|Year : 2014 | Volume
| Issue : 2 | Page : 330-336
Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: A phase II study
Sunitha Susan Varghese1, Thomas Samuel Ram1, Simon Pradeep Pavamani1, Elsa Mary Thomas2, Visalakshi Jeyaseelan3, Peringulam Narayan Viswanathan1
1 Department of Radiation Oncology Unit I, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Radiology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||14-Jul-2014|
Sunitha Susan Varghese
Department of Radiation Oncology Unit I, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Clinical trial registration CTRI/2008/091/000029
Background: Cervical cancer is the most common gynecological cancer in Indian women. This study was initiated to assess whether the combination of paclitaxel and cisplatin with radiation was feasible in Indian women.
Aims and Objectives: The aim of this study was to assess the immediate tumor response and toxicity of weekly cisplatin and paclitaxel along with radiotherapy in the treatment of cervical cancer.
Materials and Methods: Women with primary untreated squamous cell carcinoma of the cervix with FIGO stages IB2 to IIIB were treated with weekly injections of cisplatin 30 mg/m2and paclitaxel 40 mg/m2 for 4 weeks along with radiotherapy. A total of 25 patients were enrolled in this study. Disease was assessed prior to treatment by pelvic examination and contrast enhanced computed tomography scan of the abdomen and pelvis. Response was assessed 6 weeks after completion of treatment using the same parameters. Clinical and radiological response was documented. The toxicity was assessed and was graded using the common toxicity criteria Version 3.0. Intention to treat analysis was used when reporting results.
Results: A total of 23 patients completed the intended treatment. There was a complete response rate of 88%, 12% were not available for response assessment. The major toxicity was Grade 3 diarrhea (48%). The mean duration of treatment was 58 days.
Conclusions: Combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of cervix had a high incidence of acute toxicity. There was no increase in immediate tumor response and progression free survival with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemo radiation with cisplatin alone.
材料和方法：25例未经治疗的原发性FIGO分级IB2到IIIB期的宫颈鳞状细胞癌的妇女，每周注射顺铂3030 mg/m2，紫杉醇30 mg/m2，共4周，同步放射治疗。治疗前用CT扫描腹部和盆腔进行疾病的评估。6周的治疗完成后，使用相同的参数。临床和放射学的反应被记录。使用通用毒性标准版本3.0对毒性进行了评估和分级。
Keywords: Cervical cancer, cisplatin, concurrent chemotherapy, paclitaxel, radiotherapy
|How to cite this article:|
Varghese SS, Ram TS, Pavamani SP, Thomas EM, Jeyaseelan V, Viswanathan PN. Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: A phase II study. J Can Res Ther 2014;10:330-6
|How to cite this URL:|
Varghese SS, Ram TS, Pavamani SP, Thomas EM, Jeyaseelan V, Viswanathan PN. Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: A phase II study. J Can Res Ther [serial online] 2014 [cited 2019 Nov 13];10:330-6. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/330/136621
| > Introduction|| |
Carcinoma of the uterine cervix is the seventh most common cancer world-wide.  Cervical cancer is the most common cancer in South Indian women with incidence of 19.4-43.5/100,000/year. 
Invasive disease can present as early stage, locally advanced and metastatic.  In the past, treatment for locally advanced carcinoma of the cervix has been radical radiotherapy. In 1999, five randomized studies including nearly 2,000 patients were published demonstrating that the survival rate with radiation plus concomitant chemotherapy with cisplatin based regimen was superior to that obtained with radiation alone. ,,,, Subsequently, a meta-analysis based on 19 trials including 4,580 patients concluded that chemo irradiation with Cisplatin offers an absolute survival benefit of 12% at 5 years.  Since then, cisplatin based chemo irradiation has been accepted as the standard of care for all patients with cervical cancer stage greater than IB1.  Subsequently various chemotherapeutic agents have been combined with cisplatinum to evaluate whether there is any added benefit.
Paclitaxel, a microtubule stabilizing chemotherapeutic agent, has broad activity against a number of solid tumors including cancers of the ovary, breast, lung, and endometrium ,,,, and it blocks cells in the G2-M phase of the cell cycle, which is the most radiosensitive phase of the cell cycle.  Thus, Paclitaxel has a rationale as a radiation sensitizer. ,,, The combination of cisplatin and paclitaxel was tried in recurrent and metastatic carcinoma of the cervix and was found to be safe and effective. ,,, Moore et al. reported that this combination gave 36.2% overall response rate in patients with recurrent and metastatic carcinoma cervix.  The same combination was also tried as radio sensitizer in cervical carcinoma and was found to be tolerable and feasible with high response rates. ,,,,, Chen et al.  did a phase I study where weekly paclitaxel was combined with 3 weekly cisplatin. The maximum tolerated dose (MTD) of this trial was reported as paclitaxel 50 mg/m 2 /week with cisplatin 50 mg/m 2 once in 3 weeks. There was another phase I study by Pignata et al.,  which reported cisplatin 30 mg/m 2 and paclitaxel 50 mg/m 2 as the MTD. Both these studies reported tumor response rates more than 90%. Disilvestro et al.  did a phase I/phase II study where cisplatin and paclitaxel where used as radio sensitizers in cervical cancer. The MTD reported was cisplatin 40 mg/m 2 /week and paclitaxel 40 mg/m 2 /week. The phase II part of this study reported a complete response rate of 89.4% with acceptable toxicity profile. There was another phase II study by Miglietta et al.  where cisplatin 75 mg/m 2 and paclitaxel 175 mg/m 2 was given once every 3 weeks for four cycles. First cycle was given as neoadjuvant chemotherapy, second and third cycles where given along with external radiotherapy and the fourth cycle was given with brachytherapy. They reported a complete response rate of 100%. A phase I study was carried out in India to find out the MTD of the combination of cisplatin and paclitaxel as concurrent chemotherapy in women with locally advanced squamous cell carcinoma of the cervix.  This study concluded that cisplatin 30 mg/m 2 /week and paclitaxel 40 mg/m 2 /week for four cycles along with radiation was well- tolerated and this dose was recommended for further phase II trials. The present phase II study used the Indian phase I MTD to find out the efficacy and toxicity of combined cisplatin and paclitaxel along with radiation in the treatment of locally advanced squamous cell carcinoma of the uterine cervix.
| > Materials and methods|| |
The study was initiated after obtaining clearance from the Institutional Review Board. Patients were included in the trial after getting a written informed consent. We decided to accrue 25 patients who fulfill the inclusion criteria. The inclusion criteria were women with squamous cell carcinoma of the uterine cervix with stages 1B2 to III B, with good performance score (Eastern Cooperative Oncology Group 0, 1 or 2) and an informed consent. Patients were excluded from the trial if they have any histopathology other than squamous cell carcinoma, any history of previous treatment for cervical cancer, hepatic, renal or cardiac dysfunction, poor hematological reserve (hemoglobin <8 g/dl, total count <3,000/mm 3 , platelet count <1 lakh/mm 3 , absolute neutrophil count <1000/mm 3 ) or pre-existing peripheral neuropathy. Pregnant women, women with synchronous malignancies or concurrent infections and those with age >70 years or <18 years were also excluded. From March 2008 to September 2008, 84 patients with cervical cancer were screened to accrue 25 eligible patients for this study. [Table 1] shows reasons for excluding patients from this trial. Furthermore, refer to [Figure 1] for the flow chart on trial enrollment. The patient characteristics are listed in [Table 2].
|Figure 1: Flowchart for patient accrual for the study of concurrent chemo irradiation with weekly cisplatin and paclitaxel in locally advanced squamous cell carcinoma of uterine cervix|
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|Table 2: The characteristics of patients enrolled in the phase II trial of concurrent chemo irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of the uterine cervix|
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All patients were staged with clinical examination, chest X-ray, abdomino-pelvis ultrasound, cystoscopy and proctoscopy. After initial staging all patients who were eligible for the study underwent a computed tomography (CT) scan of the abdomen and pelvis. Patients were excluded if they had enlarged paraaortic nodes or liver metastasis.
All patients underwent conventional planning and simulation with the help of a Varian Ximatron simulator. External radiation portals extended from L4-L5 junction to 3 cm below the palpable cervical growth or up to the introitus if the vagina was involved. Lateral borders were 1.5-2 cm lateral to the brim of the lesser pelvis. The anterior border of the lateral portal was kept 3 cm anterior to the body of L5 vertebra and posterior border at S2/S3 junction.
External beam radiation therapy was delivered using linear accelerator with 6 MV/15 MV photons or a Teletherapy cobalt unit. A dose of 50 Gy was delivered in 25 fractions, using a four field box technique and was treated 5 days/week. This was followed by a single application of low dose rate intracavitory brachytherapy to deliver a dose of 27-30 Gy to point A.
Concurrent chemotherapy was administered using Inj. cisplatin 30 mg/m 2 /week and injection paclitaxel 40 mg/m 2 /week. Chemotherapy was started in the 1 st week of radiation therapy and repeated every week for 4 weeks (treatment details are listed in [Table 3]).
Weekly assessment was carried out and toxicity was graded according to the common toxicity criteria version 3.0. Hemogram, renal and liver function tests were repeated every week prior to clinical examination. If there was any Grade 3 toxicity, chemotherapy, and radiotherapy were withheld.
|Table 3: Treatment details of patients eligible for analysis in the phase II study of concurrent chemo irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced carcinoma of uterine cervix|
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Assessment of tumor response was done using clinical assessment and response evaluation criteria in solid tumors (RECIST)  criteria.
For clinical assessment, pelvic examination findings were considered. A pelvic examination was carried out before starting treatment and the extent of the tumor was described. Pelvic examination to assess tumor response was repeated 6 weeks after completion of brachytherapy and findings were documented. A clinical complete response was documented if there was no evidence of residual disease on pelvic examination at the end of 6 weeks. If there was any suspicion of residual disease at the end of 6 weeks, a biopsy was taken from the suspected area. If the biopsy was negative for any residual disease, it was considered as complete response. If biopsy was positive for residual disease, it was considered as a partial response.
Contrast enhanced CT scan of the abdomen and pelvis with slice thickness of 5 mm was carried out to measure the tumor size. CT scan was performed before starting treatment and 6 weeks after completion of treatment. All CT scans were read by the same radiologist and measurements taken. The cervical growth and enlarged pelvic nodes were taken as the target lesion. The tumor response was reported as per RECIST  criteria. Intention to treat analysis is used in reporting results.
| > Results|| |
Of the 25 patients enrolled, 24 patients completed external radiotherapy. A total of 18 patients received 6 MV photons, 1 patient received 15 MV photons, and 6 patients received external radiotherapy from telecobalt unit. Median time to complete external radiotherapy was 45.5 days (range: 34-77 days). There was a median of 14 days break during external radiotherapy (range: 0-46 days). The patient who discontinued treatment during external radiation therapy (RT) had multiple episodes of Herpes Zoster and gluteal abscess, which caused prolonged treatment break. Another patient was not willing for brachytherapy. Hence, only the remaining 23 patients underwent brachytherapy. There was a median gap of 10 days between external radiotherapy and brachytherapy (range: 2-21 days). A total of 21 patients received 30 Gy to point A and two patients received 27 Gy to point A. The median duration of the total treatment was 58 days (range: 45-93 days). 21 patients (84%) completed all the four cycles of chemotherapy. 3 patients (12%) received only three cycles of chemotherapy. 1 patient (4%) received only 2 cycles of chemotherapy. [Table 4] shows the time taken by patients to complete the entire treatment and [Table 5] lists the major causes of break during the treatment.
|Table 5: Toxicities causing treatment break during concurrent chemo irradiation with weekly cisplatin and paclitaxel in the treatment of patients with locally advanced squamous cell carcinoma of the uterine cervix*|
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Toxicity assessment was done for all patients who were enrolled into the trial. All toxicities were graded according to (common toxicity criteria) CTC V.3.0
Leucopenia was the most common Grade 3 hematological toxicity seen (20%) followed by anemia (8%) and neutropenia (8%). Those patients who had Hemoglobin less than 8 g/dl received a blood transfusion. Thrombocytopenia was not seen in any patient. There was no Grade 4 hematological toxicity.
The most common toxicity seen in this study was Grade 3 diarrhea. Twelve patients (48%) developed Grade 3 diarrhea and four patients developed Grade 2 diarrhea. One patient developed Grade 3 abdominal pain and five patients developed Grade 3 functional proctitis. There was no incidence of Grade 4 GI toxicity.
The hematological and GI toxicities are listed together in [Table 6].
|Table 6: Hematological and gastrointestinal toxicities reported for patients accrued in the phase II study of concurrent chemo irradiation with weekly Cisplatin and Paclitaxel in locally advanced carcinoma of the uterine cervix (N=25)|
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The major genitourinary toxicity encountered in this study was vaginal mucositis. Six patients (24%) developed Grade 3 vaginal mucositis. None of the patients developed vaginal dryness or cystitis. One patient developed Grade 4 dermatitis. This patient was treated with 6 MV photons from a linear accelerator. Six patients (24%) developed Grade 3 dermatitis. There was no neurological toxicity, allergy or derangement of hepatic or renal function. One of our patients developed Grade 2 scalp alopecia.
There was one incidence of gram-negative septicemia after the fourth cycle of chemotherapy. This patient was found to have a urinary tract infection, which progressed to septicemia. This was a non-neutropenia septicemia. She required hospitalization and intravenous antibiotics for 14 days. She recovered completely after 2 weeks.
Clinical tumor response
Out of 25 patients who were enrolled into the trial, 22 patients came for follow-up at the end of 6 weeks. Hence, only 22 patients were available for the assessment of clinical response. 18 patients had complete clinical response. Four patients were suspected to have residual disease, but proved to have no residual disease histopathologically. Hence, our complete response rate was 88% (22/25) and 12% (3/25) patients were not available for assessment of disease response.
Tumour response with RECIST criteria
Only eighteen patients came for CT abdomen and pelvis at the end of 6 weeks. Eight patients (32%) had a partial response and 10 patients (40%) had stable disease and seven patients (28%) were not available for assessment.
Follow-up of patients
We followed-up the patients once in 3 months in the 1 st year, once in 6 months in the 2 nd year and once a year thereafter. We completed a median follow-up of 33 months (range: 2-58 months). Those patients who had documented disease recurrence or death were considered as disease progression. Those patients who were not contactable after repeated efforts were considered as lost on follow-up. 16/25 (64%) patients were alive and disease free. 2/25 (8%) had local disease recurrence and succumbed to illness. Another two patients (8%) had distant metastases and died. 5/25 (20%) patients had lost on follow-up. [Figure 2] shows the Kaplan Meier curves for overall survival and disease free survival. Late toxicities reported include 3/25 patients (12%) with Grade 2 proctitis, one patient (4%) with Grade 3 cystitis and one patient (4%) developed Grade 3 avascular necrosis of the left femur, which needed surgical intervention. There was no treatment related deaths or Grade 4 toxicities.
|Figure 2: Kaplan Meier curves showing overall survival and progression free survival in patients with locally advanced squamous cell carcinoma of cervix receiving combination chemotherapy with cisplatin and paclitaxel along with radiation therapy|
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| > Discussion|| |
The aim of this study was to find out the immediate tumor response rate and the acute toxicity of this combination regimen. This study addresses the clinical question of the feasibility of escalating the systemic therapy along with radiotherapy in treating carcinoma cervix. The strengths of this study include its prospective design and that the dose of chemotherapy was based on a Phase I data from Indian population.  Even though, most of the similar trials used six cycles of concurrent chemotherapy along with radiation, we used only four cycles as per the phase I study by Prasad et al.  In our Institution, we experienced that patients receiving concurrent chemo irradiation with single agent cisplatin had a higher incidence of prolonged cytopenia if chemotherapy was given beyond the 4 th week of external radiotherapy; thus, delaying the brachytherapy and extending the overall treatment time to more than 8 weeks (Unpublished data).
The median duration of the entire treatment was 58 days (8 weeks + 2 days). This is comparable with the median duration of treatment in studies where cisplatin alone was used as radio sensitizer. Rose et al.  in (gynecology oncology group) GOG 120 reported a median duration of 63 days for completing treatment. The median duration was 58 days in the Phase III trial by Morris et al.  In combination chemotherapy where paclitaxel and cisplatin were used as radio sensitizers, Miglieta et al.  reported 63 days as the median duration and 59 days by Disilvestro et al. 
A median treatment time of 58 days in our study shows that there were prolonged breaks during treatment for 50% of the study population. This may be because of the high incidence of Grade 3 toxicities in this treatment group. The most common Grade 3 toxicity encountered in this study was diarrhea. 12 patients (48%) developed Grade 3 diarrhea. This toxicity necessitated suspension of radiation therapy. There was a break of 14 days (median) during external radiotherapy. In view of high burden of infective diarrhea in this region, stool culture was done for all patients presenting with Grade 3 diarrhea. No infective pathogen was identified. Hence all diarrheas were classified as radiation enteritis. In the phase I study by Pignata et al.  incidence of Grade 3 diarrhea was 66%. In Disilvestro et al.  the incidence of Grade 3 GI toxicity was 16%. Miglietta et al.  reported no major GI toxicity. The incidence of Grade 3 GI toxicity in Keys et al.  was 12%. Other similar studies have not reported any significant diarrhea.
The most common hematological toxicity seen in the present study was Grade 3 leucopenia (20%). Incidence of Grade 3 neutropenia was only 8%. There was no incidence of febrile neutropenia or Grade 4 hematological toxicity, in our study. The most common toxicity reported by Chen et al., was Grade 2 anemia (62%). The incidence of Grade 3 leucopenia in Disilvestro et al. was 56%. Keys et al. reported 21% hematological toxicities.
Other major toxicity seen in the present study was vaginal mucositis and dermatitis. One patient developed Grade 4 dermatitis. All patients who developed Grade 3 dermatitis or mucositis were given a break during radiation therapy and they recovered completely. Prasad et al. reported similar incidence of dermatitis and vaginal mucositis in their phase I study. 
CT and magnetic resonance imaging (MRI) are the two primary imaging modalities for follow-up of treated cervical carcinoma. Even though, MRI is better in identifying post radiation fibrosis from residual or recurrent disease, CT scan is also an effective imaging modality in follow-up of patients with carcinoma cervix because of its advantages of rapid acquisition time, lack of bowel motion artifact and fewer contra indications than MRI.  Even though there is literature to suggest  exclusion of target lesion in the irradiated area, we included it as there was no measurable disease outside the irradiated volume. It was difficult to differentiate between post irradiation changes and residual disease in CT scans. Hence, there are no radiological complete responses. There were partial responses or stable diseases. All scans which showed stable disease had a reduction in the size of the lesion compared to pre-treatment scan, but it was not adequate to consider as a partial response as per RECIST criteria. The category of stable disease as evaluated by RECIST criteria on CT scan is probably overestimated due to inability of CT scan to accurately detect residual disease in the post-irradiated cervix. None of the patients had an increase in the tumor dimensions after treatment compared to the pre-treatment scans.
We observed an overall complete response rate of 88%.The response rate dropped because three patients were not available for follow-up at the end of 6 weeks. In similar phase II studies, Disilvestro et al.  noted a complete response rate of 89.4% whereas Miglietta et al.  had 100% complete response rates. The high incidence of complete response rate in Miglieta et al. is probably because they used one cycle of neoadjuvant chemotherapy followed by concurrent chemo radiotherapy. Moreover, they used a high dose of paclitaxel (175 mg/m 2 once in 3 weeks for four cycles) compared to our study (40 mg/m 2 /week for four cycles).
With a median follow-up of 33 months (range: 2-58 months), our disease free survival was 64%. Disilvestro et al.  reported overall survival of 89.4% at 1 year and Miglietta et al.  had 88% survival at 2 years. In studies where cisplatin alone was used as radio sensitizer, Keys et al.  reported 83% 3 year survival. Morris et al.  had 67% disease free survival at 5 years and Rose et al.  reported 67% progression free survival at 2 years.
Limitations of the study
One of the drawbacks of this study was that there was no comparative arm with standard treatment regimen to compare the response and toxicities. High rates of lost on follow-up was also a limitation. Another drawback was in using RECIST criteria to quantify the response rates for carcinoma cervix. With CT abdomen and pelvis, it was difficult to distinguish between post RT changes or residual disease. This concurs with the authors of RECIST criteria that this criterion cannot be used optimally to assess tumor response in the irradiated area.
| > Conclusions|| |
Combination chemotherapy with cisplatin and paclitaxel along with radiotherapy in patients with locally advanced squamous cell carcinoma of cervix had a high incidence of acute GI toxicity. There was no increase in immediate tumor response with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemo radiation with cisplatin alone.
| > Acknowledgments|| |
The authors wish to acknowledge Dr. Reddy's Laboratories Ltd. for supporting this study financially and for providing Mitotax TM (Paclitaxel) for the study. The authors wish to thank Dr. Jacob John for his valuable suggestions in preparing this manuscript.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]