. on 44 patients with Stage IB2-IVA of uterine cervical carcinomas who were treated with external radiotherapy 50 Gy in 25 fractions and then concurrent ifosfamide + cisplatin and LDR-ICRT to total dose of 85 Gy.[24] The average duration of radiation was 45.1 days. Adjuvant chemotherapy every 3 weeks was given for three cycles. The clinical complete response rate was 100%. Grade III and IV leukopenia occurred in 25% and 11% of the cycles, respectively. Blood transfusion was prescribed in 60% of patients. Late effects in the rectum and bladder were observed in 16% of cases. After a median follow-up of 34 months (range, 20–54 months), the recurrence-free and the overall survival rates were 84% and 91%, respectively. Major delayed local complications occurred in 7 cases (16%). These results indicate that concomitant chemo-brachyradiotherapy with ifosfamide and cisplatin is a feasible combination for patients with locally advanced carcinoma of the cervix uteri. In comparison to our study, the treatment outcome in this study was probably better because of the use of two chemotherapeutic agents; however, the acute and late toxicities were more common. Strauss et al. treated 27 patients with Stage IIB-IIIB cervical cancers with concurrent cisplatin and HDR-ICRT in Germany.[25] Complete response rate was 92.3%, and 80% of the patients were disease-free in 20 months of follow-up. Acute effects including Grade 3 hematological toxicities and late effects were seen in 29.6% and 7.4% of cases, respectively. These toxicities were more in comparison with the present study, and complete response and disease-free survival were 77% and 58% versus 92.3% and 80%, respectively. Very good local control in advanced local disease patients with low metastasis rates (only 5%) as compared to the present study was reported. Aghili et al. treated 31 cases with chemoradiation by external radiotherapy and MDR-ICRT by 24 Gy in two fractions concurrently with 35 mg/m2 cisplatin from October 2007 to May 2008 and the 12 months of overall survival was 78% and 22 cases were disease-free.[22] Acute effects were abdominal pain in 23%, cystitis in 19%, vaginitis in 18%, and proctitis in 15% of cases. There were Grade 1 and 2 leukopenia in 85% and 15% and Grade 1 and 2 anemia in 95% and 5% of the cases, respectively; there were no Grade 3–4 acute toxicities. Late effects were cystitis in 24%, proctitis in 12%, abdominal pain in 4%, and rectal fistula in 3% of cases. As compared to our study, toxicities are slightly more, but at the same time, chemotherapy dose was more and brachytherapy dose delivered was by MDR-ICRT.

Another study done by Chandel and Jain in 2013 and a total of 64 patients of locally advanced cervical cancers were treated by 50 Gy by external and 18 Gy (3 fractions of 6 Gy each) by HDR brachytherapy with concurrent chemotherapy Inj. cisplatin 35 mg/m2 being used on weekly.[6] They reported 75% overall disease-free survival at 30 months of follow-up. Acute effects include Grade 2, 3 leukopenia in 11% and 6%, respectively, and late effects such as rectal toxicity Grade 2, 3 in 2.5% and 5%, respectively. As compared to our study, the results were slightly better, but at the same time, chemotherapy dose was more and follow-up was for slightly less time. Acute hematological toxicities were less common in our study, but the other acute side effects were similar. Disease-free survival for carcinoma cervix patients treated at the same rural center and reported by the same author in 2007 by Jain et al. for Stage II and III was 44% and 33%.[26] Patients were treated by the same radiation dose EBRT 50 Gy and HDR-ICRT 21 Gy in 3 fractions, but the follow-up was for longer duration and concurrent chemotherapy with brachytherapy was not given.


 > Conclusion Top


Brachytherapy with the addition of concurrent chemotherapy is effective and feasible with acceptable toxicity for advanced stages of cancer of the uterine cervix. We had small number of patients for this study, but still the judicial use of concurrent chemotherapy with brachytherapy in selective carcinoma cervix cases with large residual disease after EBRT with concurrent weekly chemotherapy would be of much importance by adding radiosensitizing and cumulative dose effect. For all these reasons, further studies on concurrent chemotherapy with brachytherapy are required to arrive at any standard conclusion.

Acknowledgement

We thank to Mr. Rohit and Datir Bhaskar (Clerk) for providing technical support for taking out hospital records from medical record section of the Institute.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer cervix in India. Indian J Med Res 2009;130:219-21.  Back to cited text no. 1
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Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-53.  Back to cited text no. 12
    
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Toita T, Kakinohana Y, Ogawa K, Adachi G, Moromizato H, Nagai Y, et al. Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cervical cancer: Analysis of dose and fractionation schedule. Int J Radiat Oncol Biol Phys 2003;56:1344-53.  Back to cited text no. 14
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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