Expert Opinion on Pharmacotherapy

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer

Pharmacotherapy for the treatment of recurrent cervical cancer: an update of the literature

Cervical cancer is the fourth most common cause of cancer-related death worldwide. High-risk locally advanced or recurrent/metastatic cervical cancers have a poor prognosis with routine treatments. The objective of this study is to analyze the data available in the literature on therapies and molecules currently in use to improve the prognosis of recurrent cervical cancer. An extensive literature search was conducted by authors to identify relevant trials on various databases. Articles in English published until September 2023 that investigate different pharmacotherapy strategies for the treatment of recurrent cervical cancer, were included. Results of various pharmacological regimens including different combinations of chemotherapy, immune checkpoint inhibitors, DNA damage repair inhibitors and antibody-drug conjugates were analyzed. In recent years, there have been significant improvements in the outcomes of recurrent/metastatic cervical cancer. However, these improvements do not address the unmet need in terms of oncological outcomes. The introduction of immunotherapy and targeted therapies showed advantages in cervical cancer patients. New therapies and combination strategies must be implemented. Centralization of care and enrollment in clinical trials are of paramount importance. Primary and secondary prevention remains the fundamental goal to reduce the burden of cervical cancer.

State of the art and up-and-coming angiogenesis inhibitors for ovarian cancer

Angiogenesis inhibitors have clearly shown activity in ovarian cancer in various settings; however, preliminary data did not reflect significant survival benefit. Bevacizumab has been extensively studied and is approved for use in ovarian malignancy. However, the efficacy of bevacizumab is modest and most treated patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Newer therapies are being evaluated and their role of these newer therapies is upcoming and promising. Recent research focuses on the role of this drug group in frontline, maintenance and recurrent settings. Combination of PARP inhibitors with angiogenesis inhibitors has recently shown to improved survival rates. Potential strategies need to be devised for selecting patients most likely to benefit from such therapy.

An overview and update of hyperthermic intraperitoneal chemotherapy in ovarian cancer

Despite, the strong rationale and evidence of the benefit of postoperative intraperitoneal chemotherapy in advanced ovarian cancer, it has not been widely adopted, mainly due to its high morbidity and logistical difficulties. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a more tolerable and technically feasible method of intraperitoneal chemotherapy, whereas other potential advantages include homogenous drug distribution, application before tumor regrowth and combination with hyperthermia, which is directly cytotoxic and enhances the efficacy of many drugs. In this review, the authors explain the rationale and indications for cytoreductive surgery (CRS) and HIPEC in advanced ovarian cancer. Data of major clinical studies, meta-analyses, and recent randomized trials are discussed. After many encouraging clinical studies and meta-analyses, a recent randomized study demonstrated survival benefit for HIPEC during interval CRS in primary ovarian cancer, without increased morbidity, whereas another implied its benefit in recurrent ovarian cancer. Results of recently completed and numerous ongoing randomized studies will further determine the benefit of HIPEC in ovarian cancer at different time points. Patient selection and appraisal of the best protocols are crucial. The field of gynecological oncology will most likely evolve to include HIPEC eventually as a routine treatment for ovarian cancer.

Combinational therapies for the treatment of advanced cervical cancer

From a therapeutic standpoint, invasive cervical cancer can be designated as early, locally advanced, and advanced stages. Systemic treatment remains the primary therapeutical modality for advanced cervical cancer patients who are not candidates for local curative treatments (surgery and radiation). In this review, the author discusses recent clinical studies published in PubMed on the treatment of advanced cervical carcinoma. The author also provides his expert perspectives on the current state of play. Survival outcomes for advanced cervical cancer patients have been steadily improving since 1981, when single-agent cisplatin was adopted as the standard of care. In 2014, bevacizumab increased median overall survival (MOS) to 17 months when combined with standard chemotherapy (platinum-paclitaxel). In 2021, the checkpoint inhibitor (CPI) pembrolizumab, when used in the first line added to platinum-paclitaxel-bevacizumab, increased mOS to 24 months. Two other CPIs are in phase III trials as first-line treatments. As for second-line therapy, cemiplimab has shown increased survival compared to single-agent chemotherapy, and a phase III trial with tisotumab vedotin is currently ongoing. Nevertheless, there is still an unmet need for new more effective treatments and significant efforts are needed in the discovery of drugs for advanced cervical cancer beyond the current 'me-too' drugs.

Developments in pharmacotherapy for the preservation of ovarian function during cancer treatment

Advances in small molecule maintenance therapies for high-grade serous ovarian cancer

Ovarian cancer is one of the most lethal gynecological tumors with a lack of effective treatment modalities especially in advanced/recurrent disease. Nevertheless, recently, new small molecules have emerged as an effective approach for the management of ovarian cancer patients, especially in the maintenance setting. This review summarizes the role of small molecules used in the management of high-grade serous ovarian cancer. The authors performed a critical review of current evidence and ongoing studies. Of note, tyrosine kinase inhibitors (TKIs) and poly(ADP-ribose) polymerase (PARP) inhibitors are the most intriguing medications in this setting. Protein-targeted therapies against tumor tissues have progressed significantly in the last years due to an enhanced knowledge of the biological and molecular processes of carcinogenesis. Treatment with small molecules allows the targeting of specific proteins involved in cancer biology. TKIs seem promising but further data are necessary to assess the pros and cons of adopting this treatment modality. PARP inhibitors represent the new standard of care for ovarian cancer patients harboring either a BRCA mutation or with homologous recombination deficiency (HRD). Interestingly, the accumulation of data has highlighted that PARP inhibitors provide benefits even in patients with HR proficient tumors.

Advances in paclitaxel combinations for treating cervical cancer

Cervical cancer is the fourth common cancer in women worldwide. While, in the past, locally advanced stage disease was treated by pelvic radiotherapy, nowadays the National Cancer Institute strongly recommends chemoradiation protocols. Weekly cisplatin was previously the standard of care in this setting; however, the low response rate and the short median progression-free survival (PFS) of patients have led researchers to investigate combinatory regimens. This article is based on literature searches up until April 2019, with current trial registers also analyzed. All data available on this topic has been summarized in this narrative review. In recent years, it has been demonstrated that cisplatin-based doublets, and in particular, cisplatin plus paclitaxel, are superior to cisplatin as a monotherapy in terms of response rate and progression-free survival of patients with advanced cervical cancer. This double regime combined with bevacizumab is also considered the first-line option for metastatic or recurrent disease. Dose-dense paclitaxel in neo-adjuvant chemotherapy combinations is a promising option in patients with locally advanced cervical cancer. Exploration of novel biological therapies and

An update on current pharmacotherapy for vulvar cancer

Limited data on the role of pharmacotherapy for patients with locally advanced, recurrent, or metastatic vulvar cancer are available. This article aims to provide an overview of the current treatment options for patients with vulvar cancer. PubMed (MEDLINE), Embase, CENTRAL, Scopus, and Web of Science databases, as well as ClinicalTrials.gov were searched to review the current evidence as well as future perspectives on the role of pharmacotherapy in patients with vulvar carcinoma. There has been no consensus on the pharmacotherapy for patients with locally advanced, recurrent, or metastatic vulvar cancer. Concurrent platinum-based chemoradiation is the most widely used treatment modality for primary treatment or for neoadjuvant settings. Chemotherapy in metastatic disease is considered a palliative treatment. Anti-EGFR tyrosine kinase inhibitors seem to show promising anti-tumor activity in patients harboring EGFR alteration. Similarly, growing evidence supports the adoption of immune checkpoint inhibitors in both neoadjuvant and metastatic settings. Molecular and genomic profiling is advocated to identify target mutations. The

Selection of maintenance therapy during first-line treatment of advanced ovarian cancer based on pharmacologic characteristics

Maintenance therapy with bevacizumab and the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and niraparib after first-line treatment of advanced ovarian cancer has been approved. However, it is not clear which one should be used for which patients. This paper presents a detailed analysis of data from phase 3 trials in ovarian cancer evaluating bevacizumab (ICON7, GOG-0218), olaparib (SOLO1, PAOLA-1), and niraparib (PRIMA, PRIME). We will discuss how the results of these trials relate to the 'rebound effect,' in which the risk of progression increases after discontinuation of bevacizumab in patients receiving bevacizumab, and to the significant difference in tissue permeability between olaparib and niraparib. In patients with homologous recombination deficiency and no macroscopic residual disease (R0) after primary debulking surgery (PDS), the combination of bevacizumab plus olaparib seems to be the best regimen. Olaparib monotherapy is suitable for patients with BRCA mutations other than PDS R0. Bevacizumab is most useful in cases with a short duration of the rebound effect, i.e. short survival. Niraparib is useful in others but may be more useful in Asians.

Recent progress in the use of pharmacotherapy for endometrial cancer

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. The ESGO/ESTRO/ESP updated evidence-based guidelines in 2020, introducing molecular classification to guide EC treatment. The genomic-based approach has identified four prognostic subgroups of EC. Each of these may benefit from a tailored treatment depending on the molecular profile, the histotype, and stage of disease for the adjuvant and the metastatic/recurrent setting. Several clinical trials are now ongoing to identify the best treatment according to the molecular profile of EC. This review analyzes tailored treatment for EC according to the molecular profile, both in the adjuvant and in the metastatic/recurrent setting. The authors review the results of clinical studies and highlight ongoing trials. Several new agents are under evaluation in order to personalize EC treatment according to specific molecular profiles in the adjuvant, advanced, and recurrent settings. Clinical trials investigating the impact of molecular classification have yielded encouraging results. EC can no longer be considered a single tumor entity susceptible to a single treatment modality but rather be split into four distinct types, requiring tailored treatments.

Pharmacotherapy for cervical cancer: current standard of care and new perspectives

Cervical cancer, while highly preventable, remains an international public health challenge especially in under resourced regions. Although early-stage cervix confined cancers are often amenable to surgical resection, larger tumors deemed locally advanced cervical cancer (LACC) necessitate systemic therapy as part of chemoradiation therapy. Moreover, systemic therapy is the standard therapeutic approach for those presenting with primary metastasis or recurrence. While several agents have been approved to treat recurrent cervical cancer including checkpoint inhibitors as well as both biomarker agnostic and specific antibody drug conjugates, the development of agents added to chemoradiation has been less fruitful. Until recently, the addition of novel therapies to chemoradiation has been negative in terms of improving outcomes; however, results of a recent Phase III clinical trial (NCT04221945) in LACC demonstrated that the addition of pembrolizumab to standard of care chemoradiation was associated with an improvement in progression-free survival and resulted in an FDA approval for this therapy. This observation led to the first change in treating LACC since the early 2000s. Improvements in systemic therapy both alone and in combination with chemoradiation for cervical cancer have been realized. Ongoing research is needed for therapeutic options following immunotherapy.

Pharmacotherapeutic treatment options for recurrent epithelial ovarian cancer

Almost 80% of epithelial ovarian cancer present in advanced stage at diagnosis and despite excellent response to surgery and chemotherapy, more than 70% cancers recur. Subsequent therapies become decreasingly effective in controlling the disease, with each successful therapy being effective for a shorter duration. As a result, there is a need for novel therapeutic strategies to effectively treat recurrence. In this extensive literature review of high-quality articles, we have focused on surveillance strategy to detect recurrence early, classification of recurrence based on timeline, role of surgery, chemotherapy, and targeted agents such as anti-angiogenetic drugs, PARP inhibitors, and immune checkpoint inhibitors in platinum-sensitive and platinum-resistant disease, respectively. Recurrent ovarian cancers (ROC) are represented by a heterogenous group of patient population in terms of platinum-free interval (PFI), histology, molecular characteristics and immune recognition. In today's era of precision medicine, chemotherapy should be combined with appropriate targeted agent in a multipronged approach to prolong survival and provide better quality of life outcomes by minimizing side effects.

Immunotherapy in older adults with gynecologic cancers: rethinking age as a limiting factor

As the global population ages, understanding immune checkpoint inhibitor (ICI) efficacy and safety in the older cancer patients is critical. ICIs represent a major advance, but their effectiveness relative to age-related immune changes warrants investigation. This review synthesizes current clinical and preclinical evidence examining how aging influences ICIs response. We discuss age-related immunological changes (immunosenescence), alterations in the tumor microenvironment, mechanistic insights from preclinical aging models, and clinical trial/real-world data on ICIs efficacy and safety including immune-related adverse events (irAEs) across various cancers in older patient, referencing meta-analyses and specific trial outcomes. Extensive clinical data suggest ICIs often provide significant survival benefits and are generally well-tolerated in appropriately selected older patients, with outcomes frequently comparable to younger cohorts, although efficacy can vary by tumor type, performance status (PS), and biomarkers. While irAEs require careful management considering comorbidities and frailty, overall incidence is not consistently higher in older adults. Treatment decisions should be individualized, integrating biological age indicators, PS, and comorbidities, rather than relying solely on chronological age. Future research should focus on identifying robust biomarkers and tailored strategies to optimize ICIs use in this demographic.