Abstract
In India, majority of women’s with cervical cancer have locally advanced disease. The chemo-radiotherapy (CRT) followed by brachytherapy is the standard treatment for patients with locally advanced cervical cancer (LACC) disease for almost decades. But in developing countries like India with higher incidence and limited radiotherapy facilities, this may result in a delay in treatment initiation. These factors may further contribute to detrimental outcomes. Several researchers have tried to study role of neo-adjuvant chemotherapy (NACT) in LACC with the aim that neo-adjuvant chemotherapy may arrest the disease progression, prevent distant metastasis and therefore improve overall and disease-free survival. However, there is only limited literature so far, comparing NACT followed by CRT with the standard treatment arm alone. Therefore the review article aims to evaluate role of neo-adjuvant chemotherapy (NACT) followed by chemo-radiotherapy in LACC.
Introduction
Cervical cancer is the fourth most common cancer among women globally, with an estimated 661,021 new cases and 348,189 deaths in 2022 [ ]. In India, it is the second most common cancer, contributing to approximately 122,844 new cases and 67,477 deaths annually [ ]. It is a major health concern for Indian women, with a cumulative lifetime risk of 2.5 % and a cumulative death risk of 1.4 %. The peak age for developing cervix cancer is typically between 45 and 54 years [ ].
Surgery and chemo-radiation are widely utilized treatments for cervical cancer. In locally advanced cervical squamous cell carcinoma (LACC), pelvic radiotherapy along with concurrent cisplatin-based chemotherapy followed by brachytherapy is the standard of care [ ].
However, 5-year overall survival (OS) rate for LACC is only 50 %–60 % [ ]. According to the 2016 American Cancer Society (ACS), the 5-year OS rate for stage IIB cervical cancer is about 58 %, stage IIIA is 35 %, stage IIIB is 30 %, and stage IVA is about 16 % [ ] which is disappointing.
In India, about 80 % of females suffer from LACC (FIGO stages IIB, III and IV) due to lack of screening [ ].
Moreover, in developing nations, there exists a heightened prevalence of cervical cancer, exacerbated by the limited accessibility of radiotherapy facilities, thereby causing delays in the initiation of treatment [ ]. These factors may impact local control and disease prognosis. A retrospective review concluded that treatment time >56 days significantly increased pelvic failure incidence (P = 0.02) [ ] and a study also concluded that delaying treatment ≥4 months substantially raised mortality in cervix cancer patients [ ].
Neo-adjuvant chemotherapy (NACT) was first reported by Frei. in advanced malignant tumours [ ]. The NACT aimed to arrest the disease progression, increase radiosensitivity complete response (CR), prevent distant metastasis (DM) and improve disease-free survival (DFS).
The role of NACT in cervical cancer has been examined in several studies but only a few single-arm prospective studies and randomized control trials have been conducted to assess the outcomes of NACT followed by chemo-radiotherapy (CRT) with or without comparison with the standard of care.
Therefore the review article aims to evaluate various prospective studies and randomized trials assessing the role of NACT followed by CRT in LACC with or without comparison to the standard of care. The review will help us to assess whether the addition of NACT would improve OS, DFS, distance metastasis-free survival (DMFS) or will just add to the toxicity profile (TP).
Methods
The review thoroughly examined studies from 2010 to 2024 by searching PUBMED, EMBASE and Google Scholar using search keys: cervix carcinoma and neoadjuvant therapy, neoadjuvant therapy in cervical cancer versus standard of care, and carcinoma cervix induction chemotherapy, LACC and NACT followed CRT versus CRT. Initial search included more than 6500 studies. Of which 20 studies fulfilling the inclusion criteria were analyzed ( Fig. 1 ). Data collection included key details like authorship, publication year, study design, participant enrollment, eligibility criteria, treatment, and outcomes such as response rate (RR), DFS, PFS, OS, and TP.
Trials and discussion
Cervical cancer is the second most common cancer among Indian women, with most cases diagnosed in advanced stages. CRT has been the standard of care in LACC since 1999 [ , , ].
An individual patient data meta-analysis based on 18 trials from 11 countries confirmed the benefit of CRT. However, the estimated improvement in 5-year OS was only 6 % (i.e., from 60 to 66 %, HR:0.81), with a DFS rate of 58 % [ ].
The advantage of combining chemotherapy with radiotherapy has been observed regardless of age, histology, and grade; however, it seems to be less effective in patients with more advanced tumours [ ].
Despite years since CRT’s introduction, there have been no new breakthroughs in LACC treatment. However, research is exploring new treatment options such as immunotherapy. Moreover in developing countries like India long waiting and lack of access to radiotherapy, may result in delayed treatment and impact local control. If the effectiveness of NACT is demonstrated, it could potentially alleviate treatment delays and enhance outcomes in resource-constrained communities .
| Year | Author | Study Type | N | Stage | Arm | NACT Chemo regimen | RT/Brachytherapy dose | Median Follow Up (months) | Response | PFS | OS | DFS | Recurrence/Distant Metastasis/Failure | Toxicity profile |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomized control trial | ||||||||||||||
| 2018 | Tripathi et al. [ ] | Prospective randomized | 80 | IIA to IIIB | NACT —CRT (N = 40)vs CRT alone (N = 40) | Cisplatin + Paclitaxel, 3 weekly, 2 cycle | 50 Gy/25 # followed by 7 Gy x 3 # | – | CR:85 % vs 82.5 % P= >0.05 | – | – | – | – | Statistically insignificant |
| 2019 | da Costa et al. [ ] | Open-label randomized phase 2 trial | 107 | IIB to IVA | NACT —CRT (N = 55) vs CRT alone (N = 52) | Cisplatin 50 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on day 1 and day 8 every 3 weeks for three cycles. | 45–50.4 Gy in 25–28 # + cisplatin 40 mg/m2 weekly followed by 7 or 7.5 GY x4 # | 31.7 | CR: 56.3 % vs 80.3 % (p = 0.008) | (3 years) 40.9 % vs 60.4 % | (3 years) 60.7 % vs 86.8 % (p = 0.007) | Paraaortic lymph node recurrence (16.3 % vs 3.8 %, P = 0.033), distant failure (16.3 % vs 7.6 %, P = 0.170) | Hypomagnesemia (27.2 % v 7.6 %; P = 0.030), Neuropathy (25.4 % v 1.9 %; P = 0.002) | |
| 2022 | Jing li et al [ ] (Ongoing trial) | Prospective, randomized, open-labeled, multicentered phase III study | 300 | IIB–IVA | NACT —CRT (N = 150)vs CRT alone (N = 150) | dd cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles | 45 Gy/5 # + cisplatin 40 mg/m2 weekly followed by Brachytherapy (85 Gy) | – | – | – | – | – | – | – |
| 2023 | Jing li et al. [ ] (Medium term Effect) | Phase III trial | 50 | IIB to IVA | NACT —CRT (N = 50) | dd cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles | 45 Gy/5 # + cisplatin 40 mg/m2 weekly followed by Brachytherapy (85 Gy) | 28 | CR + PR: 90 % | 3 years: 73.6 % | 3 years: 83.9 % | – | – | Grade 3/4 during NACT Hematological toxicity: 40 % Non hematological toxicity: 32 % Grade 3/4 during CRT Hematological toxicity: 52 % Non hematological toxicity: 32 % |
| 2023 | Interlace Trial [ ] (Ongoing trial) | Prospective randomized phase III trial | 500 | IB1 node-positive,IB2,II,IIIB, IVA | NACT —CRT (N = 250)vs CRT alone (N = 250) | Carboplatin AUC2 + paclitaxel 80mg/m2, 6 weeks | RT + CT followed by Brachytherapy (EQD2 dose 78Gy) | 64 | – | (5 years) 73 % vs 64 % (p = 0.013) | (5 years) 80 % vs 72 % (p = 0.04) | – | Grade 3 adverse events: 59 % vs. 48 % | |
| 2024 | Fenghu Li et al. [ ] | Prospective, single-center, open-label randomized controlled clinical trial | 146 | IB2 to IVA | NACT —CRT (N = 76)vs CRT alone (N = 76) | Cisplatin + paclitaxel 3 weekly, 2 cycle | RT (50.4 Gy/28 #, 56.35–60.2 GY for LN mets) + CT followed by Brachytherapy (6Gy x 5 #) | 21 | CR: (1 year) 87.7 % vs 67.6 % P = 0.000 | (1 year) 90 % vs 85 % (2 years) 81 % vs 78 % P = 0.340 | (1 year) 96 % vs 89 % (2 years) 89 % vs 79 % P = 0.017 | 4.11 % vs. 7.35 % P = 0.021 | Thrombocytopenia 16.4 vs. 13.2 %, p = 0.045 Treatment-related adverse events in both groups were grade 3 | |
| Prospective single arm | ||||||||||||||
| 2013 | McCormack et al. [ ] | Phase II singe arm study | 45 | IB2-IVA | NACT–CRT | DD carboplatin AUC2 and paclitaxel 80 mg m2 weekly, 6 cycles | RT (50.4 Gy in 28 #) + CT (Cisplatin 40 mg/m2, 4–6 cycles) -→ Brachytherapy (15 Gy x 2 #) | 39.1 | CR or PR: 70 % (95 % CI: 54–82) post-NACT and 85 % (95 % CI: 71–94) post-CRT | 3 years 68 % | 3 years 67 % | – | – | Grade 3/4 toxicities were 20 % during NACT & 52 % during CRT |
| 2013 | Bikramjeet singh et al [ ] | Pilot study | 28 | IIB–IVA | NACT—-CRT | Paclitaxel and carboplatin weekly, 6 cycles | RT (50.4 Gy in 27 #) + CT –→ Brachytherapy (7 Gy x 3 #) | 12 | Post NACT CR: 7.1 %, PR: 60.7 % Post CRT CR: 85.7 %, PR: 7.1 % | – | – | – | – | Grade III/IV neutropenia: 28.5 %/29 % |
| 2013 | Rodriguez Riao et al [ ] | Prospective | 47 | IB2 – IVA | NACT—CRT | Cisplatin + Paclitaxel + Capcetabine, 3 cycles | NR | NR | Clinical RR: 100 % Pathological CR: 48.9 % | – | – | – | – | Anemia: 55 % grade 3 neutropenia 14.8 % (both were manageable) HFS and alopecia: 100 % Neuropathy grade 3 : 12.7 %. |
| 2016 | Katke et al [ ] | Prospective | 95 | IIB to IVA | NACT—CRT | Paclitaxel + cisplatin 3 weekly, 3 cycle | RT (50 Gy in 28 #) + CT (35 mg/m2, weekly) –→ Brachytherapy | 18 | CR: 75.78 % PR: 13.68 % | – | 1 year: 74.73 % | 1 year: 69.47 % | – | Acceptable toxicity |
| 2017 | Azevedo et al. [ ] | Phase II, prospective, non-randomized trial | 50 | IB2–Iva | NACT —CRT | Cisplatin + gemcitabine 3 weekly, 2 cycles | RT (50.4 Gy in 28 #) + CT –→ Brachytherapy (7 Gy x4 #) | 23.4 | Response rate 81 % at the end of treatment | 1 year: 73.4 %, 3 years:53.9 % | 1 year: 93.9 % 3 years: 71.3 % | – | – | Grade 3/4 toxicity, 20 % during NACT and 44 % during CRT |
| 2020 | Shimoji et al. [ ] | 37 | IB1-IVA | NACT — EF-CCRT | Cisplatin + paclitaxel, 2 cycle, 21 days apart | EF-RT (45 Gy/25 #) -→ Boost Primary: 5.4 Gy/3 # and Nodal: 6–10 Gy/3–5 #-→ followed by Brachytherapy 6 Gy x 3 # | 38 | CR: 75.7 % | 3 years: 48.5 % IB: 64.8 % IIB: 60 % IIIB:29.4 % (p = 0.0482) | 3 years: 70.1 % IB: 100 % IIB: 80 % IIIB:47.1 % (P: 0.0024) | – | – | Post NACT Grade 3 neutropenia: 10.8 % Neutropenic fever: 5.4 % Post EF-CCRT Hematological toxicity: 17.6 % Non hematological toxicity: 8.1 % | |
| 2023 | Ahmadloo et al. [ ] | Phase II single arm | 74 | IB3-IVA | NACT—CRT | Paclitaxel + carboplatin, 3 weekly, 4 cycles | RT (45–50 Gy) + CT (40 mg/m2, weekly)–→ Brachytherapy (total 80–90 Gy) | CR:60.8 %, PR: 14.9 % | – | – | – | – | Grade III neutropenia: 2.7 % | |
| Retrospective study | ||||||||||||||
| 2012 | Paulson et al. [ ] | Retrospective | 116 | II- III | NACT —CRT | Paclitaxel + cisplatin every 3 weeks (median number of cycles: 5) | NR | – | CR: 38.8 % PR:18.4 % | 65.3 % | 93.9 % | – | – | – |
| 2016 | Narayan et al. [ ] | Retrospective | 612 | IB2 –IVA | NACT —CRT (309) vs CRT alone (303) | Cisplatin + paclitaxel + 5 FU (TPF), 3 weekly, 2 cycle & Cisplatin + 5-FU (PF), 3 weely, 2 cycle | RT (50 GY/25 #) + CT followed by Brachytherapy | – | – | – | No impact P = 0.689 | (5 years) 58.3 % vs 41.8 %, P = 0.001 | – | Grade 3/4 hematologic toxicities NACT > CRT (p = 0.001) TPF > PF (p = 0.029) |
| 2021 | Baillie et al. [ ] | Retrospective | 126 | II-IV | NACT–CRT | Cisplatin/Paclitaxel (63 %) Or Carboplatin/Paclitaxel (35 %) | NR | 30 | – | – | 3 years: 61.8 % | Survival was poorer in patients with neutrophil lymphocyte ratio (NLR) ≥5 and in those not receiving CCRT. | ||
Can NACT followed by CRT in cervical cancer be an effective approach? ( Table 1 )
There have been few RCTs and prospective studies that have reviewed outcomes of patients who received NACT followed by CRT in cervix cancer.
A phase II trial by Mc Cormack et al . including 46 patients with stage IB2-IVA cervical cancer majority belonging to stage IIB (50 %) or IIIB (28 %) and of this 11 % (5/46) presented with para-aortic lymph node (PALN) were treated with NACT (dose-dense carboplatin AUC2 and paclitaxel 80 mg m2) weekly for six cycles followed by CRT concluded that OS and progression-free survival (PFS) at 3 years were 67 % and 68 %, respectively, with 68 % patients presenting with complete (7.1 %) or partial response (CR or PR) (60.7 %) post NACT and 85 % with CR post CRT. Grade 3/4 toxicities were 20 % during NACT (11 % haematological, 9%non-haematological) and 52 % during CRT (haematological:41 %,non-haematological: 22 %). The author further concluded that the treatment regimen is feasible with acceptable toxicity [ ].
Inspired by the results of the Mc Cormack et al. trial [ ] a pilot study including 28 patients with LACC (Stage IIIB:71.4 %) was conducted in India using a similar regime but with a paclitaxel dose reduced from 80 to 60 mg/m2 and the study was also open to patients with ECOG>1 unlike in previous trial inclusive of ECOG 0–1 only. In this study, 67.8 % of patients responded to NACT (CR:7.1 %, PR:60.7 %) while 23/24 patients achieved CR after CRT, with grade III/IV neutropenia as the main haematological toxicity seen in 28.5 % and 29 % of patients, respectively during NACT and CRT, concluding that NACT (Carboplatin/Paclitaxel regimen) in LACC as feasible approach [ ].
Another prospective study from India , using Paclitaxel (175 mg/m2)/Cisplatin (60mg/m2, divided into Day 1, Day 2) 3 weekly, 3 cycle as NACT regimen followed by CRT observed CR and PR in 75.78 % and 13.68 % respectively, while 1 year OS and DFS rate was 74.73 % and 69.47 %, respectively with acceptable toxicity [ ].
A phase II study by Rodriguez Riao et al . enrolled 47 patients of stage IB2–IVA cervix cancer, of which stage IIB accounted for 89.4 % of patients. In this study, the NACT regimen cisplatin/paclitaxel/capecitabine was given for 3 cycles prior to CRT. The clinical RR reported was 100 % without diseases progression, while the pathological response was evaluated by taking biopsy post-treatment was 48.9 %. The most common haematologic toxicity observed was anaemia and grade 3 neutropenia, 55 % and 14.8 % respectively, while grade 3 neuropathy was observed in 12.7 %. 100 % of patients presented with hand-foot syndrome and alopecia. Therefore, the author concluded that NACT followed by CRT may be an effective and safe alternative for treating LACC [ ].
Shimoji et al. conducted a phase II study, enrolling 37 cervix cancer patients of stage IB1–IVA, with the majority staged as IIB (10/37) and IIIB (17/37) and 19/37 patients presented with PALN. In this study patients received 2 cycles NACT (cisplatin 50mg/m2/paclitaxel 175mg/m2) 21 days apart followed by extended field CRT followed by brachytherapy. It was observed that 3-year OS and PFS rates were 70.1 % and 48.5 %, respectively, whereas the 3-year OS and PFS were significantly worse in stage IIIB. In stage IIB 12/17 patients died of the disease. 5.4 % of patients presented with neutropenic fever post NACT, while 17.6 % of patients suffered haematological toxicity post-extended filed CRT. The author concluded that NACT followed by extended CRT would improve local outcomes and decrease distant failure in stage IB and II with PALN but improved strategies are required for stage IIIB with PALN to control local and distant failure [ ].
Alternative approaches to treat LACC are still being explored, although pursued over the years. In 2011, the addition of gemcitabine to CRT followed by adjuvant gemcitabine/cisplatin chemotherapy was associated with increased survival with limiting TP, which precluded its use in clinical practice [ ].
Overwhelmed by the results of the Dueñas-Gonzalez phase III trial [ ], Azevedo et al . conducted the first phase II trial to assess the role of gemcitabine (1000mgm2, Day 1, Day 8) + cisplatin (35 mgm2, Day 1, Day 8) as neoadjuvant option followed by CRT. The study included 50 LACC patients (maximum in Stage III: 44 %, IVA: 42 %) and observed that RR was 81 % at the end of treatment. PFS and OS at 3 years were 53.9 % and 71.3 %, respectively, with Grade 3/4 toxicity, 20 % during NACT and 44 % during CRT. One death occurred as a result of toxicity one week after CRT, during CRT patient presented with diarrhoea, vomiting and haematological toxicity. Also, the median interval between NACT and the beginning of CRT was 22 days (range 10–115 days). Delays occurred due to uncontrolled diabetes and sepsis, public holidays, overcrowded schedules, equipment maintenance and under repair and shortage of daily transportation to the hospital. The study’s conclusion was that NACT did not significantly improve the overall response rate in patients with LACC [ ].
In 2019 , a randomized phase II was conducted by Da Costa et al. [ ] using a similar NACT regimen cisplatin 50 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on day 1 and day 8 every 3 weeks for three cycles followed by CRT compared with CRT alone arm with maximum patient belonging to stage IIB (43.6 %) and IIIB (47.2 %) in both groups. After a median follow-up of 31.7 months, it was observed that 3 years PFS and OS rates in NACT followed by the CRT arm, were inferior compared to the CRT arm alone (40.9 % vs 60.4 % and 60.7 % vs 86.8 %, respectively). Also, the CR in the NACT arm was inferior to the CRT arm alone (56.3 % vs 80.3 %). In an exploratory analysis, higher PALN recurrence was observed in the NACT arm than those in the CRT-alone arm (P = 0.033). Thus the addition of NACT arm did not reduce DM, unlike Dueñas-Gonzalez et al. study [ ]. One potential reason for distant failure mentioned in this study was that upfront CRT targeting pelvic disease could be crucial in impeding tumor spread to higher lymph node regions.
Moreover, the TP was found to be similar in both arms, except hypomagnesemia and neuropathy were more common with the NACT arm due to which concurrent chemotherapy was discontinued in many patients (20 % vs 5.8 %). Author concluded that addition of NACT consisting of cisplatin/gemcitabine to the standard treatment arm has inferior outcomes and one of the reasons for such results would be reduced cisplatin dose intensity of 17 mg/m2/week used in NACT arm [ ].
A meta-analysis suggested that NACT with cisplatin dose intensities lower than 25 mg/m2/week had a detrimental effect on survival in contrast with dose intensities equal to or greater than 25 mg/m2/week (P = 0.020). In addition, the theory of accelerated repopulation suggests that in rapidly proliferating cancer, especially when suboptimal regimens are used, tumour regrowth may be accelerated after chemotherapy. Also, NACT with cycle lengths longer than 14 days was associated with inferior survival (P = 0.005), whereas cycle lengths of 14 days or shorter were beneficial (P = 0.046). However, the meta-analysis was conducted before CRT became standard treatment, and only trials with RT alone as local treatment were included in the analysis [ ].
Cervical tumours exhibit a substantial growth fraction and can proliferate rapidly, often with a median doubling time of only 4–4.5 days [ , ]. As a result, despite the potential for tumour volume restoration after a few cell divisions, the efficacy of chemotherapy and standard radiotherapy may diminish due to altered growth kinetics. In such cases, the chemotherapy schedule becomes pivotal: a short and intensive cycle of chemotherapy is deemed optimal to mitigate the repopulation of the tumour with resistant cells [ ].
However, this observation strengthens the argument that prolonged cycle durations and reduced cisplatin doses may have contributed to the negative outcome associated with NACT.
The study also had limitations in radiotherapy, as the majority of patients were treated with two-dimensional brachytherapy, which may further add to toxicity [ ].
Although, advancements in imaging and radiotherapy planning have improved precision in brachytherapy to enhance outcomes and reduce toxicity to normal tissues.
A phase II single-arm study [ ] while using the neoadjuvant approach (carboplatin/paclitaxel every 3 weeks, 4 cycles) demonstrated treatment discontinuation in a significant number of patients (60.8 % Post-NACT – > CRT and 31.1 % post-NACT) like study by Da costa et al. [ ] Grade III neutropenia, during NACT were 2.7 % and during CRT were 13.5 %. CR and PR were observed in 60.8 % and 14.9 % of patients, respectively [ ].
Tripathi et al . conducted an RCT, with the majority of cervix cancer patients staged as IIB –IIIB and observed that the NACT regimen cisplatin 75 mg/m2/paclitaxel 175 mg/m2, 3 weekly 2 cycles followed by CRT compared to CRT alone, in both the groups’s tumour response were similar (p > 0.05). Although the NACT group experienced more hematologic toxicities (p > 0.05) than the CRT group and gastrointestinal toxicities were slightly higher in the CRT group, but were statistically insignificant. According to the author, NACT followed by CRT can be a viable alternative to the standard of care, with an acceptable toxicity profile, but due to limited follow-up time larger prospective studies with longer follow-up are necessary to establish it has a standard of care [ ].
The INTERLACE study by McCormack et al , enrolled 500 patients from 32 centres in 5 countries, randomized to a 1:1 ratio. They compared NACT regimen, 6 weeks carboplatin Area under curve (AUC)2 and Paclitaxel 80mg/m2 followed by CRT vs CRT alone arm and posted their last updates in 2023 stating that at median follow up 64 months, 5 years PFS rate (73 % vs 64 %, P = 0.013) and OS rate (80 % vs 72 %, P = 0.04) were statistically superior in NACT arm. Grade 3 adverse events observed NACT/CRT arm was 59 % while 48 % for CRT alone arm. As of now, the INTERLACE study is still in the recruitment phase, with an anticipated completion date of December 2026 [ ].
Similar results favouring NACT addition to CRT were observed with RCT published by Fenghu Li et al comparing the NACT regimen cisplatin (60–80mg/m2)/Paclitaxel (135–175mg/m2) 3 weekly, 2 cycles followed by CRT vs CRT alone, with the majority of patients belonging to stage IIB > IIIC1r > IIIB in both the arms. In the study it was observed that 1 and 2 years OS rates, were significantly higher in NACT arm compared to the CRT arm alone, 96 % vs 89 %, and 89 % vs 79 % respectively P = 0.017, while 1 and 2 years PFS rates showed no significant difference compared to CRT arm (P = 0.340). Additionally, disease progression/DM before the last follow-up was significantly lower in the NACT arm (3 pelvic recurrences, 2 Retroperitoneal lymph node (RPLN), 2 DM) compared to CRT arm (3 pelvic recurrence, 4 RPLN, 5 DM), 11 % vs 17.6 %, P = 0.021, unlike CIRCE trial [ ], observed higher distant failure. Further exploration also revealed that 1 and 2 years OS rates and PFS rates of CR patients were significantly higher compared to PR patients in NACT arm (P = 0.000, respectively). In NACT arm, thrombocytopenia was more prevalent than in the CRT group (16.4 vs. 13.2 %,p = 0.045). while other grade 3/4 toxicity were significantly more prevalent in the CRT arm. Therefore author concluded that compared to CRT, NACT + CRT might improve the treatment completion rate, increase CR rate and 1- and 2-year OS rates, and reduce DM rate for LACC patients with large tumor masses [ ].
An ongoing phase III study by Jing Li randomized 300 patients (1:1) with IIB –IVA Cervix cancer. In the NACT arm, patients receive dose-dense cisplatin (40mg/m2)/paclitaxel (60mg/m2) weekly for 4 cycles followed by CRT + BT [ ]. Author published a medium-term effect of 50 patients enrolled in the NACT + CRT arm concluding that after a median follow-up of 28 months, the 3-year OS and PFS rates were 83.9 %, and 73.6 %, respectively. The 3-year PFS rates of IIB-IIIB, IIIC1 and IIIC2 were 92.9 %, 67.0 % and 31.2 %, respectively. The 3-year OS rates of IIB-IIIB, IIIC1 and IIIC2 were 100 %, 78.4 % and 50 %, respectively. The mPFS (median PFS) and mOS (median OS) of FIGO IIIC2 were 13 months and 23.5 months, respectively while the mPFS and mOS of FIGO IIB-IIIC1 were undefined. Therefore it was seen that lymph node involvement was associated with inferior outcomes [ ].
Also, post-NACT CR and PR rates were 10.4 % and 68.8 %, respectively, while 12 weeks after treatment completion, the CR was 72 % (total response CR + PR = 90 %). NACT respondents had superior PFS and OS compared with NACT non-responders (P < 0.01). Patients with stage IIB-IIIB had a higher probability of achieving CR (87.5 %) than those with stage IIIC1 (64.3 %) and IIIC2 (66.7 %) [ ].
Grade 3/4 haematological toxicity during NACT was 40 % [ ], which was similar to the report by Singh et al. (49.7 %) [ ] but was considerably higher than that reported by McCormack et al. (11 %) [ ]. Most patients recovered except one patient (stage IIIC1r) resulted in delayed beginning of chemoradiation and later presented with progressive disease/DM post 3 months of CRT. Thus, the gap between NACT and CCRT was significantly influenced by the development of grade 3/4 neutropenia during NACT [ ].
Hong et al. suggested in the study (N = 7355) that patients who completed radiotherapy (EBRT + Brachytherapy) over 8 weeks may experience negative outcomes, with more adverse events occurring during CCRT. The data-derived cut point was distributed around 64 days. Thus, the addition of NACT into the standard treatment regimens is likely to result in increased toxicity. Moreover, in NACT non-responding patients, there might be inherent resistance to both chemotherapy and radiotherapy. Additionally, delayed access to CRT might be detrimental [ ].
Although, Jing Li et al . concluded that the treatment regimen was found to be more feasible for stage IIB–IIIB patients with superior CR rate, PFS, and OS compared to IIIC. Therefore there is a need to investigate more effective strategies for IIIC patients [ ].
There are few retrospective studies published evaluating the role of NACT in LACC.
Paulson et al. retrospectively analyzed 116 patients with stage II-III (IIB: 81.9 %, IIIA 10.3 %, IIIB 7.8 %) cervix cancer treated with NACT regimen (N = 80) paclitaxel 175mg/m2/Cisplatin 75mg/m2 every 3 weeks, median number of cycles of NACT was 5 (1–8 cycles). The author observed that in 49 patients who underwent NACT followed by CRT, radiological CR, PR, disease progression and stable disease were seen in 38.8 %, 18.4 %, 12.2 % and 8.2 % respectively, while local recurrence and DM were seen in 2 % and 10.2 % respectively. OS and PFS in NACT followed by CRT was 93.9 % vs 65.3 %, while in CR, OS was 96 % and after PR was 91.7 % (P = 0.439). Therefore it was concluded that despite CR, NACT followed by CRT failed to have an impact on OS [ ].
A retrospective study from India by Satyanaryan et al. also concluded that NACT is a feasible option, especially for stage III, presented with better outcomes and superior DFS compared to CRT alone and with acceptable toxicity. However, no impact on OS was recorded. The author also compared two NACT regimens Cisplatin/Paclitaxel/5FU(TPF) vs cisplatin/5FU (PF) and found that the TPF group experienced more toxicity than PF (p = 0.029) [ ].
Baillie et al. in 2021, retrospectively analyzed 126 cervical cancer patients, of which 93 % were stage II, 27 % stage IV and 30 % had PALN involvement. These patients had received 3 weekly NACT regimen cisplatin/paclitaxel (63 %) or carboplatin/paclitaxel (35 %), and 86 % patients received CRT post-NACT. It was observed that 3 years OS was 61.8 % and the baseline neutrophil-lymphocyte ratio and the definitive therapy post-NACT significantly impacted survival. Also, according to the report, the rate of distant failure was lower than expected i.e.16 %. However, pelvic control was at 68.5 %. Therefore it was concluded that NACT can be an option for women with bulky cervical cancer [ ].
Which NACT regimen should be preferred??
So far majority of studies have explored cisplatin/paclitaxel or carboplatin/paclitaxel. Subgroup analysis of Meta-analysis of 21 randomized trials showed a 7 % improvement in the 5-year OS with a chemotherapy cycle length of <14 days over that shown in studies with longer cycle lengths, and cisplatin dose intensities ≥25 mg/m2/week tended to show a survival advantage [ ].
Limited studies have tried to compare different chemotherapy regimens.
In 2009, Monk et al. in a phase III trial enrolled 513 women with stage IVB, recurrent, or persistent cervical cancer and compared regimens: cisplatin/paclitaxel (PC), cisplatin/vinorelbine (VC), cisplatin/gemcitabine (GC), cisplatin/topotecan (TC), and found that cisplatin/paclitaxel regimen was superior to the others. VC, GC, and TC were not superior in terms of RR, OS, and PFS compared with PC. Although the current trial was stopped early at a planned interim analysis for futility [ ].
Kitagawa et al. conducted a phase III trial and concluded that Paclitaxel/Cisplatin (TP) was non-inferior to paclitaxel/Carboplatin (TC) and should be a standard treatment option for metastatic or recurrent cervical cancer. Also, among the patients who had not received prior cisplatin, paclitaxel/cisplatin (TP) resulted in longer OS than paclitaxel/carboplatin (TC) [ ].
A retrospective study enrolled 207 stage IIB –IIIB cervical cancer patients, treated with 2–4 cycles of NACT with regimens of Paclitaxel/Carboplatin (PC) or Topotecan/Cisplatin (TC) administered every three weeks, prior to CCRT. In this study published by Martia et al. OS, disease-specific, DFS at 5 years were 78 %, 84 % and 79 % respectively, with overall response significantly higher with PC compared to TC regimen [ ] .
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