Age distribution of patients

Disease-related characteristics

All patients had squamous cell carcinoma histopathology, except for 1 patient in Arm 1 and 2 patients in Arm 2 who were having adenocarcinoma cervix. The distribution of patients as per FIGO staging 2009 is shown in [Figure 1]; the distribution in Arm 1 was 8/23 (35%) in stage IIB, 3/23 (13%) in IIIA, 4/23 (17%) in IIIB, 5/23 (22%) in IVA, and 3/23 (13%) in IVB. In Arm 2, the stage distribution was 8/24 (33%) in stage IIB, 2/24 (8%) in IIIA, 6/24 (25%) in IIIB, 5/24 (21%) in IVA, 3/24 (13%) in IVB. Thus, the most common stage of presentation was FIGO stage IIB followed by stage IIIB and IVA in both the arms. The incidence of metastasis to pelvic, inguinal, and paraaortic lymphnodal groups based on imaging (CECT/PET CT) in both the arms is depicted in [Table 2]. In Arm 1, incidence of involvement of pelvic, inguinal and paraaortic group of lymph nodes is 20/23 (86%), 0/23 (0%), and 3/23 (13%), respectively, whereas in Arm 2, the corresponding figures were 19/24 (79%), 1/24 (5%), and 3/24 (12.5%), respectively.

Loco regional lymphnodal involvement based on imaging in both arms

Treatment-related characteristics

Majority of patients in both the treatment arms (16/23 and 19/24 in Arms 1 and 2, respectively) received 5 or more cycles of weekly concurrent injection cisplatin along with radiation. Four patients each in Arms 1 and 2 received 4 cycles of concurrent chemotherapy while remaining patients received <4>

Toxicities-related characteristics

The site-specific acute and delayed toxicities are summarized in [Tables 3] and [4], respectively.

Acute toxicities in both arms

Late toxicities

Acute toxicities

Acute toxicities were observed in a small subset of patients of both the study arms up to first 3 months of follow-up. Acute toxicities were graded as per ?Common Terminology Criteria for Adverse Events (CTCAE),? i.e., CTCAE version 4.03. Grades are divided from scale of 0?5 in which 0 stands for nil toxicity and 5 for death related to adverse events.

Anemia

In Arm 1, 14/23 (58%) of the patients had anemia of whom 50% (7 patients) had Grade 1, 22% had Grade 2 (3 patients) and 28% (4 patients) had Grade 3. In Arm 2, 12/24 (50%) of the patients had anemia, of whom 17% (2 patients) had Grade 1, 58% (7 patients) had Grade 2 and 25% (3 patients) had Grade 3. Thus, among patients developing anemia, higher proportion of patients in Arm 2 developed Grade 2 and Grade 3 anemia.

Nausea and vomiting

Nausea and vomiting (N/V) were observed in 8/23 (35%) patients of Arm 1 and 5/23 (22%) of Arm 2. Of these, 1 patient each in both arms had Grade 1 N/V while rest patients were of Grade 2. All were manageable on outpatient based symptomatic and supportive care.

Neutropenia

Neutropenia was observed in 4/23 patients (17%) of Arm 1 and 8/24 (33%) patients of Arm 2. All were Grade 3.

Neuropathy

In Arm 1, not even a single patient exhibited features of neuropathy, whereas in Arm 2, 9/24 (37%) of the patients had neuropathy, with 7/24 (29%) and 2/24 (8%) patients having Grade 2 and Grade 3 neuropathy, respectively.

Alopecia

In Arm 1, the incidence of alopecia as an acute toxicity was nil whereas in Arm 2, 4/24 (17%) of the patients had alopecia and all were Grade 1.

Miscellaneous

Apart from above mentioned toxicities, various other adverse events such as acute kidney injury, cystitis, enteritis, proctitis, skin reactions, and vaginal stricture were also noticed in small proportion of patients of both the arms within 3 months of their follow-up. They had no any significant correlation statistically and were comparable in both the arms.

Late toxicities

Late toxicities were charted in both the study groups starting after 3 months of completion of treatment protocol until the past follow-up of the patients. Late toxicities have been graded as per ?Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer? criteria 2015 for radiation-related adverse events and CTCAE version 4.03 for chemotherapy-related side effects.

Anemia: In Arm 1, 13/23 (56.5%) patients had anemia, of whom 8, 2, and 3 patients (61.5%, 15% and 23%) had Grade 1, Grade 2, and Grade 3 anemia, respectively. In Arm 2, 10/24 (41.5%) of the patients had anemia, of whom 9 and 1 patients (90% and 10%) had Grade 2 and Grade 3, respectively. Thus, relative incidence of Grade 2 and 3 anemia is more in Arm 2.

Neuropathy: In Arm 1, not even a single patient exhibited features of neuropathy, whereas, in Arm 2, 12/24 (50%) of the patients had neuropathy, with 8.5?ch (1/24) were having Grade 1 and Grade 3, while remaining 83% (10/24) were having Grade 2 neuropathy. Thus, considerably more number of patients in arm 2 developed neuropathy as compared to patients in Arm 1 (50% versus nil, respectively;?P?= 0.001).

Alopecia: In Arm 1, the incidence of alopecia as a late toxicity was nil, whereas in Arm 2, 4/24 (17%) of the patients had alopecia and they were Grade 1 (3/4, 75%) or Grade 2 (1/4, 25%).

Miscellaneous: Apart from above-mentioned toxicities, various other adverse events such as cystitis, enteritis, and proctitis were also noticed in patients of both the arms from 3 months to 6 months of their follow-up. All of them were observed almost equally in both the arms without any statistically significant correlation. No patient from any of the two arms developed neutropenia as a late toxicity.

Discussion

Since carcinoma cervix is the most common gynecological cancer in developing countries including India, studies incorporating the use of ACT in LACC after CCRT in an attempt to improve survival merit consideration. In one such Asian study based on the use of ACT after CCRT in LACC, Ali?et al.[22] reported the long-term outcome in lymph nodal?metastatic cervical squamous cell cancer after chemoradiation followed by ACT. CCRT consisted of cisplatin given once per week concomitantly with extended-field radiation therapy followed by high-dose rate BCT; while ACT comprised four courses of carboplatin and paclitaxel given every 3 weeks. The primary outcomes were local and distant failures. None of the patients had local recurrence or distal failure after a minimum follow-up period of 3 years. The authors concluded that ACT after chemoradiation has a probable role in the management of lymph nodal?metastatic cervical cancer.

In our study, the use of injection paclitaxel and carboplatin (PC regimen) in postCCRT setting was well tolerated with manageable toxicities though some studies have found unfavorable toxicity profile of this regimen. Abe?et al.[23] evaluated the efficacy and toxicities of the ACT with PC following cisplatin-based CCRT in patients with cervical cancer with lymphadenopathy (N1). Over a median 21.5months followup, no significant differences were found in the recurrence rate, PFS, OS, or median interval to recurrence with N1 cervical cancer patients between the two groups. Patients with paraaortic lymphadenopathy who received CCRT and ACT had a more favorable overall and diseasefree survival than those treated with CCRT alone. However, 16/17 patients developed Grade 3?4 leukopenia and 14/17 patients developed severe hematologic toxicity during ACT. The authors concluded that ACT consisting of full dose PC therapy after CCRT was not well tolerated in general and exhibited no benefit to N1 cervical cancer patients, but may be of therapeutic advantage over CCRT alone in cervical cancer patients with paraaortic lymphadenopathy.

In our study, only 3 patients had adenocarcinoma histopathology and most of the published data is based on results in squamous cell carcinoma of the cervix. Tang?et al.[24] compared CCRT and adjuvant cisplatin-based chemotherapy with CCRT alone in 880 patients with clinical FIGO stages IIB-IVA cervical adenocarcinoma. The patients were randomized to receive either CCRT or chemoradiation with one cycle of neo-ACT with paclitaxel and cisplatin before receiving radiation and two cycles of consolidation chemotherapy with the same drugs after RT in 3-week intervals. 340 patients relapsed, with a median follow-up duration of 60 months. Patients who received chemoradiation with ACT showed a significantly longer disease-free (P?< 0 class="i" xss=removed>P?< 0 class="i" xss=removed>P?< 0>

Apart from taxanes and platinum compounds which we used in our study, some other drugs have been studied in concurrent and adjuvant treatment in LACC, such as Gemcitabine, mitomycin C (MMC) and oral 5-fluorouracil (5FU). Alfonso Due?as-Gonz?lez?et al.[25] evaluated the role of the addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as ACT with cisplatin in improving PFS at 3 years compared with current standard of care in LACC. The patients were randomly assigned to Arm A (cisplatin and gemcitabine weekly for 6 weeks with concurrent external beam RT followed by BCT, and then, two adjuvant 21-day cycles of cisplatin plus gemcitabine) or to Arm B of CCRT followed by BCT. 515 patients were enrolled (Arm A,?n?= 259; Arm B,?n?= 256). PFS at 3 years was significantly improved in arm A versus arm B. Grade 3 and 4 toxicities were more frequent in Arm A than in arm B (86.5% vs. 46.3%, respectively;?P?< 0 class="i" xss=removed>et al.[26] found that MMC, and 5-FU together with conventional RT showed an improved survival rate when compared with conventional RT alone in patients with LACC.

Use of Cisplatin has been compared with Cisplatin-Paclitaxel (C + P regimen) in postRT cervical cancer in anecdotal studies. Moore?et al.[9] studied whether C + P improved response rate, PFS, or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix in postradiation therapy scenario. Among 264 eligible patients, 134 received cisplatin and 130 received C + P. The majority of all patients had prior radiation therapy. Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C + P (P?= 0.002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C + P (P?< 0>

In our study, we used single agent injection cisplatin in concurrent setting which is considered as the standard of care. Doublet chemotherapy as part of CCRT in LACC has been tried anecdotally in the Indian scenario. Varghese?et al.[2] assessed whether the combination of paclitaxel and cisplatin with radiation was feasible in Indian women with cervical cancer FIGO stages IB2 to IIIB; treated with weekly injections of cisplatin 30 mg/m2?and paclitaxel 40 mg/m 2 for 4 weeks along with RT. A total of 25 patients were enrolled in this study. 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. The authors concluded that combination chemotherapy with cisplatin and paclitaxel along with RT in patients with LACC had a high incidence of acute toxicity. There was no increase in immediate tumor response and PFS with this treatment regimen. Hence, this regimen offers no added benefit when compared to the chemoradiation with cisplatin alone.

Some researchers are concerned about toxicities of use of Inj Cisplatin in CCRT and have replaced it with injection carboplatin. Sangkittipaiboon [27] studied the treatment outcomes of CCRT with weekly carboplatin in 105 patients with LACC. The most acute toxicities were in Grade 1?2 (Grade 3 hematological toxicities were 3.80%). Complete response was achieved in 95 patients (90.5%). Among the 95 responders, 27 experienced recurrences: local recurrences in eight (8.4%), distant failure in 17 (17.9%), and both local and distant failure in two (2.1%). Five-year disease-free survival rate was 52.38% while 5-year OS rate was 56.19% (61.45%, 42.11%, and 0% in stage IIB, III, and IVA, respectively). The authors concluded that concurrent weekly carboplatin and radiation therapy yields high response rate with modest disease-free and OSs in LACC. The regimen is feasible with minimal toxicities but is not considered as the standard of care.

The PC regimen which we used here in the ACT has also been tried for NACT in LACC. McCormack?et al.[28] investigated the feasibility of dose-dense NACT with PC regimen before CCRT and assessed the response rate to such a regimen. Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m?2) weekly for six cycles followed by CCRT (40 mg m?2?of weekly cisplatin, 50.4 Gy, 28 fractions plus BCT). The primary end-point was response rate 12 weeks postCRT. Complete or partial response rate was 70% (95% confidence interval [CI]: 54?82) postNACT and 85% (95% CI: 71?94) postCRT. Overall and PFSs at 3 years were 67% (95% CI: 51?79) and 68% (95% CI: 51?79), respectively. Grade 3/4 toxicities were 20% during NACT (11% hematological, 9% nonhematological) and 52% during CRT (hematological: 41%, nonhematological: 22%). The authors opined that a good response rate is achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by radical CCRT; and is a feasible regimen as evidenced by the acceptable toxicity of NACT and by the high compliance to RT (98%).

Conclusion

Exhibition of ACT with injection paclitaxel and injectioncarboplatin-based protocol in locally advanced carcinoma cervix after the conclusion of CCRT followed by ICRT is a technically viable option with manageable toxicity and does not add on to any significant morbidity/mortality. Judicious follow-up and supervision is required for the patients who receive ACT so that the toxicity, if any, can be managed early in an outpatient or inpatient setting as clinically indicated. More multicentric studies should be envisaged in urban and rural settings, and data should be analyzed to evaluate further any benefit in OS and locoregional control by addition of ACT in locally advanced cervical carcinoma.

Conflict of Interest

There are no conflicts of interest.

Acknowledgments

The authors would like to thank allied specialties of Medical Oncology, Oncopathology, Gynaeoncology, Radiodiagnosis and Nuclear Medicine Department for their support in work-up and managing these cases and in carrying out the study.

• References