Introduction

This chapter will review the use of chemotherapy in all gynecological cancers. The goal is to provide an overview of current therapeutic options. Chemotherapy is part of the multidisciplinary approach to the treatment of gynecologic malignancies. In recent years, traditional chemotherapy has been augmented with the growing knowledge of tumor genomics. The identification of molecular pathways, cell signaling, and tumorigenesis has the potential to revolutionize care as we move toward “personalized medicine.”

Chemotherapy has evolved from single-agent therapy with alkylating agents and antimetabolites in the 1950s to the use of contemporary combination chemotherapy regimens that include the taxanes, platinums, anthracyclines, and other drugs.

Ovarian Cancer

Epithelial cancers of ovarian, fallopian tubal, and peritoneal origin exhibit similar clinical characteristics and behavior. As a result, they are often combined together and define as epithelial ovarian cancer (EOC) in clinical trials and clinical practice. For this chapter, we will consider all histologies under the heading EOC. EOC is the most common cause of death among women with gynecologic malignancies and the fifth leading cause of cancer death in women in the United States. Approximately 75% of women have advanced-stage disease at the time of diagnosis.

Surgery remains the backbone of the treatment, either as the initial therapy or as a delayed primary procedure. Systemic chemotherapy is central to the management of metastatic ovarian cancer. The established agents that continue to be used most frequently are carboplatin and paclitaxel. Following primary surgery, the conventional approach has been to use six cycles of standard carboplatin and paclitaxel at three weekly intervals, although alternatives are emerging. There are two options for the administration: intravenous (IV) chemotherapy alone or a combination of IV and intraperitoneal (IP) chemotherapy (IV/IP therapy). Primary cytoreductive surgery with the aim of optimal cytoreduction (i.e., no residual disease) remains the standard of care. In women who have had optimally resected disease, extended follow-up in four randomized trials has shown that IP chemotherapy with platinums and taxanes is highly effective in reducing the risk of recurrence and prolonging survival. The adoption of IP chemotherapy has been mixed because of the perceived risk of toxicity and difficulties in managing IP catheters.

For those patients in whom IV therapy has been selected, the standard treatment is to administer carboplatin and paclitaxel every 3 weeks for a total of six cycles of therapy. An alternative regimen use dose-dense schedules with weekly IV paclitaxel in combination with three-week carboplatin. The initial experience came from the Japanese data, now with mature follow-up shows significant benefit to patients who received dose-dense schedules. The downside of this schedule is that patients need more frequent attendances for treatment; however, the overall toxicity is lower.

Subsequently the European Trial MITO-7 demonstrated improved tolerability with the modified dose-dense regimen of a lower dose of weekly paclitaxel than in other dose-dense regimens over conventional dosing. We typically suggest this regimen for medically frail patients. There is no clear consensus on the role of dose-dense versus conventionally dosed therapy. In general, trials have suggested similar or improved efficacy with dose-dense regimens relative to conventionally dosed therapy, though toxicities are typically higher. Two additional trials evaluated the dose-dense regimen. ICON8 randomized almost 1600 patients to treatment with six cycles of either the standard every-3-week dosing regimen or with one of two different regimens, including once weekly carboplatin and dose-dense paclitaxel. This study failed to demonstrate a survival advantage of dose-dense over conventional schedule. Contrary to the Japanese trial, the patients who received the dose-dense regimen experienced greater toxicity. In GOG 262, women with stage II–IV EOC who had either optimally or suboptimally cytoreduced disease were randomly assigned to conventionally dosed carboplatin and paclitaxel or to dose-dense therapy, carboplatin every 3 weeks plus weekly paclitaxel. Bevacizumab administration was optional in both arms and was administered to 84% of patients. The majority of patients had stage III or IV disease. At a median follow-up of 28 months, there was no difference in survival between the dose-dense and the conventionally dosed treatment groups. While the study did not demonstrate and advantage to dose-dense over conventional treatment, a subset analysis suggested a treatment difference based on whether or not bevacizumab was administered. For those patients who were treated with chemotherapy only, dose-dense treatment prolonged progression-free survival (PFS) compared with conventional dosing. For those patients who were treated with chemotherapy and bevacizumab, PFS was similar among those treated with dose-dense versus conventionally dosed treatment.

Primary medical therapy, that is neoadjuvant chemotherapy (NACT), is now accepted as an alternative standard of care for patients who are deemed to be unlikely to obtain an optimal cytoreduction at the completion of their surgical effort or who are too frail to tolerate an aggressive surgical effort. Two important European trials, the European Organization for Research and Treatment of Cancer (EORTC) 55971 study and the UK-led CHORUS study, have shown that NACT followed by delayed primary surgery is not inferior to initial surgery in women with bulky supra-colic omental disease and/or extensive liver metastases who are not suitable for optimal resection. The medical management of first-line chemotherapy in the setting of ovarian cancer is complex and should be managed by oncologist with expertise and experience in this disease.

Recently, newer targeted agents that interfere with cell signaling pathways have become established. Bevacizumab and polyadenosine diphosphate-ribose polymerase (PARP) inhibitors have been incorporated in the upfront management of this disease.

Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF) receptor. The use of bevacizumab in frontline treatment was investigated by the Gynecological Oncology Group (GOG) 218 and the ICON 7 studies and showed a significant improvement in PFS. This improvement was seen to be the most evident in women who had residual macroscopic disease. At this time, we reserve bevacizumab for those patients with high-risk factors who do not carry a BRCA mutation.

All newly diagnosed patients with ovarian cancer are recommended to undergo genetic testing. Women who are found to have a germ line or somatic breast cancer susceptibility gene (BRCA) may benefit from maintenance therapy with a PARP inhibitor following chemotherapy. This is based on multiple clinical trials showing that use of a PARP inhibitor as maintenance therapy affords a PFS advantage, even to women without a breast cancer susceptibility gene 1/2 (BRCA1/2) mutation.

In summary, advanced-stage EOC is initially treated with surgical cytoreduction followed by first-line chemotherapy. The choice among first-line treatments is made based upon the amount of disease remaining after surgery. Patients with <1 cm of disease in any one location are considered to have optimally cytoreduced. These patients should be treated with a platinum-plus-taxane combination. The individual regimen (dose-dense vs every 3 weeks) and route of administration (IV vs IV in combination with IP) may be individualized based on the patient. All patients should undergo genetic evaluation. For those patients who do not carry a BRCA mutation and are deemed to be high-risk, they may benefit from the addition of bevacizumab to their frontline treatment and continued as maintenance therapy. Those patients who carry a germ line or somatic BRCA mutation should be treated with a PARP Inhibitor as maintenance therapy at the completion of their upfront platinum-based chemotherapy.

Relapsed Disease

In patients with relapsed disease, it is important to distinguish between platinum-sensitive and platinum-resistant disease. Platinum-resistant disease is normally defined as patients who develop recurrent disease within 6 months of completing their last dose of platinum. Platinum refractory disease is usually reserved for patients who develop resistance while receiving chemotherapy. Therefore platinum-sensitive disease refers to patients who develop recurrence beyond 6 months after completing their last dose of platinum.

The treatment-free interval following platinum chemotherapy predicts the response to second-line chemotherapy. Markman et al. and the French group GINECO23 have shown that beyond 12 months, the rate of response increases with rechallenge with carboplatin and paclitaxel. Nevertheless, a number of women have residual neuropathy, and this may influence the treatment options for recurrent disease. Carboplatin with gemcitabine is an acceptable alternative and two randomized controlled trials (CALYPSO and the Hellenic Cooperative Oncology Group) have shown that carboplatin and gemcitabine are not inferior to carboplatin and paclitaxel. In older and less fit women, single-agent carboplatin remains a useful alternative with reasonable activity.

More recent drug developments have included adding tyrosine kinase inhibitors (TKIs) and VEGF receptor antagonists for treating relapsed disease, as in first-line therapy. The OCEANS study investigated the use of additional bevacizumab and found that it appears to show a significant benefit in this setting. There is some debate as to whether it is better to use bevacizumab upfront or for relapse, and other debates have focused on retreating with bevacizumab when there has been prior exposure in first line.

Increasingly, patients are treated with multiple lines of therapy and other agents that may be used include liposomal doxorubicin, gemcitabine, topotecan, and dose-dense platinum schedules with taxanes or etoposide. Other new targeted agents remain under development and include folate receptor antagonists, antiangiogenesis agents, and other emerging TKIs.

Platinum Resistance

>Rechallenge with platinum-based regimens has low response rates, many experts recognize this as an area for exploring new investigational agents or combinations. There are multiple agents with activity in platinum-resistant EOC, but there is not one universally preferred agent for use in the first-or subsequent-line treatment. A Cochrane systematic review of trials with platinum-resistant EOC concluded that topotecan, paclitaxel, and pegylated liposomal doxorubicin have similar efficacy, but different patterns of side effects. A choice among these agents depends upon the clinician’s experience, the side effect profile, and prior therapy. The use of bevacizumab in these patients in the Aurelia trial shows that improved PFS can be achieved, and some suggest reserving bevacizumab for this setting.

BRCA Mutation

The ability to identify germ line BRCA mutations in women has had a significant therapeutic impact over the last few years. The importance to recognize families with the BRCA mutation to facilitate family screening has been known. It is recommended that all patients with a newly diagnosed ovarian cancer undergo genetic counseling and subsequent testing. However, it was not recognized that this would have any impact on treatment. The development of the PARP inhibitors has led to interest as single-agent treat and in the maintenance setting. Several PARP inhibitors are available for the treatment of ovarian cancer, as maintenance therapy after first recurrence and initial diagnosis in BRCA wild type, germ line, somatic, and HRD patients.

Uterine Cancer

Uterine or endometrial cancers are the most common gynecologic malignancy in developed countries and the second most common in developing countries. Among the different histologic types of adenocarcinomas, grade 1 and 2 endometrioid uterine cancers have a more favorable prognosis and typically present at an early stage. Other histologic types of uterine adenocarcinoma (e.g., serous, clear cell) are associated with a poorer prognosis. Women with advanced-stage or high-risk disease have a relatively poor prognosis following hysterectomy alone. As a result, adjuvant treatment is often recommended. The treatment may consist of radiation therapy, chemotherapy, or a combination of these two approaches.

Most recently, the use of carboplatin with paclitaxel has emerged as the standard of care, both for relapsed disease and in the adjuvant setting. This is based on the results of Gynecologic Oncology Group (GOG) 209. This trial compared carboplatin plus paclitaxel with paclitaxel, doxorubicin, and cisplatin in 1300 women with chemotherapy-naïve advanced endometrial cancer, including women with stage III disease, and demonstrated that carboplatin and paclitaxel results in an equivalent overall response rate, similar PFS, and is less toxic.

Women with serous uterine carcinoma should have their tumor undergo HER2 immune-histochemistry (IHC) testing, with reflex to HER2 FISH for equivocal IHC, for possible treatment of advanced-stage or recurrent disease. Those patients whose tumor cares a HER2 profile may benefit from the addition of trastuzumab. Similarly, recent studies have demonstrated a survival benefit to the addition of bevacizumab to carboplatin and paclitaxel in the management of advanced-stage and recurrent disease.

An emerging area of interest is the role of immunotherapy in the management of recurrent endometrial cancer. Pembrolizumab is an immune checkpoint inhibitor that binds to and blocks programmed death (PD)-1. The phase Ib KEYNOTE-028 trial demonstrated a durable antitumor response in patients with PD ligand 1 (PD-L1)–positive tumors. The FDA approved pembrolizumab for uterine cancers with unresectable or metastatic, microsatellite instability-high (MSI-H), or deficient mismatch repair (dMMR) solid tumors that have progressed following prior treatment and have no satisfactory alternative treatment options. The combination of pembrolizumab and lenvatinib, a multiple kinase inhibitor, has been approved for the management of treatment of patients with advanced endometrial cancer who have disease progression following prior systemic therapy. The indication applies to patients who are not candidates for curative surgery or radiation and who have disease that is not MSI-H or dMMR.

Numerous important molecular pathways are disrupted in endometrial cancer, in particular the mechanistic target of rapamycin, phosphatase and tensin homolog, and the phosphoinositide 3-kinase. Emerging treatment developments are targeting these pathways, and further trials are ongoing on the use medications in endometrial cancer.

Cervical Cancer

Chemotherapy in cervical cancer has been used most frequently concomitantly with radiation for primary treatment. Following the National Cancer Institute consensus statement in 2000, the use of weekly cisplatin in combination with pelvic radiation was recommended, and it has now become the gold standard of care. For those patients who present with metastatic disease or at the time of recurrence, systemic chemotherapy provides a role for palliative chemotherapy.

The GOG has conducted a number of studies over the past 20 years, including GOG 169, 179, 204, and 240, which have helped to determine the optimal regimens for recurrent disease. These trials have demonstrated that cisplatin with paclitaxel was superior to cisplatin alone. Cisplatin and topotecan appeared to show a benefit but when cisplatin and paclitaxel, cisplatin and topotecan, and a nonplatinum schedule of topotecan with paclitaxel were compared, no advantage over the newer regimens was shown and cisplatin/paclitaxel has reemerged as the preferred standard treatment.

Bevacizumab has been investigated to determine if it improves outcomes compared to chemotherapy alone. GOG 240 study, in which bevacizumab was added to these agents, has shown a significant improvement in both progression-free and overall survival. As a result, bevacizumab was approved for the treatment of metastatic and recurrent cervical cancer. In the second-line setting a choice among active agents must be tailored to the individual patient, with consideration to prior therapies received, residual toxicity, and performance status. In these patients, MMR/MSI testing or PD-L1 testing should be performed. Pembrolizumab has been a preferred regimen for second-line option for treating PD-L1–positive or MSI-H/dMMR cervical tumors.

Vaginal and Vulvar Cancer

Vulvar and vaginal cancers are similar to cervical cancer and are squamous and often HPV-associated. As such, the treatment of cervical cancer is also used for vulvar and vaginal cancers.

Uterine Sarcomas

Uterine sarcomas include leiomyosarcomas (LMSs), endometrial stromal sarcomas, and undifferenced uterine sarcomas. Carcinosarcomas should be managed as high-risk endometrial cancers and will not be included here. LMSs are aggressive tumors. Active drugs for LMS include doxorubicin, either alone or combined with ifosfamide, and, more recently, docetaxel and gemcitabine combinations have emerged. The benefits of adjuvant chemotherapy are unclear. However, due to their aggressive nature, oncologists often treat these tumors with systemic chemotherapy. Low-grade endometrial stromal sarcomas are generally more indolent and respond to hormonal manipulation but may also respond to combinations of carboplatin and paclitaxel or platinum, doxorubicin, and ifosfamide.

Conclusion

Gynecological cancers require a multidisciplinary approach. Chemotherapy may be used as an adjuvant therapy or for the management of locally advanced or recurrent tumors. Traditional chemotherapy drugs have probably reached a plateau for development and tailored therapy with personalized medicine is emerging. Tumor tissue with identification of the molecular pathways will be the way forward, together with greater use of recognizing the importance of genetic differences as already shown for ovarian cancer and BRCA mutations.