|Year : 2019 | Volume
| Issue : 6 | Page : 1296-1303
A comparison of six fractions per week chemoradiation versus five fractions per week of conventional chemoradiation in carcinoma cervix: A prospective controlled study
Deepak Kumar1, Satyajit Pradhan2, Sunil Choudhary2, Lalit M Aggarwal2, Avipsa Das2, Sovan Sarangdhar2, Prashant Kaser2, Satish Dewangan2
1 Department of Radiotherapy and Radiation Medicine, Banaras Hindu University, Varanasi, Uttar Pradesh; Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiotherapy and Radiation Medicine, Banaras Hindu University, Varanasi, Uttar Pradesh, India
|Date of Submission||03-Sep-2019|
|Date of Decision||29-Oct-2019|
|Date of Acceptance||30-Oct-2019|
|Date of Web Publication||24-Dec-2019|
Dr. Deepak Kumar
H-19/95 Sector -7, Rohini, New Delhi - 110 085
Source of Support: None, Conflict of Interest: None
Aims: The standard of care for carcinoma cervix stage IB2-IVA is five fractions per week of radiotherapy (RT) with concurrent cisplatin. We compared the standard treatment with six fractions per week of RT with concurrent Cisplatin to see whether the later had improved survival outcomes with comparable toxicities.
Settings and Design: 46 patients of carcinoma cervix with stage IB2-IVAwere randomized into two arms.
Materials and Methods: Study arm: 46 Gy/23 fractions/26 days, 6 fractions/week with injection CDDP 40 mg/m2 and Control arm: 46 Gy/23 fractions/31 days, 5 fractions/week with injection Cisplatin 40mg/m2. Patients in both the arms received LDR brachytherapy to a dose of 29 Gy at point A.
Statistical Analysis Used: The primary end points were disease-free survival (DFS) and overall survival (OS). Compliance to treatment and treatment toxicities were the secondary end points. P value ≤0.05 were considered significant.
Results: The study was carried out during June, 2014–April, 2015. Statistical analysis was done in May, 2019. Of 46 patients, 39 patients completed the treatment. The study and control arms had 17 and 22 patients, respectively. Median follow-up period is 45 months (range: 1–54 months). 3-year DFS rates and OS was 69.5% vs. 72.7% (P = 0.73) and 63% vs. 68% (P = 0.45) in study and in control arm, respectively. There was no significant difference in acute and late radiation toxicities between two arms.
Conclusion: Chemoradiotherapy with six fractions per week seems feasible and equally efficacious in terms of survival outcomes and toxicity profile. Further prospective randomized controlled study is required to prove the merit of altered fractionation with concurrent cisplatin.
Keywords: Carcinoma cervix, chemoradiation, Cisplatin, six-fraction radiotherapy
|How to cite this article:|
Kumar D, Pradhan S, Choudhary S, Aggarwal LM, Das A, Sarangdhar S, Kaser P, Dewangan S. A comparison of six fractions per week chemoradiation versus five fractions per week of conventional chemoradiation in carcinoma cervix: A prospective controlled study. J Can Res Ther 2019;15:1296-303
|How to cite this URL:|
Kumar D, Pradhan S, Choudhary S, Aggarwal LM, Das A, Sarangdhar S, Kaser P, Dewangan S. A comparison of six fractions per week chemoradiation versus five fractions per week of conventional chemoradiation in carcinoma cervix: A prospective controlled study. J Can Res Ther [serial online] 2019 [cited 2021 Jun 22];15:1296-303. Available from: https://www.cancerjournal.net/text.asp?2019/15/6/1296/273820
| > Introduction|| |
The NCI alerted in 1999s on the basis of five phase III randomized studies, whose results demonstrated that the addition of chemotherapy to radiotherapy (RT) enhances the radiation effect.,,,,,
Although concurrent chemoradiotherapy is the standard of care in many developed countries, this technique has been questioned by some authors for the treatment in bulky disease due to prohibitive toxicity and discontinuation of RT in developing nations. Prolonged treatment courses need to arrange for a suitable stay at a place away from home for a long period, and lengthy travel to RT center everyday results in discontinuation of effective RT treatment. Hence, these challenges are another factor to decrease local control.
Studies have reported optimal treatment time for cancer cervix to be 7 weeks, and after this period, repopulation of tumor clones results in radioresistance.
To circumvent these issues, altered fractionation could be an option to increase the tumor dose or decrease the treatment time and has already been explored previously in other sites, i.e., head and neck cancer (H and NC), lung cancer, and rectal cancer.
In carcinoma cervix, fractionation schemes such as hyperfractionation and hypofractionation had been previously tried to enhance therapeutic ratio.,,, The results had shown altered fractionation alone had comparable outcome to conventional fractionation with local control and survivals but had increase treatment toxicities. Hence, further studies were not prompted over conventional chemoradiation.
Another fractionation scheme which could also be an option to improve clinical outcome by decreasing treatment time is accelerated fractionation, i.e., treatment on weekends.
Yoon et al. and Roy et al. in their early results have shown that accelerated fractionation alone is safe and noninferior to concurrent chemoradiotherapy., Meta-analysis by Green et al. has shown that concurrent chemoradiation improved tumor control and progression-free survival compared to RT alone in patients of carcinoma cervix.
These results show that accelerated RT alone has equivalent therapeutic effects compared to conventional concomitant chemoradiotherapy. Hence, a hypothesis can be put forth that the combination of accelerated RT along with chemotherapy should result in therapeutic gain compared to conventional chemoradiotherapy.
Chemotherapy with altered fractionation is considered toxic, especially in pelvic region; however, data from phase I dose escalation studies by GOG 8801 and GOG 8901 have shown that it could be a feasible option with tolerable side effects.
However, studies involving accelerated fractionation schedules (6 fractions per week) concurrent with chemotherapy in carcinoma cervix have never been explored.
The present study compares 6 fractions per week of radiation with concurrent chemotherapy versus conventional chemoradiation using 5 fractions per week. The purpose is to explore advantage of reducing treatment time to translate in clinical outcome.
| > Materials and Methods|| |
This prospective controlled study involving 46 patients was conducted from June 2014 to April 2015.
Ethical clearance was done from the Institute Ethics Committee before the start of study. Written and inform consent was obtained from patients before recruitment in the study.
Patients and characteristics
Patient inclusion criteria were histopathological proven cases of carcinoma cervix (squamous cell carcinoma (SCC), adenocarcinoma, or adenosquamous carcinoma), disease Stage IB2-IVA, age ≤60 years, ECOG performance status grade 0–2, no prior history of cancer, or synchronous malignancy, hemoglobin level >8 mg/dl, Total Leukocyte count (TLC) >4000/mm 3, platelet count >100000/mm 3, serum creatinine-0.6–1.5 mg/dl, and written informed consent of the patients. Baseline hemoglobin level during treatment has been kept ≥10 mg/dl.
Exclusion criteria were poor performance status and derange hemogram or blood chemistry.
Patients were clinically evaluated, and physical character and extension of disease were assessed and recorded. Clinical Staging was done using FIGO 2009 Staging System. Para-aortic sampling was not done.
Radiological assessment was done in each patient with Contrast enhance computed tomography (CECT) of whole abdomen and pelvis, X-ray chest Posteroanterior (PA) view and with elctrocardiogram (ECG). When suspicion of bladder and rectum involvement was present, cystoscopy and colonoscopy were performed, respectively.
Patients enrolled for the study were included either in study arm or control arm. Matching for age at interval of 5 years and stage was done during inclusion of patients between the two arms.
Patients under study arm received concurrent chemoradiation with radiation delivered in six fractions per week from Monday to Saturday. Patients in control arm received concurrent chemoradiation with radiation delivered in five fractions per week.
Pelvic RT was planned using either two parallel opposed anterior posterior radiation portals (pelvic separation ≤18 cm) or four field box technique (>18 cm). Using a telecobalt unit, the dose delivered was 46 Gy in 23 fractions with 2 Gy per fractions. External beam radiation therapy (EBRT) was planned to be completed in 26 days (3 weeks and 5 days) in study arm and in 31 days (4 weeks 3 days) in control arm.
Intracavitary application was done 1 week following completion of EBRT using Fletcher Suit applicator with appropriate uterine tandem and ovoids' combination. Toxicity assessment of patient was done before the procedure. A dose of 29 Gy was delivered to point A using low-dose rate (138 cGy/h) system through Cesium-137 source.
Total duration of treatment of patient was kept as 33 days (4 week and 5 days) in study arm and 38 days (5 week 3 days) in control arm.
Patients received weekly cisplatin at a dose of 40 mg/m 2 weekly (each Monday) with necessary premedication and hydration. Chemotherapy was given 1–4 h before radiation. Patients were assessed weekly with hemogram and clinical chemistry. Creatinine Clearance (Cockroft–Gault formula) was calculated for dose modification if any, before administering chemotherapy.
Treatment induced toxicity assessment was done weekly during treatment and on each follow-up for systemic toxicities of skin, gastrointestinal. genitourinary and in hematological system.
Chemotherapy and radiation therapy were withheld in case of Grade III/IV toxicity, absolute neutrophil count <1000/mm 3, or platelet count <50,000/mm 3. Appropriate delay was allowed for recovery. Intravenous antibiotic was injected when the patient developed febrile neutropenia. Acute toxicity was recorded as toxicities occurring within 3 months (90 days) of completion of treatment. Late toxicity was recorded as any toxicities post 3 month of treatment.
Follow-up and response evaluation
Follow up was done at intervals of 1 month for the first three visits and then every 3 months up to 2 years, 6 monthly for 2nd–5th year, and thereafter annually.
Response assessment was done according to WHO criteria. Complete response: complete regression of the disease, partial response: as at least >50% reduction in tumor size, and stable disease: as no change or a <50% reduction. Progressive disease: >25% increase of one or more lesions, or appearance new lesions.
Suspicion of a recurrence or distant failure was confirmed by histology from lesion along with CECT abdomen or ultrasonography whole abdomen.
Primary endpoints was to assess and compare response to treatment, disease-free survival (DFS), locoregional control, and overall survival (OS) rates between the treatment arms. Secondary endpoints were to compare compliance to treatment and treatment-related toxicities between two arms. Patterns of failure and recurrences were also studied.
Statistical analysis was done in May 2019. Chi-square test and Fisher's exact probability test were used to compare baseline characteristics, response rate, treatment characteristics, and toxicities among both arms. DFS and OS were estimated by Kaplan and Meir survival plot. Comparison of survival between two arms was done by Log rank test. P < 0.05 was considered as statistically significant. Statistical software package SPSS version 16.0 (SPSS Inc., Chicago, IL, USA 2007) was used for data analysis.
| > Results|| |
Of 46 patients, enrolled in the study, 22 were in study arm and 24 in control arm. Seven (5 - study arm and 2 - control arm) patients did not complete planned treatment. Finally, 39 patients were assessable, 17 patients were study arm, and 22 patients in control arm [Figure 1]. Demographic profile of patients in both arms is described in [Table 1]. Median age of presentation was 50 years, and 53.8% (21/39) was multiparous. Majority of patients had SCC as most common histology. Distribution of patients among different stages was not significantly different in both the arms.
|Figure 1: Flow chart showing randomization and assessable patient in both study and control arm|
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|Table 1: Demographic profile of patients and tumor characteristics between study arm and control arm|
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Median duration of completion of external beam radiation was 28 days in contrast to planned 26 days in study arm and was 31.5 days against planned 31 days in control arm (P = 0.004) [Table 2]. The difference in treatment time in the two arms was significant (P = 0.011). Equivalent dose in 2 Gy per fraction (EQD2) in both the arms is 71.8 Gy. However, considering time factor in treatment EQD2 in study arm and control arm is 63.8 Gy and 61.3 Gy respectively.
Median duration of follow-up was 44.0 months (range, 1–54 months) and 45 months (range, 3–53 months) in study and control arm (P = 0.51), respectively.
At first follow-up, majority of patients had complete clinical response in both the arms. Treatment outcomes are described in [Table 3].
|Table 3: Response to treatment and outcome among study arm and control arm|
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Locoregional control rates was 76.4% (13/17) and 72.7% (16/22) in study arm and control arm, respectively. One patient each in study arm and control arm died without disease. Median survival was 46 months versus 47.5 months in study arm and control arm, respectively (P = 0.46).
At last follow-up, 3-year DFS rates were 69.5% versus 72.7% in study arm and in control arm, respectively (P = 0.73), and 3-year OS is 63% (11/17) versus 68% (15/17) (P = 0.70) [best scenario; [Figure 2] and 59% (10/17) versus 68% (15/17) (P = 0.49) [worst scenario; [Figure 3] in study arm and control arm, respectively. There were no statistical significant difference in terms of response to treatment, local control, and OS.
|Figure 2: Kaplan–Meier survival plot showing probability of survival in months between two arms of study, 3-year overall survival - 63% versus 68% P = 0.70 (best scenario)|
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|Figure 3: Kaplan–Meier survival plot showing probability of survival in months between two arms of study, 3-year overall survival 59% versus 68%, P = 0.4 (worst scenario)|
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Severe grades of toxicities as grade III and grade IV among study versus control arm as skin toxicity were 2/17 Vs 0/22 (P=0.44), GI were 2/17 Vs. 6/22 (P=0.05), and in hematological system were 1/17 Vs. 1/22 (P=0.86) [Table 4]. One patient both from study and control arm developed Grade 4 hematological toxicity as pancytopenia and so managed by blood transfusion, IV antibiotic, and platelet transfusion. At first follow-up, i.e. after 1 month of treatment, toxicities in all system were reduced to Grade 0–2 and after 90 days, toxicities in all system were reduced to Grade 0–1 in majority of the patients.
Late toxicities was manifested mainly as Grade I–II rectal bleeding except in one patient belonging to control arm suffered Grade IV GI toxicity as rectal stricture after a year of treatment and required surgical intervention [Table 4].
| > Discussion|| |
Carcinoma cervix in India is ranked as third most common (8.4%) cancer in both sexes and second most common (16.5%) among females. Total incidence rate is 96,922 cases per year and with total 60,078 deaths per year. Cochrane meta-analysis has shown graded survival benefits between stages of disease from chemoradiotherapy over radiation alone. It has analyzed 5-year OS advantage of 10% at Stage IB-IIA, 7% for IIB, and 3% in Stage III-IVA.
The cure rate of SCC depends on overall treatment time due to accelerated repopulation of tumor clonogens. After a definite period, on an average, a dose increment of 0.6 Gy per day is required to overcome the clonogenic regeneration. It starts at 3rd week (19 days) of radiation therapy in carcinoma cervix.
Mean treatment duration in the study arm was 37 days (range 34–47) and 41 days in control arm (range 33–65 days). The range in the control arm was wide as one patient underwent late intracavitary application because of financial constraints. Treatment time extended for >38 days in 6 patients of study arm because intracavitary treatment was delayed in three patients due to Grade III/IV hematological toxicities and others had some logistic issues. Furthermore, treatment delay >42 days in 5 patients in control arm patients was due to their financial strain. Reasons were cost for their stay during treatment although treatment charges were waived off for all.
The benefits of reduction of treatment time are illustrated elegantly by Overgaard et al., through the famous DHANCA-6/7 study. One week reduction in treatment time resulted in a significant therapeutic gain.
Since SCC of cervix has similar radiobiological properties as of H and NC, outcome of altered fractionation on head and neck may be extrapolated in cervical cancer.
Yoon et al. in their phase I/II study in 43 patients with Stage IB1-IIIB used 6 fractions per week of external RT alone followed by high dose rate brachytherapy in patients with carcinoma cervix and obtained a 3-year OS, loco-regional control, and distant metastasis free survival rates of 74.4%, 87.8%, and 84.7%, respectively.
Another study similar to above by Roy et al., among 60 patients of carcinoma cervix with Stage IB2-IIIB, results shown that after a median follow-up of 15 months early response to treatment using pure accelerated radiation alone was as equivalent to conventional chemoradiation.
However, the present study did not show therapeutic advantage as per our hypothesis, could be attributed to two possible reasons, i.e., first, the sample size of present study is small (n = 39) so it is difficult to draw a significant difference between two arms of study. Second, the planned dose of chemotherapy was 4 cycles in accelerated chemoradiotherapy arm compared to 5 cycles in conventional chemoradiotherapy arm (16% higher in conventional arm). Hence, one cycles less of chemotherapy might have partly masked the effect of acceleration.
There is lack of comparable data similar to the present study in carcinoma cervix. However, two randomized phase III, controlled trials with similar concept to the current study had already been carried out in locally advanced H and NC. GORTEC 99-02, with stage III-IV (nonmetastatic) H and NC, consisted of three arms: conventional chemoradiotherapy (n = 279) versus chemoradiotherapy with accelerated fractionation (n = 280) versus very accelerated RT (n = 281) alone. Another similar study, RTOG 0129, included 721 patients with Stage III-IV H and NC, and compared patients receiving two cycles at 3 weekly interval of concomitant chemotherapy (cispatin 100 mg/m2) plus 72 Gy RT in 6 weeks with patients receiving three cycles of Cisplatin chemotherapy plus conventional 70 Gy RT in 7 weeks. These studies did not observe added benefits of accelerated radiation therapy with concomitant chemotherapy when compared with conventional chemoradiotherapy.
Both studies reported that the expected therapeutic gain of acceleration of RT has been compensated by extra chemotherapy cycles administered in the conventional schedule, a similar finding in the current study.
Cumulative dose of cisplatin need to be administered for concurrent chemo-RT in carcinoma cervix is still not established. Concurrent chemotherapy given as cisplatin even in landmark five randomized their cumulative dose varies between 100 mg/m2–150 mg/m2.,,,, In our study, cumulative dose of cisplatin in accelerated arm was 160 mg/m 2 compared to 200 mg/m 2 in conventional arm. A retrospective multi-institutional study from India, analyzed 1930 patients with Stage IIB-IVA, and observed that best survival are seen with optimal RT (Dose ≥45 Gy) and ≥150 mg as cumulative dose of cisplatin during whole course of RT. Furthermore, mean and median number of chemotherapy cycles was four, and 66% of patient received 4 or more cycles of cisplatin (40 mg/m 2) in conventional fractionation schedule. Considering this as evidence, patient in study arm also received at least 4 cycles of chemotherapy and with an acceptable cumulative dose.
The basic mechanism of different fractionation schemes to increase the therapeutic effects by either decrease the treatment time or increase the dose delivered to the tumor.
Therefore, the equation for calculation of biological effective dose (BED) with incorporating time factors as treatment duration (T) and tumor doubling time teff.
BED = nd (1 + d/α/β) − 0.693/α.teff(T–Tk)
Where n is the number of fractions, d dose per fraction, α/β is tissue respond to fractionation and dose rate, Tk is kick off time or time to start repopulation (21 or 28 days), teff is potential cell doubling time (3.5–5 days). The entity 0.693/α.teff can be expressed as constant K and is calculated as 0.6 Gy/day. It is the dose wasted due to accelerated repopulation of tumor cells if treatment time extends beyond Tk.
Hence, the simplified equation of BED is:
BED = nd (1 + d/[α/β]) −0.6 (T-21)
Considering time factor for calculation of BED for early reacting tissue (α/β =10), BED10 at point A in study arm was 76.6 Gy, and for control arm, it was 73.6 Gy. There is an incremental benefit of 3 Gy (4%) in dose on acceleration of radiation. Dose of radiation prescribed in current study is as per the department protocol.
Altered fractionation in the pelvic region is considered to be toxic because the rapidly dividing tissues of bowel and bladder come in the treatment field and cause unacceptable acute side effects. However, toxicity in the present study was comparable and well tolerated by patients between the two treatment arms.
Compared to control arm, 2 patients in study arm developed severe skin toxicity and appropriate delay was given for recovery. Due to Grade IV hematological toxicity in one patient from each arm, treatment was withheld for 8 days and 3 days in study arm control arm, respectively. Furthermore, patients were treated on telecobalt unit, and so, toxicity could have been more curtailed if treated with conformal techniques on a linear accelerator unit.
However, results of the current study should be considered with caution as the number of patients receiving chemoradiotherapy is small (study arm n = 17, control arm n = 22) which is a major limitation of this study. Furthermore, our assumptions of equivalence of accelerated RT to conventional chemoradiotherapy are based on results of phase II studies.
One major observation of present study is that 19/22 (86.4%) of patient completed their treatment in study arm as per schedule. This suggests feasibility of carrying out accelerated fractionation with concurrent cisplatin. This can also be advantageous in reducing the need of additional one more cycle of chemotherapy. So, this precludes systemic toxicity from chemotherapy and also financial, mental, physical burden related to treatment course.
| > Conclusion|| |
Concomitant chemoradiotherapy with accelerated fractionation (6 fractions per week) can be a feasible treatment modality for patients with carcinoma cervix. The absence of therapeutic gain is accounted due to a missed dose of chemotherapy in accelerated RT arm.
Overall treatment time is reduced by 5 days and also relief from administration of additional one more cycle of chemotherapy. Acute and late toxicities from treatment are comparable between the arms. Hence, these benefits could be translated in treatment for carcinoma cervix cases, especially in developing countries where any shortening of the treatment time could result in a partial relief of the financial burden resulting from outstation stay for prolonged periods during the period of treatment.
Does outcome of the present study could be replicated on large sample size without significant acute and late toxicity still needs to be explored? Further, phase II/III studies are needed to assess the need and benefit if any, of acceleration of RT along with chemotherapy in patients with carcinoma cervix.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]