OUTBACK Trial: No Cervical Cancer Survival Gain With Adjuvant Chemotherapy

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The OUTBACK Trial investigators have found that the use of adjuvant carboplatin plus paclitaxel chemotherapy does not improve overall survival (OS) from locally advanced cervical cancer in women given a standard course of cisplatin-based chemoradiation with curative intent. 

“Pelvic chemoradiation with concurrent weekly cisplatin continues to be the standard of care for the treatment of locally advanced cervical cancer”, Linda Mileshkin, from the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, told delegates at the 2021 ASCO Annual Meeting. 

She recommended that “further research should focus on adjuvant therapies that may be more tolerable and effective when given after standard therapy.” 

The phase III study included women with FIGO stage IB1+LN, IB2, II, IIIB or IVA squamous cell carcinoma, adenocarcinoma or adenosquamous cell cancer without nodal disease above L3/4. All participants received 40–45 Gy of external beam radiotherapy in 20–25 fractions with nodal boost and brachytherapy, given concurrently with up to five cycles of weekly cisplatin 40 mg/m2, the presenter said. 

At 5 years, 72% of the 463 patients randomly assigned to receive four cycles of adjuvant carboplatin AUC 5 and paclitaxel 155 mg/m2 every 3 weeks were alive, as were 71% of the 456 patients who were not given adjuvant chemotherapy. 

The 5-year rates of progression-free survival (PFS) were also comparable in the adjuvant and no-adjuvant chemotherapy arms, at 63% and 61%, respectively, although subgroup analysis detected significant improvements in both survival endpoints for women aged at least 60 years who were not given adjuvant treatment. 

And sensitivity analysis based on completion or noncompletion of standard chemoradiotherapy found no significant difference in OS or PFS between patients given chemoradiotherapy with or without adjuvant therapy. 

The majority of patients in the adjuvant and no-adjuvant treatment arms did not have recurrence, at 72% and 67%, respectively, while a corresponding 10% and 7% had locoregional disease, and 9% and 11% distant recurrence with or without locoregional disease. 

The presenter noted that adherence to standard chemoradiation was “very good”, with 83–84% of patients receiving all five cycles of cisplatin, 92% receiving radiotherapy without interruption, 94–95% undergoing brachytherapy, and 67–68% completing radiotherapy within 8 weeks, so that 77% completed the full treatment regimen. 

And 62% of patients given adjuvant therapy completed all four cycles, with the full carboplatin and paclitaxel doses given without delay in 70% and 69% of patients, respectively. 

However, 22% of patients assigned to receive adjuvant chemotherapy did not begin this course of treatment. Linda Mileshkin reminded delegates that the OUTBACK investigators previously reported that women were less likely to begin adjuvant therapy if they were aged over 60 years, non-White or had not completed chemoradiation.  

The presenter said that “as expected”, adjuvant treatment was associated with significant increases in grade 1–2 and 3–5 anaemia, neutrophil and platelet count decreases, peripheral sensory neuropathy and some gastrointestinal toxicities, as well as grade 1–2 alopecia, fatigue, myalgia and urinary tract pain. 

But febrile neutropenia occurred in just 2% of both patient groups, there were no deaths related to study treatment or evidence of late radiation toxicity and after 1 year of follow-up, only the rate of grade 2 peripheral sensory neuropathy remained significantly higher in the adjuvant therapy arm (7 vs 2%). 

And while global quality of life scores on the QLQ-C30 measure were poorer during and 3–6 months after adjuvant chemotherapy, scores at 12–36 months were comparable in the two treatment groups. 

Session discussant Kunle Odunsi, from the University of Chicago in Illinois, USA, questioned whether alternative drug regimens or biological therapies may offer effective adjuvant treatment options.  

But he noted that the causes of distant failure after treatment for locally advanced cervical cancer are not “fully understood” and that “detailed phylogenetic analysis” is required to elucidate and determine how to disrupt the dissemination of circulating tumour cells and the transition to the epithelial phenotype required for metastases. 

Kunle Odunsi concluded that novel strategies are necessary to combat recurrent cervical cancer, such as vaccination against human papillomavirus, which continues to have a presence in cervical tumours, re-sensitising of tumour cells to chemotherapy, targeting intrinsic cell mechanisms and the prevention of immune system evasion by cervical cancer. 

Reference 

Mileshkin LR, Moore KN, Barnes E, 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). J Clin Oncol;39(suppl 15; abstr LBA3). DOI: 10.1200/JCO.2021.39.15_suppl.LBA3