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Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2021 ASCO Annual Meeting
  • CME

Joyce O'Shaughnessy, MD
Angeles Alvarez Secord, MD, MHSc
Released: August 12, 2021

Cervical Cancer

Chemoradiation With or Without Adjuvant Chemotherapy in Locally Advanced Cervical Cancer (OUTBACK): Study Design

Angeles Alvarez Secord, MD:
The tragedy with cervical cancer is that women are often diagnosed at a younger age, and many have young children. In addition, this is a group considered to have a strong unmet need globally.56 Cervical cancer accounted for more than 600,000 cancer cases and more than 340,000 deaths worldwide in 2020.57 Thus, improving survival outcomes for this patient population is incredibly important.

At the opening plenary session of the 2021 ASCO annual meeting, Mileshkin and colleagues presented results from the highly anticipated OUTBACK trial. OUTBACK was an international, randomized phase III trial evaluating concurrent chemoradiation (CRT) either alone or followed by 4 additional cycles of adjuvant chemotherapy with paclitaxel and carboplatin in patients with cervical cancer suitable for CRT with curative intent.58 There was strong rationale to conduct this study. It was based on data in the literature as well as a previous study by Dueñas-González and colleagues showing that the use of adjuvant cisplatin and gemcitabine chemotherapy after patients were treated with CRT improved survival outcomes compared with concurrent CRT alone.59 One important difference from the Dueñas-González study is that it included patients with para-aortic nodal disease and may have enrolled a higher‑risk population. In the OUTBACK trial, patients had either International Federation of Gynaecology and Obstetrics stage IB1 with a positive lymph node, IB2, or stage II‑IVA disease, and patients could have squamous cell carcinoma, adenocarcinoma, or adenosquamous cancer. Patients were required to have an ECOG performance status of 0‑2 and were not allowed to have nodal disease higher than L3/L4. Of note, the study protocol was amended to increase the sample size from 780-900 due to nonadherence to adjuvant chemotherapy, as well as a lower event rate than anticipated. This allowed for 80% power and a 2-sided α of 0.05 to detect an 8% absolute improvement in OS at 5 years. A total of 926 patients were enrolled. The primary endpoint was OS. Secondary endpoints included PFS, patterns of disease recurrence, radiation protocol compliance, patient‑reported outcomes, and safety.

OUTBACK: Baseline Characteristics

Angeles Alvarez Secord, MD:
In OUTBACK, the median age was 45 years (range: 22-88) for the CRT arm and 46 (range: 21-99) for the CRT plus adjuvant chemotherapy (ACT) arm, respectively. Comparing the CRT arm with the CRT plus ACT arm, 75% vs 73% of patients had an ECOG performance status of 0; 72% vs 73% of patients were White, 15% vs 11% of patients were Black, 5% vs 7% were Asian, and 2% vs 3% were Aboriginal/Pacific Islander. The population shows a bit more representation from diverse ethnic groups, likely due to the international nature of this trial.

It is important to note that approximately 50% of women in each arm smoked, and we know that there is a very strong link between smoking and development of cervical cancer.60 Looking at disease and tumor‑related characteristics, approximately 50% of patients in either arm had some nodal involvement. Extended‑field radiation was planned in 13% of patients in each arm, and there was very balanced representation of disease stage, including IB1 (all node positive), IB2, IIA (33% vs 33%), IIB (43% vs 43%), and stage IIIB/IVA (24% vs 24%). In both treatment arms, the predominant histology was squamous (79% vs 83%).

OUTBACK: Treatment Adherence

Angeles Alvarez Secord, MD:
One of the important outcomes evaluated in this study was treatment adherence, which we need to better understand in order to improve outcomes for patients with cervical cancer. In the CRT alone arm and the CRT plus ACT arm, respectively, 84% and 83% of patients received 5 cycles of cisplatin therapy during chemoradiation. In the CRT plus ACT arm, 22% of patients did not go on to receive the prescribed adjuvant chemotherapy per the protocol, and only 62% of patients received all 4 cycles of ACT.

Another important criterion evaluated was receipt of brachytherapy. Fortunately, 94% to 95% of patients received brachytherapy, but only 77% of patients in each arm completed CRT. In this group, the odds of not starting ACT doubled in patients aged older than 60 years and in non‑White patients, and it tripled in those not completing chemoradiation. Additional studies are needed to better interpret those results, but they clearly show that we need to improve treatment adherence in patients with cervical cancer.

OUTBACK: OS and PFS

Angeles Alvarez Secord, MD:
The 5-year survival outcomes were very disappointing in that adding more chemotherapy did not improve survival. The 5‑year OS in women who received CRT alone was 71% vs 72% in those who received CRT plus ACT (HR: 0.90; 95% CI: 0.70-1.17; = .8). Essentially, these Kaplan-Meier curves were superimposed and there was no OS benefit from adding ACT.

PFS results were similar. The 5‑year PFS was 61% with CRT alone vs 63% with CRT plus ACT arm (HR: 0.86; 95% CI: 0.69-1.07; P = .6). Treatment effects were consistent across all the patient subgroups except those were stratified based on younger than 60 years vs 60 years or older, where younger patients had a greater overall survival and PFS benefit with ACT after CRT (interaction P = .01 and .03, respectively).

OUTBACK: Disease Recurrence

Angeles Alvarez Secord, MD:
The bar graphs represent the disease status for the 2 study arms. In the CRT-alone arm, 67% of patients had no progression recorded at the time of this analysis. Similarly, in the CRT plus ACT arm, 72% of patients had no progression recorded. Overall, close to 70% of patients without disease recurrence is quite good, although we still need to do better for the 30% of patients who did experience persistence or recurrent disease. Approximately 9% to 11% of patients in each arm experienced distant recurrence either with or without locoregional disease.

Identifying patients at highest risk for distant recurrences remains an area of high unmet need in patients with cervical cancer. I see this also as an opportunity to do better.

OUTBACK: AEs

Angeles Alvarez Secord, MD:
Ultimately, we have to assess outcomes in the context of toxicity, and we see that the addition of adjuvant chemotherapy results in greater toxicity in nearly every category. Compared with patients in the CRT-alone arm, patients in the CRT plus ACT arm experienced significantly (P <.0001) higher levels of grade 3 or higher hematologic events of anemia (8% vs 18%), neutrophil count decrease (8% vs 20%), and platelet decrease (1% vs 4%). Rates of any-grade nonhematologic toxicity were also significantly higher (P <.0001) when comparing the CRT-alone arm with CRT plus ACT arm: alopecia (9% vs 79%), fatigue (80% vs 91%), and myalgia (11% vs 39%), and considerable peripheral neuropathy (29% vs 75%). Hearing impairment (10% vs 14%) was also noted.

OUTBACK: AEs, Long-term Safety, Global Quality of Life

Angeles Alvarez Secord, MD:
Fortunately, most of the toxicity differences between treatment arms resolved over time. However, at 1 year there was still a higher rate of peripheral neuropathy in the ACT arm compared with CRT alone (7% vs 2%). Peripheral sensory neuropathy is one of the things I am most concerned about for my patients, because it can be very debilitating and painful for patients and can limit their ability to do the things they want to do. Notably, global quality of life scores per the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire were worse for patients receiving CRT plus ACT both during and for 3 to 6 months after ACT but were comparable to CRT alone for Months 12 to 36.

OUTBACK: Clinical Implications

Angeles Alvarez Secord, MD:
My takeaway from the OUTBACK trial is that more chemotherapy is not always better for patients with cervical cancer. The addition of ACT to CRT in this specific patient population did not translate into improved OS or PFS outcomes, did not improve disease control, and lent itself to increased toxicity that negatively affected quality of life for patients with potentially curable cervical cancer. I think it’s clear that adding ACT to CRT is not the answer for enhancing outcomes in patients with locally advanced cervical cancer or those with stage IB disease with positive lymph nodes. 

This study also raises an important question: What changes can we make to improve outcomes for these patients? One of the most important aspects of this study is the recognition of noncompliance with completion of CRT treatment. We know that patients who do not complete their chemoradiation or who do not receive brachytherapy have worse outcomes. In addition, a significant delay in treatment can negatively affect patient outcomes as well. It is clear that we need to better identify the barriers to patients being able to complete their therapy. Is it toxicity? Is it social determinants of health? Is it health literacy? By understanding those barriers, we’ll be able to enhance both patient and provider education and, hopefully, improve therapy completion rates. Ultimately, I believe that will really help patients.

OUTBACK also highlighted the unmet need for novel therapies for patients with disease recurrence. The ongoing phase III KEYNOTE‑826 trial (NCT03635567) is evaluating pembrolizumab vs placebo in combination with platinum-based chemotherapy with or without bevacizumab as first-line treatment of patients with recurrent or metastatic cervical cancer. A recent press release reported that the addition of pembrolizumab to paclitaxel and carboplatin‑based chemotherapy improved OS and PFS in patients in this disease setting, and I look forward to seeing those results presented at a future meeting.

To date, there are no good FDA-approved treatment options for patients with recurrent cervical cancer, and enrollment in a clinical trial may be a good option if available. Ongoing trials of interest in recurrent cervical cancer include the CALLA study (NCT03830866), KEYNOTE‑A18 (NCT04221945), GOG‑3047 (NCT04221945), and ATOMICC (NCT03833479). If no suitable clinical trial is available, the best option would be to keep a patient under close surveillance.

Finally, there is now a heightened awareness of the lack of patient representation across racial and ethnic groups in clinical trials, with many trials enrolling primarily White women. Improving patient representation in trials will require a multipronged, dedicated approach that engages multiple key stakeholders. We must also consider who is developing clinical trials and the diversity and locations of the participating sites in the United States and globally. We should reach out to key leaders in local communities to build dialogue and help engage women from diverse groups. We need to acknowledge and address the distrust that exists in specific communities regarding healthcare and clinical trials and work on issues with health literacy. There will not be a quick and easy fix for this. It will take a great deal of dedicated effort, but these changes will be vital to conduct clinical trials that can translate into better health outcomes for all women.

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