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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 100-104

A comparative study of hyperfractionated radiotherapy versus conventional radiotherapy with concurrent chemotherapy for the treatment of locally advanced squamous cell carcinoma of the cervix


1 Department of Radiation Oncology, S. N. Medical College, Agra, Uttar Pradesh, India
2 Department of Radiation Oncology, AIIMS, Rishikesh, Uttarakhand, India
3 Department of Pathology, S. N. Medical College, Agra, Uttar Pradesh, India
4 Department of Obstetrics and Gynaecology, S. N. Medical College, Agra, Uttar Pradesh, India

Date of Submission21-Jun-2020
Date of Decision13-Jul-2020
Date of Acceptance29-Jul-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Dr. Pragya Singh
Department of Radiation Oncology, AIIMS, Rishikesh, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_30_20

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  Abstract 


Aim: The aim of the study was to see the feasibility of hyperfractionated radiotherapy with concurrent chemotherapy in the treatment of locally advanced carcinoma cervix and to evaluate the result in terms of locoregional control, acute toxicities, weekly tumor regression rate, and radiation dose required for 50% and 80% reduction of previous tumor volume and to compare results with standard protocol in a retrospective manner. Materials and Methods: A pilot study of patients of carcinoma uterine cervix FIGO Stage IIB to IVA was undertaken. The study group consisted of 11 patients, treated by hyperfractionated schedule of 60 Gy/50 fractions/5 days/week over 5 weeks. Two fractions of 120 cGy per fraction per day were given at interval of 6 h. Injection cisplatin (50 mg/m2) I/V was administered on day 1, followed by injection 5-fluorouracil (750 mg/m2) I/V for 5 days, and the same regimen was repeated in the last week of external radiotherapy. After observing encouraging results, we compared our study with standard protocol in a retrospective manner which included 11 patients as a control group, who were treated by conventional fractionation of 50 Gy/25 fractions, 2 Gy/fraction/5 days/week for 5 weeks with injection cisplatin 50 mg I/V weekly. Results: The observed complete response was 72% and 81.8% in the control and study groups, respectively. Acute toxicities such as nausea, vomiting, and anemia were observed slightly higher in the study group, but all were well managed. The weekly tumor regression rate was much better in the study arm. Treatment-resistant depression (TRD) 50 and TRD80were also in favor of the study arm. Conclusion: Hyperfractionated radiotherapy along with concurrent chemotherapy has produced a promising local control of locally advanced cervical cancer with an acceptable complication rate as compared to standard protocol.

Keywords: Concurrent chemotherapy, conventional radiotherapy, hyperfractionated radiotherapy, treatment-resistant depression 50, treatment-resistant depression 80, tumor regression rate


How to cite this article:
Gupta S, Singh P, Tyagi A, Agrawal P, Singh S. A comparative study of hyperfractionated radiotherapy versus conventional radiotherapy with concurrent chemotherapy for the treatment of locally advanced squamous cell carcinoma of the cervix. J Radiat Cancer Res 2020;11:100-4

How to cite this URL:
Gupta S, Singh P, Tyagi A, Agrawal P, Singh S. A comparative study of hyperfractionated radiotherapy versus conventional radiotherapy with concurrent chemotherapy for the treatment of locally advanced squamous cell carcinoma of the cervix. J Radiat Cancer Res [serial online] 2020 [cited 2020 Dec 5];11:100-4. Available from: https://www.journalrcr.org/text.asp?2020/11/3/100/296553




  Introduction Top


Cervical cancer is the fourth most common cancer affecting women worldwide, with 528,000 new cases every year.[1] India shares more than one-fifth of cancer burden contributing approximately 6%–29% of all female cancers.[2] Its incidence is 30.7/100,000 women with peak of occurrence between 55 and 59 years.[1] Every year, approximately 67,477 females die due to this disease.[3] Etiology includes poor genital hygiene, multiple sexual partners, first coitus at younger age, early childbirth, human papillomavirus and sexually transmitted disease infection, and immunocompromised status.[4] Most of the patients present in advanced stage.

After the National Cancer Institute alert in 1999, concomitant cisplatin-based chemoradiotherapy has become a widely used protocol for treating locally advanced carcinoma cervix.[5] Standard treatment for locally advanced stage is now concurrent chemoradiotherapy. Concurrent chemotherapy has a synergistic effect with radiation by increasing cell killing and radiosensitization in a hypoxic environment.

Altered fractionated approach has shown promise to increase therapeutic ratio by better tumor control and the same or slightly increased early toxicities when compared to standard regimen. Hyperfractionation shows improved tumor control by increasing total dose delivery. Delivering a smaller dose per fraction allows a normal cell to regenerate fully as sufficient time is given in between fractions and simultaneously decreasing tumor repopulation and increasing reoxygenation.


  Materials and Methods Top


This study was conducted at our institute from January 2016 to June 2017 after taking approval from the institutional ethical committee and obtaining written consent from individual research participants. For this pilot study, previously untreated 11 patients of carcinoma cervix were enrolled. All patients were biopsy-proven squamous cell carcinoma of FIGO Stage IIB to IVA. The control arm involved 11 patients which were biopsy-proven squamous cell carcinoma and were taken for retrospective analysis. Patients for the control group were taken randomly from a previous study assessing weekly tumor response of standard regimen. Patients with Karnofsky Performance Status of 70–100 were included in this study. Pretreatment evaluation included history, physical examination, and local examination. Investigations included hematological, biochemical examination, chest X-ray, ultrasonography abdomen and pelvis, contrast-enhanced computed tomography abdomen and pelvis, proctoscopy, and cystoscopy (if required).

In the study group, patients received twice-daily radiation doses of 1.2 Gy/fraction to the whole pelvis by two-field/four-field technique at 6-h intervals, 5 days/week up to total dose of 60 Gy in 50 fractions in 5 weeks. Radiotherapy was delivered by Theratron Phoenix Cobalt-60 teletherapy machine after surface marking of treatment fields and verification by marker X-rays. Dose was calculated at a tumor center. For radiotherapy treatment, comfortably filled bladder protocol was followed for each patient. Chemotherapy was given in weeks 1 and 5 of radiotherapy. Injection cisplatin was given on day 1 of the 1st week of pelvic external radiation at a dose of 50 mg/m2 I/V before radiotherapy. Injection 5-fluorouracil was initiated after the injection cisplatin at a dose of 750 mg/m2/day as a continuous intravenous infusion for 5 days. This same regimen was repeated during the last week of the external beam radiation. For the control group, those patients, who received external beam radiotherapy of total dose of 50 Gy/25 fractions in 5 weeks, along with injection cisplatin 50 mg weekly were taken. Demographic profile of patients, tumor characteristics, weekly treatment response, and acute toxicities data were collected from patient's clinical file maintained for an individual patient in the department.

Before initiation of chemotherapy, premedication and intravenous hydration were given to each patient. Both the groups received intracavitary radiotherapy of 7 Gy to point A per fractions up to 3 fractions by high-dose-rate microselectron, 1 week apart. Intracavitary radiation therapy (ICRT) was given 1 week after completion of external beam radiation therapy (EBRT). For ICRT, Fletcher Suit applicator was used and dose was calculated as per Manchester planning system. Bladder points and rectal points were taken as limiting factors.

Locoregional response was assessed by weekly ultrasonography of the whole abdomen and pelvis. Weekly tumor regression rate, treatment-resistant depression (TRD) 50, and TRD80 were recorded for each patient. Patients were monitored for skin, vaginal mucosa, upper and lower gastrointestinal, genitourinary, and hematological toxicities on a weekly basis. The Radiotherapy and Oncology Group Criteria were used to assess the toxicity. Response assessment was done according to the WHO criteria, and complete response was considered as complete disappearance of clinically evident tumor after completion of radiotherapy. Partial response was defined as >50% reduction in the product of two perpendicular diameters of tumor. No response was considered as no clinically detectable change in disease after treatment completion.

For statistical analysis, data were collected and entered in Microsoft Excel spreadsheet. All care was taken to ensure that there is no data entry error. Categorical variables were described as frequency and proportion. Continuous variables were described as mean ± standard deviation. We compared proportions using Chi-square test and Fisher's exact test as and when required. The means in the two groups were compared using Student's t-test. P < 0.05 was considered statistically significant. The data was analysed using SPSS version 20.0, manufactured by IBM, Armonk, New York, U.S.


  Results Top


The majority of the patients were below 50 years of age, while the mean age was 47 years in both the groups. Most of the patients were with parity of 3–6. The majority of them presented with blood mixed discharge per vaginum as a chief complaint. The majority of the patients represented with Stage IIB. Ulceroproliferative growth was a common pattern. Well-differentiated squamous cell carcinoma was dominant histology in both the groups [Table 1].
Table 1: Patient's demography profile

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Cutaneous and mucosal toxicities were similar in both the groups. Gastrointestinal toxicity was greater in the study group but was manageable and did not cause any interruption of treatment. Genitourinary Grade 2 toxicity was similar in both the groups.

Hematological toxicities of higher grade were observed in the study arm, but all were well managed. Anemia was managed by blood transfusion. The fall in white blood cell count was transient, and a patient recovered with symptomatic management in the form of I/V antibiotics. Thrombocytopenia was similar in both the arms. Statistically, the difference in toxicities was nonsignificant [Table 2].
Table 2: Acute toxicity during external beam radiotherapy

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Out of 11 patients in the study group, 81.8% of the patients showed complete response 1 week after the completion of EBRT as compared to 72.72% in the control group. The partial response in the study and control groups was 18.18% and 27.27%, respectively [Table 3].
Table 3: Tumor response after completion of external beam radiation therapy

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In the study arm, average tumor regression was 46.08%, 75.58%, 92.66%, and 95.41% at the 2nd week, 3rd week, 4th week, and 5th week. Consecutively, while in the control arm, theses values were 3.07%, 56.65%, 79.10%, and 95.5%. In the study arm, tumor regression was far better from the 2nd to 4th week, but at the end of the 5th week, a similar result was observed [Figure 1].
Figure 1: Comparison of average weekly tumor regression between the two arms

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The mean TRD50 and TRD80 Value were lesser in study group as compared to control group thus favoring study group [Table 4] and [Table 5].
Table 4: TRD50 and TRD80 of individual patients

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Table 5: Comparison of TRD50 and TRD80

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  Discussion Top


Survival curves of mammalian cells exposed to ionizing radiation display the characteristic pattern of initial shoulder followed by straight line. This type of curves has been mathematically represented by a linear-quadratic model, where α is linear and β is quadratic component of cell killing. The ratio α/β is the dose in gray at which linear and quadratic components of cell killing are equal. Late responding tissues have a low α/β ratio (practically, α/β = 3 Gy); acute responding tissues, on the other hand, present a higher α/β ratio (assumed as α/β = 10 Gy). Among tumors, squamous cell carcinoma of uterine cervix has a high α/β ratio, whereas the most normal pelvic tissues which usually limit the increase of dose in the pelvis have a low α/β ratio. These characteristics theoretically qualify squamous cell carcinoma of the cervix for hyperfractionated radiotherapy treatment.[6]

Tubiana-Mathieu et al. treated 35 patients with concomitant cisplatin and 5-fluorouracil and split-course hyperfractionated radiotherapy. In 21 out of 24 evaluated patients, eight patients showed complete responses, nine showed partial responses, and four nonresponses were obtained. Acute toxicity mostly involved gastrointestinal and hematological, which was manageable.[7]

Shahi K.S. etal. included 22 patients in the study (12 in the study group and 10 in the control group). The control group was treated by conventional fractionation –60 Gy/30 fractions (f), 2 Gy/f, 5 days/week for 6 weeks. The study group was treated in hyperfractionation schedule 72 Gy/60f, 5 days/week over 6 weeks. Two fractions of 120 cGy/day were given at interval of 6 h. No severe acute toxicity was observed, but moderate acute reactions were high. The commonest site of complication was small bowel where severe toxicity occurred slightly higher in the study group than the control group. The complete response was 80% and 91.7% in the control and study groups, respectively.[8] Viswanathan et al. compared hyperfractionation radiotherapy with conventional radiotherapy in carcinoma cervix and concluded that hyperfractionation may result in better tumor control both at 1 year and at 5 years following the treatment of cervical cancer. However, hyperfractionation could lead to increased late bowel complications and must be used judiciously in the treatment of cervical cancer.[9]

In our study, the acute reactions were higher (though statistical nonsignificant) in the hyperfractionation group, but there seemed to be better tumor control over time. Grade 2 and 3 gastrointestinal toxicities were higher in the hyperfractionation group. It was observed that the bone marrow suppression was more in the study group due to the combined effect of chemotherapy and increased radiotherapy dose to the pelvic hematopoietic tissues. In our study group, 81.8% of the patients showed complete response as compared to 72.72% in the control group as a biologically effective dose in hyperfractionated schedule was 67.2 Gy as compared to 60 Gy in conventional schedule. In our study, weekly tumor regression in weeks 2nd, 3rd, 4th, and 5th was 46.08%, 75.58%, 92.66%, and 95.41%, respectively, while in the control group, these were 3.07%, 56.65%, 79.10%, and 95.5% consecutively.

Datta et al. concluded in their study that extent of tumor regression to External radiotherapy is an important predictor for treatment outcome in cancer cervix as evident from TRD50 and TRD80 values of EXTRT tumor regression curves and also concluded that TRD80 has been observed to be the most significant parameter in this study.[10]

In our study, TRD50 and TRD80 in the control versus study group were 30.27 Gy versus 28.91 Gy (P = −0.683) and 39.91 Gy versus 33.89 Gy (P = −0.044), respectively. These values are in favor of hyperfractionation schedule.


  Conclusion Top


Hyperfractionated radiotherapy along with concurrent chemotherapy is a quite feasible approach and showed encouraging result with equivocal toxicity when compared with standard protocol. TRD50 and TRD80 should also be extracted for assessing treatment response.

The drawback of this study was small sample size and retrospectively comparison from standard protocol, so long term study enrolling more no. of patients and prospective comparison from standard protocol is required to comment on the statistical significance of hyperfractionation schedule in ca cervix.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Lyon, France: IARC; 2013. Available from: http://www.globocan.iarc.fr/. [Last accessed on 2015 Feb 17].  Back to cited text no. 1
    
2.
Bobdey S, Sathwara J, Jain A, Balasubramaniam G. Burden of cervical cancer and role of screening in India. Indian J Med Paediatr Oncol 2016;37:278-85.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Bruni L, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. ICO/IARC Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in India. Summary Report; 17 June 2019.  Back to cited text no. 3
    
4.
Kumar RV, Bhaskar S. Potential opportunities to reduce cervical cancer by addressing risk factors other than HPV. J Gynaecol Oncol 2013;2464:295-7.  Back to cited text no. 4
    
5.
National Cancer Institute: 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 2011 May 04].  Back to cited text no. 5
    
6.
Hall EJ. Time, dose and fractionation in radiotherapy. In: Hall EJ, editor. Radiobiology for the Radiologist. 7th ed.. Philadelphia: J. B. Lippincott Co.; 2012. p. 391-409.  Back to cited text no. 6
    
7.
Tubiana-Mathieu N, Bonnier P, Delaby F, Murraciole X, Lejeune C, Hadjadj DJ, et al. Treatment of carcinoma of the uterine cervix with concomitant cisplatin, 5-fluorouracil and split course hyperfractionated radiotherapy. Eur J Obstet Gynecol Reprod Biol 1998;77:95-100.  Back to cited text no. 7
    
8.
Shahi KS, Nirdosh P, Gupta V, Singh A. Role of Hyperfactionated external beam radiotherapy in stage IIB to III and postoperative cases of carcinoma cervix: An evaluation. Int J Oncol 2008;6:1-4.  Back to cited text no. 8
    
9.
Viswanathan FR, Varghese C, Peedicayil A, Lakshmanan J, Narayan VP. Hyperfractionation in carcinoma of the cervix: Tumor control and late bowel complications. Int J Radiat Oncol Biol Phys 1999;45:653-6.  Back to cited text no. 9
    
10.
Datta NR, Rajkumar A, Basu R. Tumor regression dynamics with external radiotherapy in cancer cervix and its implications. Indian J Cancer 2004;41:18-24.  Back to cited text no. 10
[PUBMED]  [Full text]  


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