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Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.
We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.
Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer
de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285.
In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.1 Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.1 However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).2 The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death.
Adjuvant therapy in high-risk endometrial cancer
To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.3 As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.4 For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.5,6
Continue to: Benefit observed with adjuvant chemoradiotherapy...
Benefit observed with adjuvant chemoradiotherapy
In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.7 Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology.
Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m2 IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m2 IV every 3 weeks).
At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016).
The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm.
Results from similar trials
Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.8 There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.8
In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.9 No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.9
The conflicting data regarding the ideal adjuvant therapy for endometrial cancer suggests that treatment decisions should be individualized. Pelvic EBRT with concurrent adjuvant chemotherapy should be considered in women with stage III endometrial cancer or serous cancers as combination therapy improves survival, although dual modality treatment is associated with increased toxicity. Chemoradiation appears to have less benefit for women with stage I–II cancers with other pathologic risk factors.
Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment
Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.10 Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.11 Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.12 As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence.
Continue to: PARP inhibitors are changing the face of treatment...
PARP inhibitors are changing the face of treatment
Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.13 The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.14
Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.20
Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy.
Efficacy of veliparib with chemotherapy and as maintenance monotherapy
In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.21
Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy.
Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles.
Progression-free survival extended
At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization).
In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm.
Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.
For women with newly diagnosed, previously untreated stage III or IV high-grade serous ovarian carcinoma, carboplatin, paclitaxel, and veliparib induction therapy followed by single-agent veliparib maintenance therapy resulted in a significant improvement in median progression-free survival compared with induction chemotherapy alone. However, veliparib use was also associated with a higher incidence of adverse effects that required dose reduction and/or interruption during both the combination and maintenance phases of treatment.
Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma?
Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.11 The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.22
Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified.
Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...
Overall survival after secondary cytoreduction followed by chemotherapy
Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.22 Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy.
All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained).
Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion.
Shorter survival, decline in quality of life
Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms.
At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection.
Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications.
While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period.
For women with platinum-sensitive, recurrent ovarian cancer, a secondary cytoreductive surgery followed by chemotherapy was not associated with an improvement in overall survival when compared with chemotherapy alone. Secondary cytoreductive surgery should not be used routinely in women with recurrent ovarian cancer.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;20:7-34.
- Colombo N, Creutzberg C, Amant F, et al; ESMO-ESGOESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27:16-41.
- Randall ME, Filiaci VL, Muss H, et al; Gynecologic Oncology Group Study. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:36-44.
- Syeda S, Chen L, Hou JY, et al. Chemotherapy, radiation, or combination therapy for stage III uterine cancer. Obstet Gynecol. 2019;134:17-29.
- Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95:266-271.
- Susumu N, Sagae S, Udagawa Y, et al; Japanese Gynecologic Oncology Group. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008;108:226-233.
- de Boer SM, Powell ME, Mileshkin L, et al; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20:1273-1285.
- Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer. J Clin Oncol. 2019;37:1810-1818.
- Matei D, Filiaci V, Randall ME, et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019;380:2317-2326.
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
- Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN guidelines insights: ovarian cancer, version 1.2019. J Natl Compr Canc Netw. 2019;17:896-909.
- Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
- Moore KN, Mirza MR, Matulonis UA. The poly (ADP ribose) polymerase inhibitor niraparib: management of toxicities. Gynecol Oncol. 2018;149:214-220.
- Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: a trailblazing and transformative journey. Clin Cancer Res. 2018;24:4062-4065.
- Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764-775.
- Mukhopadhyay A, Plummer ER, Elattar A, et al. Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival. Cancer Res. 2012;72:5675-5682.
- Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/ NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.
- Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949-1961.
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
- Coleman RL, Fleming GF, Brady MF, et al. Veliparib with firstline chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
- Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
- Bommert M, Harter P, Heitz F, et al. When should surgery be used for recurrent ovarian carcinoma? Clin Oncol (R Coll Radiol). 2018;30:493-497.
- Santillan A, Karam AK, Li AJ, et al. Secondary cytoreductive surgery for isolated nodal recurrence in patients with epithelial ovarian cancer. Gynecol Oncol. 2007;104:686-690.
- Zang RY, Harter P, Chi DS, et al. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer. 2011;105:890-896.
- Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006;106:1933-1939.
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30: 2039-2045.
Zhen Ni Zhou, MD, PhD
Dr. Zhou is a Fellow in the
Division of Gynecologic
Oncology, New York–
Presbyterian/Columbia
University Medical Center and
Weill Cornell Medical Center,
New York, New York.
Jason D. Wright, MD
Dr. Wright is the Sol Goldman
Associate Professor, Chief of
the Division of Gynecologic
Oncology, Vice Chair of
Academic Affairs, Department
of Obstetrics and Gynecology,
Columbia University College of
Physicians and Surgeons,
New York, New York.
Dr. Wright reports that he is a consultant to Clovis Oncology and Tesaro, Inc, and has received research funding from Merck. Dr. Zhou reports no financial relationships relevant to this article.
Zhen Ni Zhou, MD, PhD
Dr. Zhou is a Fellow in the
Division of Gynecologic
Oncology, New York–
Presbyterian/Columbia
University Medical Center and
Weill Cornell Medical Center,
New York, New York.
Jason D. Wright, MD
Dr. Wright is the Sol Goldman
Associate Professor, Chief of
the Division of Gynecologic
Oncology, Vice Chair of
Academic Affairs, Department
of Obstetrics and Gynecology,
Columbia University College of
Physicians and Surgeons,
New York, New York.
Dr. Wright reports that he is a consultant to Clovis Oncology and Tesaro, Inc, and has received research funding from Merck. Dr. Zhou reports no financial relationships relevant to this article.
Zhen Ni Zhou, MD, PhD
Dr. Zhou is a Fellow in the
Division of Gynecologic
Oncology, New York–
Presbyterian/Columbia
University Medical Center and
Weill Cornell Medical Center,
New York, New York.
Jason D. Wright, MD
Dr. Wright is the Sol Goldman
Associate Professor, Chief of
the Division of Gynecologic
Oncology, Vice Chair of
Academic Affairs, Department
of Obstetrics and Gynecology,
Columbia University College of
Physicians and Surgeons,
New York, New York.
Dr. Wright reports that he is a consultant to Clovis Oncology and Tesaro, Inc, and has received research funding from Merck. Dr. Zhou reports no financial relationships relevant to this article.
Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.
We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.
Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer
de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285.
In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.1 Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.1 However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).2 The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death.
Adjuvant therapy in high-risk endometrial cancer
To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.3 As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.4 For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.5,6
Continue to: Benefit observed with adjuvant chemoradiotherapy...
Benefit observed with adjuvant chemoradiotherapy
In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.7 Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology.
Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m2 IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m2 IV every 3 weeks).
At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016).
The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm.
Results from similar trials
Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.8 There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.8
In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.9 No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.9
The conflicting data regarding the ideal adjuvant therapy for endometrial cancer suggests that treatment decisions should be individualized. Pelvic EBRT with concurrent adjuvant chemotherapy should be considered in women with stage III endometrial cancer or serous cancers as combination therapy improves survival, although dual modality treatment is associated with increased toxicity. Chemoradiation appears to have less benefit for women with stage I–II cancers with other pathologic risk factors.
Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment
Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.10 Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.11 Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.12 As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence.
Continue to: PARP inhibitors are changing the face of treatment...
PARP inhibitors are changing the face of treatment
Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.13 The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.14
Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.20
Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy.
Efficacy of veliparib with chemotherapy and as maintenance monotherapy
In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.21
Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy.
Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles.
Progression-free survival extended
At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization).
In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm.
Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.
For women with newly diagnosed, previously untreated stage III or IV high-grade serous ovarian carcinoma, carboplatin, paclitaxel, and veliparib induction therapy followed by single-agent veliparib maintenance therapy resulted in a significant improvement in median progression-free survival compared with induction chemotherapy alone. However, veliparib use was also associated with a higher incidence of adverse effects that required dose reduction and/or interruption during both the combination and maintenance phases of treatment.
Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma?
Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.11 The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.22
Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified.
Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...
Overall survival after secondary cytoreduction followed by chemotherapy
Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.22 Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy.
All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained).
Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion.
Shorter survival, decline in quality of life
Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms.
At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection.
Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications.
While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period.
For women with platinum-sensitive, recurrent ovarian cancer, a secondary cytoreductive surgery followed by chemotherapy was not associated with an improvement in overall survival when compared with chemotherapy alone. Secondary cytoreductive surgery should not be used routinely in women with recurrent ovarian cancer.
Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.
We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.
Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer
de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285.
In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.1 Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.1 However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).2 The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death.
Adjuvant therapy in high-risk endometrial cancer
To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.3 As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.4 For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.5,6
Continue to: Benefit observed with adjuvant chemoradiotherapy...
Benefit observed with adjuvant chemoradiotherapy
In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.7 Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology.
Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m2 IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m2 IV every 3 weeks).
At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016).
The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm.
Results from similar trials
Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.8 There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.8
In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.9 No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.9
The conflicting data regarding the ideal adjuvant therapy for endometrial cancer suggests that treatment decisions should be individualized. Pelvic EBRT with concurrent adjuvant chemotherapy should be considered in women with stage III endometrial cancer or serous cancers as combination therapy improves survival, although dual modality treatment is associated with increased toxicity. Chemoradiation appears to have less benefit for women with stage I–II cancers with other pathologic risk factors.
Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment
Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.10 Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.11 Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.12 As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence.
Continue to: PARP inhibitors are changing the face of treatment...
PARP inhibitors are changing the face of treatment
Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.13 The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.14
Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.20
Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy.
Efficacy of veliparib with chemotherapy and as maintenance monotherapy
In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.21
Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy.
Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles.
Progression-free survival extended
At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization).
In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm.
Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.
For women with newly diagnosed, previously untreated stage III or IV high-grade serous ovarian carcinoma, carboplatin, paclitaxel, and veliparib induction therapy followed by single-agent veliparib maintenance therapy resulted in a significant improvement in median progression-free survival compared with induction chemotherapy alone. However, veliparib use was also associated with a higher incidence of adverse effects that required dose reduction and/or interruption during both the combination and maintenance phases of treatment.
Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma?
Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.11 The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.22
Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified.
Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...
Overall survival after secondary cytoreduction followed by chemotherapy
Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.22 Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy.
All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained).
Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion.
Shorter survival, decline in quality of life
Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms.
At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection.
Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications.
While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period.
For women with platinum-sensitive, recurrent ovarian cancer, a secondary cytoreductive surgery followed by chemotherapy was not associated with an improvement in overall survival when compared with chemotherapy alone. Secondary cytoreductive surgery should not be used routinely in women with recurrent ovarian cancer.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;20:7-34.
- Colombo N, Creutzberg C, Amant F, et al; ESMO-ESGOESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27:16-41.
- Randall ME, Filiaci VL, Muss H, et al; Gynecologic Oncology Group Study. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:36-44.
- Syeda S, Chen L, Hou JY, et al. Chemotherapy, radiation, or combination therapy for stage III uterine cancer. Obstet Gynecol. 2019;134:17-29.
- Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95:266-271.
- Susumu N, Sagae S, Udagawa Y, et al; Japanese Gynecologic Oncology Group. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008;108:226-233.
- de Boer SM, Powell ME, Mileshkin L, et al; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20:1273-1285.
- Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer. J Clin Oncol. 2019;37:1810-1818.
- Matei D, Filiaci V, Randall ME, et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019;380:2317-2326.
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
- Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN guidelines insights: ovarian cancer, version 1.2019. J Natl Compr Canc Netw. 2019;17:896-909.
- Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
- Moore KN, Mirza MR, Matulonis UA. The poly (ADP ribose) polymerase inhibitor niraparib: management of toxicities. Gynecol Oncol. 2018;149:214-220.
- Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: a trailblazing and transformative journey. Clin Cancer Res. 2018;24:4062-4065.
- Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764-775.
- Mukhopadhyay A, Plummer ER, Elattar A, et al. Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival. Cancer Res. 2012;72:5675-5682.
- Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/ NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.
- Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949-1961.
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
- Coleman RL, Fleming GF, Brady MF, et al. Veliparib with firstline chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
- Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
- Bommert M, Harter P, Heitz F, et al. When should surgery be used for recurrent ovarian carcinoma? Clin Oncol (R Coll Radiol). 2018;30:493-497.
- Santillan A, Karam AK, Li AJ, et al. Secondary cytoreductive surgery for isolated nodal recurrence in patients with epithelial ovarian cancer. Gynecol Oncol. 2007;104:686-690.
- Zang RY, Harter P, Chi DS, et al. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer. 2011;105:890-896.
- Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006;106:1933-1939.
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30: 2039-2045.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;20:7-34.
- Colombo N, Creutzberg C, Amant F, et al; ESMO-ESGOESTRO Endometrial Consensus Conference Working Group. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27:16-41.
- Randall ME, Filiaci VL, Muss H, et al; Gynecologic Oncology Group Study. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006;24:36-44.
- Syeda S, Chen L, Hou JY, et al. Chemotherapy, radiation, or combination therapy for stage III uterine cancer. Obstet Gynecol. 2019;134:17-29.
- Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006;95:266-271.
- Susumu N, Sagae S, Udagawa Y, et al; Japanese Gynecologic Oncology Group. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008;108:226-233.
- de Boer SM, Powell ME, Mileshkin L, et al; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20:1273-1285.
- Randall ME, Filiaci V, McMeekin DS, et al. Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer. J Clin Oncol. 2019;37:1810-1818.
- Matei D, Filiaci V, Randall ME, et al. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019;380:2317-2326.
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
- Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN guidelines insights: ovarian cancer, version 1.2019. J Natl Compr Canc Netw. 2019;17:896-909.
- Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
- Moore KN, Mirza MR, Matulonis UA. The poly (ADP ribose) polymerase inhibitor niraparib: management of toxicities. Gynecol Oncol. 2018;149:214-220.
- Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: a trailblazing and transformative journey. Clin Cancer Res. 2018;24:4062-4065.
- Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764-775.
- Mukhopadhyay A, Plummer ER, Elattar A, et al. Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum, and survival. Cancer Res. 2012;72:5675-5682.
- Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/ NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.
- Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949-1961.
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
- Coleman RL, Fleming GF, Brady MF, et al. Veliparib with firstline chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415.
- Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939.
- Bommert M, Harter P, Heitz F, et al. When should surgery be used for recurrent ovarian carcinoma? Clin Oncol (R Coll Radiol). 2018;30:493-497.
- Santillan A, Karam AK, Li AJ, et al. Secondary cytoreductive surgery for isolated nodal recurrence in patients with epithelial ovarian cancer. Gynecol Oncol. 2007;104:686-690.
- Zang RY, Harter P, Chi DS, et al. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer. 2011;105:890-896.
- Chi DS, McCaughty K, Diaz JP, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006;106:1933-1939.
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30: 2039-2045.