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Ovarian cancer remains one of the most challenging malignancies to treat. Targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as one of the most exciting new treatments for ovarian cancer, particularly in women with BRCA1 or BRCA2 mutations or those without a functional homologous recombination repair pathway. Perhaps the most advantageous characteristic of PARP inhibitors is their mechanism of action, which targets cancer cells on the basis of their inherent deficiencies while seemingly avoiding normally functioning cells. Although health-care providers might assume a low toxicity profile because of their specific mechanism of action, PARP inhibitors are not completely benign and overall show a class effect adverse-event profile. Further complicating this situation, three different PARP inhibitors have been approved by the US Food and Drug Administration since 2014, each with their own specific indications and individual toxicity profiles. The diversity of adverse events seen both within and across this class of drug underscores the importance of having a comprehensive reference to help guide clinical decision making when treating patients. This Review characterises and compares all toxicities associated with each PARP inhibitor, both in monotherapy and in novel combinations with other drugs, with a particular focus on potential management strategies to help mitigate toxic effects. Although the excitement surrounding PARP inhibitors might certainly be warranted, a thorough understanding of all associated toxicities is imperative to ensure that patients can achieve maximal clinical benefit.

In this prospective randomized trial, minimally invasive radical hysterectomy resulted in lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer. A prospective randomized trial and an epidemiologic study that used large cancer databases (National Cancer Database and SEER) both showed that minimally invasive radical hysterectomy was associated with shorter survival in early cervical cancer than open abdominal radical hysterectomy.

Late-stage distribution and bulky intraperitioneal disease are the hallmarks of ovarian cancer presentation, which is managed primarily by surgical resection and chemotherapy. However, advances in surgical resection objectives, alternative chemotherapy administration schedules, and novel therapeutics based on increasing knowledge of disease biology are making strides to improve outcomes. This Review covers all elements of the definition, treatment, and biology of ovarian cancer. The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics, despite prolific drug development. Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free survival and overall survival, although the cure rates have been affected only modestly. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, growth in our armamentarium offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial 'ovarian' cancer and describes the direction and early results of clinical investigation. Key Points Ovarian cancer continues to be characterized by late-stage presentation and bulky intraperitoneal disease burden at presentation Surgery and chemotherapy are the mainstays of primary therapy; 'optimal' surgical cytoreduction is being re-defined as resection of all macroscopic disease Advances in adjuvant chemotherapy have leveraged intraperitoneal administration, dose-dense paclitaxel and the addition of biological agents predominately targeting angiogenesis Maintenance therapy is a promising strategy as a primary or subsequent adjuvant approach, but as yet is not been proven to increase overall survival Recurrence therapy has improved post-progression outcomes, although cures are elusive Closely tied to a wider understanding of the underlying biology of ovarian cancer, drug development is increasingly focused on specific new targets in the hope of optimizing the therapeutic index

Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.

ObjectiveThe objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer.MethodsFrom April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2–IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size <2 cm; (4) no lymphovascular space invasion; (5) depth of invasion <10 mm; (6) negative imaging for metastatic disease; and (7) negative conization margins. Cervical conization was performed to determine eligibility, with one repeat cone permitted. Eligible women desiring fertility preservation underwent a second surgery with pelvic lymph node assessment, consisting of sentinel lymph node biopsy and/or full pelvic lymph node dissection. Those not desiring fertility preservation underwent simple hysterectomy with lymph node assessment. Women who had undergone an ‘inadvertent’ simple hysterectomy with an unexpected post-operative diagnosis of cancer were also eligible if they met the above inclusion criteria and underwent a second surgery with pelvic lymph node dissection only.Results100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23–67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients—that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0–68.3). Three patients developed recurrent disease within 2 years of surgery—that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%).DiscussionOur prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

The standard initial management of epithelial ovarian cancer consists of surgical staging, operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy, and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel. Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes. However, 75% of patients present with advanced (stage III or IV) disease and, although more than 80% of these women benefit from first-line therapy, tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis. Second-line treatments can improve survival and quality of life but are not curative. Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg, bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes.

Key Points Many cancer targets are difficult to block with conventional therapies. Although RNA interference (RNAi) as a therapeutic approach is appealing, many challenges to delivery must be overcome. Nanoparticles hold promise for the safe and effective intracellular delivery of RNAi-based molecules. Physiological barriers and systemic toxicity of nanoparticle-based carrier systems create multiple challenges to bringing RNAi-based therapeutics to the clinic. Nanoparticles can be used to help avoid immune-mediated responses to systemic RNAi-based therapy. Solutions to improving tumour specificity and the ability to monitor and control short-term and long-term RNAi-based therapies are crucial next steps before clinical use. As the technology for delivery improves, so we will also need to improve our understanding of the heterogeneity of RNAi processing in different cancer types. Various resistance mechanisms to RNAi-based therapies must be anticipated. Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many to consider using RNA interference (RNAi) as a therapeutic approach. This Review explores current challenges to the development of synthetic RNAi-based therapies and considers new approaches to circumvent biological barriers. Inherent difficulties with blocking many desirable targets using conventional approaches have prompted many to consider using RNA interference (RNAi) as a therapeutic approach. Although exploitation of RNAi has immense potential as a cancer therapeutic, many physiological obstacles stand in the way of successful and efficient delivery. This Review explores current challenges to the development of synthetic RNAi-based therapies and considers new approaches to circumvent biological barriers, to avoid intolerable side effects and to achieve controlled and sustained release.

Mirvetuximab soravtansine-gynx (MIRV) is a conjugate of a folate receptor alpha (FRα)-directed antibody and the maytansinoid microtubule inhibitor, DM4. Accumulating pre-clinical and clinical data supported the safety and anti-tumor activity of MIRV in tumors expressing FRα. In 2017, a phase I expansion study reported the first experience of MIRV in FRα-positive platinum-resistant ovarian cancer with promising results. However, the phase III FORWARD I study failed to demonstrate a significant benefit of MIRV in FRα-positive tumors. On the basis of the data reported from this latter study, MIRV was then explored in the FRα-high population only and using a different folate receptor assay. The phase II SORAYA trial supported the adoption of MIRV in this setting. Hence, the US Food and Drug Administration granted accelerated approval of MIRV for patients with FRα-positive platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1–3 prior systemic treatment regimens. Moreover, the results of the MIRASOL trial showed a significant reduction in the risk of tumor progression or death among patients treated with MIRV versus chemotherapy. VENTANA FOLR1 (FOLR-2.1) was approved as a companion diagnostic test to identify FRα patients. MIRV appears to be a significant asset in managing advanced or recurrent ovarian cancer. Further trials are needed to confirm these promising results, even in the neoadjuvant, adjuvant, and maintenance settings.

In the phase 3 LACC trial and a subsequent population-level review, minimally invasive radical hysterectomy was shown to be associated with worse disease-free survival and higher recurrence rates than was open radical hysterectomy in patients with early stage cervical cancer. Here, we report the results of a secondary endpoint, quality of life, of the LACC trial. The LACC trial was a randomised, open-label, phase 3, non-inferiority trial done in 33 centres worldwide. Eligible participants were women aged 18 years or older with International Federation of Gynaecology and Obstetrics (FIGO) stage IA1 with lymphovascular space invasion, IA2, or IB1 adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma of the cervix, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who were scheduled to have a type 2 or 3 radical hysterectomy. Participants were randomly assigned (1:1) to receive open or minimally invasive radical hysterectomy. Randomisation was done centrally using a computerised minimisation program, stratified by centre, disease stage according to FIGO guidelines, and age. Neither participants nor investigators were masked to treatment allocation. The primary endpoint of the LACC trial was disease-free survival at 4·5 years, and quality of life was a secondary endpoint. Eligible patients completed validated quality-of-life and symptom assessments (12-item Short Form Health Survey [SF-12], Functional Assessment of Cancer Therapy–Cervical [FACT-Cx], EuroQoL-5D [EQ-5D], and MD Anderson Symptom Inventory [MDASI]) before surgery and at 1 and 6 weeks and 3 and 6 months after surgery (FACT-Cx was also completed at additional timepoints up to 54 months after surgery). Differences in quality of life over time between treatment groups were assessed in the modified intention-to-treat population, which included all patients who had surgery and completed at least one baseline (pretreatment) and one follow-up (at any timepoint after surgery) questionnaire, using generalised estimating equations. The LACC trial is registered with ClinicalTrials.gov, NCT00614211. Between Jan 31, 2008, and June 22, 2017, 631 patients were enrolled; 312 assigned to the open surgery group and 319 assigned to the minimally invasive surgery group. 496 (79%) of 631 patients had surgery completed at least one baseline and one follow-up quality-of-life survey and were included in the modified intention-to-treat analysis (244 [78%] of 312 patients in the open surgery group and 252 [79%] of 319 participants in the minimally invasive surgery group). Median follow-up was 3·0 years (IQR 1·7–4·5). At baseline, no differences in the mean FACT-Cx total score were identified between the open surgery (129·3 [SD 18·8]) and minimally invasive surgery groups (129·8 [19·8]). No differences in mean FACT-Cx total scores were identified between the groups 6 weeks after surgery (128·7 [SD 19·9] in the open surgery group vs 130·0 [19·8] in the minimally invasive surgery group) or 3 months after surgery (132·0 [21·7] vs 133·0 [22·1]). Since recurrence rates are higher and disease-free survival is lower for minimally invasive radical hysterectomy than for open surgery, and postoperative quality of life is similar between the treatment groups, gynaecological oncologists should recommend open radical hysterectomy for patients with early stage cervical cancer. MD Anderson Cancer Center and Medtronic.

BackgroundObservational studies have supported the practice of offering minimally invasive interval debulking surgery after neoadjuvant chemotherapy for well-selected patients with advanced epithelial ovarian cancer. However, there are no prospective randomized data comparing the oncologic efficacy of minimally invasive and open interval debulking surgery in epithelial ovarian cancer.Primary objectiveThe primary objective of this study is to examine whether minimally invasive surgery is non-inferior to laparotomy in terms of disease-free survival in women with advanced stage epithelial ovarian cancer that responded to three or four cycles of neoadjuvant chemotherapy.Study hypothesisWe hypothesize that in patients who had a complete or partial response to neoadjuvant chemotherapy, minimally invasive interval debulking surgery is not inferior to laparotomy.Trial designThe Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE) trial is an international, prospective, randomized, multicenter, non-inferiority phase III trial to compare minimally invasive surgery vs laparotomy in women with advanced stage high-grade epithelial ovarian cancer that had a complete or partial response to three or four cycles of neoadjuvant chemotherapy and normalization of CA-125. The first 100 participants will be enrolled into a pilot lead-in to determine feasibility. The study will be considered feasible and will continue to Phase III under the following conditions: the accrual rate reaches at least 80% of the target rate after all pilot sites are open; the crossover rate in the minimally invasive group is less than 25%; and the difference of complete gross resection between the minimally invasive and open group is less than 20%. If the study is determined to be feasible, all remaining participants will be enrolled into the Phase III stage.Major inclusion/exclusion criteriaPatients with stage IIIC or IV high-grade epithelial ovarian, primary peritoneal or fallopian tube carcinoma who had a complete or partial response to three or four cycles of neoadjuvant chemotherapy based on imaging and normalization of CA-125 will be enrolled. Patients with evidence of tumor not amenable to minimally invasive resection on pre-operative imaging will be excluded.Primary endpointThe primary endpoint is non-inferiority of disease-free survival in minimally invasive vs laparotomic interval debulking surgery.Sample sizeTo demonstrate non-inferiority with a margin of 33% in the hazard ratio (HR=1.33), 549 patients will be randomized.