The treatment of recurrent or metastatic cervical cancer is an unmet medical need given dismal outcomes. This retrospective study includes data from a public sector tertiary care cancer centre hospital with high volume of such patients. As cervical cancer affects patients from low-socioeconomic strata, there is limited access to pembrolizumab and bevacizumab.

Several important conclusions can be drawn from the present study. Amongst, the total 302 patients, 83 patients, were found unfit for chemotherapy and were planned for upfront symptomatic and palliative care only. Some of the reasons for not giving chemotherapy included poor prognostic factors like poor ECOG PS, recurrence within 1 year and raised baseline serum creatinine. The PFS and OS in those treated with symptomatic and palliative care were not calculated as many of these patients went back home and subsequent follow-up was not available.

It is pertinent, to note that even in the first line of treatment, palliative radiotherapy alone as a modality of treatment was given to 70 patients in our study. In a phase 2 study, called Sharon Project by Eleonora et al. [7], palliative short-course hypo- fractionated RT brought a response rate of 96.0% (95% CI = 78.9 –  > 99.9%) with a median duration of palliation of 6 months and symptomatic relief. Patients frequently present with locally advanced disease with associated symptoms for which palliative radiation can reduce vaginal bleeding or discharge and pain due to primary lesion or metastatic disease. Thus, palliative radiotherapy alone may be an option for patients who are found unfit for palliative chemotherapy.

Among the 302 patients, palliative intent chemotherapy was given in 149 (49.3%) patients in first line. This study confirms that paclitaxel and carboplatin doublet is a tolerable, and efficacious regimen with around half of the patients completing the planned 6 cycles. The median PFS in the current study is 8.5 months in first-line treatment. These results are similar to the Indian study done by Sharada Mailankody et al. [8], in which palliative intent chemotherapy with paclitaxel and carboplatin in recurrent cervical cancer was found to be a safe and effective option with more than half of the patients completing the prescribed chemotherapy. Targeted therapies, bevacizumab and pembrolizumab were used in a limited number of patients in our study due to cost constraints. Of note, 82% of patients in our hospital, belonged to the low-socioeconomic group for whom the treatment expenses were funded through government schemes, and targeted therapy and immunotherapy were not financially feasible in their case. In this study, only 4 (2.7%) patients received bevacizumab with chemotherapy in the first line and 3 (2.0%) patients received pembrolizumab in second line. In the present study, 49% of patients received first-line palliative intent chemotherapy, 19.5% of patients received second line, and only 2.0% of patients received third-line palliative chemotherapy. This is likely due to the aggressive biology of metastatic cervical cancer and limited options of treatment beyond progression in the first line of treatment.

Though retrospective in nature, the median PFS of the present study was similar to the control arm of KEYNOTE − 826 [9,10,11]. However, 60% patients in that study received Bevacizumab. Table 2 shows the comparisons of PFS and OS from landmark studies.

Moore’s risk criteria for our patient population was also analysed, which is a prognostic index based on five factors; race, performance status, use of prior cisplatin, pelvic disease, and progression-free interval < 365 days. Most of the patients receiving chemotherapy in this study fell into mid-risk and Moore’s criteria. In the GOG-240 study, Moore’s score was prospectively validated, and it was shown that benefit of adding bevacizumab is greatest in mid-risk and low-risk subgroups [12].

There are several high risk factors associated with recurrent and metastatic cervical cancer. In the present study, around 48% of patients had associated hydronephrosis which is a poor prognostic marker associated with dismal outcomes. In a large nationwide retrospective Chinese study by Yang, You-Rong, et al. out of 2225 patients with cervical cancer, 445 patients had concomitant hydronephrosis and had higher morbidity and mortality [13]. Thirty-one (10.3) % of patients in the present study had deep venous thrombosis, which is a common comorbid condition associated with advanced cervical cancer. In a large Korean retrospective analysis, venous thromboembolism occurred in 1.1% of patients with cervical cancer. The incidence of thromboembolism was highest in the study during chemotherapy and slowly decreased over time [14].

Although there were chemotherapy toxicities, the platinum and taxane combination chemotherapy regimens were generally well-tolerated, and grade 3/4 peripheral neuropathy was seen in only 8.1% of patients in this study. In a similar Brazilian study by Alvaro Garces et al. [15], the incidence of neurotoxicity was as high as 30%. In the Japanese landmark JCOG0505 clinical trial, comparing carboplatin doublet versus cisplatin doublet, the incidence of grade 3 sensory neuropathy was 4.9% and for motor neuropathy, it was 2.4%. A limitation of this study was that being retrospective in nature, all toxicities may not have been captured.

Interestingly, a small group of patients, five patients in the first line and eight patients in the second line, who were unfit for receiving intravenous chemotherapy, received oral metronomic chemotherapy (OMCT). The various oral metronomic regimens used were cyclophosphamide, tamoxifen, valproate, methotrexate and celecoxib and capecitabine. Of note, even in second line of treatment, one patient on oral capecitabine and the other on oral cyclophosphamide attained a PFS of 15 months and 18 months, respectively. Oral metronomic therapy thus needs to be prospectively studied so that a low cost therapy can be explored in patients with recurrent cervical cancer.In a similar Indian study by Baruah et al. [16], the use of continuous low-dose oral cyclophosphamide resulted in an overall response rates of 23% and lesser toxicities. Another case series has also explored the use of Bevacizumab with low-dose oral cyclophosphamide [17]. One of the limitations in our study was that the exact date of death could not be ascertained as many patients went back to their native place after being planned for supportive and palliative care.

In a previously retrospective analysis of 1388 patients of locally advanced cervical cancer, it was found that post-chemoradiotherapy distant relapse was most common [18]. In this study, also 64% patients received only palliative care post-relapse. Data from the pooled analysis of survival of patients with cervical cancer from 11 population-based cancer registries in India found that those with distant metastasis had a dismal outcome of 18% [19]. Thus, there is an urgent need for early detection and improving primary treatment outcomes as post-relapse many patients are in poor performance status and are unable to receive any cancer directed therapy.

Future trials looking at drug repurposing to improve outcome in recurrent setting would be relevant to patients with difficulty in access to care. Thus, this study helps to understand the real-world scenario, the need for greater access to advances in treatment and for future studies exploring low cost treatments.