Chemoradiation and Image guided Brachytherapy along with or sans Induction chemotherapy in Locally Advanced Cervical Cancer An Open labelled Phase III Randomized Controlled Trial (CASCADE Study)

According to GLOBOCAN estimates the global incidence of cervical cancer in 2022 was 662044 cases with 348709 deaths. Low and middle income countries (LMICs) such as India rank second in incidence with 127526 cases (19.2 percentage of the global total) and first in mortality 79906 deaths (22.9 percentage of the global total) from this disease in 2022 (1). Following the release of NCI alert in 1999 Concurrent cisplatin based chemotherapy (CT) and radiotherapy (CTRT) plus brachytherapy is considered the standard of care for locally advanced cervical cancers FIGO 2018 stage IB3, IIA2 and upto IVA (2). Moreover, meta-analysis of 13 trials comparing concurrent chemoradiation with radiotherapy alone demonstrated a 6 percent improvement in 5-year overall survival (OS) and an 8 percent increase in disease-free survival (DFS) with the addition of chemotherapy (3). Subgroup analysis from this metanalysis indicated that the benefit of chemotherapy decreases with advancing stage. Specifically, the 5-year survival benefits were 10percent for stage IB to IIA, 7percent for stage IIB, and approximately 3percent for stage III-IVA.

Data on advancements in radiotherapy techniques, specifically Volumetric Arc Therapy (VMAT) and Image-Guided Adaptive Brachytherapy (IGABT), have been retrospectively reviewed in the RetroEMBRACE study. The results showed a 5year overall survival (OS) rate of approximately 65 percent for FIGO Stage IB-IVA (4). About 75 percent cases in this review belonged to Stage IIB and IIIB with a 5yr OS approximately 70 percent and 42 percent respectively. RetroEMBRACE and EMBRACE-I study showed significant improvement in local failure rates with these techniques making distant failure the most common pattern of failure in these patients (5). An additional benefit of 19 percent in 5-year overall survival was observed in two trials which used adjuvant CT after chemoradiation. However, benefit from these trials cannot be validated due to less mature follow up data (6,7). The OUTBACK Trial investigated the effectiveness of adjuvant chemotherapy following definitive chemoradiation in patients with locally advanced disease. The trial involved administering four cycles of Paclitaxel (at 155 mg per metre square) and Carboplatin (AUC 5) every three weeks. The results showed no significant differences in overall survival (OS) progression-free survival (PFS) or distant metastasis rates between the groups indicating that addition of adjuvant CT was without any benefit in this patient population (8).

The role of Induction chemotherapy (IC) has not been clearly defined in literature. IC may have several benefits like reduction in tumor volume which may help reduce tumor hypoxia thereby increasing radiosensitivity, treating micrometastatic disease elsewhere, and reducing lymph nodal burden. IC can also be used as an important prognostic tool for assessing treatment response which may predict the benefit of radical treatment (9).  A systematic review of 18 trials involving 2094 patients revealed the impact of chemotherapy cycle length and cisplatin dose on survival. Trials with chemotherapy cycles of 14 days or less (HR=0.83 P=0.046) or cisplatin dose intensities of at least 25 mg per metre square per week (HR=0.91, P=0.20) showed a survival benefit from neoadjuvant chemotherapy (NACT). Conversely trials with cycle lengths exceeding 14 days (HR=1.25, P=0.005) or cisplatin dose intensities below 25 mg/m² per week (HR=1.35, P=0.002) indicated a detrimental effect on survival from NACT (10). However, a high degree of heterogeneity in study groups prevented evaluating subgroups that might show benefit with addition of IC.

Newer approaches in IC include reduction in cycle length with use of dose dense regimens, inclusion of taxanes along with platinum-based chemotherapy, eliminating delay between induction chemotherapy & definitive chemoradiation and balancing the need for systemic treatment with tolerability. Retrospective study by Narayan et. al analyzed the survival outcomes of 713 patients undergoing NACT with PF (Cisplatin with 5FU) or TPF (Taxane Cisplain 5FU) before chemoradiation. An improvement in 5yr DFS was seen in cases receiving PF/TPF as compared to chemoradiation alone (58.3 vs 41.8 percent p = 0.001). Although TPF was associated with increased grade 3 or 4 hematological toxicities use of neoadjuvant chemotherapy showed significant benefit in terms of both response rates and survival considering it a feasible option in stage IIB and IIIB disease (11). The UK based CxII Trial was a single arm Phase II trial assessed the response rate, while evaluating the feasibility of dose-dense neoadjuvant chemotherapy with paclitaxel and carboplatin before radical chemoradiation. Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg per metre sq) weekly for six cycles and showed 70 percent complete and partial response rates after NACT and 85 percent post CTRT. The 3yr OS and PFS were 67 percent and 68 percent respectively with 20 percent grade 3 or 4 toxicities (11 percent hematological and 9 percent non-hematological) during NACT showing the feasibility of this regimen for larger trials (12).

The GCIG INTERLACE trial demonstrated that included 77 percent Stage II and 58 percent node negative cases improved long-term outcomes for locally advanced cervical cancers. IC preceding chemoradiotherapy resulted in a 5 year PFS rate of 73 percent and OS rate of 80 percent. In contrast, chemoradiation alone yielded a 5 year PFS rate of 64 percent and an OS rate of 72 percent. Grade 3 or more adverse events were observed in 59 percent of patients receiving IC plus chemoradiotherapy (CTRT) and in 48 percent of those undergoing CRT alone (13). However, Lindergaard etal (14) compared the outcomes of Experimental arm of INTERLACE Study and standard EMBRACE studies and found no significant difference in disease outcomes indicating that the use of advanced techniques in radiation therapy like Intensity Modulated Radiation Therapy (IMRT), with Image Guided Radiation Therapy (IGRT), Image Guided Adaptive Brachytherapy (IGABT), Elective Para-aortic irradiation in high-risk patients might minimize the need for IC.

Hence, in Indian context this study is being taken up to assess the benefit if any of adding IC in the treatment of Locally advanced cervical cancer patients treated with Advanced radiation technology.