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ORIGINAL ARTICLE
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A prospective randomized trial comparing accelerated concurrent chemoradiotherapy with conventional concurrent chemoradiotherapy in locally advanced carcinoma cervix (IIA–IVA)


1 Department of Radiation Oncology, Tertiary Cancer Centre, IGMC, Shimla, Himachal Pradesh, India
2 Department of Radiology, Tertiary Cancer Centre, IGMC, Shimla, Himachal Pradesh, India

Date of Submission20-Aug-2019
Date of Decision16-Sep-2019
Date of Acceptance30-Dec-2019
Date of Web Publication28-Oct-2020

Correspondence Address:
Poorva Vias,
Department of Radiation Oncology, Tertiary Cancer Centre, IGMC, Shimla, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_626_19

 > Abstract 


Introduction: Cervical cancer ranks fourth in women worldwide. The management requires a multidisciplinary approach. Concomitant chemoradiotherapy with cisplatin, followed by brachytherapy, is the standard approach. Accelerated radiotherapy (ART) can be used to decrease the treatment duration which can further lead to better outcomes.
Materials and Methods: Stages II, III, and IVA of carcinoma cervix were studied for 1 year. Ninety patients were randomized in control and study arms, 45 patients in each arm. The total dose of radiation was 50 Gy/25#/5 weeks from Monday to Friday in the control arm and 50 Gy/25#/4 weeks from Monday to Saturday in the study arm, with injection cisplatin 40 mg/m 2 intravenous infusion weekly in both the arms.
Results: The response was similar in both the arms at the first follow-up as well as at median follow-up. However, acute toxicities in the ART arm were more, but they were managed conservatively.
Conclusion: ART can be used in patients of cervical cancers to decrease the total treatment time. The results were similar in both the groups but need to be studied over more number of patients.

Keywords: Accelerated radiotherapy, cervical cancer, concurrent chemoradiotherapy, external beam radiotherapy, intracavitary brachytherapy



How to cite this URL:
Vias P, Angural H, Seam RK, Gupta MK, Gupta M, Fotedar V, Negi A. A prospective randomized trial comparing accelerated concurrent chemoradiotherapy with conventional concurrent chemoradiotherapy in locally advanced carcinoma cervix (IIA–IVA). J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299461




 > Introduction Top


Carcinoma cervix is one of the most commonly diagnosed cancers in women worldwide. According to GLOBOCAN, there were 569,847 new cases of cervical cancer worldwide which is the fourth most common cancer in women worldwide.[1] India accounts for a quarter (27%) of world cervical cancer burden with 96,922 new cases. Cervical cancers rank third in women in India. In our institute, the incidence of uterine cervix accounts for approximately 58.66% of all female malignancies with about 80%–90% of patients presenting in advanced stage with bulky central disease. The developed countries have reduced the incidence and mortality from cervical cancers primarily due to the regular annual screening of women with Pap smear. Almost all cases of cervical cancer show the prevalence of high-risk human papillomavirus infection.[2]

In early stage, cervical cancer surgery has been the primary treatment modality. In locally advanced carcinoma cervix, IIB–IVA, external beam radiotherapy (EBRT), followed by intracavitary brachytherapy (ICBT), has been the preferred treatment modality. To quote NCCN “in patients with intact cervix, the primary tumor and regional lymphatics at risk are typically treated with definitive EBRT to a dose of approximately 45 Gy, ― the primary cervical tumor is then boosted using brachytherapy, with an additional 30–40 Gy to point A.”[3]

Despite the significant progress in radiation techniques, radiotherapy (RT) given alone has failed in a number of patients with cervical cancer, and overall 5-year survival rates in Stage IIB, IIIB, and IV cancer ranged from 65% to 75%, 35%–50%, and 15%–20%, respectively.[4],[5] Therefore, the need arises to increase the radio response of tumors.

Cisplatin has been the most active agent identified which acts through the formation of free radicals formed by altered binding of platinum to DNA and inhibition of repair of sublethal damage.[6] Many other drugs have been tried but have not been so effective. For improving the therapeutic ratio by RT, other strategies such as extended-field irradiation and hypoxic-cell sensitizers have only shown marginal improvement and are not used routinely.[7],[8] Altered fractionation like accelerated fractionated RT has also been one of the approaches that have shown promise.[9] Accelerated fractionation aims to minimize tumor repopulation during treatment sessions by shortening the overall treatment time (OTT). Theoretically, it is attractive but has no proven benefit over conventional RT, and moreover, there have been reports of more toxicity associated with it.[9],[10],[11],[12]

The main aim of this modality is to decrease OTT with comparable toxicities, and therefore, one may expect an increase in the probability of tumor control for given total dose. Since the treatment time is thought to have little or no influence on the response of late-reacting normal tissue, a reduction in OTT would not be expected to affect the incidence and severity of late normal tissue injury, provided the size of dose per fraction is not increased and interfraction interval is sufficient for repair to be completed. This study was done with the aim of getting equivalent or better response with comparable toxicities.


 > Materials and Methods Top


This prospective comparative study was conducted in our institute in patients suffering from locally advanced carcinoma of the cervix. The patients were enrolled in the study starting from July 2016 to June 2017. Cases included in this study were previously untreated, staged by FIGO staging 2008, Stage IIA–IVA, histologically proven invasive squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma, age ≤70 years, hemoglobin ≥10 g%, normal renal and liver function tests, and Karnofsky Performance Score ≥70.

Randomization was carried out by stratification, and the treatment assignment was stratified according to clinical stages of disease. Patients were randomized into two groups: one study group and one control group based on the treatment they received.

Control arm

Patients were subjected to standard conventional concurrent chemoradiotherapy (CRT) with EBRT 50 Gy in 25# over 5 weeks with injection cisplatin 40 mg/m 2 once a week. EBRT was given by Teletherapy Theratron 780e and Equinox Cobalt-60 machines. Patients were treated by anteroposterior–posteroanterior (AP-PA) fields for AP-PA separation 18 cm or less using skin to surface distance (SSD) technique at 80 cm or four-field box technique (AP, PA, and two lateral fields) for AP-PA separation more than 18 cm using SAD technique. ICBT was done after a gap of 1–2 weeks, using Microselectron Iridium based high-dose rate (HDR) system, giving a dose of 18–21 Gy in two or three divided fractions to point A. If they were not fit for ICBT, the patients were subjected to supplement radiation therapy. 20 Gy was given over ten fractions at 200 cGy/# over 2 weeks with injection cisplatin weekly.

Study arm (accelerated CRT arm)

Patients were subjected to six fractions per week (accelerated) RT 50 Gy in 25# over 4 weeks and 1 day along with injection cisplatin 40 mg/m 2 once a week for a total 25#. Brachytherapy given was the same. Supplementary treatment includes 20 Gy in ten fractions in 1½ weeks at 200 cGy/# with injection cisplatin weekly for the patients who were unfit for ICBT.

Assessment of status and toxicity

Patients were assessed every week for toxicities and for suitability of brachytherapy 1–2 weeks after completion of EBRT. The response was assessed clinically as complete response (CR), partial response (PR), stable disease, and progressive disease. Toxicities were monitored and Common Terminology Criteria for Adverse Events criteria were utilized to assess and document them.

Follow-up

The first follow-up was done at 6 weeks. A complete gynecological examination accompanied with systemic examination was performed, and subsequent follow-up was done at every 2 months. Patients were examined locally and for any acute and late toxicity.

Secondary treatment

Patients who had a persistent tumor on completion of treatment were considered for salvage surgery if resectable. Adjuvant chemotherapy was administered in patients with unresectable disease.

The permission was taken from the institutional ethical committee.

Statistical analysis

Response rate was the primary end point for analysis. The data obtained from both the arms were analyzed by Student's t-test and Chi-square test. P <0.05 was taken as statistically significant. The statistical significance was defined as: P >0.05 – nonsignificant, P = 0.05–0.01 – significant, and P < 0.01 – highly significant.


 > Results Top


Patient characteristics were balanced in both the arms on the basis of age, stage, histology, and type of growth [Table 1].
Table 1: Patient characteristics

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One hundred and thirty patients of carcinoma cervix were assessed for eligibility, out of which ninety patients were enrolled in the study. Forty-five patients were randomized in each conventional and accelerated radiotherapy (ART) arm.

Response at first follow-up

CRs were seen in thirty-four patients (68.88%) in the ART group and thirty-two patients (64.44%) in the CRT group. The difference between the groups was not statistically significant (P = 0.488). PR was achieved in ten patients (22.2%) in the study arm and nine patients (20%) in the control arm [Table 2].
Table 2: Response at first follow-up

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Responses at median follow-up

The median follow-up was 5 months. The CR rates at median follow-up in the study (ART) and control (CRT) arms were 75.55% (34 patients) versus 71.11% (29 patients) (P = 0.297).

Acute toxicities during treatment

Hematotoxicity

Overall, hematotoxicity was seen mainly in the study group as compared to the control group (28 patients in the study group versus 22 patients in the control group, P = 0.214). There was an incidence of hematotoxicity of Grade III in nine patients in the study group and six patients in the control group [Figure 1].
Figure 1: Hematological toxicity

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Cutaneous toxicity

It was seen in all the patients (45) in the study arm and 42 (93.3%) of the patients in the control arm. There was no statistical difference between the two arms (P = 0.8121). Cutaneous toxicity of higher grade (Grade III) was seen more commonly in the study arm as compared to the control arm, but the difference was statistically not significant (17.77% vs. 13.33%, P = 0.538) [Figure 2].
Figure 2: Cutaneous toxicity

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Gastrointestinal toxicity

About 100% of the patients in the study arm and 42 patients in the control arm suffered gastrointestinal toxicity. Gut toxicity in the study group was Grade III in 11.11% of the patients, whereas the same in the control arm was 6.6%. The difference was not statistically significant (P = 0.762). Grade II gastrointestinal toxicity was observed more in the study arm, and the difference was statistically significant (53.33% vs. 26.66%, P = 0.0256) [Figure 3].
Figure 3: Gastrointestinal toxicity

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Renal toxicity

Two patients experienced renal toxicity in the control arm and one incident was reported in the study arm. A nonsignificant difference (P = 0.631) was seen when the arms were compared [Table 3].
Table 3: Renal toxicity and genitourinary toxicity

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Genitourinary toxicity [Table 3]

There was not much difference between the two arms in genitourinary toxicity with nine incidents in the ART arm and seven in the CRT arm both of Grade 1. The difference is not significant (P = 0.789).


 > Discussion Top


Despite the reduction in the incidence of cervical malignancy in the western world, it still remains prevalent in the developing world.

The treatment failure in carcinoma cervix is still predominantly locoregional in two-thirds of the cases,[13],[14] and the improvement in local modalities of treatment would definitely assist in improving the treatment outcome.

In an attempt to improve the local control rate, our study had attempted to increase the therapeutic ratio in carcinoma cervix through exploiting the difference between inherent properties of early- and late-reacting tissues and inhibiting tumor repopulation in the locally advanced setting in carcinoma of the cervix. Accelerated regimens have already been shown to be effective in other sites as head-and-neck cancer and shown improved outcomes. Yoon et al.[15] extended the Accelerated Fractionation schedule to cervical cancer. The findings were “six fractions per week of External radiotherapy and brachytherapy is an effective treatment for patients with a carcinoma of the uterine cervix and can be used as a possible alternative to concomitant chemoradiotherapy in elderly patients or in patients with comorbidity.” Hence, it was imperative that it be tested in carcinoma cervix, to know whether it could similarly be effective in this setting.

The median treatment time in the first phase (EBRT) for the study group (ART) was 28 days and in the control group (CRT) was 33 days. About 84.4% of the patients had completed their treatment within the planned period in the first phase in the study arm, whereas in the control arm, 95.5% did so. Seven (15.5%) patients in the study arm had exceeded the planned time mainly due to gastrointestinal and skin reactions, the maximum time being 3 days. Two patients in the control arm completed the treatment in more than the planned time period, and it was mainly due to hematological toxicity. Thus, the adherence to treatment in the control arm was better than the study arm without many breaks.

Differences in the CRs were favoring the study arm. Thirty-one patients (68.88%) achieved CR in the ART group and 29 patients (64.44%) in the CRT group on the first follow-up with a statistically insignificant difference (P = 0.488). This was a little bit in favor of our expectations as the study group with its decreased OTT was expected to perform better. The overall responses though were not much different in the study versus the control arm, but this trend had continued on subsequent follow-ups.

In the Phase II study of accelerated fractionation done at Samsung Medical Center,[15] 50.4 Gy had been given at 1.8 Gy/# in accelerated schedule, followed by brachytherapy. This study had included elderly patients, those with comorbidities, or those who had refused chemotherapy, and their results had been slightly better as compared to our study arm. The overall response rate was seen to be 97.7% with 79.1% CRs in their study. However, their study had included patients with smaller tumors and stages as compared to our study with number of patients with <5 cm tumor diameter constituting 67.4% and Stages
The biologically effective doses of the two regimens were not quite different being 51 Gy for the ART arm as compared to 50 Gy for the CRT arm. Thus, the doses in our study and control arms were not quite different. This equivalence of biological effective dose could have been one of the reasons for the almost similar control rates in the ART arm.

The following observations can be made from our study:

  1. We observed a better CR at the first follow-up in the study group (68.88%) when compared to the control arm (64.44%), but the difference was not statistically significant (P = 0.488)
  2. At a median follow-up of 5 months, this difference persisted with CR rates at median follow-up in the study (ART) arm being 75.55% versus 71.11% in the control (CRT) arms (P = 0.297)
  3. Hematotoxicity of all grades was seen predominantly in the study group 62.22% versus 48.88%, but it did not cause any serious hindrances in both RT and chemotherapy schedules
  4. Gastrointestinal as well as cutaneous toxicity of higher grades was seen to be more in the study group, but the difference had not reached statistical significance.



 > Conclusion Top


Treatment with accelerated chemoradiotherapy has shown in this study to have a slightly superior locoregional control over the conventional chemoradiotherapy arm. The accelerated schedule was seen to be feasible with conservatively manageable hematological, cutaneous, and gastrointestinal toxicities. Accelerated treatment is an attractive alternative to conventional CRT, especially in countries with 6 days a week working schedule. Moreover, shortening of OTT will increase the turnover on treatment machine which will help to treat more number of patients and will reduce the waiting list. Further, as we know that the total duration of treatment time (8–9 weeks) has prognostic value and with this treatment schedule, we can reduce the total duration of treatment which may lead to better results, but this needs to be confirmed in a larger prospective randomized trial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

 
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