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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 103-108

Can pure accelerated radiotherapy given as six fractions weekly be an option in locally advanced carcinoma cervix: Results of a prospective randomized phase III trial


1 Department of Radiotherapy, Regional Cancer Centre, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Radiation Oncology, Swami Rama Cancer Hospital and Research Institute, Government Medical College, Haldwani, Nainital, Uttarakhand, India
3 Radiation Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication13-Apr-2016

Correspondence Address:
Mukesh Sharma
Department of Radiotherapy, Regional Cancer Centre, Indira Gandhi Medical College, Shimla - 171 001, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148676

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 > Abstract 


Context: Concurrent chemoradiation is presently the standard of care in locally advanced malignancy of the cervix uteri. But accelerated radiotherapy regimes have not been investigated much.
Aims: We conducted a randomized trial to compare the results of pure accelerated radiotherapy given as six fractions weekly to standard chemoradiotherapy in locally advanced carcinoma cervix patients.
Settings and Design: This was a prospective, phase III trial in which 106 patients of locally advanced (stage II and III) carcinoma cervix were randomized into two arms.
Subjects and Methods: The study arm (ART) received 50 Gy accelerated radiotherapy in 25 fractions, six fractions weekly; while control (CRT) arm was treated with concurrent chemoradiation 50 Gy in 25 fractions with weekly injection cisplatin. This was followed by intracavitary brachytherapy (ICBT; total dose of 85 Gy to point A) in both the arms. Fifty-one patients completed treatment in the ART arm and 50 patients in the CRT arm. In these patients, response to treatment, toxicity, and overall survival (OS) and disease-free survival (DFS) were compared between both the arms.
Statistical Analysis Used: Survival analysis was done using Kaplan.Meier estimates, logrank test was used to compare differences, while proportions were compared using the Fisher's t-test.
Results: At a median follow.up of 36. months there was no difference between the two arms in terms of OS. (61 vs 62%,P = 0.9009) as well as DFS. (60 vs 64%,P = 0.6411)
Conclusions: Accelerated radiotherapy given as six fractions per week is an effective alternative to concomitant chemoradiation in locally advanced carcinoma cervix and has shown lesser toxicities in our study.

Keywords: Accelerated, cervix, chemoradiation, effective, locally advanced, radiotherapy, six fractions per week


How to cite this article:
Sharma M, Revannasiddaiah S, Gupta M, Seam RK, Gupta MK, Rastogi M. Can pure accelerated radiotherapy given as six fractions weekly be an option in locally advanced carcinoma cervix: Results of a prospective randomized phase III trial. J Can Res Ther 2016;12:103-8

How to cite this URL:
Sharma M, Revannasiddaiah S, Gupta M, Seam RK, Gupta MK, Rastogi M. Can pure accelerated radiotherapy given as six fractions weekly be an option in locally advanced carcinoma cervix: Results of a prospective randomized phase III trial. J Can Res Ther [serial online] 2016 [cited 2019 Dec 10];12:103-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/103/148676




 > Introduction Top


Cancer of the cervix has undergone crucial transitions, both in incidence and in treatment in the recent times. Recent estimates place cervix as the fourth most common cause of cancer in the fairer sex with 266,000 deaths worldwide as of 2012.[1] India (responsibly!!) shares more than one-fifth of the total cancer burden.[1] The reason is primarily the inability to provide screening services to its burgeoning population. In this context it becomes imperative to take measures to alleviate the distress of those suffering from this illness.

Though cervical malignancies are not more radiosensitive than other epithelial malignancies, the relative success of radiation therapy has been seen mainly due to initial presentation in early or locally advanced stages, relatively higher tolerance of the nearby structures, orderly progression of lymph node metastasis, and the suitable organ anatomy for brachytherapy. For improving the treatment results various strategies have been tried like hyperbaric oxygen, blood transfusions, erythropoietin, hypoxic cell sensitizers, extended field irradiation, neutron therapy, and hyperthermia; but they have not made any major contribution.

In recent times the most significant development in the treatment of carcinoma cervix has been the introduction of chemoradiation. Cisplatin has been the most active agent identified. After the NCI alert in 1999,[2] cisplatin-based concurrent chemoradiotherapy has become widely used in the treatment of locally advanced carcinoma cervix. However, this has not been without its hazards, with safety concerns hindering its administration in elderly patients; in those with preexisting medical problems (with abnormal renal, hepatic, or bone-marrowfunction); and in patients who refuse chemotherapy. There are financial problems as well (cost of the chemotherapy and cost for managing toxicities). Besides, locoregional relapse still remains a problem in a substantial percentage of patients despite cisplatin-based chemoradiotherapy. Differences in race, socioeconomic factors, and lack of radiotherapy facilities are the issues that have impeded standardization of chemoradiation in the low-income countries. Thus, newer and efficacious perspectives are needed.

Altered fractionated radiotherapy has also been one of the approaches that have shown promise to increase the therapeutic ratio. Theoretically, hyperfractionation and accelerated hyperfractionated radiotherapy are attractive options, but none has been proven to be of any benefit over conventional radiotherapy in carcinoma of the cervix and there have been reports of increased acute toxicity associated with them.[3],[4],[5],[6]

Pure accelerated fractionation regimens intend to reduce the overall treatment time (OTT) without simultaneous changes in the fraction size or total dose. Accelerated fractionation aims to minimize tumor repopulation during treatment sessions by shortening the OTT, and therefore, increasing the probability of tumor control for a similar total dose. Shortening OTT should limit the extent of accelerated tumor repopulation, and therefore, one may expect an increase in the probability of tumor control for given total dose. Altered fractionation employing accelerated schedules have improved local control and sometimes survival in a number of randomized trials for head and neck,[7] lung,[8] and bladder cancer.[9] In the Danish head and neck study group, where efficacy of five vs six weekly radiotherapy fractions in squamous cell carcinoma of the head and neck region were compared; shortening the OTT improved locoregional control rates significantly by 10% without significant late toxicity.[7] This schedule has not been much investigated in carcinoma cervix. This study on pure accelerated regime of external beam radiotherapy (EBRT) given as six fractions per week was designed to reduce the OTT, thereby taking care of accelerated repopulation of malignant cells. This trial has made a comparison between accelerated radiotherapy and concurrent chemoradiotherapy in terms of toxicity, pelvic control, and survival to see whether this approach would be an effective option for the treatment of carcinoma cervix.


 > Subjects and Methods Top


This prospective randomized study was conductedat our institute from July 2010 till June 2011. Initial ethical clearance was taken according to the institutional guidelines. During the above mentioned period, 224 patients suffering from carcinoma of the uterine cervix of varying stages had presented at our institute (13% of all the malignancies). Over 131 patients were worked up. Out of 106 patients who were registered, 101 completed treatment and were evaluated. Signed informed consent was taken from all patients involved in the study. All the 101 patients were histologically proven invasive squamous cell, adeno and adenosquamous carcinoma of locally advanced stages (II, III International Federation of Gynecology and Obstetrics (FIGO) staging 2009), carcinoma cervix with Karnofsky performance status <60, normal renal and liver function tests, and aged less than 65 years.

Each patient underwent complete physical examination, including pelvic examination for clinical staging (under anesthesia if needed). Other investigations included complete hemogram, blood biochemistry, urine routine and microscopic examination, chest X-ray (posteroanterior (P-A) view), ultrasound abdomen and pelvis, and computed tomography (CT) abdomen and pelvis. To exclude the bladder involvement; urine cytology, cystoscopy, or intravenous pyelography was done in patients who were either symptomatic or showed bladder or rectum involvement on ultrasonography (USG) or CT.

Based upon the clinical stage, computer generated charts were used to randomize patients into the study or control group. In the study arm, patients underwent six fractions per week (accelerated) radiotherapy (ART) alone: 50 Gy for a total 25# in 4 weeks. In the control group (CRT), patients were treated with standard concurrent chemoradiotherapy. EBRT 50 Gy in 25 fractions within 5 weeks concurrently with injection cisplatin 40 mg/m 2 on D1 of every week. Intracavitary brachytherapy (ICBT) was given at the earliest (using Selectron remote controlled LDR system, 137Cs based), giving a dose of 35 Gy to point A. If the patients were not fit for ICBT, they were treated with supplement radiation therapy. A total of 20 Gy were given over 10 fractions at 200cGy per fraction over 2 weeks with injection cisplatin weekly in the control arm. In the study arm, 20 Gy was given in 10 fractions in 1.5 weeks at six fractions per week.

EBRT was given by teletherapy Theratron 780e and Equinox Cobalt 60 machines. Pelvic radiation was delivered by anteroposterior and posteroanterior parallel ports or a four-field box technique (anteroposterior, posteroanterior, and two lateral fields) for patients with separation greater than 20 cm. Minimum margins were the upper margin of L5 (superiorly), the lower margin of the obturator foramen or the lowest extension of the disease (inferiorly), and 1.5–2.0 cm beyond lateral margins of bony pelvis and its widest plane (laterally). For the lateral fields, the anterior margin was the anterior edge of symphysis. The posterior margin at the S2–S3 interspace was used. Midline shielding was added after 44 Gy to decrease the dose to bladder and rectum in both the arms so that intracavitary dose is not compromised and the total dose can be can be given upto 85 Gy.

The irradiated volume included the whole uterus, the paracervical, parametrium uterosacral regions as well as the external iliac, hypogastric, and obturator lymph nodes. Planned duration was 6–9 weeks. Radiotherapy was to be withheld if the patient had a leukocyte count less than 3,000 per mm 3 and delays of 1 week were to be allowed in the event of gastrointestinal or genitourinary toxicity. Patients were assessed at the end of treatment for disease response and every week for toxicities. Toxicities were monitored and Eastern Cooperative Oncology Group (ECOG) toxicity criteria were utilized to assess and document hematologic toxicities and the Radiotherapy and Oncology Group (RTOG) acute morbidity criteria to assess toxicities from radiotherapy.

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 till 1 year and subsequently 3 monthly. Patients were examined locally for any acute and late toxicity. Late toxicities were graded according to the RTOG criteria. Patients who were having persistent tumor were considered for salvage surgery if the disease was resectable. Adjuvant chemotherapy was administered in patients with unresectable disease.

Toxicity, response to treatment, overall survival (OS), and disease-free survival (DFS) were compared between the two arms. Survival time was measured from randomization. For OS, deaths regardless of any cause were taken as incidents; while for DFS, all recurrences (whether local or distant) and deaths due to any cause were considered as events. The distribution was estimated by product limit method. Logrank test was used to compare the survival differences between the different subgroups. Cox proportional hazards regression was used for hazard ratio. Fisher's t-test was used to compare proportions. P values less than 0.05 were considered significant. Medcalc software version 13.3.1 was used for statistical analysis.


 > Results Top


Of the 106 patients enrolled, 54 patients had been assigned to ART group and 52 to the CRT group. Five patients had been excluded. One had refused treatment after the first phase, one was found to have paraortic lymph nodes, and one with bone secondaries while on treatment. Two patients (one in each arm) had died of treatment-related causes. Fifty-one patients completed treatment in the study group and 50 patients in the control group [Figure 1].
Figure 1: Flowchart

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Patient's characteristics have been tabulated in [Table 1]. A significant number of our subjects had stage III disease with most of them presenting in 4th and 5th decades of life. The dominant histology was well-differentiated squamous cell carcinoma with majority of females having bilateral parametrial involvement. There were no significant differences among the treatment groups.
Table 1: Characteristics of patients

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During EBRT, delays in the ART arm were seen in five patients (7.7%) mainly due to gastrointestinal complications due to which the treatment had to be stopped. Treatment delay was seen in two (4%) patients in CRT arm due to gastrointestinal complications. The median treatment time for EBRT was 29 days in the study arm and 35 days in the CRT arm (P < 0.0001). In the CRT arm, 86% of the patients had received all of the planned 5-weekly cisplatin injections. Thirty-three patients were fit for ICBT in the ART arm, while 37 patients were fit in the CRT arm. No significant differences in these parameters were seen in the two groups. Median OTT in ART arm was 51 days and in CRT arm was 59 days. The difference was significant (P < 0.0001).

Response assessment

At the first follow-up at 6 weeks, complete responses were seen in 33 patients (65%) in the ART group and 42 patients (84%) in CRT group. The difference between the groups was statistically significant in favor of the control arm (P = 0.0397). But on subsequent follow-up examination at 3 months, the difference was neutralized, 40 (78%) patients had complete responses in the ART arm, while in the CRT arm 42 patients (84%) had complete responses (P = 0.6119).

Toxicities

Acute adverse events have been tabulated in [Table 2]. Hematotoxicity was seen mainly in the control group as compared to the study group (1.9% in the study group vs 12% in control group; (P = 0.031). Incidences of cutaneous toxicity of higher grades (Grade III or IV) were comparable in both the arms (13.7 vs 8%, P value nonsignificant). Gut toxicity was similar in both arms. In the study group it was Grade III or greater in 25.4% of the patients; whereas, the same in the control arm was 20% (P value insignificant). Two patients had died while receiving the treatment in each arm. In the ART group the death was due to gastrointestinal perforation secondary to subacute intestinal obstruction, while in the CRT arm the death was due to metabolic disturbances. Both the patients had preexisting cardiac comorbidities associated. Renal toxicity was observed in two (4%) patients in the CRT arm. Metabolic disturbances were identified mainly in the CRT arm (3 vs. 18%, P = 0.00279).
Table 2: Acute toxicities seen during treatment (<60 days)

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No significant differences in the late toxicities have been seen between the two arms.

Survival

At the median follow-up of 36 months, 19 patients (37%) in the ART arm had died as compared to 18 patients (38%) in the CRT arm. The relative risk of death was 1.0349 (95% confidence interval (CI) 0.6194–1.729) in the ART arm. The 3-year OS was 61% in the ART group in comparison to 62% in the CRT arm (P value = 0.9009) with a hazard ratio 1.042 (95% CI 0.5486–1.977) [Table 3]. Kaplan meier survival curves have been outlined in [Figure 2].
Table 3: Recurrence and survival status of patients

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Figure 2: Kaplan–Meier survival curves. (a) Disease-free survival and (b) overall survival. ART = Study arm (accelerated radiotherapy), CRT = control arm

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Of the 18 patients (35%) who had treatment failure in study group, 14 (27%) had local failure. One patient had relapsed in the paraortic lymph nodes, one had metastatic bone disease, one had lung metastasis, and two had relapsed at multiple sites. Seventeen (34%) had treatment failure in the CRT arm, 13 (26%) had local failure, and 1 patient each with lung and paraortic recurrence. Two patients had relapses at multiple sites. The relative risk of relapse being 1.0381 (95% CI 0.6074–1.7741) in the study arm. The DFS at 3 years was 60% in ART vs 64% in the CRT arm with a P value of 0.6411 (hazard ratio 1.168, 95% CI 0.6069–2.244) [Table 3].


 > Discussion Top


The recent Cochrane review on concurrent chemoradiotherapy shows a 6% absolute survival benefit and an 8% DFS benefit at 5 years in carcinoma cervix.[10] The survival benefit with increased follow-up is less than the 2001 meta-analysis. Moreover, there is suggestion of a decreasing relative effect of chemoradiotherapy on survival with increasing tumor stage, with estimated absolute survival benefit of 7% for stage IIB and 3% for stage IIIA–IVA at 5 years. The treatment failure in carcinoma cervix still remains primarily locoregional and improvisations in local therapy need to be made to improve the treatment results.

Our results indicate that the accelerated schedule of radiotherapy given 6 days a week was feasible in patients with locally advanced carcinoma of the cervix without excessive morbidity. The study intent was to produce a difference in treatment times between the two treatment arms by shortening the OTT and we were successful in this aspect. The treatment time was significantly less during EBRT as well as overall (P < 0.0001). Hematotoxicity, renal toxicity, and metabolic toxicities were mainly seen in the control arm (P = 0.031, P value insignificant, and P = 0.0279, respectively). Rest of the toxicities in the ART group was comparable to the standard chemoradiation arm. At initial examination, the local response was found to be better in the CRT arm (P = 0.0397), but on subsequent follow-up examinations the difference was diluted. Thus, as compared to the ART arm the CRT schedule acted swiftly, while the study arm took some time to exhibit its optimal response. At 3 months, equivalent efficacy was seen with both the regimes in terms of complete responses. At a median follow-up of 36 months, both the arms were equally successful in terms of OS as well as DFS.

Accelerated radiotherapy in carcinoma cervix has not been an extensively researched topic. Extending a similar argument to carcinoma cervix, a phase II study was conducted at Samsung Medical Center, Seoul evaluating sixweekly fractions of EBRT with high-dose rate (HDR) brachytherapy. 50.4 Gy had been given at 1.8 Gy per fraction in the accelerated schedule followed by ICBT. The study had included patients with smaller tumors and stages as compared to our study with no of patients with < 5 cm tumor diameter constituting 67.4% andstages < IIA constituting 20% of tumors, while stage IIIB constituted only 20% of the tumors. This study had the limitation of a small study group (43 patients) and cases included were older patients (> 65), those with co morbidities, cases not found to be good for concurrent chemoradiation, the tolerability and efficacy of this scheme was found to be good. The 3-year OS, locoregional, and distant metastasis-free survival rates were 74.7,87.8, and 84.7%, respectively. Thus, it was presented as a possible alternative to concomitant chemotherapy in elderly patients and or those with comorbidity without increased toxicities.[11]

In another nonrandomized trial by Roy et al., 60 patients were enrolled. Half the patients received accelerated EBRT (six fractions weekly), while the other half received standard CRT regime. This was followed by ICBT in both the arms. The early responses of the study arm were comparable to concurrent chemoradiation and this regime had shown lesser toxicities for the ART arm. At a median follow-up of 15 months, the DFS was comparable between the two arms.[12]

Ours was a randomized trial, though it was not without its limitations. The number of patients was not much, it was a single institutional study which has its own biases and a fewer patients had underwent brachytherapy. Our study had a significant proportion of higher stage patients and most of the patients had bilateral parametrial involvement.

The study results establish the fact that this schedule of six fractions per week radiotherapy is an attractive and affordable option for carcinoma cervix patients with lesser toxicity and needs to be explored further. In the developing countries with less resources and many high volume centers, such a plan can also help in optimization of available radiotherapy setups and treating a larger number of patients. It is the developing countries like India that face the maximum burden of carcinoma cervix and novel strategies need to be tried. Besides it can be viewed as an equally effective option for the elderly, patients who refuse, have contraindications to chemotherapy or have comorbidities.

To conclude, the accelerated fractionation regime of six fractions per week EBRT followed by ICBT has been seen to be equally efficacious as concurrent chemoradiation in our study. The results will increase our options of treating carcinoma cervix. This approach can definitely be a potent and more tolerable option for selected patients of locally advanced carcinoma cervix who cannot undergo definitive chemoradiation.

 
 > References Top

1.
Globocan 2012 Cancer statistics. Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx [Last accessed on 2014 Jul 10].  Back to cited text no. 1
    
2.
NCI Press Office NCI Issues Clinical Announcement on Cervical Cancer: Chemotherapy plus Radiation Improves Survival. Available from: http://www.nih.gov/news/pr/feb99/nci-22.htm [Last accessed on 2014 Jul 15].  Back to cited text no. 2
    
3.
Ohno T, Nakano T, Kato S, Koo CC, Chansilpa Y, Pattaranutaporn P, et al. Accelerated hyperfractionated radiotherapy for cervical cancer: Multi-institutional prospective study of forum for nuclear cooperation in Asia among eight Asian countries. Int J Radiat Oncol Biol Phys 2008;70:1522-9.  Back to cited text no. 3
    
4.
Kavanagh BD, Gieschen HL, Schmidt-Ullrich RK, Arthur D, Zwicke r R, Kaufman N, et al. A pilot study of concomitant boost accelerated super fractionated radiotherapy for stage III cancer of the uterine cervix. Int J Radiat Oncol Biol Phys 1997;38:561-8.  Back to cited text no. 4
    
5.
MacLeod C, Bernshaw D, Leung S, Narayan K, Firth I. Accelerated hyperfractionated radiotherapy for locally advanced cervix cancer. Int J Radiat Oncol Biol Phys 1999;44:519-24.  Back to cited text no. 5
    
6.
Faria SL, Ferrigno R. Hyperfractionated external radiation therapy in stage IIIB carcinoma of uterine cervix: A prospective pilot study. Int J Radiat Oncol Biol Phys 1997;38:137-42.  Back to cited text no. 6
    
7.
Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomized controlled trial. Lancet 2003;362:933-40.  Back to cited text no. 7
    
8.
Ball D, Bishop J, Smith J, O'Brien P, Davis S, Ryan G, et al. A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: Final report of an Australian multi-centre trial. Radiother Oncol 1999;52:129-36.  Back to cited text no. 8
    
9.
Horwich A, Dearnaley D, Huddart R, Graham J, Bessell E, Mason M, et al. A randomized trial of accelerated radiotherapy for localized invasive bladder cancer. Radiother Oncol 2005;75:34-43.  Back to cited text no. 9
    
10.
Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: Individual patient data meta-analysis. Cochrane Database Syst Rev 2010;14.  Back to cited text no. 10
    
11.
Yoon SM, Huh SJ, Park W, Lee JE, Park YJ, Nam HR, et al. Six fractions per week of external beam radiotherapy and high-dose-rate brachytherapy for carcinoma of the uterine cervix: A phase I/II study. Int J Radiat Oncol Biol Phys 2006;65:1508-13.  Back to cited text no. 11
    
12.
Roy C, Bhanja Choudhury K, Pal M, Chowdhury K, Ghosh A. Pure accelerated radiation versus concomitant chemoradiation in selected cases of locally advanced carcinoma cervix: A prospective study. J Obstet Gynaecol India 2012;62:679-86.  Back to cited text no. 12
    


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