|Year : 2022 | Volume
| Issue : 3 | Page : 330-335
A prospective comparative study of concurrent chemoradiation in advanced carcinoma cervix patients with weekly cisplatin vs. weekly cisplatin and paclitaxel
Amit K Mukherjee1, Linkon Biswas2, Soumyo Bose2, Shyam Sharma2, Srikrishna Mandal2
1 Department of Radiotherapy, Asansol District Hospital, SB Gorai Rd, Mohishila Colony, Hamid Nagar, Asansol, West Bengal 713301, India
2 Department of Radiotherapy, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal 700014, India
|Date of Submission||14-Apr-2022|
|Date of Acceptance||01-Aug-2022|
|Date of Web Publication||29-Sep-2022|
Dr. Shyam Sharma
Department of Radiotherapy, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal 700014
Source of Support: None, Conflict of Interest: None
Background: Cisplatin-based concurrent chemoradiation is the standard treatment for carcinoma cervix. However, there is a need to explore alternative chemotherapeutic agents to further improve the treatment outcome. In this study, weekly paclitaxel and cisplatin-based chemoradiation was compared with weekly cisplatin-based chemoradiation in terms of disease control and toxicity profile. Materials and Methods: Sixty-four patients with FIGO stage IB2-IIIB squamous cell carcinoma of the uterine cervix were divided (by simple random sampling) into two groups: control arm patients who received radiotherapy (50 Gy in 25 fractions over 5 weeks) with concurrent weekly cisplatin (40 mg/m2) and study arm patients received same radiation dose with weekly cisplatin (30 mg/m2) and paclitaxel (40 mg/m2). After that, all patients received brachytherapy 21 Gy/three fractions, one fraction/week. All patients were followed up weekly during treatment, then 4–6 weeks after treatment completion, and thereafter monthly for at least 6 months. Results: The overall treatment response (complete+ partial response) was numerically higher in the cisplatin-containing control arm, but not significant (93% vs. 80%, P-value = 0.406). High-grade early rectal (60% vs. 25%, P-value = 0.014) and acute gastrointestinal toxicity (66% vs. 6%, P-value <0.001) were significantly higher in the cisplatin and paclitaxel-containing arm. Hematological, renal, late rectal, and bladder toxicities were also numerically higher in the study arm, but not statistically significant. Conclusion: There was no significant benefit of weekly paclitaxel and cisplatin as an alternative to weekly cisplatin-based chemoradiation in the treatment of carcinoma cervix.
Keywords: Carcinoma cervix, concurrent chemoradiation, weekly cisplatin, weekly cisplatin, paclitaxel
|How to cite this article:|
Mukherjee AK, Biswas L, Bose S, Sharma S, Mandal S. A prospective comparative study of concurrent chemoradiation in advanced carcinoma cervix patients with weekly cisplatin vs. weekly cisplatin and paclitaxel. MGM J Med Sci 2022;9:330-5
|How to cite this URL:|
Mukherjee AK, Biswas L, Bose S, Sharma S, Mandal S. A prospective comparative study of concurrent chemoradiation in advanced carcinoma cervix patients with weekly cisplatin vs. weekly cisplatin and paclitaxel. MGM J Med Sci [serial online] 2022 [cited 2022 Nov 29];9:330-5. Available from: http://www.mgmjms.com/text.asp?2022/9/3/330/357470
| Introduction|| |
According to GLOBOCAN 2020 data, carcinoma cervix is the second most common malignancy among Indian women and it has been estimated that every year around 1.2 lakh new cases occur in India. Worldwide cervical cancer ranks fourth for both incidence (6.6%) and mortality (7.5%) in women.
After the results of five randomized clinical trials (GOG-85, RTOG-9001, GOG-120, GOG123, and SWOG-879), which revealed better survival outcomes for patients treated with cisplatin-based chemoradiation, the U.S. National Cancer Institute stated that concurrent chemotherapy should be incorporated in a woman who requires radiation therapy for the treatment of cervical cancer.,,,, A meta-analysis of 18 trials with concurrent chemotherapy and radiation in patients with cervical cancer concluded that concomitant chemoradiation improved overall survival (OS), progression-free survival (PFS), and loco-regional disease control in patients with cervical cancer. Based on this evidence, the International Federation of Gynecology and Obstetrics (FIGO) recommended concurrent chemoradiation as the standard primary treatment of cancer cervix (FIGO Stage IB–IVA) in 2000. Since then, cisplatin became a widely accepted primary chemotherapeutic agent used along with radiotherapy., But, despite the use of concomitant chemoradiation with cisplatin, many patients continue to fail in the local (20–25%) and at distant sites (10–20%).,,, In 2005, the Cochrane database systemic review of concurrent chemoradiation in carcinoma of the cervix also reiterated an absolute benefit of 10% in OS and 13% in PFS, regardless of whether or not platinum was used.
Hence, among many chemotherapeutic options, with radiosensitizer property as the ideal drug(s), their combination and schedule are still a matter of exploration. A variety of agents such as carboplatin, paclitaxel, 5-fluorouracil (5-FU), and gemcitabine have been studied as concurrent chemotherapeutic drugs with variable results in cervical cancer. But, to improve the survival rates and tolerability, there is a need to further explore the use of alternative chemotherapeutic agents.
This study was conducted primarily to compare standard cisplatin-based chemoradiation with cisplatin and paclitaxel-based chemoradiation in terms of tumor response and treatment-related toxicities for the treatment of carcinoma uterine cervix.
| Materials and methods|| |
It was a double arm, single institutional prospective, comparative study in patients with histologically proven squamous cell carcinoma of the uterine cervix, FIGO stage IB2–IIIB, aged between 20 and 70 years having adequate hematological, hepatic, and renal parameters, and an ECOG score of 0–2. Patients who underwent hysterectomy or radical surgery, recurrent cervical carcinoma, previous history of any other malignancy, or chemotherapy or radiotherapy were excluded. The study was conducted between January 2018 and June 2019.
Eligible patients were allocated into two groups by simple random sampling (by lottery).
Control arm (concurrent weekly cisplatin)
Patients of this arm were treated with concurrent weekly cisplatin (40 mg/m2) along with external beam radiotherapy.
Study arm (concurrent weekly cisplatin + paclitaxel)
In this arm, patients were treated with concurrent weekly cisplatin (30 mg/m2) and paclitaxel (40 mg/m2) along with external beam radiation therapy (EBRT).
In both arms, EBRT was given at a dose of 50 Gy in 25 fractions over 5 weeks in conventional fractionation. After completion of EBRT, patients of both arms received intra-cavitary brachytherapy for three fractions of 7 Gy every week for 3 weeks. Treatment was withheld if the patient had a leukocyte count less than 3000/mm3, and delays of 1 week will be allowed in the event of treatment-related toxicities. Blood transfusions were given if hemoglobin is less than 9 g/dL.
A telecobalt machine (Theratron 780E) was used to deliver EBRT with conventional two-dimensional fields based on anatomical landmarks.
- Two AP-PA (antero-posterior and postero-anterior) portals;
- Four field techniques (AP-PA and two lateral pelvic fields) in patients with large (>20 cm) interfiled distance.
Patients were assessed weekly with clinical examinations, hematological, and clinical parameters during the treatment for the assessment of acute toxicities using CTCAE (National Cancer Institute, Common Terminology Criteria for Adverse Events scale v4.03).
Treatment response evaluation was done 4–6 weeks after the completion of radiation therapy (EBRT followed by intra-cavitary radiotherapy) with clinical examination and contrast-enhanced computed tomography (pelvis)/contrast-enhanced magnetic resonance imaging (pelvis). RECIST (Response Evaluation Criteria in Solid Tumors) was used for response evaluation. Thereafter, all patients were followed up monthly for at least 6 months. Every scheduled follow-up had a mandatory gynecological examination.
Statistical analysis was conducted using the IBM SPSS Statistics version 20.0 (SPSS Inc., Chicago, IL, USA) and the online GraphPad Quick Calcs application. For normally distributed data, the mean values between the two arms were compared for the test of significance using the unpaired t-test. Inter-arm mean differences were compared for the test of significance using paired t-test. For comparing proportions of different events between the two arms, Pearson’s χ2 test was applied as a test of significance. Any P-value less than 0.05 has been considered significant.
| Results|| |
A total of 64 patients were eligible for allocation in the two arms of this study, but 30 and 31 patients were finally analyzed in the study and control arms, respectively [Figure 1].
|Figure 1: Consort diagram (workflow map) of the study. ICRT = intra-cavitary radiotherapy|
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Baseline characteristics of patients including mean age, stage of disease at presentation, and performance status at the initiation of the study were comparable between both the arms of the study [Table 1].
|Table 1: Comparison of baseline characteristics between the two arms of the study|
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Overall response (complete response + partial response) was numerically higher in the control arm (93% vs. 80%). About 12% of the patients in the study arm had the progressive disease in comparison to 3% in the control arm and stable disease was 6% and 3%in the study and control arms, respectively. But the differences were not statistically significant (P = 0.406) [Table 2].
Assessment of treatment-related toxicity
Grade II acute rectal toxicity was significantly higher in the study arm containing paclitaxel and cisplatin both as concurrent chemotherapy than in the only cisplatin-containing control arm (60% vs. 25%, P-value = 0.014) [Table 3]. Incidences of acute gastrointestinal (GI) toxicity were significantly more in the study arm (66% vs. 6%, P <0.001), although a majority of patients who experienced GI toxicity were of Grade I type [Table 4]. Although grade (Grade II and above) of hematological toxicity was numerically higher (60% vs. 45%) in the study arm, the difference was not statistically significant (P = 0.570) [Table 5].
Incidence of Grade II and more acute nephrotoxicity was 43% in the study arm when compared with 29% in the control arm. The nephrotoxicity profile was comparable between both the arms (P = 0.545) [Table 6].
Acute skin toxicity was more pronounced in the study arm (50% of the patients experienced Grade II to III skin toxicity), and the difference was statistically significant (P ≤ 0.001). Both the arms of the study were comparable in terms of late rectal toxicity, with only 6% of the study arm and 3% of the control arm patients experiencing Grade III toxicity (P = 0.623).
Late bladder toxicity was numerically slightly higher in the study arm (20% vs. 16%), but all the cases were of Grade I toxicity and there was no statistical significance for this difference (P = 0.694).
| Discussion|| |
Concurrent chemoradiation with cisplatin has been the cornerstone of treatment of carcinoma cervix in an advanced stage. Unfortunately, using concomitant chemoradiation with cisplatin alone has recurrences and progression of the disease (pelvic and distant involvement).,, Considering this fact, this study was done by adding paclitaxel, a taxane, a radiosensitizer in the cervical cell line along with cisplatin to assess the tumor response within acceptable toxicity limits.
Concurrent chemoradiation using paclitaxel has been evaluated in different studies. Cerrotta et al. evaluated the feasibility of concurrent radiotherapy and paclitaxel administration. Complete response (CR) was reported in 63%. Out of 12 CR patients at the end of treatment, 10 maintained complete local remission for a median follow-up of 47 months.
In this study, the study arm (cisplatin + paclitaxel) showed CR in 63.3% of the cases in comparison to 67.7% of the control arm (cisplatin). Partial response was also numerically higher in the control arm (25.8% vs. 16.6%). But these differences were not statistically significant (P = 0.406).
A phase II study conducted by Jeyaseelan and co-workers documented that combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of the cervix had no increase in immediate tumor response and PFS, but was associated with a high incidence of acute toxicity. Hence, this regimen offers no added benefit when compared with chemoradiation with cisplatin alone.
Kalaghchi et al. studied women with primary untreated squamous cell carcinoma of the cervix with FIGO stages IB2–IIIB who were treated with weekly injections of cisplatin 30 mg/m2 and paclitaxel 35 mg/m2 for 5–6 weeks along with radiotherapy. There was a CR rate of 84% after 3 months. In conclusion, combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of the cervix was well tolerated, but it seems that there was no increase in tumor response and PFS with this treatment regimen.
But some studies document a combination of paclitaxel and cisplatin as a better concurrent regimen than cisplatin alone for the treatment of carcinoma cervix. A study by Thakur et al. compared cisplatin-based chemoradiotherapy and paclitaxel-based chemoradiation. Eighty-one women with newly diagnosed carcinoma cervix with FIGO stages IIA–IIIB were randomized into two arms—cisplatin 40 mg/m2/week for 5 weeks was given in the control arm, whereas cisplatin 30 mg/m2/week and paclitaxel 50 mg/m2/week for 5 weeks were given in the study arm. The study arm showed a CR of 84%, compared with 75.6% in the control arm (P = 0.4095). The median follow-up result shows better disease-free survival (DFS) in the latter (64.3% vs.79.5%) and OS (78.6% vs. 87.2%). This prospective study concluded that there was a potential benefit with the addition of paclitaxel to the standard regimen of concurrent cisplatin-based chemotherapy for carcinoma cervix, although the differences were not statistically significant. Moore et al. in a phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent or persistent squamous cell carcinoma of the cervix inferred objective responses to be 19% (6% complete plus 13% partial) of patients receiving cisplatin vs. 36% (15% complete plus 21% partial) receiving cisplatin + paclitaxel (P=0.002). They concluded that cisplatin+ paclitaxel is superior to cisplatin alone concerning response rate and PFS with sustained quality of life.
In this study, mild-to-moderate rectal toxicity was observed during treatment (within the first 8 weeks). It was significantly pronounced in the study arm: Grade II toxicity was observed in 17 patients (56.66%) against 8 in the control arm (25.8%). The P-value is 0.014 which is significant. The majority of the patients faced mild-to-moderate GI toxicity (22 out of 61, 36.06%), but for Grade II and above, GI toxicity was significantly more in the study arm (66.6% vs. 6%). The P-value is less than 0.001. About 10% of the study arm (paclitaxel + cisplatin) patients had Grade III hematological toxicity compared with 3% of the control arm (cisplatin only). But this difference was not statistically significant (P = 0.570). The nephrotoxicity profile was comparable in both the arms (P = 0.545). Skin toxicity was significantly more pronounced in the study arm (50% of the patients facing Grade II and above toxicity, P <0.001), likely attributable to the addition of paclitaxel as a radiosensitizer. Regarding late rectal toxicity, both the arms of the study were comparable, with only 6% of the study arm and 3% of the control arm patients experiencing Grade III toxicity (P = 0.623). Late bladder toxicity was numerically slightly higher in the study arm (20% vs. 16%), but all the cases were of Grade I toxicity and there was no statistical significance for this difference (P = 0.694).
There are many studies echoing the fact that a combination of cisplatin and paclitaxel-based concurrent chemoradiation was associated with increased acute treatment-related toxicities. Thakur et al., in their phase III trial, observed an increase in acute toxicities in the study arm in comparison to the control arm in terms of hematological grade II (35% vs. 12.2%), GI grade III (20% vs. 7.4%), and GI grade IV (12.5% vs. 2.4%) toxicities. A phase II study conducted by Jeyaseelan and co-workers documented that the major toxicity associated with cisplatin+ paclitaxel-based chemoradiation was Grade III diarrhea (48%). Papadimitriou et al. showed Grade III or IV hematological toxicities including anemia in 18% of the patients and granulocytopenia in 15% of the patients treated with cisplatin+paclitaxel-based chemoradiation. About 53% of the patients developed some degree of neurotoxicity; 21% of the cases were grade II or worse.
This study has its limitations also: first, our sample size was small, so any statistical data have to be interpreted with caution. Secondly, it was a single institutional study; hence, results derived cannot be extrapolated to the entire population and the entire study duration was almost 18 months including patient accrual, intervention, and assessment. So, the late toxicity profile, DFS/PFS, OS, and quality of life issues cannot be assessed appropriately.
| Conclusion|| |
There were no significant benefits of using the combination of weekly paclitaxel and cisplatin in concurrent chemoradiation of carcinoma cervix in contrast to weekly cisplatin alone; rather, acute toxicities were more pronounced in the case of paclitaxel and cisplatin combination-based concurrent chemoradiation. So, weekly cisplatin-based concurrent chemoradiation is still the appropriate choice for the treatment of carcinoma cervix.
The Institutional Ethics Committee of Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India approved the study protocol titled “A prospective comparative study of concurrent chemoradiation in advanced carcinoma cervix patient with weekly cisplatin versus weekly cisplatin and paclitaxel” vide their letter no No/NMC/8019 dated December 13, 2017.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]