In locally advanced cervical cancer, it is well-known that brachytherapy boost following pelvic XRT provides a marked survival benefit. More recent attempts to substitute brachytherapy with IMRT/SBRT boost has been associated with overall survival detriment even worse than omitting chemotherapy (NCDB analysis Gills 2014). However, in medically unfit patients who require interstitial brachytherapy (and thus anesthesia), there does not exist any suitable alternatives. Thus, SBRT may be the best alternative, and trials evaluating how to optimize delivery (dose, target volume, constraints, and optimal patient/tumor selection) become critical. In this phase II study, SBRT dosing, volumes, and constraints were mirrored to that of HDR brachytherapy. A range of patients, stage IB2-IVB and ECOG0-3 were enrolled. Notably, the trial was closed due to concerning toxicity (with 2-year grade 3+ toxicity of ~27%), primarily rectal. The study proposed a possible rectal constraint and acknowledged that suboptimal outcomes (in toxicity, and LC/OS) were likely due to suboptimal patient selection/large tumor size. This trial thus draws light to the need for further evaluation and optimization of SBRT boost delivery, by determining the most suitable patients/tumors, and optimal dosing/dosimetric parameters that may be distinct from HDR brachytherapy parameters.

Reference (PubMed Link): Albuquerque K, Tumati V, Lea J, et al. A phase ii trial of stereotactic ablative radiation therapy as a boost for locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2020;106:464-471.

Key Institution: UT Southwestern
Keywords: Cervical cancer, SBRT boost, brachytherapy 

Despite standard definitive chemoradiation (CRT) for locally advanced cervical cancer (LACC), both local and distant recurrences are common. This phase II randomized trial from Brazil randomized 107 patients with FIGO IIB to IVA cervical cancer to standard CRT with or without neoadjuvant chemotherapy (NAC) consisting of gemcitabine and cisplatin every 3 weeks for 3 cycles to evaluate the efficacy and safety of this regimen. Primary end point was 3-year progression-free survival (PFS) and secondary end points included response rate, 3-year locoregional control, 3-year overall survival, safety and quality of life.  

In this randomized phase II trial, there was significantly worse progression-free survival and overall survival with neoadjuvant chemotherapy. At 3 years, the PFS was significantly worse with NAC decreasing from 60 to 41% and OS was also significantly worse from 87 to 61%. The disease response was lower with neoadjuvant chemotherapy with complete response rate of 56.3% in NAC arm compared to 80.3% in CRT alone arm. Toxicities were similar in both arms unlike prior phase III trial demonstrating worse toxicity with adjuvant chemotherapy. 

In this trial, NAC (gem/cis) was well tolerated overall but associated with lower CRR, PFS and OS compared to standard chemoradiation for LACC. Therefore, NAC with cisplatin and gemcitabine with definitive CRT is not superior and possibly inferior to CRT alone. The reasons for this possible detrimental effect of NAC are unclear but hypotheses include delay in initiation and comprise in delivery of definitive CRT. The standard treatment should remain concurrent cisplatin-based CRT. We should continue evaluating new treatment strategies to improve outcomes in LACC. 

Reference (PubMed Link): da Costa SCS, Bonadio RC, Gabrielli FCG, et al. Neoadjuvant chemotherapy with cisplatin and gemcitabine followed by chemoradiation versus chemoradiation for locally advanced cervical cancer: A randomized phase ii trial. J Clin Oncol 2019;37:3124-3131.

Key Institution: Universidade de São Paulo, São Paulo, Brazil
Keywords: Cervical, Chemotherapy, Neoadjuvant, Survival

For women with high risk endometrial cancer, PORTEC 3 investigated the benefit of combined adjuvant chemotherapy and radiation vs. pelvic radiation alone. This article reported on a post-hoc survival analysis. 

Eligibility criteria included women with FIGO Stage 1, Grade 3 disease with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I–III disease with serous or clear cell histology. They were then randomized to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously). The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analyzed according to the first site of recurrence. A post-hoc analysis to analyze patterns of recurrence with 1 additional year of follow-up was done.

At a median follow-up of 72·6 months, 5-year overall survival was 81·4% with chemoradiotherapy versus 76·1% with radiotherapy alone (p=0·034), and 5-year failure-free survival was 76·5% versus 69·1% (p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%) in the radiotherapy-alone group (p=0·047). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone.

(Open Access)

Reference (PubMed Link): de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (portec-3): Patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol 2019;20:1273-1285.

Key Institution: Netherlands, UK 
Keywords: Endometrial cancer, radiation therapy, chemotherapy, failure free survival

This trial assessed the addition of chemotherapy to Stage I (deeply invasive) grade 3 endometrial cancer and demonstrated improvement in failure free survival though no improvement in overall survival. This trial demonstrates that current practice patterns of EBRT alone for these patients is sufficient given additional toxicities associated with chemotherapy. Currently standard of care remains EBRT alone for this cohort of patients.

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Journal & Date: Lancet Oncology, Volume 19, No. 3, p295–309, March 2018
Key Institution:  International, multicenter
Keywords: Endometrial cancer, Radiotherapy, Chemotherapy, Clinical Trial