|Ahead of print publication
The tolerance to chemoradiation for cervical cancer patients: A comparative prospective study of rural versus urban population
Mohan Kumar Somashekar1, Janaki Manur Gururajachar1, TR Arul Ponni2, Kirthi Agrahara Koushik2, Ram Charith Alva2
1 Department of Radiation Oncology, Ramaiah Medical College and Hospital, Bengaluru, Karnataka, India
2 Department of Radiation Oncology, Ramaiah Medical College, Bengaluru, Karnataka, India
|Date of Submission||24-Apr-2020|
|Date of Decision||08-Jun-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||03-Aug-2021|
Mohan Kumar Somashekar,
Department of Radiation Oncology, Ramaiah Medical College and Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Context: Rural versus urban cervical cancer.
Aims: This study aims to study the difference in toxicities and clinical outcome of chemoradiation in urban and rural cervical cancer patient.
Settings and Design: This was a prospective study.
Subjects and Methods: In a double-arm prospective study, cervical cancer patients were treated with chemoradiation followed by brachytherapy. Patients were monitored weekly for hematological, gastrointestinal toxicities, and electrolyte imbalance. Acute toxicities and long-term outcome were compared between the two groups.
Statistical Analysis Used: Kaplan–Meier survival curves for analysis of disease free and overall survival and Pearson's Chi-square test and Fisher's exact tests for analysis of toxicities were used.
Results: Fifty-seven patients from urban and 114 from rural region were studied. There were no difference between the two groups as far as the patient characteristics, overall treatment time (OTT), hematological, electrolyte imbalance, local control, and disease-free survival between the two groups. Associated comorbidities were significantly higher (53% vs. 17%) with P < 0.0001 in urban population. Grade II and III enteritis were significantly higher 15.78% versus 21.05% (P = 0.00001) and 12.28% versus 11.40% (P = 0.03) in urban patients, respectively.
Conclusions: Tolerance to chemoradiation, disease-free survival, and overall survival are similar in both urban and rural patients of cervical cancer, with more enteritis in urban group. However, this did not increase OTT.
Keywords: Chemoradiation, rural versus urban, tolerance
|How to cite this URL:|
Somashekar MK, Gururajachar JM, Arul Ponni T R, Koushik KA, Alva RC. The tolerance to chemoradiation for cervical cancer patients: A comparative prospective study of rural versus urban population. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322907
| > Introduction|| |
Cervical cancer is the second leading cancer among women in India constituting 18.2% of all cancers. The standard treatment of concurrent chemo radiation, as per the Cochrane meta-analysis showed an improvement in overall and progression-free survival by 10% and 13%, respectively. Radiotherapy is administered in the form of external beam radiotherapy (EBRT) and intracavitary or interstitial brachytherapy. Cisplatin or Carboplatin are the drugs used for concurrent chemotherapy (CTRT) in cervical cancer. Nausea, vomiting, enteritis, and hematological toxicities are the major concerns during concurrent chemoradiation for cervical cancer. CTRT increases Grade 3 or higher acute radiation enteritis to 31.6% compared to 11.6% when radiation alone is given (P < 0.001). Addition of cisplatin to pelvic radiation enhances the hematological toxicities. Dehydration because of enteritis adds to the dyselectrolytemia induced by cisplatin. Although uniform protocol is followed, many patients tolerate the treatment well and some develop higher toxicity. This may be due to the differences in the lifestyle, food habits, genetic makeover, and environmental factors.
Our medical college is attached to a tertiary care hospital and caters to both rural and urban women suffering from cervical cancer. As per 2011 census 68.84% of the population of India lives in rural area and the rural cancer registry from Barshi which was set up in 1987 reflects higher occurrence of cervical cancer than the rest of the registries. Around 50% of rural women get married before 15 years while it is 23 years for their urban counterpart. In addition, they observed that women attended hospital to the extent of 10% only in Stage I cancer. This becomes very important especially with cancers which have control rate of more than 80% as in cervical cancer. Hariharan has reviewed the health status of rural women and observed that it is affected by multiple issues such as young age at first childbirth, multiple pregnancies, nutritional deficiencies, lesser periodic health check-up, and typical attitude of keeping the interest of the family above their personal issues.
The repercussion of these could be subclinical most of the times but at times disease like cancer and its treatment may show up as low tolerance and noncompliance to treatment which in turn leads to lower long-term disease control. This study is an effort to see if tolerance to chemo radiation is different among rural compared to urban women. The primary aim was to study the tolerance but we have also looked into the follow-up and treatment outcome.
| > Subjects and Methods|| |
The sample size for the present study was calculated based on the study carried out by Saibishkumar who observed 28% of rural patients had treatment interruptions as opposed to 10% of urban patients. Keeping the power of the study to be 80% and with an alpha error of 10%, it is estimated that nearly 57 patients to be included in each arm. However, it was noted that more number of patients were from rural area and to avoid the selection bias 114 patients were included in the rural arm as suggested by the statistician. One hundred and seventy-one patients diagnosed as cervical cancers were prospectively enrolled in the study between January 2015 and September 2018 after the approval of the institution's ethical committee. The patients were enrolled in the rural group if their residential area was under panchayat governance and in urban group if their residential area is under municipality governance. Clinical examination and CT or MRI imaging were used for staging. All patients underwent apart from biopsy, complete blood count, renal function test, liver function test, serum electrolyte level, electrocardiograph, ECHO cardiogram, and chest X-ray before starting the treatment. After obtaining the informed consent 114 rural and 57 urban cervical cancer patients were treated with EBRT on Elekta Synergy 6 MV photon linear accelerator using three-dimensional conformal radiotherapy technique to a dose of 45 Gy in 25 fractions over 5 weeks. Weekly chemotherapy of cisplatin to a dose of 40 mg/m2 over 5 weeks was given during EBRT. Patients with compromised renal or cardiac function received carboplatin instead of cisplatin. Around 10–15 days after the completion of EBRT, patients underwent brachytherapy either intracavitary or interstitial application to a dose of 6.5 Gy X 4 fractions given at 6 h interval over 2 days using BEBIG multisource brachytherapy machine with cobalt-60 source.
During the treatment, patients were monitored for enteritis and hematological toxicities. Common toxicity criteria version 3 was used to grade the toxicities. Complete blood count, serum creatinine, serum levels of sodium, potassium, calcium, and magnesium were tested weekly during concurrent CTRT and 15 days after the completion of brachytherapy. Blood transfusion was done when the hemoglobin dropped to <9 g/dl. Electrolyte imbalance was corrected accordingly. Patients were assessed at 2 weeks after the brachytherapy and subsequently once in 2 months for the first 6 months, once in 3 months for next 1 year, and once in 6 months later. All patients underwent clinical examination during the follow-up. Contrast-enhanced CT scan imaging and biopsy were done for patients with recurrent disease. Events in terms of enteritis, hematological toxicities, recurrence, disease control, and death were documented.
Descriptive statistics was carried out using Microsoft excel and the statistical software SPSS IBM version 18 was used for analysis of the a. Kaplan–Meier survival curves were used to analyze the disease-free and overall survival. Pearson's Chi-square test and Fisher's exact tests were used to analyze events of toxicities in the groups.
| > Results|| |
One hundred and fourteen patients from rural and 57 patients from the urban area were the subjects of the study. The patient's characteristics are shown in the [Table 1]. Majority of the patients in both the groups had Stage III disease. The median age was 51 years in urban and 50 years in rural group. Associated comorbidities such as diabetes and hypertension were higher in the urban group compared to rural population 53% versus 17% (P = 0.00001).
Average duration of EBRT was 35 days (range 33–56 days) in both the groups and a median gap of 15 days was seen in both the groups between the completion of EBRT and brachytherapy. One patient in each group defaulted and came back to complete the treatment over 73 and 85 days. Four patients had a delay of 34, 39, 44, and 79 days between completion of EBRT and brachytherapy because of logistic and family issues. Forty-seven (41.22%) patients in the rural and 22 (38.59%) patients in the urban group completed EBRT beyond 35 days because of enteritis and hematological toxicities. Forty-two (73.69%) patients in the urban group and 90 patients (78.95%) patients in rural group could complete the entire treatment within 56 days. Fifteen patients (26.31%) in urban and 24 patients (21.05%) in the rural group had prolonged overall treatment time (OTT) beyond 56 days. All patients received minimum of three cycles of chemotherapy. Eighty-three patients in rural and 39 patients in the urban group could complete all the five cycles of chemotherapy during external beam radiation (72.8% vs. 68.42% P = 0.6). The cumulative dose of cisplatin used ranged from to 150–350 mg and was similar in both the groups.
Treatment outcome and toxicities are summarized in [Table 2] and [Table 3]. The median hemoglobin level at presentation was 11.3 g/dl in the rural group and 11.5 g/dl in the urban group. Eleven patients in the rural and eight in the urban group had hemoglobin of <9 g/dl at presentations (9.64% vs. 14.03%). Forty-four patients had blood transfusion in the rural arm while 18 patients had blood transfusion in the urban arm during the treatment (38.59% vs. 31.57 P = 0.4).
There were no significant hematological toxicities noticed in both the groups during the first 3 weeks of concurrent CTRT but after completion of three cycles of weekly chemotherapy the frequency of Grade 3 neutropenia was higher among rural patients but not statistically significant (P = 0.12) and Grade 3 lymphopenia were significantly higher among rural patients compared to the urban patients (P = 0.028). Eighteen patients (15.78%) in the rural and twelve patients (21.05%) in the urban group had Grade 2 enteritis during the treatment with a P = 0.4. Thirteen patients (11.40%) in the rural and seven patients (12.28%) in the urban group developed acute Grade 3 enteritis which was not statistically significant (P = 1.0). There were no significant differences in the development of Grade 3 hyponatremia and hypokalemia between the groups (P = 0.18). Grade II hyponatremia was seen in 35%, 30%, 28%, 24% in rural patients verses 14%, 23%, 39%, and 23%, respectively before 2nd, 3rd, 4th, and 5th cycle of chemotherapy which was not significant.
The median follow-up was 33 months with range of 17–61 months, two patients (3.5%) in the urban and three patients (2.63%) in the rural group developed local recurrence. The median disease-free survival was 32 months in the urban and 25 months in the rural patients, respectively. The disease-free survival at 2 years was higher among urban patients but not statistically significant (P = 0.2).The median overall survival was 28 months in the urban and 32 months in rural patients (P = 0.15). Two patients had chronic Grade III proctitis in the rural group and treated with argon photo coagulation. One patient had Grade III cystitis and was treated conservatively.
| > Discussion|| |
CTRT in cervical cancer patients is associated with considerable frequency of acute and chronic complications which require timely monitoring and management. Several factors affect the severity of complications such as the radiotherapy technique, chemotherapy dose, associated comorbidities, nutrition, and supportive care. Enteritis, cystitis, proctitis, hematological toxicities, and electrolyte imbalance are the major toxicities encountered during chemoradiation. When treatment-related factors are constant, the toxicity pattern may be attributed to the patient-related factors. This prospective study was conducted to see if the tolerance of chemoradiation is different between urban and rural population. Similar studies are done by Arunkumar et al., Jain et al., and Ritika et al.
Arunkumar et al. in an urban-based prospective randomized study of concurrent CTRT for cervical, esophagus, and head and neck cancer analyzed changes in the electrolytes after five cycles of 40–50 mg/m2 given weekly once. However, we included only cervical cancer, it was a double arm prospective study and we analyzed after every cycle of cisplatin.
In our previous retrospective study on 30 cervical cancer patients of rural background treated with concurrent chemoradiation and low-dose rate brachytherapy, we had observed 23.33% of acute Grade 3 enteritis and 47% of Grade 2 hyponatremia. In that study, only two (6.66%) patients out of 30 completed all five cycles of weekly chemotherapy. In the present study, 83 patients (72.8%) in rural and 39 patients (68.42%) in the urban group could complete all the five cycles of chemotherapy. The better tolerance to chemoradiation may be because of more conformal radiation.
There are no studies comparing the treatment outcome in urban versus rural population. Jain et al., in a single arm study from a rural center in India looked into the treatment outcome in 214 cervical cancer patients treated with EBRT on cobalt machine along with two sessions of 7.5 Gy of high-dose rate brachytherapy and reported 5-year disease-free survival rate of 58%, 44%, 33%, and 15% for Stages I, II, III, and IV, respectively. In their study, 35 patients (16.3%) had developed local recurrence and 17 patients (7.9%) had developed distant metastases. In the present study, two patients (3.50%) in the urban and three patients (2.63%) in the rural group developed local recurrence, the better outcome probably is the addition of chemotherapy in our study.
Saibishkumar et al. in their study of 214 rural patients observed 42% DFS, 29% persistent disease, and 16.3% of patients had both local and distant metastasis. Results, compared to the present study were inferior as it was done between 1997 and 2001 and chemo was not administered. They observed that the reasons for poor outcome were illiteracy, poverty, ignorance, and poor transport facilities.
OTT is an important predictor of survival and pelvic control. Petereit et al. found that overall survival drops by 0.6% and pelvic control by 0.7% per day when the OTT goes beyond 56 days. In our retrospective study of rural patients, we found that 20% of rural patients had treatment interruptions as opposed to 10% in a study by Saibishkumar et al. Jain et al. observed that 24% of patients defaulted during EBRT and the median OTT was 61 days. In our study, few patients in both groups had a longer OTT due to their personal problems. However, this did not translate into a long-term lower disease control.
In our study, toxicities such as hematological, electrolyte imbalance, and late sequelae were similar in both the groups. In our study, we specially looked for grade III and higher toxicity which was 5.26% in both groups for hyponatremia which was not significant. Two percent of rural patients had Grade III and higher toxicity which was again not significant compared to their counter parts. Arunkumar et al. in the study of concurrent chemoradiation observed significant hypomagnesemia (P = 0.05) and hypocalcemia (P = 0.05) but the grade of the toxicity is not mentioned. This cannot be compared to the present study as we looked at cervical cancer patients only where as they had included different sites such as head and neck, cervix, and esophagus and so the radiation is completely different and site dependent. The same in our earlier study was 60%, 89%, and 26.66%, respectively, Ritika et al. We did not observe any significant difference between the two groups in this comparative study. Although we had planned to monitor magnesium levels, we could not do in all patients due to financial constraints.
Most of the patients did not have any symptoms due to electrolyte imbalance. Routine estimation before weekly chemotherapy was always done and hence any abnormality was corrected.
We would like to highlight that the urban population had significantly higher enteritis. Although we could not find any particular reason, we found that they were less likely to stick to the diet advice. Another reason that could be possible is that the urban population had significantly higher comorbidities such as diabetes and hypertension.
Strengths and limitations
The strength of our study is that it is a prospective study, second, lot of efforts had to be done for follow-up like collecting additional address/phone number preferably of relatives who live in our city, reply card in Kannada with details of the presence or absence of symptoms, alive or dead and also by getting the help of other patients. Limitations were that we could not analyze changes in the magnesium level as it involved patients spending the money. Also, considering incidence of the disease, the patient number was smaller.
| > Conclusions|| |
Every effort should be made to provide chemoradiation for cervical cancer even for rural patients as the tolerance to treatment, disease-free survival, and overall survival are similar between rural and urban population. Although more enteritis was seen in urban patients, they could complete the entire schedule of chemotherapy as well as radiation on time so that the long-term outcome also will be similar.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]