PD-L1 expression in vulvar cancer: a systematic review and meta-analysis.

Programmed cell death ligand-1 (PD-L1) expression in cancer may predict clinical response to immunotherapeutic treatment with PD-1/PD-L1 inhibitors. Within the vulvar cancer field, PD-L1 expression has only been assessed by a few studies. We conducted a meta-analysis to examine the prevalence of PD-L1 positivity in vulvar cancer. PubMed, Embase, and Cochrane were searched for articles reporting on PD-L1 expression in vulvar cancer. Study selection and data extraction were performed independently by two authors. We extracted data on PD-L1 prevalence in vulvar cancer according to combined positive score (CPS) and tumour proportion score (TPS). Cutoff values for positivity were ≥1 or ≥10 for CPS and ≥1% and ≥5% for TPS. Random-effects models were used to estimate pooled PD-L1 prevalence, with 95% confidence intervals (CIs). Tests of between-study heterogeneity were evaluated by the I2 statistics. Sources of heterogeneity were explored by subgroup analyses and meta-regression. In total, 19 studies were included. Pooled PD-L1 prevalence in vulvar cancer was 83.4% (95% CI: 70.8-91.3; I2 = 80.0) and 53.9% (95% CI: 37.4-69.6; I2 = 93.0) according to CPS and TPS, respectively. Based on TPS, human papillomavirus (HPV)-associated vulvar squamous cell carcinomas (SCC) showed a lower PD-L1 prevalence (39.9%; 95% CI: 13.3-74.2) compared with HPV-independent SCC (62.6%; 95% CI: 33.7-84.6), but meta-regression showed no significant variation in PD-L1 prevalence by HPV status. PD-L1 prevalence was similar in advanced (44.9%; 95% CI: 29.8-61.1) and localized vulvar cancer (56.7%; 95% CI: 18.9-76.7). In conclusion, PD-L1 expression in vulvar cancer is frequent but between-study heterogeneity was high. Based on a subgroup of heterogenous studies, we found no strong variation in PD-L1 prevalence according to HPV status and stage.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Clinical experiences with online adaptive radiotherapy of vulvar carcinoma.

BACKGROUND AND PURPOSE: Radiotherapy for vulvar carcinoma is challenging due to relatively high risk of locoregional disease recurrence, a technically challenging target, and postoperative lymphocele, and a high risk radiation sequelae. We aim to explore, if it is possible to reduce dose to normal tissue, while maintaining CTV coverage for this patient group with online adaptive radiotherapy. MATERIALS AND METHODS: 20 patients with vulvar carcinoma (527 fractions) were treated with online adaptation on a Varian Ethos accelerator. Setup CBCTs were acquired daily for adaptive planning. Verification CBCTs were acquired immediately prior to dose delivery. CTV dose coverage and dose to bladder and rectum were extracted from the scheduled and adapted plans as well as from adapted plans recalculated based on verification CBCTs. In addition, analysis of the decision of the adaptive procedure was performed for 17 patients (465 fractions). RESULTS: Mean CTV D95% and standard deviation was 98% ± 5% for the scheduled plan compared to 100.0 ± 0.3% and 100.0 ± 0.8% for the adapted plan on the setup and verification CBCT respectively. Dose to OARs varied substantially and did not show any benefit from adaption itself, however a margin reduction was implemented after the first patients treated. The adapted plan was chosen for 63.5% of the fractions and dominant reasons for not adapting were 'no significant dosimetric gain' (75 fractions, 14%) and 'Medical doctor (MD) not available for treatment' (50 fractions, 9.5%). The median adaption time was 15 min and the 25th and 75th percentile was 12 and 17 min, respectively. CONCLUSION: CTVs and PTVs dose coverage were significantly improved with adaptation compared to image-guided RT. This gain was robust during the treatment time.

Treatment and outcomes of a Danish ovarian cancer population.

INTRODUCTION: Ovarian cancer has the highest mortality rate among gynaecological cancers and is the tenth most frequent cancer among women. 80% of patients with advanced stage disease will experience a progression either during or after treatment. METHODS: This was a retrospective, observational study of all women referred to adjuvant or neoadjuvant treatment for ovarian cancer between 1 June 2013 and 31 May 2014 at two university hospitals in Denmark. RESULTS: We included 142 women diagnosed with ovarian cancer. The median overall survival from diagnosis was 48.5 months (95% confidence interval (CI): 36.6-57.9 months). Median survival after the first, second, third, fourth and fifth progression was 19.3 (95% CI: 13.9-27-3), 11.4 (95% CI: 7.7-18.8), 9.5 (95% CI: 6.3-12.7), 8.3 (95% CI: 7.6-11.5) and 5.6 (95% CI: 2.9-not assessed) months, respectively. Median progression-free survival from diagnosis was 15.6 months (95% CI: 14.3-18.4 months). Median progression-free survival after first, second, third, fourth and fifth progression was 9.2 (95% CI: 7.7-10.6), 6.0 (95% CI: 3.5-7.7), 3.3 (95% CI: 2.6-4.6), 4.9 (95% CI: 3.6-8.3) and 3.0 (95% CI: 2.4-5.7) months, respectively. The most frequently used treatment at first progression was carboplatin and pegylated liposomal doxorubicin (n = 37). The most used non-platinum containing treatment at progression was pegylated liposomal doxorubicin (n = 26) followed by paclitaxel (n = 23). CONCLUSIONS: Ovarian cancer remains a highly aggressive disease with most patients diagnosed in advanced stages. Treatment has not changed much in the past 15 years and the same is evident for the overall survival. FUNDING: Tobias Berg received an unrestricted research grant from the Danish Cancer Society. TRIAL REGISTRATION: not relevant.

Gemcitabine for recurrent ovarian cancer - a systematic review and meta-analysis.

INTRODUCTION: More than 80 % of women with advanced ovarian cancer relapse either during or after adjuvant therapy. Platinum-sensitive women are rechallenged with a platinum-combination therapy and platinum-resistant women are challenged with non-platinum drugs. Gemcitabine is one of many treatments that can be used both as single-agent or as combination therapy for the treatment of recurrent ovarian cancer. METHODS: We included all randomised controlled trials investigating patients treated with gemcitabine for recurrent ovarian cancer and reporting data on overall survival, progression-free survival and toxicity. CENTRAL, EMBASE and MEDLINE were searched on the 31st of May 2019. RESULTS: We included six randomised controlled trials that evaluated gemcitabine either alone or as combination therapy. Two studies compared gemcitabine to pegylated liposomal doxorubicin in women with platinum-resistant recurrent ovarian cancer. Difference in overall and progression-free survival was non-significant. Gemcitabine treatment was associated with significantly more neutropenia, whereas pegylated liposomal doxorubicin was associated with significantly more hand-foot syndrome. One study evaluated carboplatin and gemcitabine to carboplatin. Difference in overall survival was non-significant, but progression-free survival was longer with gemcitabine and carboplatin (HR: 0.72, 95% CI 0.58-0.9). One study evaluated gemcitabine with gemcitabine and pertuzumab. Overall survival and progression-free survival was similar between the two arms. One study compared gemcitabine and carboplatin to gemcitabine, carboplatin and bevacizumab. Overall survival was similar in the two arms. Progression-free survival was significantly better in the bevacizumab arm (HR 0.48 95% CI 0.39-0.61). One study compared etoposide and gemcitabine to etoposide. The study showed similar overall survival and progression-free survival. DISCUSSION: The results show that gemcitabine is an active and safe agent in the treatment of both platinum-sensitive and resistant recurrent ovarian cancer but might highlight the need of new randomised studies in heavily pre-treated patients.

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial.

PURPOSE: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-gBRCAmut and non-gBRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS: In the gBRCAmut and non-gBRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gBRCAmut and non-gBRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

Reduction of cardiac and pulmonary complication probabilities after breathing adapted radiotherapy for breast cancer.

PURPOSE: Substantial reductions of cardio-pulmonary radiation doses can be achieved using voluntary deep inspiration breath-hold (DIBH) or free breathing inspiration gating (IG) in radiotherapy after conserving surgery for breast cancer. The purpose of this study is to evaluate the radiobiological implications of such dosimetric benefits. METHODS AND MATERIALS: Patients from previously reported studies were pooled for a total of 33 patients. All patients underwent DIBH and free breathing (FB) scans, and 17 patients underwent an additional IG scan. Tangential conformal treatment plans covering the remaining breast, internal mammary, and periclavicular nodes were optimized for each scan, prescription dose 48 Gy. Normal tissue complication probabilities were calculated using the relative seriality model for the heart, and the model proposed by Burman et al. for the lung. RESULTS: Previous computed tomography studies showed that both voluntary DIBH and IG provided reduction of the lung V50 (relative volume receiving more than 50% of prescription dose) on the order of 30-40%, and a 80-90% reduction of the heart V50 for left-sided cancers. Corresponding pneumonitis probability of 28.1% (range, 0.7-95.6%) for FB could be reduced to 2.6% (range, 0.1-40.1%) for IG, and 4.3% (range, 0.1-59%) for DIBH. The cardiac mortality probability could be reduced from 4.8% (range, 0.1-23.4%) in FB to 0.5% (range, 0.1-2.6%) for IG and 0.1% (range, 0-3.0%) for DIBH. CONCLUSIONS: Remarkable potential is shown for simple voluntary DIBH and free breathing IG to reduce the risk of both cardiac mortality and pneumonitis for the common technique of adjuvant tangential breast irradiation.