RESULTS OF ADJUVANT PACLITAXEL AND CARBOPLATIN AFTER CONCURRENT CHEMO RADIATION (CCRT) IN LOCALLY ADVANCED CERVICAL CANCER (LACC)

This study aims to evaluate the feasibility and benefit of adjuvant chemotherapy (ACT) after CCRT in such patients to the improve treatment outcome. Material and Methods: From July 2017-June 2018, eighty patients of LACC were prospectively evaluated. All patients received radiation upto 50Gy with Cisplatin 40 mg/ m 2 followed by intra-cavitary radiotherapy- 3fractions of 7 Gy each (28 Gy equivalent). Adjuvant chemotherapy with Paclitaxel (175 mg/m 2 ) +Carboplatin (AUC 5) was planned for all patients to a median of four cycles (range 3–6 cycles). Results: Eighty evaluable patients were enrolled for adjuvant chemotherapy. Disease-free survival after a median follow-up of 14 months (range 8-20) was 83.75% showing a significantly long term tumor control. The adjuvant chemotherapy was well tolerated. Hematologic and neurologic toxicities were most common side effects in our study however, they were manageable. Conclusion: Incorporating adjuvant chemotherapy with Paclitaxel and Carboplatin after concomitant chemoradiation is effective, safe and may be a very promising treatment protocol for advanced cervical cancer. Four weeks after completion of brachytherapy response evaluation was done by abdominal and pelvic imaging (CECT /MRI) and gynaecological examination. Complete response (CR) was determined after gynecologic examination and defined as complete radiologic disappearance of the cervical lesion/s and no visible tumor. Partial response (PR) was determined by CT/MRI and gynecologic examination and defined as a decrease in tumor diameter of >50%. Stable disease (SD) was defined as <50% response to chemoradiation. who had curative as to who did not achieve complete after CCRT to a of four (range Each chemotherapy cycle consisted of i.v.in 0.9% with codan set over 3hrs and Carboplatin according to Calvert formula (carboplatin dose = [creatinine clearance + 25] x AUC) i.v.in 500 mL 5% glucose over 60 min both on the same day every 3weekly. To avoid hypersensitivity reactions dexamethasone 16 graniset 3 mg and ranitidine 50 mg were administered i.v.to all patients prior to initiation of Paclitaxel infusion. Patients went off study in, unacceptable toxicity or withdrawal of consent. The disease control and DFS were calculated using the Kaplan–Meier method.


ISSN: 2320-5407
Int. J. Adv. Res. 8(04), 1086-1093 1087 each year in Indian women [1] . Nearly 90% of cervical cancer deaths occur in developing parts of the world as patient's presents in advanced stages due to suboptimal screening, lack of awareness and appropriate healthcare infrastructure [2] . Concurrent chemoradiation therapy (CCRT) is the standard of treatment for patients with locally advanced cervical cancer International Federation of Gynaecology and Obstetrics (FIGO) stage IIB to IVA, but majority of such patients do not survive five years post treatment [3][4][5][6][7] .
Improving survival by giving adjuvant chemotherapy (ACT) is a modality to target residual lesion in the pelvis and also helps to eradicate occult disease to prevent metastasis. Other treatment modifications, chemotherapeutic drugs, targeted agents or consolidation chemotherapy are under study. A Phase III study has demonstrated that adding bevacizumab in patients with persistent, recurrent or metastatic cervical carcinoma increases progression-free survival (PFS) and overall survival (OS) [8] .
In a Phase III study,Duenas-González A et al reported increased progression-free survival (PFS) with the use adjuvant gemcitabine and cisplatin after concurrent chemoradiation with the same drugs as compared to use of cisplatin alone with radiation in patients with stage IIB to IVA carcinoma cervix. The use of adjuvant or consolidation chemotherapy have also explored in many trialssome of which showed an increased response rate, while the other did not report this advantage [9][10][11][12] .However, inconsistency in study design,chemotherapeutic interventions and result of survival benefit has been seen among various trials of ACT for LACC.
Paclitaxel has also shown to exert activity in advanced cervical cancer, alone and in combination with platinum analogues [13][14][15][16] . The combination of carboplatin and paclitaxel after radiotherapy has shown to be feasible in nonsmall cell lung cancer or head and neck cancer [17][18][19] . In these studies, local toxicity such as mucositis, oesophagitis and pneumonitis was increased, but this seldom resulted in treatment delay, while chemotherapy was hardly delayed for myelo-toxicity.Carboplatin has a number of advantages over cisplatin as it is less nephro-or neurotoxicity and has fewer gastrointestinal side-effects, albeit at the cost of more bone marrow depression [20][21] .
We aimed to determine the role of adjuvant paclitaxel and carboplatin combination after concurrent chemoradiation in locally advanced cervical cancer patients.Because this regimen can be given in an outpatient setting; a feasibility study was hence performed.

Material and Methods:-
From July 2017-June 2018 this study was done to compare the feasibility and benefits of using CCRT plus ACT in patients of diagnosed cervical cancer FIGO stage IIB-IVA, with median follow up-14 (range 8-20) months.

Eligibility criteria: Inclusion criteria:
Women with FIGO stage IIB-IVA cervical carcinoma ,histological proven squamous cell carcinoma or adenocarcinoma who met the following criteria were eligible: no prior chemotherapy or pelvic radiotherapy, no concurrent other anti-tumour or investigational therapy; ECOG performance status ≤ 2; age > 30 and< 75 years; life expectancy ≥ 6 months; adequate bone marrow (leukocyte count ≥ 3.0 x 109/L or platelet count ≥ 100 x 109/L); adequate hepatic and renal functions defined as bilirubin ≤1.5× and serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase ≤1.5× of the upper normal value; and creatinine clearance ≥40 mg/dL were recruited. Consent to participate were taken.

Exclusion criteria:
Patients with enlarged para-aortic lymph nodes on CT or MRI, cardiac failure, renal impairment/failure, peripheral or central neuropathy, uncontrolled diabetes mellitus or HIV/HBsAg/HCV infection, pregnancy or lactation.

Study design and treatment:
All patients received RT to whole pelvis 50Gy ⁄ 25 fractions, one fraction per day, five days per week by a 6-15 MV photon beam with 3DCRT technique. Cisplatin 40 mg/ m 2 was administered weekly simultaneously with radiation. HDR-Intracavitary brachytherapy (ICBT) was given one week after completing external radiotherapy -3fractions of 7 Gy each (28 Gy equivalent) to reference point A (2 cm. superior and 2 cm lateral to the cervical os) on weekly basis. Overall treatment time (OTT) ranged from 55 to 65 days.

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Four weeks after completion of brachytherapy response evaluation was done by abdominal and pelvic imaging (CECT /MRI) and gynaecological examination. Complete response (CR) was determined after gynecologic examination and defined as complete radiologic disappearance of the cervical lesion/s and no visible tumor. Partial response (PR) was determined by CT/MRI and gynecologic examination and defined as a decrease in tumor diameter of >50%. Stable disease (SD) was defined as <50% response to chemoradiation.
Adjuvant chemotherapy was administered to all the patients who had curative response as well as to patients who did not achieve complete response after CCRT to a median of four cycles (range 3-6 cycles). Each chemotherapy cycle consisted of Paclitaxel 175 mg/m2 i.v.in 500 mL 0.9% NaCl glass bottle with codan set over 3hrs and Carboplatin AUC-5 according to Calvert formula (carboplatin dose = [creatinine clearance + 25] x AUC) i.v.in 500 mL 5% glucose over 60 min both on the same day every 3weekly. To avoid hypersensitivity reactions dexamethasone 16 mg, graniset 3 mg and ranitidine 50 mg were administered i.v.to all patients prior to initiation of Paclitaxel infusion. Patients went off study in, unacceptable toxicity or withdrawal of consent. The disease control and DFS were calculated using the Kaplan-Meier method.

Observation and Results:-
A total of 80 patients were treated and analyzed.The clinical characteristics of all patients are listed in Table- The complete response and partial response rates were 69/80 (86.25%) and 8/80 (10%), respectively while stable disease was found in 3 patients. Two patients developed local recurrence and distant metastases were observed in one patient (Table-2).
Disease free survival at the median follow up of 14 months was 83.75%. One patient died from the disease (Table-3).   Treatment related toxicity was evaluated as shown in Table-4.
The most troublesome side effects were hematologic and neurologic toxicities.   Mean survival time in Complete response category was 19.574 and Non complete response categories collectively was 13.909 (Table-5). All above tests were statistically significant means there was statistically significant difference in survival curves of CR and NCR categories, the disease free survival was better in complete response category than NCR category (Figure -1 ).

Discussion:-
For almost two decades in patients with bulky IB2-IVA disease CRT has been the standard of care (as endorsed by the National Cancer Institute) which is based on of five randomised trials, three in LACC, demonstrating an improvement in both disease-free survival (DFS) and OS with CRT over standard RT. The absolute survival benefit in FIGO stage I/II disease was 10% for CRT compared with RT alone and 3% for those with FIGO stage III/IVA.
Recurrences in cervical cancer patients can be seen in the form of local pelvic lesion and/ or distant metastases. A 10%-20% recurrence rate has been reported following primary surgery or radiotherapy in women with stage IB-IIA cervical tumors with no evidence of lymph node involvement, while up to 70% of patients with nodal metastases and/or more locally advanced tumors will relapse [22][23][24][25] .In bulky pelvic tumors the rate of local disease recurrence/ persistence is far more common than developing distant metastases. With RT alone the pelvic failure rate as reported by Perez et al is 10% in stage IB, 17% in stage IIA, 23% in stage IIB, 42% in stage III, and 74% in stage IVA [26] . For patients in stage IA/ IB the reported incidence of distant metastases is 3%, and16% while in stage IIA/IIB is 26% and 31%, in stage III is 39%, and in stage IVA is 75%.
Lung (21%) is the most common site of distant metastases followed by bone (16%) predominantly involving the lumbar and thoracic spine, para-aortic nodes (11%), abdominal cavity (8%), and supraclavicular nodes (7%). Patients who relapsed in lymph nodes had a median survival of 24 weeks, while those who relapsed in other organs had a median survival of only 12 weeks [27] .
Most of the recurrences occurred during the follow up period within two years in stage II and III cervical cancers.Moderately differentiated carcinoma was associated with nodal recurrence while adenocarcinoma with distant metastasis. Histology, stage, age, treatment duration, toxicity gap, ICRT type, response and follow up pattern as variables was undertaken to study recurrences in LACC -of which stage, histology, toxicity gap and follow up pattern were found to effect survival.
New treatment strategies are being investigated for patients who are still potentially curable after radical treatment. However, most women are treated with palliative intent, it is possible to identify subgroups of patients with high potential who would have a substantially better prognosis and in whom the objective of treatment is cure [28][29] .
Such approaches include -(1.1) Neoadjuvant chemotherapy -An ongoing Phase III Multicentre trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with LACC-to analyse the overall survival , progression free survival , adverse events, quality of life and patterns of first relapse (local and/or systemic) -results awaited (INTERLACE) [30] .
(1.2) Tang et al [31] demonstrated that using one cycle of neoadjuvant chemotherapy with paclitaxel and cisplatin before receiving radiation and two cycles of consolidation chemotherapy with the same drugs after radiotherapy at 3-week intervals improved localized disease ,distant metastases,overall and disease-free survival .
(2.1) Adjuvant chemotherapy-A Phase III trial of adjuvant chemotherapy with paclitaxel plus carboplatin to determine improvement in overall survival, progression-free survival, acute and long-term toxicities, patterns of disease recurrence and quality of life (OUTBACK) [32] .
(2.2) Jelavić et al has reported an increase in distant disease free survival with the use of concomitant chemoradiotherapy by adding cisplatin and ifosfamide along with LDR brachytherapy followed by adjuvant chemotherapy for four cycles with the same drugs [33] .
In our study, first follow-up after RT was done at four weeks and adjuvant chemotherapy was given to patients with complete response so as to eradicate the potential micrometastasis in order to prevent local and distant metastasis.This group of patients were found to have better clinical outcome and longer DFS without any unmanageable toxicity.Patients with suboptimal response/residual tumor were given adjuvant chemotherapy with the clinical understanding of their subsequent local and distant pattern of failure to achieve improved outcome and early CR.

Conclusion:-
Considering the poor prognosis of LACC and limited salvage treatment options for the patients with recurrent disease, the use of adjuvant chemotherapy is an attempt to improve the treatment outcome seems reasonable.Incorporating adjuvant chemotherapy with Paclitaxel and Carboplatin after concomitant chemoradiation 1092 is highly effective, safe and may be a very promising treatment protocol for advanced cervical carcinoma. We are still enrolling patients in view of encouraging results and in order to get long term follow up and to assess maximum disease free survival.Future large trials are required to demonstrate the need and efficacy, toxicities and QoL.

Disclosure:
The authors declare no conflict of interest.