No benefit from adjuvant chemotherapy after standard cisplatin-based chemoradiation for women with locally advanced cervical cancer
The international randomised phase III OUTBACK trial in women with locally advanced cervical cancer was designed to determine the effect of adjuvant chemotherapy after cisplatin-based chemoradiation. Results of this trial, presented at ASCO 2021, now demonstrate that this strategy does not lead to an improved overall or progression-free survival. Furthermore, the therapy was associated with increased side effects.
Cervical cancer is a major global health problem with more than half a million new diagnoses each year. A significant proportion of these patients dies each year, rendering cervical cancer the fourth leading cause of cancer-related death in women. For women with locally advanced cervical cancer, concurrent cisplatin and radiation with brachytherapy has been the standard of care since 1999. However, despite this regimen, a significant proportion of patients still relapses after this treatment and dies due to the development of distant metastases. The OUTBACK trial was designed to address this issue and hypothesised that the addition of adjuvant chemotherapy after standard cisplatin-based chemoradiation could reduce the risk for distant failures.
OUTBACK enrolled 926 women with advanced cervical cancer who were suitable for chemoradiation with curative intent. Women were randomised 1:1 to receive standard concurrent chemoradiation (CRT; control) or the same followed by four cycles of adjuvant chemotherapy (ACT) with carboplatin and paclitaxel. The standard CRT that was given in both treatment groups consisted of 40-45 Gy of external beam chemoradiotherapy (EBRT) in 20-25 fractions including a nodal boost, when relevant, plus brachytherapy. Cisplatin (40 mg/m2) was given weekly for five cycles during radiation. Women in the ACT arm received an additional four cycles of carboplatin and paclitaxel. Primary endpoint of the trial was overall survival. The target sample size of 900 patients provided 80% power with 95% confidence to detect an improvement in OS at five years from 72% (control) to 80% (ACT), with some over-accrual to account for non-compliance with ACT and loss to follow-up.
No survival benefit from adjuvant chemotherapy
In total, 919 of 926 women recruited from April 2011 to June 2017 were eligible and included in the primary analysis: 463 assigned to ACT, 456 to control. Of the patients randomized to ACT, 361 (78%) women actually initiated the treatment. Baseline demographics as well as disease characteristics were well balanced between the study arms. Adherence to chemoradiation was very good, with 84% of patients receiving the planned five cycles of weekly cisplatin. Chemoradiation was fully completed (5x cisplatin, 45 Gy EBRT, brachytherapy) in 77% of women in both treatment arms. As mentioned earlier, 22% of patients in the ACT group did not receive this treatment at all. However, of women who did initiate treatment, most were able to complete all four cycles of treatment at full doss without dose delay. The five-year OS rate reported in OUTBACK was similar in both arms, at 71% in the CRT arm and 72% in the CRT+ACT arm (HR [95%CI]: 0.90 [0.70-1.17]; p=0.8). The median OS was not reached in either group. Moreover, the PFS rate at five years was similar in the ACT and control arm at 63% and 61%, respectively (HR [95%CI]: 0.86 [0.69-1.07], p=0.61). A similar lack of treatment effects was observed in almost all subgroups. Nevertheless, a reduced effect of ACT was seen in women who were aged 60 years or older with interaction p-values of 0.01 for OS and 0.03 for PFS. Patterns of disease recurrence were similar in the two treatment groups.
As expected, established toxicities of carboplatin and paclitaxel such as haematological toxicity, alopecia, fatigue and myalgia and neuropathy were seen at significantly higher rates in the ACT arm. Febrile neutropenia rates, however, were low at only 2% in both arms. There were no deaths related to study treatment in either arm. Beyond one year, the only difference between the two treatment arms consisted of an increased rate of peripheral neuropathy for patients treated with ACT (7% vs. 2% grade 2 sensory). Importantly, there was no sign of increased late radiation toxicity. Overall health and quality of life was measured using the global health scale QLQ-C30 and indicated that scores were impaired in the ACT arm during and after chemotherapy. However, similar scores were reported from months 12 to 36.
Adjuvant chemotherapy given after standard cisplatin-based chemoradiation for women with locally advanced cervical cancer does not improve OS or PFS. These findings do not support the use of adjuvant chemotherapy with carboplatin and paclitaxel after chemoradiation with weekly cisplatin. Therefore, pelvic chemoradiation with concurrent weekly cisplatin continues to be the standard of care for the treatment of locally advanced cervical cancer.
Mileshkin L, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). Presented at ASCO 2021; Abstract LBA3.