Introduction

Cervical cancer is the second most commonly diagnosed cancer and the third leading cause of cancer-related death among females in less developed countries. In developing countries, however, it remains the second most common cause for both cancer incidence and mortality. There are approximately 96,922 new cases and around 60,078 deaths each year among Indian women. Nearly 90% of cervical cancer deaths occur in developing parts of the world as patients present in advanced stages due to suboptimal screening and lack of knowledge and appropriate health care infrastructure.1

The standard treatment for locally advanced cervical cancer (LACC) is concurrent chemoradiation (CCRT). However, overall survival (OS) rates for stage IIB and III to IV cancer are approximately 60 to 65% and 25 to 50%, respectively, which are frustratingly low.2 Therefore, development of new treatment strategies to improve survival rate is imperative.

The aim of chemotherapy preceding local modalities is to reduce the volume of the disease, making subsequent irradiation or surgery more effective while controlling the micrometastatic disease. A comprehensive meta-analysis was performed including 4,727 cases from 13 publications to precisely assess the prognostic role of NACT in LACC.3 The response rate, specifically the clinical and pathological responses to NACT, ranged from 58.49 to 86.54% and 7.5 to 78.81%, respectively; the treatment response indicated that LACC was sensitive to chemotherapy. (These data are from previous studies.) Neoadjuvant chemotherapy (NACT) plays an unproven role in cervical cancer treatment, particularly when followed by CCRT.3456 Particularly in developing nations, the incidence of advanced cervical cancer is high, and access to radiotherapy (RT) facilities is limited. These factors result in a delay in treatment initiation, contributing to worse prognosis.

If the benefit of NACT is validated, it may lessen delays in treatment and improve outcomes in communities with scarce resources. We have conducted a clinical study comparing the efficacy and side effects of patients with cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] 2020 stage IIB to IIIC1 cancers) who were assigned to three cycles of NACT paclitaxel 175 mg/m² and carboplatin (AUC: 5) followed by CCRT with interdigitated brachytherapy versus CCRT with sequential induction chemotherapy (ICRT).

Eligibility Criteria

Study Protocol

The patients fulfilling the above criteria were randomly assigned to the study arm or the control arm in a 1:1 ratio with informed consent.

Observation and Results

Treatment Compliance

During NACT, 6 patients discontinued NACT because of severe myelosuppression (three NACT cycles). Three patients delayed the initiation of chemoradiation by approximately 3 weeks (two had grade 3 neutropenia with high fever) and 4 weeks (the other had grade 3 anemia). The number of weekly cisplatin doses concurrent with RT was four to five cycles of chemotherapy. In nine patients, the dose of cisplatin had to be reduced as five patients had grade 3 neutropenia, three had grade 3 thrombocytopenia, and one had renal insufficiency (Table 4).

Table 4

Adverse reactions/toxicity

Toxicity	Study arm A			Control arm B
	Grade II	Grade III	Grade IV	Grade II	Grade III	Grade IV
Anemia	3	2	1	2	1	0
Neutropenia	6	4	4	3	3	0
Thrombocytopenia	2	2	0	2	3	0
Hypersensitivity	3	0	0	1	0	0
Anorexia/nausea	5	5	4	4	4	2
Vomiting	5	3	3	4	3	2
Diarrhea	2	4	2	2	2	0
Neurotoxicity	2	1	0	1	0	0

The patients were followed up in an outpatient department every 1 month for the first 3 months and then at 3-month intervals. The median follow-up period was 12 months (range: 7–23 months, 23.90 ± 10.23 months). This time was calculated from the beginning of treatment. Four patients developed recurrence and/or lung metastasis, 9 and 7 patients in arms A and B defaulted for treatment during RT and were lost to follow-up in due course (Fig. 1).

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Fig. 1: Tumour Stage.

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When the data were analyzed with the help of chi-squared test, it was not found to be significant (p = 0.981; Fig. 2).

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Fig. 2: Response at 1 month.

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When the data were analyzed with the help of chi-squared test it was not found to be significant (p = 0.933; Fig. 3).

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Fig. 3: Response at 3 months.

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Discussion

The idea/concept behind NACT is to acquire proper negotiation of OS before starting HDRICBT in the first week of EBRT. In India too, dose/fraction varies from institution to institution. Apart from dose/fraction and number of fractions, overall treatment time (OTT) has a significant impact on treatment outcome. Treatment with EBRT and brachytherapy should be completed in less than 8 weeks as better local tumor control and survival can be expected with relatively shorter treatment courses.8910

In a study by Petereit et al,8 the impact of OTT was retrospectively analyzed. For all stages combined, the 5-year survival (65 and 54%, p = 0.03) and pelvic control rates (87 and 72%, p = 0.006) were significantly different when the OTT was more than 55 days. Shorter treatment duration was significant for 5-year OS and pelvic control for stages IB/IIA and III but not for stage IIB. The authors claimed that survival decreased by 0.6%/d and pelvic control decreased by 0.7%/d for each additional day of treatment beyond 55 days for all stages of disease.

Similarly, a study conducted by Lanciano et al9 demonstrated a quite significant decrease in survival (p = 0.0001) and pelvic control (p = 0.0001) as the OTT increased from less than 6, 6 to 7.9, 8 to 9.9, and greater than 10 weeks. Stage III accounted for the majority of negative effects due to prolongation of OTT. When the analysis was performed by stage to evaluate the effect of OTT with respect to the extent of pelvic disease, it continued to be an independent prognostic factor for infield pelvic control (p = 0.01) and survival (p = 0.02) for stage III but not for stages I and II.

One of the methods to decrease the OTT is to interdigitate the HDRICBT at some stage in EBRT. According to the American Brachytherapy Society (ABS) guidelines, HDRICBT may be interdigitated with EBRT to shorten the OTT, with the later typically given in 1.8-Gy fractions to achieve 45 Gy. However, very few studies are available on the timing of HDRICBT insertion during the EBRT course.

Despite the availability of an effective screening program and the papillomavirus vaccine, a large proportion of patients are diagnosed with cervical cancer at an advanced stage and suffer from local recurrences and distant metastases. A Cochrane meta-analysis reported a stage-dependent advantage of CCRT over RT, with 5-year survival benefits of 10% for women with stage IB to IIA cervical cancer, 7% for women with stage IIB cervical cancer, and 3% for women with stage III to IVA cancer.11

Marita et al13 retrospectively analyzed the survival of 207 stage IIB to IIIB cervical cancer patients who received two to four cycles of platinum based NACT prior to CCRT. The results revealed that the 5-year survival rates for stage IIB to IIIA and IIIB cancers were 84 and 61%, respectively, which are superior to the survival rates of traditional CCRT reported in the literature. A randomized open-label phase II trial enrolled 107 patients, 55 randomly assigned to the NACT arm and 52 to the CCRT-alone arm. NACT was associated with an inferior 3-year PFS (40.9 vs. 60.4%), a lower 3-year OS rate (60.7 vs. 86.8%), and a lower complete response rate (56.3 vs. 80.3%). Similarly, a meta-analysis of 21 randomized trials showed no increase in OS despite a significant reduction in tumor volume by primary chemotherapy compared to RT alone with RT preceded by chemotherapy. However, subgroup evaluation showed a 7% improvement in the 5-year OS with a chemotherapy cycle length of less than 14 days over that shown in studies with longer cycle lengths, and cisplatin dose intensities ≥25 mg/m² per week tended to show a survival benefit.

Concerning the distribution and metabolism of these drugs, Koshiba et al14 found that paclitaxel was retained in cervical cancer tissues for 6 days after i.v. administration of a dose of 60 mg/m², but could not be detected after 2 weeks, suggesting that a weekly schedule was most effective for tumor cell death rather than the standard thrice weekly regimen. Thus, administering NACT at shorter intervals (dose dense) may result in enhanced cell death and overcome accelerated repopulation. A dose-dense (weekly) schedule is likely to result in improvement in outcomes.

The preliminary outcomes from two phase II studies47 have been reported on patients who received NACT with weekly paclitaxel (60–80 mg/m²) and carboplatin (AUC = 2) for 6 weeks followed by CCRT. Following NACT, a response rate of 67.5 to 70% was achieved, mostly partial responses. Post-CCRT, 85 to 100% of eligible patients achieved CR. Grade 3 to 4 hematologic toxicity was observed in approximately 20% of patients. A 3-year OS rate of 68% was observed in 42 stage IB2 to IVA patients. These observations are encouraging. The approach is now being evaluated in a randomized trial (Induction chemotherapy plus chemoradiation (INTERLACE) trial). The combination of paclitaxel and carboplatin used in a weekly schedule maximizes the potential additive/synergistic interactions with different mechanisms of action.

Which NACT regimen is the best? Regarding chemotherapy in the treatment of advanced metastatic or recurrent cervical cancer, cisplatin has been considered the most effective agent. The cisplatin/paclitaxel (TP) combination is superior to other regimens. In a phase III trial comparing four regimens (cisplatin/paclitaxel, cisplatin/vinorelbine, cisplatin/gemcitabine, and cisplatin/topotecan), the cisplatin/paclitaxel combination appeared superior to the others.15 According to the results from JCOG0505 (Japan Clinical Oncology Group), among patients who had not received prior cisplatin, TP resulted in longer OS than TC (23.2 vs. 13.0 months).

Gupta et al16 randomly allocated 635 patients with FIGO stage Ib2 to II squamous cell cervical cancer to receive either three cycles of Paclitaxel (PTX) (175 mg/m²) plus Carboplatin (CBDCA) (AUC: 5–6) every 3 weeks, followed by radical surgery or standard CDDP-based CCRT. The 5-year disease-free survival (DFS) was significantly lower in the NACT arm than in the CCRT arm (69.3 vs. 76.7%; hazard ratio [HR] = 1.38; 95% confidence interval [CI] = 1.02–1.87; p = 0.038), whereas the corresponding 5-year OS rates were similar (75.4 vs. 74.7%; HR = 1.025; 95%CI = 0.752–1.398; p = 0.87). In subgroup analyses, the detrimental effect of NACT plus surgery on DFS was even greater in patients with stage IIb disease (67.2 vs. 79.3%; HR = 1.90; 95%CI = 1.25–2.89; p = 0.003), whereas no significant DFS difference was observed between the two arms in patients with stage Ib2 or IIa disease. The rates of rectal toxicity (5.7 vs. 13.3%, p = 0.002), bladder toxicity (2.8 vs. 7.3%, p = 0.017), and vaginal toxicity (19.9 vs. 36.9%, p < 0.001).

The ongoing INTERLACE trial aims to investigate whether additional ICRT chemotherapy given on a weekly schedule immediately before standard chemoradiation leads to an improvement in the OS and DFS. On a similar background, we conducted a randomized trial to compare the response and toxicity of NACT followed by CCRT with HDRICBT versus CCRT alone for newly diagnosed stage IIB to IIIC1 cervical cancer patients.

Conclusion

Considering the poor prognosis of LACC, the use of NACT with HDRICBT is an attempt to improve the treatment outcome. In a busy department where resources are limited, NACT with HDRICBT is an alternative option for the current standard CCRT as its tolerance and toxicity is at par with CCRT. We are still enrolling patients considering the encouraging results to obtain a longer-term follow-up and assess the maximum DFS. Future large trials are required to demonstrate the need and efficacy, toxicities, and quality of life.