CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 03, 2023
Expiration: August 02, 2024
Cervical Cancer
Lauren Prescott, MD, MPH:
I would like to move on to highlighting 2 key studies presented at ASCO 2023 for cervical cancer. I will start by going over the long-awaited results from the international Canadian Cancer Trials Group CX.5-SHAPE trial led by Dr Marie Plante, from Laval University, in Quebec, Canada, followed by the the final OS analyses of KEYNOTE 826, presented by Dr Bradley Monk, from Phoenix, Arizona.
CCTG CX.5-SHAPE: Radical vs Simple Hysterectomy and Pelvic Node Dissection for Low-Risk Early-Stage CC
Lauren Prescott, MD, MPH:
Cervical cancer is a highly preventable disease and low-risk early-stage cancer can be potentially cured. The standard of care for low-risk early-stage disease is radical hysterectomy with pelvic lymph node dissection or assessment. Retrospective data suggest that in patients with low-risk early-stage cervical cancer, less radical surgery is feasible and is associated with lower morbidity.5
The randomized, noninferiority phase III SHAPE trial was undertaken to evaluate whether simple hysterectomy is associated with similar efficacy and less surgical morbidity vs radical hysterectomy in patients with low-risk cervical cancer (N = 700).6
In the SHAPE trial, low risk cervical cancer was defined by histologic subtype squamous or adenocarcinoma (no neuroendocrine or carcinosarcomas), early stage (IA2 or 1B1), low depth of stromal invasion (<10 mm on Loop Electrical Excision Procedure [LEEP]/cone; <50% on MRI), and grade 1-3 (including not assessable). Overall, tumors included in the SHAPE trial were small, nonaggressive, and were less likely to metastasize to the parametria justifying performing a simple hysterectomy. Per trial protocol, both groups required a pelvic lymph node dissection with the option of sentinel lymph node mapping. The primary endpoint was rate of pelvic recurrence at 3 years.
CCTG CX.5-SHAPE: Baseline Characteristics
Lauren Prescott, MD, MPH:
We saw an equal distribution of 350 patients in each study arm. There were slightly more patients in the simple hysterectomy group who had a LEEP/cone prior to their procedure (73% vs 65%), but overall the baseline characteristics were well balanced between arms.
CCTG CX.5-SHAPE: Surgical and Treatment Parameters
Lauren Prescott, MD, MPH:
The route of surgery was at the discretion of each surgeon and was not a randomization criterion. It is important to note that during the timeframe that the SHAPE trial was open, the standard of care had shifted from minimally invasive radical hysterectomy to open (or abdominal) radical hysterectomy in light of the results from the Laparoscopic Approach Carcinoma of the Cervix (LACC) trial, which unexpectedly demonstrated that minimally invasive surgery was associated with significantly lower OS and disease-free survival compared with open radical hysterectomy.7 These changes to the standard of care while the SHAPE trial was underway may account for some of the imbalance we see in this table regarding the type of surgery that patients received while on this study. There was a modest imbalance with open surgery rate being notably higher in the radical hysterectomy arm vs the simple hysterectomy arm (29% vs 17%).
CCTG CX.5-SHAPE: Clinical Outcomes After Median Follow-up of 4.5 Yr
Lauren Prescott, MD, MPH:
As a reminder, this was a noninferiority study with the primary outcome being pelvic recurrence at 3 years. Data reported at ASCO by Dr Plante showed that in the simple hysterectomy group the 3-year rate of pelvic recurrence was 2.52% compared with 2.17% in the radical hysterectomy group. With the upper limit of the confidence interval set at less than 4%, the authors determined the primary endpoint was met and simple hysterectomy was deemed noninferior to radical hysterectomy in patients with early-stage low-risk cervical cancer.
There also was no difference in 3-year pelvic recurrence-free survival (RFS), extra-pelvic RFS, or 3-yr OS (all P values >.05). Of note, there were 4 (1.1%) deaths in the simple hysterectomy group and 1 (0.3%) in the radical hysterectomy group attributed to cervical cancer.
Ritu Salani, MD, MBA:
As Dr Prescott suggests, of the criticisms for the SHAPE trial given the hint of slightly higher 3-year pelvic recurrence was the use of more minimally invasive surgery (laparoscopic) in the simple hysterectomy group vs radical hysterectomy group that used more abdominal procedure. In this trial the type of surgery was not a stratification factor, and surgery type was not standardized because of the changes in treatment landscape following publication of the LACC trial results. Thus, a control for the type of surgery would have been ideal to better define any true signal vs noise. We understand that neither the LACC nor the SHAPE study are perfect, but we can try to use these data to the best of our ability. I think recurrence rates are equivalent in both treatment arms.
We also know of a proof of principle study by Rendón and colleagues at MD Anderson in Houston exploring outcomes with laparoscopic radical trachelectomies vs radical trachelectomy that suggested there was no difference in outcome.8
CCTG CX.5-SHAPE: Intraoperative Complications
Lauren Prescott, MD, MPH:
In clinical practice, when we counsel patients about the difference between radical vs simple hysterectomy we often talk about the risk of perioperative complications. Of note, although there was a numerical trend for increased risk of intraoperative urinary complications for radical hysterectomy vs simple hysterectomy in bladder (0.9% vs 2.69%) and ureter (0.9% vs 1.5%), it was not statistically significant (both P >.05).
Ritu Salani, MD, MBA:
I also think that you can say confidently that doing simple hysterectomy compared with radical hysterectomy does not afford a worse outcome regarding intraoperative complications for our patients.
CCTG CX.5-SHAPE: Acute and Late Surgery-Related AEs
Lauren Prescott, MD, MPH:
When we looked at acute and late surgery-related complications, there was a statistically significant increase in post op urinary complications in both the acute perioperative period (urinary incontinence: 5.5% vs 2.4%, P <.048; urinary retention: 11.0 vs 0.6%, P <.0001) as well as late surgery related AEs (urinary incontinence: 11.0% vs 4.7%, P <.003; urinary retention: 9.9% vs 0.6%, P <.0001) for the radical hysterectomy group vs the simple hysterectomy group.
CCTG CX.5-SHAPE: QoL and Sexual Health
Lauren Prescott, MD, MPH:
Authors evaluated the female sexual function index (FSFI) scale of desire, arousal, lubrication, and FSFI total score, and the female sexual function distress scale and all measures showed significantly less impact with the use of simple hysterectomy vs radical hysterectomy (all P <.05). The EORTC QLQ-cervical cancer module 24 also demonstrated a more favorable outcome in the simple hysterectomy group. There were significant differences in sexual vaginal functioning and sexual pain noted at 3, 6, and 12 months as well, all favoring the simple hysterectomy group.
CCTG CX.5-SHAPE: Clinical Implications
Lauren Prescott, MD, MPH:
My takeaway from the SHAPE trial was, that in a highly selective early stage low risk cohort of patients with cervical cancer, simple hysterectomy is noninferior to radical hysterectomy with decreased risk of acute and late-onset postoperative complications, specifically urinary complications, and preserved sexual function. I believe the SHAPE study has the potential to change the standard of care in this population with low-risk cervical cancer.
This was an incredibly well-done study conducted over a long period of time and authors should be congratulated for their persistence in recruiting patients in this international study, particularly in low- to moderate income countries.
Ritu Salani, MD, MBA:
I think these results can be integrated into practice and I have already talked to a patient about using this approach. I believe we are not complicating the outcome for cancer care and may be improving long-term outcomes in the form of fewer surgery-related complications.
A question we may get from a colleague is: ‘for a patient with early-stage, low-risk disease who has completed chemoradiation and brachytherapy boost and has come back with a positive biopsy for residual disease, what would be the best approach?’ I would say that the first thing I would consider is whether this is an isolated lesion on the cervix, and whether this patient may require more time for treatment to work and give them more time and monitor them with a repeat biopsy. If it has been 6 months after radiation therapy, I will likely offer them a hysterectomy if I think it is feasible. Often, additional brachytherapy can also be considered.
Lauren Prescott, MD, MPH:
In my practice I do not offer additional brachytherapy for recurrent disease even if small as most of my patients received a very high dose for curative intent treatment up front and not candidates for additional treatment.
Pembrolizumab + CT ± Bevacizumab vs Placebo + CT ± Bevacizumab in CC (KEYNOTE-826): Final OS Analysis
Lauren Prescott, MD, MPH:
The second study that I would like to highlight is the abstract for the final OS results from the international, randomized, phase III KEYNOTE-826 that evaluated addition of pembrolizumab to standard chemotherapy
with or without bevacizumab as first line treatment for patients with persistent, recurrent, or metastatic cervical cancer (N = 617). The trial had dual primary endpoints of PFS and OS per RECIST 1.1 by investigator.
KEYNOTE-826 was a very exciting study for us, and after the initial results for were published in the New England Journal of Medicine, it changed the standard of care with the addition of pembrolizumab to frontline chemotherapy in this patient population.
KEYNOTE-826: Final Analysis of OS
Lauren Prescott, MD, MPH:
After a median follow-up of 39.1 months,[Monk 2023] the addition of pembrolizumab to frontline chemotherapy continued to demonstrate significant improvements in OS in patients with PD L1 CPS of ≥1 (median: 28.6 vs 16.5; HR: 0.60; P <.0001), PD L1 CPS ≥10 (median: 29.6 vs 17.4; HR: 0.58; P <.0001), and all-comers (median: 26.4 vs 16.8; HR: 0.63; P <.0001). The OS rates all favored the pembrolizumab-containing arm at 12 and 24 months.
The subgroup analyses indicated an efficacy benefit with pembrolizumab across most key groups irrespective of bevacizumab use.
KEYNOTE-826: Final Analysis of PFS
Lauren Prescott, MD, MPH:
Similarly, the addition of pembrolizumab to frontline chemotherapy demonstrated sustained and clinically significant improvements in PFS in patients with PD L1 CPS of ≥1 (median: 10.5 vs 8.2; HR: 0.58; P <.0001), PD L1 ≥10 (median: 10.4 vs 8.1; HR: 0.52; P <.0001), and all-comers (median: 10.4 vs 8.2; HR: 0.61; P <.0001). The PFS rates all favored the pembrolizumab-containing arm at 12 months.
Ritu Salani, MD, MBA:
It was encouraging to see that with longer follow-up the median for OS was notably improved from the previous interim analysis.9 Pembrolizumab is an active agent in this setting and together this data reaffirms adding pembrolizumab to frontline chemotherapy and not reserving it for later lines of therapy or at relapse.
KEYNOTE-826: Final Analysis of ORR and DoR
Lauren Prescott, MD, MPH:
When we looked at response and duration of response, the results were very exciting. When compared to chemotherapy alone, the ORR in patients with PD L1 CPS of ≥1 was 68.5% (complete response [CR]: 25.6%) vs 50.9% (CR: 14.5%), in PD L1 CPS ≥10 was 69.6% (CR: 24.7%) vs 50.3% (CR: 12.6%), and for all-comers 66.2% (CR: 24.7%) vs 51.5% (CR: 14.2).
This patient population with progressive or recurrent cervical cancer has traditionally been very difficult to treat. To achieve CRs in approximately 25% of patients is quite remarkable. Median duration of response ranged from 18 to 28 months with pembrolizumab vs 10.1 to 10.4 for chemotherapy alone.
KEYNOTE-826: Updated Safety and Treatment Exposure
Lauren Prescott, MD, MPH:
The updated safety data did not show anything new or of concern with the addition of pembrolizumab and AEs were comparable to those published in the interim results.9
Approximately 82% of patients in the pembrolizumab-containing arm and 75% in the chemotherapy-only arm had grade ≥3 AEs. AEs led to treatment discontinuation of any treatment in approximately 41% of patients receiving pembrolizumab vs 29% in the chemotherapy-only group. AEs of any cause led to discontinuation of all treatments in 4.9% vs 5.5% of patients receiving pembrolizumab vs chemotherapy, respectively.
Immune-related AEs led to discontinuation of any treatment in 6.5% of patients receiving pembrolizumab vs 0.3% in those receiving chemotherapy only.
Sixteen (5.2%) and 15 (4.9%) deaths were reported in the pembrolizumab-containing arm and the chemotherapy-only arm, respectively. A total of 2 (0.7%) deaths in the pembrolizumab arm were immune AE–related.
This is a group of patients that needs robust supportive care treatment and for a disease that itself is causing a significant symptom burden.
KEYNOTE-826: Clinical Implications
Lauren Prescott, MD, MPH:
My takeaway from the final OS analyses from KEYNOTE-826 is that the addition of pembrolizumab to frontline chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer continues to be the standard of care in this setting.
The benefit observed for ORR, PFS, and OS was consistent across subgroups, including those with or without bevacizumab use, which is important because there are many patients who are not able to receive bevacizumab due to contraindication and other AEs from bevacizumab.
Ritu Salani, MD, MBA:
With the frontline use of pembrolizumab in advanced or recurrent cervical cancer, we also have to think about our options for those who relapse.
In patients relapsing on frontline chemotherapy plus pembrolizumab as in KEYNOTE-826, I think tisotumab vedotin would be my first option. I am looking forward to data from the confirmatory innova TV 301 trial (NCT04697628) of tisotumab vedotin vs chemotherapy (eg, topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in the near future. Other than tisotumab vedotin, pemetrexed, topotecan, and even rechallenge with a platinum based regimen, or even gemcitabine, may be an option with some activity, but with a more challenging safety profile. Patients with recurrent cervical cancer are often fragile from their prior chemotherapy regimen (eg, myelosuppression, neuropathy) and these issues can play a role in the selection of therapy for recurrent disease.
Other promising agents in development include antibody–drug conjugates (ADCs) against HER2. The DESTINY-PanTumor-02 trial (NCT04482309) is evaluating the ADC trastuzumab deruxtecan in patients with expression of HER2. Preliminary data from that study reported in a press release suggests an encouraging response of 50% in patients with cervical cancer.
I also believe there is more work to be done for increasing access of these novel therapies for women with cervical cancer perhaps by leveraging clinical trials. Access to the latest advances in gynecologic cancer care remains a challenge and most women with cervical cancers who do not have insurance or are underinsured may struggle to get these novel medications. However, I am hopeful that things like immunotherapy will be accessible to patients with the appropriate prognostic markers, and with the use of early-access and compassionate use programs. I strongly believe the latter will help improve access to these drugs for patients. And although these programs may require a little extra work from the patients and providers alike, it is absolutely worth it for patients. I think it is also great to have clinical trials available at your site, as a potential option to offer patients, and to facilitate access to care that is independent of their insurance status.
The government and regulatory policies also play an important role in facilitating access to cancer therapies for our patients. We recently experienced the loss or nonrenewal of the “expanded access to Medicaid program” in a number of states, and this has become a substantial challenge for some patients who find themselves without access to care leading to poor outcomes. For example, states without Medicaid expansion have some of the highest rates of maternal mortality and cervical cancer development.
Quite often, new approvals may inadvertently result in increasing disparities because now there is a therapy most patients can’t access for a variety of reasons. Therefore, we must keep equitable care delivery top of mind and raise awareness about how we can deliver life-prolonging or life-saving therapies to patients who need them most.
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