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Cisplatin versus gemcitabine as concurrent chemoradiotherapy in squamous cell carcinoma cervix: A comparative study of clinical response and toxicities


1 Department of Radiation Oncology, Government Medical College, Amritsar, Punjab, India
2 Department of Radiation Oncology, Government Medical College, Patiala, Punjab, India
3 Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Bathinda, Punjab, India

Date of Submission19-Aug-2020
Date of Decision30-Sep-2020
Date of Acceptance29-Dec-2020
Date of Web Publication30-Jul-2021

Correspondence Address:
Ramandeep Singh,
Department of Radiation Oncology, Government Medical College, Amritsar, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1184_20

 > Abstract 


Cervical cancer ranks as the four leading cause of cancer death in women worldwide. It is the third most common cancer in India. Most patients present in advanced stages. Concurrent chemoradiation is the standard of treatment for locally advanced cervical cancer.
Aims: The aim of the study was to compare the treatment response and hematological, gastrointestinal, and skin toxicity of cisplatin versus gemcitabine as concurrent chemoradiotherapy.
Materials and Methods: This study was conducted from February 2017 to August 2018. Sixty patients of squamous cell carcinoma cervix with Stage IIB to IIIB were randomly allocated to either weekly gemcitabine (observation arm) 150 mg/m2 or cisplatin (control arm) in the dose of 35 mg/m2 along with concurrent radiotherapy. Treatment response and toxicities of both drugs were evaluated.
Statistical Method: Statistical analysis was conducted using the Statistical Package for the Social Sciences version 20. Descriptive statistics such as frequency, percentages, mean, standard deviation, and range were used to describe the treatment characteristics.
Results: Gemcitabine arm has more Grade 2 (23.3% vs. 10%) and Grade 3 (3.3% vs. none) hematological toxicity as compared to cisplatin arm. For gastrointestinal toxicity, Grade 2 toxicity was observed more in cisplatin arm (23.3%) as compared to 13.3% in gemcitabine arm. Skin toxicity was found to be insignificant. There was complete response of 86.7% in cisplatin arm, while 73.3% in gemcitabine arm.
Conclusion: Cisplatin has a better treatment response as compared to gemcitabine as concomitant chemotherapy agent with external beam radiation therapy. Hematological toxicity was more in gemcitabine arm and gastrointestinal toxicity was more in cisplatin arm. The skin toxicities were comparable in both the arms.

Keywords: Carcinoma cervix, cisplatin, concurrent chemoradiotherapy, gemcitabine



How to cite this URL:
Singh R, Singh Banipal RP, Goyal LD. Cisplatin versus gemcitabine as concurrent chemoradiotherapy in squamous cell carcinoma cervix: A comparative study of clinical response and toxicities. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322707




 > Introduction Top


Cervical cancer is one of the most common cancers worldwide. According to GLOBOCAN 2018, there are 570,000 cases and 311,000 deaths from cervical cancer worldwide. Carcinoma cervix ranks as the fourth most frequently diagnosed and fourth leading cause of cancer death in women worldwide. Cervical cancer ranking is second in incidence and mortality behind breast cancer in lower human development index settings.[1],[2]

Concurrent chemoradiation is the standard of treatment for Stage IIB to IVA of carcinoma cervix.

Cisplatin is a platinum containing anticancer drug (alkylating like agent). When cisplatin and radiation are used concomitantly, substantial enhancement of cell killing is observed. Coughlin and Richmond[3] suggested two mechanisms for radiation enhancement by cisplatin: (a) in hypoxic or oxygenated cells, free radicals with altered binding of cisplatin to DNA are formed at the time of irradiation and (b) interaction inhibits repair of sublethal damage.

Gemcitabine is a deoxycytidine analog, which is a cell cycle–specific (S-phase) cytotoxic agent that kills cells in S-phase undergoing DNA synthesis. Gemcitabine acts as radiosensitizer in the treatment of cervical cancer.[4] It may inhibit repair of DNA damage, induce cell redistribution, and increase the radiosensitivity of hypoxic cells due to tumor shrinkage.

Since the beginning, cisplatin was used as concurrent chemotherapeutic agent in carcinoma cervix, but due to its toxicities such as nephrotoxicity, ototoxicity, nausea, vomiting, and severe electrolyte imbalance, sometimes, the treatment has to stop in between and also aggressive hydration and diuresis is to be needed with cisplatin, Gemcitabine then introduced as concurrent chemotherapeutic agent whose toxicity is mainly myelosuppression. Hence, this study was planned to compare the treatment response and toxicities of these two drugs as concurrent chemotherapeutic agent in carcinoma cervix.


 > Materials and Methods Top


This study was conducted from February 2017 to August 2018.

Inclusion criteria

  • Histologically proven squamous cell carcinoma cervix
  • FIGO Stage IIB to IIIB
  • Age above 18 years
  • Written and informed consent
  • ECOG performance score (≤3).


Exclusion criteria

  • Stage IV
  • Prior oncological treatment.
  • Pregnant and lactating females
  • Impaired renal function (if creatinine >2 mg/dl).


The first sixty patients fulfilling inclusive criteria were randomized into two arms using research randomizer software.

Arm A

  • 5, 6, 8, 9, 11, 12, 16, 17, 18, 19, 24, 25, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 40, 41, 43, 51, 53, 56, 60.


Arm B

  • 2, 3, 4, 7, 10, 13, 14, 15, 20, 22, 23, 26, 32, 33, 39, 42, 44, 45, 46, 47, 48, 49, 50, 52, 54, 55, 57, 58, 59.


Patients were divided into two arms (A and B) with thirty patients in each arm.

Arm A (Cisplatin arm)

  • Patients received external beam radiation therapy (EBRT) to whole pelvis to the dose of 50 Gy, delivered in 25# over 5 weeks along with weekly cisplatin intravenous at dose of 35 mg/m2. This is followed by three applications of intracavitatory brachytherapy to the dose of 7.5 Gy/# per week at point A.


Arm B (gemcitabine arm)

  • Patients received EBRT to whole pelvis to the dose of 50 Gy, delivered in 25# over 5 weeks along with weekly gemcitabine intravenous at 150 mg/m2. This was followed by three applications of intracavitataory brachytherapy to the dose of 7.5 Gy/# per week at point A.


It was an 18-month study with follow-up of every patient for 6 months.

Clinical response was evaluated by clinical examination (per speculum, per vaginal, and per rectal examination). Chest X-ray, contrast-enhanced computed tomography (CT) whole abdomen, intravenous pyelography, proctosigmoidoscopy, and cystoscopy were also done in select cases.

Toxicities were measured in terms of hematological parameters, gastrointestinal toxicities, and skin toxicities using RTOG criteria.

Statistical analysis was conducted using the Statistical Package for the Social Sciences version 20 (IBM, SPSS Inc., US). Descriptive statistics such as frequency, percentages, mean, standard deviation, and range were used to describe treatment characteristics. Inferential statistics were applied to draw inferences. Comparisons of both treatment groups for nominal/categorical characteristics were done using Chi-square test, Fisher's exact, and Yate's corrected test where ever applicable. For continuous variables, mean values were compared between the groups using the t-test. A P < 0.05 was considered statistically significant.


 > Results Top


Patients in both arms were comparable in all baseline characteristics (age distribution, residence, marital status, parity, histopathology, and stage). The data are depicted in [Table 1].
Table1:Demographicprofile

Click here to view


The mean age ± standard deviation in Arm A was 50.8 ± 7.5 and in Arm B was 51.6 ± 8.8. In our study, majority (60%) of patients were in the fifth and sixth decades.

Nearly 66.67% in Arm A and 70% in Arm B were from rural area. Majority of the patients were para 3 or more.

All patients in both arms had squamous cell carcinoma.

Majority of the patients in both arms were of FIGO Stage IIB and IIIB. Nearly 46.67% of patents in Arm A and 30% patients in arm B were of Stage IIB and 36.67% of patients in Arm A and 43.33% in Arm B were of Stage IIIB

In the study, majority of patients in Arm A (76.67%) and in Arm B (73.33%) were able to complete treatment in <60 days.

Treatment-related toxicities occurred in majority of the patients.

In 1st week, 86.67% of patients in Arm A and 60% of patients in Arm B have no hematologic toxicity, and 6.67% patients in Arm A and 33.33% patients in Arm B have Grade 1 hematologic toxicity which was statistically significant [Graph 1]. In 2nd week, 26.7% of patients in Arm A and 60% of patients in Arm B have Grade 1 hematologic toxicity, 6.7% patients in Arm A and 13.3% patients in Arm B have Grade 2 hematologic toxicity, and 3.3% (one patient) in Arm B has Grade 3 hematologic toxicity, which was statistically significant with P = 0.003 [Graph 2]. In 3rd week, 83.3% of patients in Arm A and 56.7% of patients in Arm B have Grade 1 hematologic toxicity, 6.67% patients in Arm A and 36.67% of patients in Arm B have Grade 2 hematologic toxicity, and 6.7% of patients in Arm B has Grade 3 hematologic toxicity with statistically significant P = 0.025 [Graph 3]. In 4th week, 76.7% of patients in Arm A and 50% of patients in Arm B have Grade 1 hematologic toxicity, 10% of patients in Arm A and 50% of patients in Arm B have Grade 2 hematologic toxicity with statistically significant P = 0.001 [Graph 4]. In 5th week, 63.3% of patients in Arm A and 76.7% of patients in Arm B have Grade 1 hematologic toxicity and 13.3% of patients in Arm A and 23.3% of patients in Arm B have Grade 2 hematologic toxicity with statistically significant P = 0.014 [Graph 5].



The most common overall hematological toxicity was Grade 1 leukopenia in 56.7% of patients of gemcitabine arm versus 50% in cisplatin arm. Grade 2 toxicity of 23.3% was more in gemcitabine arm compared to 10% in cisplatin arm with statistically significant P = 0.001. Severe toxicity (Grade 3) was observed as 3.3% in gemcitabine arm as compared to none in cisplatin arm and difference was not statistically significant. None of the patients have Grade 4 hematologic toxicity in any arm [Table 2]. Grade 2 or Grade 3 hematologic toxicity was managed by growth factor, i.e., granulocyte colony-stimulating factor in the form of injection filgrastim given subcutaneously, especially in gemcitabine arm.

In 1st week, maximum patients have either no or only Grade 1 gastrointestinal toxicity on both arms [Graph 6], In 2nd week, almost same number of patients in both Arm A and Arm B have Grade 2 gastrointestinal toxicity [Graph 7]. In 3rd week, 70% of patients in Arm A and 50% of patients in Arm B have Grade 1 gastrointestinal toxicity [Graph 8], and 30% of patients in Arm A and 26.7% patients in Arm B have Grade 2 gastrointestinal toxicity. No patient has Grade 3 or 4 gastrointestinal toxicity. In 4th week, 46.7% of patients in Arm A and 66.7% of patients in Arm B has Grade 1 gastrointestinal toxicity, 43.3% of patients in Arm A and 20% patients in Arm B have Grade 2 gastrointestinal toxicity [Graph 9], and 10% of patients in Arm A and 13.3% patients in Arm B have Grade 3 gastrointestinal toxicity. No patient has Grade 4 gastrointestinal toxicity. In 5th week, 66.7% of patients in both Arm A and arm B have Grade 1 gastrointestinal toxicity, 33.3% of patients in Arm A and 16.7% patients in Arm B have Grade 2 gastrointestinal toxicity [Graph 10], and 6.7% of patients in Arm B have Grade 3 gastrointestinal toxicity. No patient has Grade 4 gastrointestinal toxicity.
Table 2: Overall hematological toxicity grades

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Overall gastrointestinal toxicity of Grade 1 was reported in 50% of patients in cisplatin arm and 46.7% in gemcitabine arm. Statistically significant Grade 2 toxicity was observed in cisplatin arm compared to gemcitabine (23.3% vs. 13.3%) with P = 0.03. Grade 3 toxicity was observed more in gemcitabine arm (6.7% vs. 3.3%). None of the patients had Grade 4 gastrointestinal toxicity [Table 3].
Table 3: Overall gastrointestinal toxicity grades

Click here to view


Skin toxicity was not significant [Table 4].
Table 4: Overall skin toxicity grades

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Nearly 13.33% of patients in Arm A and 40% in Arm B had to underwent hospital admissions either for blood transfusions and managing acute toxicities [Table 5].
Table 5: Distribution of patients according to number of hospital admissions

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Complete response to treatment was observed in 86.7% (twenty six patients) in cisplatin arm and 73.3% (twenty two) in gemcitabine arm with nonsignificant P = 0.196. Two patients (6.67%) in cisplatin arm and six patients (20%) in gemcitabine arm had partial response with P = 0.128 [Table 6]. Two patients in cisplatin arm and two in gemcitabine arm died before the completion of treatment within 6 months.
Table 6: Distribution of patients according to treatment response assessed at completion of treatment (at 6 months)

Click here to view


Thus, Arm A shows a comparatively better response and less toxicity than Arm B, although it was statically insignificant with overall P = 0.311 NS.


 > Discussion Top


Cisplatin-based concomitant chemoradiation is regarded as the standard treatment for locally advanced cervical cancer[5] five Phase III trials have demonstrated a significant survival advantage for the concomitant administration of radiotherapy with cisplatin-based chemotherapy. Although the trials vary in terms of stages of disease, dose of radiation, and schedule of radiation and cisplatin, they all demonstrated a significant survival benefit for the combined approach.[6],[8],[9],[10]

Gemcitabine is a cell cycle-specific cytotoxic agent that has shown antitumor activity against a variety of solid tumor, for example, lung, pancreas, breast, and bladder. Hernandez et al.[4] have demonstrated the radiosensitizing effect of gemcitabine against cervical cancer cell lines. Gemcitabine has shown promising radiosensitizing effect in preclinical as well as in clinical Phase II trials. There are three Phase II trials using gemcitabine alone or in combination with cisplatin concurrently with radiation showing good results. Pattaranutaporn et al.[11] have also shown efficacy and feasibility of weekly concurrent gemcitabine with radiation in Stage IIIB cervical cancer.

Hematological toxicities of cisplatin and gemcitabine reported in literature are leukopenia of Grade 1 or 2 in majority and only with few patients showing Grade 3 or 4 toxicity.[12],[13],[14]

Overall hematologic toxicity of Grade 1 was reported in 50% in Arm A versus 56.7% in Arm B patients over all weeks of EBRT. These results are comparable in the study done by Singh et al.,[12] in which 52% in cisplatin arm and 56% in gemcitabine arm patients had Grade 1 leukopenia.

Grade 2 toxicity was 10% in Arm A compared to 23.3% in Arm B which was statistically significant with P = 0.001. Similarly, in a study done by Singh et al.,[12] 12% of patients in cisplatin arm and 20% in gemcitabine arm which had Grade 2 leukopenia, whose results are almost comparable with our study.

Grade 3 hematologic toxicity was comparable with Verma et al.,[13] in which no patient in cisplatin arm and one patient in gemcitabine have Grade 3 leukopenia similar to this study. In our study, no patient in either of arm has Grade 4 hematologic toxicity; similarly, in studies by Srivastava et al.[14] and Singh et al.,[12] no patient had Grade 4 hematologic toxicity.

The overall gastrointestinal toxicity grading in this study is 50% in Arm A and 46.7% in Arm B as Grade 1 (almost equal in both arms). However, Grade 2 gastrointestinal tract (GIT) toxicity was different in cisplatin arm compared to gemcitabine (23.3% vs. 13.3%) with significant P = 0.031.

Grade 3 diarrhea was seen more in gemcitabine arm compared to cisplatin arm which was seen in weeks 4 and 5 of EBRT (13.3% vs. 10% in week 4, 6.7% vs. 0% in week 5). This is similar to study done by Bhatt et al.[15] (14% vs. 3%) and Singh et al.[12] (16% vs. 12%).

Pattaranutaporn et al.[11] reported only one case of Grade 3 diarrhea out of 19 patients receiving gemcitabine.

No patient in our study has Grade 4 GIT toxicity; this is in comparison with Srivastava et al.[14] and Singh et al.,[12] in which also there was no patient of Grade 4 hematologic toxicity.

Cisplatin is more emetogenic than gemcitabine. In our study, nausea and vomiting were more common in cisplatin arm as compared to gemcitabine arm. Grade 3 toxicity of 10% and 6% in cisplatin and gemcitabine arm was seen in Chufal et al.[17] and 12% versus 4% in cisplatin and gemcitabine arm in Singh et al.[12] Nausea and vomiting were prevented with the use of antiemetic agents granisetron before starting chemotherapy and oral ondensetron after chemotherapy.

None of the patients had significant skin toxicity of Grade 3 or Grade 4. In a study done by Bhatt et al.,[15] there was also no Grade 3 or 4 skin toxicity.

In 2019, Drokow et al. concluded that gemcitabine and cisplatin appear to be tolerable, efficient, and feasible when combined with conformal radiotherapy. No interruption was observed during the treatment. The treatment was completed by all patients, and toxicity was well tolerated. Nausea was recorded in nine (8.6%) patients. Diarrhea and anorexia were also of Grade 1 and 2. Thrombocytopenia was observed in 9.6%.[18]

Fabri et al. in 2019 concluded that the use of consolidation chemotherapy resulted in longer overall survival and progression-free survival, mostly due to control of distant relapses. Patients at higher risk of distant relapse showed the greatest benefit. Distant metastasis at 3 years was 80.4% versus 62.5%, and at 5 years, it was 80.4% versus 54.8% in favor of patients who were treated with consolidation local recurrence at 3 years was 92.7% versus 79.5%, and at 5 years, it was 92.7% versus 79.5% in favor of patients who were treated with consolidation CT.[19]

There was complete response in 86.7% of cases in cisplatin arm compared to 73.3% in gemcitabine arm. Similar results were also seen in other studies, in which cisplatin showed better results compared to gemcitabine. Srivastava et al.[14] showed that 93.33% of patients in cisplatin arm and 70% of patients in gemcitabine arm showed complete response. In other study done by Kundu et al.,[16] 55.56% of patients in cisplatin arm and 48.89% in gemcitabine arm had complete response.

Limitations of the study

As the time period of the study was 1½ year, so limited number of patients came under the study with total 60 including 30 in each arm. The statistical power was also limited.


 > Conclusion Top


This study has shown that hematological toxicity was more in gemcitabine arm and gastrointestinal toxicity was more in cisplatin arm and skin toxicities were comparable with both drugs. Cisplatin as weekly concurrent chemotherapy is a better option than gemcitabine in terms of treatment response.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Bray F, Ferlay J, Soerjomataram I, Siegel LR, Torre AL, Jenal A. Global cancer statistics 2018: GLOBOCON. Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;00:27-31. doi: 10.3322/caac.21492.  Back to cited text no. 1
    
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Coughlin CT, Richmond RC. Biologic and clinical developments of cisplatin combined with radiation: Concepts, utility, projections for new trials, and the emergence of carboplatin. Semin Oncol 1989;16:31-43.  Back to cited text no. 3
    
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Hernandez P, Olivera P, Duenas-Gonzalez A. Gemcitabine activity in cervical cancer cell line. Cancer Chemother Parmacol 2001;48:488-92.  Back to cited text no. 4
    
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Vreololjak E, Hamm W. Current state of the art of concomitant chemoradiation in carcinoma cervix. Eur J Gynaecol Oncol 2003;24:475-9.  Back to cited text no. 5
    
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Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-53.  Back to cited text no. 6
    
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Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL, et al. Cisplatin, radiation, adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky Stage 1B cervical carcinoma. N Eng J Med 1999;340:1154-61.  Back to cited text no. 7
    
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Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999;340:1137-43.  Back to cited text no. 8
    
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Peters WA, Liu PY, Barrett RJ, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18(8):1606-13.  Back to cited text no. 9
    
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Whitney CW, Sauce W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative paraaortic lymphnodes: A gynaecologic oncology group and South West Oncology group study. J Clin Oncol 1999;17:1339-48.  Back to cited text no. 10
    
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Pattaranutaporn P, Thirapakawong C, Chansilpa Y, Therasakvichya S, Ieumwananontachai N, Thephamongkhol K. Phase II study of concurrent gemcitabine and radiotherapy in locally advanced stage IIIB cervical carcinoma. Gynecol Oncol 2001;81:404-7.  Back to cited text no. 11
    
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Singh V, Singh SK, Singh JK, Shahbabu B, Chauhan R, Kumari A. Feasibility of weekly cisplatin versus gemcitabine concomitant with radiation in the management of locally advanced carcinoma cervix. JMSCR 2017;05:25734-42.  Back to cited text no. 12
    
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Verma AK, Arya AK, Kumar M, Kumar A, Gupta S, Sharma DN. Weekly cisplatin or gemcitabine concomitant with radiation in athe management of locally advanced carcinoma cervix. J Gynecol Oncol 2009;20:221-6.  Back to cited text no. 13
    
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Srivastava N, Sahani K, Srivastava M. Comparative efficacy of cisplatin vs. gemcitabine as concurrent chemotherapy for untreated locally advanced cervical cancer: A randomized trail. Internet J Med Update 2007;2:4-9.  Back to cited text no. 14
    
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Bhatt ML, Matin A, Srivastava M, Pant MC, Srivastava K, Gupta S, et al. Evaluation of gemcitabine versus cisplatinum as an adjunct to radiotherapy in locally advanced carcinoma uterine cervix. J Clin Oncol 2007;25:16012.  Back to cited text no. 15
    
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Kundu S, Basu S, Acharya S, Dastidar AG, Roy A. Chemoradiation in locally advanced cervical cancer. Indian J Med Paediatr Oncol 2008;29:12-8.  Back to cited text no. 16
  [Full text]  
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Chufal KS, Rastogi M, Srivastava M, Pant MC, Bhatt ML, Srivastava K. Concurrent chomoradiotherapy for locally advanced cervical cancer using gemcitabine: Non randomized comparison of three sequential protocols. Cancer Ther 2007;5:43-54.  Back to cited text no. 17
    
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Drokow EK, Zi L, Qian H, Xu L, Foli F, Ahmed HAW, et al. Tolerability, Efficacy and Feasibility of Concurrent Gemcitabine and Cisplatin (CGP) Combined with intensity modulated radiotherapy for loco-regionally advanced carcinoma of the cervix. J Cancer 2020;11:2632-8.  Back to cited text no. 18
    
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Fabri VA, Queiroz AC, Mantoan H, Sanches SM, Guimarães AP, Ribeiro AR, et al. The impact of addition of consolidation chemotherapy to standard cisplatin based chemoradiotherapy in uterine cervical cancer: Matter of distant relapse. J Oncol 2019;2019:1217838. doi:10.1155/2019/1217838.  Back to cited text no. 19
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

 
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