Ovarian preservation in premenopausal women with early uterine leiomyosarcoma is a controversial clinical topic. Estrogen/progesterone receptor activation may play an important role in tumor development in uterine leiomyosarcoma and there is evidence that receptor expression is associated with survival. Whilst the retrospective evidence from large databases or smaller studies showed no adverse impact of ovarian preservation on survival, the high rate of recurrence even in early stages, the high rate of estrogen receptor expression, and the emergence of hormonal treatment for uterine leiomyosarcoma should drive clinicians to consider oophorectomy for patients with hormone-receptor positive uterine leiomyosarcoma.

Uterine carcinosarcoma (UCS) are rare tumors with high aggressive behavior. Chemotherapy is the mainstay of treatment either in the adjuvant and the metastatic setting. Previous carcinogenetic theory considered carcinosarcoma as a biphasic tumor with an epithelial and mesenchymal component and were treated accordingly with drugs directed towards these two components (i.e. cisplatin-ifosfamide). Actually UCS are reclassified as epithelial cancers with metaplastic de-differentiated components and drugs with proven activity in epithelial tumors (i.e. carboplatin-paclitaxel) have been implemented in the treatment algorithm. The paper will review literature evidences in UCS treatment and will support the strategy which identify carboplatin-paclitaxel as the standard of care.

Uterine papillary serous cancer (UPSC) accounts for only 10% of endometrial malignancies, however, attributes to over 50% of endometrial cancer deaths annually [1]. USPC is commonly more aggressive than the endometrioid subtype, with a higher propensity for lymphovascular invasion as well as intraperitoneal and intra-abdominal spread at time of diagnosis.

Uterine sarcomas are rare gynecologic malignancies, being 3–7% of all uterine malignant tumors, and approximately 1% of all female gynecologic cancers. Leiomyosarcomas (LMS) encompass approximately 1% of all the uterine cancers. Leiomyosarcoma is the most common uterine sarcoma, with an extremely aggressive clinical behavior. Consequently, this neoplasm is associated with a poor prognosis and very high risk of recurrence even among women with early-stage disease. The reported recurrence rates range between 45% and 73%. The main sites of these recurrences are the abdomen or the pelvis; a high proportion of uterine LMS will recur in the lung, with pulmonary metastases.

Ardent support of secondary cytoreductive surgery as a strategy in the treatment paradigm for patients with recurrent ovarian cancer has been levied for decades, largely by analogy to primary cytoreduction [1]. The primary rationale follows that removal of as much tumor as possible augments the effectiveness of subsequent chemotherapy and may enhance a more favorable tumor microenvironment for natural immune surveillance. However, the merit of this, as with any intervention, should be addressed in randomized clinical trials, if possible, to control bias, and compared to appropriate reference treatment assessing clinically relevant endpoints. This “tried and true” approach has been the foundation upon which current treatment standards have been defined. In the setting of recurrent ovarian cancer, a prolific expansion in efficacious therapies has been witnessed, challenging clinical trial endpoints, such as overall survival (OS), which may not be reached years after an index intervention [2].

Intraperitoneal (IP) chemotherapy, the delivery of unheated chemotherapy into the peritoneal cavity through a catheter connected to an implanted port, was once a strongly recommended, though controversial, treatment for women with advanced ovarian cancer after optimal cytoreductive surgery. Historically, direct drug delivery to the IP cavity and improved pharmacokinetics yielded improved progression-free and overall survival outcomes. However, the improved disease control and survival came at the cost of significantly increased toxicity, worse quality of life, and added expense. The most recent randomized clinical trial of IP therapy identified a less toxic regimen but failed to demonstrate any survival benefit. The negative results of this study, taken in the setting of more recent advances in biologic therapies, illustrate that in the modern therapeutic landscape for ovarian cancer there is no role for IP chemotherapy. IP therapy is too toxic, too expensive, and historical IP therapy survival outcomes are no longer relevant.

Maintenance therapy with oral PARP inhibitors has been demonstrated to significantly expand the progression-free survival of patients with advanced HGSOC in response to front-line platinum-based chemotherapy. Currently, three options have been approved for patients with BRCAmut tumors (Olaparib, niraparib, or Olaparib-bevacizumab) and two options for patients with BRCAwt/HRD tumors (niraparib or Olaparib and bevacizumab). The reason for the controversy we are discussing in this chapter is the lack of evidence from randomized trials comparing single-agent PARPi versus PARP-i combined with bevacizumab. Both strategies have shown similar benefits in the hazard ratio, but medians are not comparable due to the different patient populations included and differences in tumor assessment. Nevertheless, several arguments support the single-PARPi option as the preferred one.

Inguino-femoral lymph node metastasis in vulvar cancer accounts for increased risk of recurrence and 50% decrease in survival. Adjuvant radiotherapy for single positive IFLN vulvar cancer has persisted as a controversial topic since the publication of GOG 37. Retrospective data from Germany indicates that there is no difference in survival for patients with single node positive vulvar cancer treated with adjuvant radiotherapy or observation. Radical surgery, even with SLNB, followed by radiotherapy can lead to devastating and difficult-to-treat complications including wound infections, lymphedema, pain, and bone fractures. Considering these complications, overall quality of life, and the limited data demonstrating improved survival benefit, it would be beneficial to withhold adjuvant radiotherapy for patients with single-positive IFLN vulvar cancer. Further studies aimed at understanding the molecular landscape and investigating targeted and immunotherapy for vulvar cancer will aid in the treatment of this complex cancer.

The value of tertiary surgery in recurrent ovarian cancer is not well known due to the weak evidence we have, coming exclusively from retrospective series. Nevertheless, these retrospective studies have shown that achieving a complete cytoreduction at the time of the tertiary surgery improves patient overall survival compared with any residual tumor left. Unfortunately, there are not prospectively validated criteria predictive of complete cytoreduction; thus, patient selection is highly biased, and indiscriminate tertiary surgery outside of specialized centers should not be accepted.

Sentinel lymph node (SLN) biopsy is now the standard of care over inguinofemoral lymphadenectomy (IFL) in properly selected patients with early-stage squamous cell carcinoma (SCC) of the vulva. Patients with negative SLN do well without further intervention. However, a standardized treatment paradigm following the findings of a positive SLN remains lacking. Based on results from the GROINSS-V-II trial, patients with a micrometastasis of ≤2 mm receiving adjuvant inguinofemoral radiation therapy had a two-year ipsilateral isolated groin recurrence rate of 1.6%, and can avoid the morbidity of complete inguinofemoral lymphadenectomy (IFL). The approach for patients with SLN macrometastases (>2 mm) remains undefined – if such patients are treated without further IFL, careful attention to radiation treatment planning, dose, and the addition of concurrent cisplatin-based chemotherapy should be considered.

Neo-adjuvant chemotherapy (NACT) for cervical cancer reduces preoperatively the tumor size and metastatic spread. In addition, long-term adverse events of radiochemotherapy (CCRT), such as early menopause, dyspareunia, radio-enteritis and fistulas can be avoided.

Immune checkpoint inhibitors (ICIs) have attracted attention recently and have received fast-track approvals from the Food and Drug Administration (FDA) in multiple cancer types, including cervical cancer and endometrial cancer. Normally, the expression of immune checkpoint receptors such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on T cells provides negative feedback mechanisms to prevent autoimmunity. Multiple cancers, including epithelial ovarian cancer (EOC), exploit these mechanisms to inhibit T cell activation, allowing them to escape immune detection. ICIs block immune checkpoint receptors, allowing for unchecked activation of cancer-targeted T cells leading to tumor cell destruction. Despite the success in various other cancer types, there are no approved immune therapies for ovarian cancer, as response of EOC to ICIs thus far have been modest.

When considering the best overall management strategy of recurrent granulosa cell tumors (GCT), given the long survivals and multiple recurrences many patients will experience, chemotherapy is an important component of overall treatment. The recommended first-line chemotherapy regimen includes BEP (bleomycin, etoposide, and cisplatin) and more recently carboplatin and paclitaxel. While chemotherapy has not shown strong OS benefit, the extension of PFS is meaningful and can lead to longer intervals between surgery and perhaps an overall decrease in the total number of surgeries a patient has in their lifetime. There is ongoing research to better understand the various systemic treatment approaches for GCT, bevacizumab, hormonal therapies, and immunotherapy. Overall, a multimodal approach is essential for the effective treatment of recurrent GCT with systemic chemotherapy being an important part of the treatment paradigm for this tumor.

The decision to proceed with primary debulking surgery is complex and depends on multiple factors including patient (age, performance, and nutrition status), center (surgeon/team expertise, volume, ancillary services) and disease factors. Routine laparoscopy has been proposed to assess disease factors: specifically, extent of disease and complexity of surgery required for successful resection. However, laparoscopy requires additional OR time and equipment, lacks sensitivity, and does not accurately assess several of the most agreed upon barriers to successful cytoreduction. Standardized laparoscopic scoring systems have demonstrated high specificity to predict suboptimal debulking, but primarily in single institution studies. These systems are difficult to validate externally, likely due to differing non-disease-related factors. We favor a multi-modality approach beginning with careful patient and center selection and pre-operative imaging. Suitable candidates then undergo exploration via mini-laparotomy at the time of planned debulking surgery to minimize morbidity while maximizing oncologic outcomes.

High-risk stage I ovarian cancer includes clear cell and grade 3 tumours. ESMO–ESGO guidelines suggests carboplatin in monotherapy for six cycles or the combination of carboplatin and paclitaxel for a minimum of three cycles as available options for adjuvant treatment in this setting. Nevertheless, there is not a study that compare the two options. On the basis of data available, three cycles of carboplatin plus paclitaxel represents an effective strategy to reduce the probability of recurrence in high-risk early-stage ovarian cancer patients, especially in non-serous tumors. Three cycles compared with six cycles of carboplatin and paclitaxel do not significantly alter the recurrence rate in high-risk ovarian cancer, but six cycles are associated with more toxicity.

Adjuvant hysterectomy (AH) following concurrent chemoradiation (CCRT) for the management of locally advanced cervical cancer (LACC) is still subject for debate. While it is still not standard of care to perform adjuvant hysterectomy after CCRT due to limited data supporting this approach, as well as possible increased morbidity, there are practitioners who choose this approach in the hope of decreasing local recurrence, especially in the setting of chemo and radiation-resistant tumors after excluding metastatic disease. In this review we will focus on the available data that supports AH in the management of LACC.

Advanced malignant ovarian germ cell tumors (MOGCT), like their testicular counterparts, are exquisitely sensitive to platinum- and etoposide-based chemotherapy. More than 40 years ago Einhorn and colleagues discovered that bleomycin added to this combination was an effective treatment. The resulting five-day bleomycin etoposide and cisplatin (BEP) chemotherapy given three-weekly for three to four cycles depending on disease extent was internationally adopted. Subsequently, many other regimens have been developed attempting to reduce toxicity and/or improve efficacy. However, no randomized controlled trial data exists to demonstrate that any of these are superior to BEP chemotherapy. Moreover, as MOGCT differs from testicular disease in that relapses after primary chemotherapy have much lower survival rates, de-escalation of primary treatment is to be discouraged. Consequently, there is no debate as BEP remains the current standard of care for women presenting with advanced MOGCT.

Overall survival for FIGO stage III–IV epithelial ovarian cancer remains low, with only 10% of women remaining disease-free at 10 years of follow-up. Cytoreductive surgery for newly diagnosed advanced ovarian carcinoma, when performed by high-volume surgeons at high-volume centers, has the potential to place the vast majority of patients (approximately 85%) into sustained clinical remission following completion of adjuvant systemic platinum- and taxane-based chemotherapy. However, because most of these patients are ultimately destined to relapse, there has been great interest in identifying effective and tolerable maintenance therapies that can significantly prolong progression-free survival (PFS) and even possibly improve overall survival (OS) in select subpopulations. The molecular signatures exhibited among patients with germline and/or somatic BRCA mutations, as well as those with homologous recombination deficient BRCA-wild type tumors, characterize distinct patient cohorts that may derive benefit from maintenance therapy using the poly-ADP-ribose polymerase I inhibitor olaparib alone or when combined with the anti-angiogenesis agent bevacizumab, respectively. Patients whose tumors are homologous recombination-proficient should be offered maintenance therapy with bevacizumab which can significantly improve PFS by approximately six months and possibly impact OS among those with FIGO stage IV disease.