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Epithelial ovarian cancer: Evolution of management in the era of precision medicine

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Colombo, C. Sessa, A. Ledermann, W. McCluggage, I. McNeish, P. Pignata, I. Ray-Coquard, I. Vergote, T. Baert, I. Belaroussi, A. Dashora, S. Olbrecht, F.

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The ESMO—ESGO consensus conference manuscript on ovarian cancer was developed by a multidisciplinary panel of 40 leading experts and presents evidence-based recommendations in several areas in an effort to improve the quality of care for women with ovarian cancer. Careers at ESMO. Radiation-induced DNA damage may potentiate the effects of drugs such as gemcitabine and other antimetabolites that inhibit DNA synthesis by incorporating into new DNA strands as they are synthesized.

Other potential mechanisms by which radiation and chemotherapy may act synergistically include changes in the microenvironment such as decreased hypoxia, stabilized vasculature, and enhanced immune activation 77 , Low-dose fractionated WAR was combined with gemcitabine in patients with pancreatic cancer with acceptable toxicity in a small, single institutional trial This led to a multi-institutional phase I study combining low-dose WAR with gemcitabine and erlotanib in patients with pancreatic cancer in which treatment was well tolerated with encouraging efficacy Dose-limiting toxicities were primarily hematologic but also included one Grade 3 diarrhea.

Increased PARP activity is a well-described mechanism by which tumor cells avoid apoptosis caused by DNA damaging agents; it has been linked to drug resistance and the ability of tumor cells to withstand genotoxic stress 83 — PARP inhibitors interrupt the catalytic effects of PARP and have demonstrated activity particularly in cancers with defects in homologous recombination such as ovarian cancers with BRCA mutations and other markers of homologous recombination repair Although cancer cells with defective homologous recombination e.

In a preclinical model of the combination of PARP inhibition and radiation, significant cell death in vitro was demonstrated as well as inhibition of tumor growth in a pancreatic cancer mouse xenograft model Patients with gynecologic malignancy had the best responses and a platinum sensitive ovarian cancer patient with a germline BRCA mutation was an exceptional responder with a response of several years A maximum tolerated dose of mg BID was identified in an expansion cohort of ovarian cancer patients with overall reasonable toxicity Clinical trial of PARP inhibitors plus radiation therapy are ongoing in breast cancer, rectal, head and neck and non-small cell lung cancer Table 3.

A proposed randomized Phase 2 trial of PARP inhibitor with or without radiation in ovarian cancer will provide additional insight into the role of the combination in this disease. Radiation can induce multiple forms of DNA damage, which is repaired within the cell by various methods. Defective non-homologous end joining NHEJ has been demonstrated in ovarian cancer cell lines Enhanced radiation response with inhibitors of NHEJ has been demonstrated in pancreatic cancer cell lines and may be rational in ovarian cancer as well Immunotherapy has revolutionized cancer care over the last few years.

The immune environment is crucial to prognosis in ovarian cancer and efforts are underway to translate this to novel therapeutic applications The potential contribution of the immune system in response to radiation therapy has been demonstrated—induction of tumor associated antigens have been shown to develop after radiation in colorectal and prostate cancers 96 — An abscopal effect of radiation presumably works through the release of tumor antigens occurring when radiation exerts DNA damage to a tumor site and likely related to systemic secretion of specific cytokines and chemokines triggering a systemic immune response against local tumor antigens — This effect has been demonstrated in preclinical and animal models as well as reported in several case series 69 , — Several proof of principal trials are ongoing to determine whether the abscopal effect can be augmented by administering radiation therapy in conjunction with immune activating agents Table 3.

Ovarian cancer has demonstrated sensitivity to radiation therapy. Toxicity in the historical setting has limited present day use of this treatment modality. However, an updated understanding of the molecular differences of distinct histologic subtypes of ovarian cancer with differential response to both chemotherapy and radiation therapy has generated renewed interest in the potential application of radiation therapy in ovarian cancer.

EF and ST participated in developing the concept of this manuscript, researching and writing, manuscript preparation, and approval of the final manuscript draft. WM and LL participated in researching and writing this manuscript, manuscript preparation, and approval of the final manuscript draft. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Cancer statistics, CA Cancer J Clin 67 1 :7— Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer — shifting the paradigm.

Hum Pathol 42 7 — Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective.

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Histopathology 55 5 Improved classification of epithelial ovarian cancer: results of 3 Danish cohorts. Int J Gynecol Cancer 21 9 — The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol 4 — Dembo AJ. Epithelial ovarian cancer: the role of radiotherapy. Palliative benefit of radiation therapy in advanced ovarian cancer.

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Frontiers | Radiation Treatment in Women with Ovarian Cancer: Past, Present, and Future | Oncology

Complications associated with intraperitoneal 32P. Gynecol Oncol 53 2 —5. External beam pelvic radiotherapy plus intraperitoneal radioactive chronic phosphate in early stage ovarian cancer: a toxic combination. Intraperitoneal radioactive phosphorus 32P versus observation after negative second-look laparotomy for stage III ovarian carcinoma: a randomized trial of the gynecologic oncology group. J Clin Oncol 21 15 — Adjuvant therapy in stage I and stage II epithelial ovarian cancer.

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Am J Clin Oncol 17 1 —6. The role of adjuvant therapy in stage I ovarian cancer. Am J Obstet Gynecol 2 — A randomized trial comparing whole abdominal radiotherapy with chemotherapy following cisplatinum cytoreduction in epithelial ovarian cancer. Clin Oncol 2 1 :4—9. Int J Gynecol Cancer 5 2 — A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group Study.

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J Clin Oncol 11 3 —8. Consolidation radiotherapy after carboplatin-based chemotherapy in radically operated advanced ovarian cancer. Gynecol Oncol 72 2 —9. Consolidation treatment of advanced FIGO stage III ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer 13 3 — Salvage therapy with whole-abdominal irradiation in patients with advanced carcinoma of the ovary previously treated by combination chemotherapy.

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Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma. Impact on survival with adjuvant radiotherapy for clear cell, mucinous, and endometriod ovarian cancer: the SEER experience from to J Gynecol Oncol 27 5 :e Clear cell carcinoma of the ovary: a review of the literature.

Gynecol Oncol 3 — Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation. J Clin Oncol 30 14 — Postoperative whole abdominal radiotherapy in clear cell adenocarcinoma of the ovary. Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Ann Oncol 22 2 —7.

The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma. Gynecol Oncol 2 — Patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma. Int J Gynecol Cancer 24 9 — Involved-field radiation therapy for locoregionally recurrent ovarian cancer. Gynecol Oncol 2 —5. Impact of tumor volume-directed involved field radiation therapy integrated in the management of recurrent ovarian cancer.

Gynecol Oncol 96 3 —4. Long-term benefit of tumor volume-directed involved field radiation therapy in the management of recurrent ovarian cancer. Int J Gynecol Cancer 26 4 — Radiation therapy for chemotherapy-resistant recurrent epithelial ovarian cancer. Oncology 86 4 —8. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of consecutive cases. Ann Surg 3 —18; discussion 18— J Clin Oncol 27 10 — J Clin Oncol 27 10 —8. Stereotactic radiosurgery for gynecologic cancer. J Vis Exp 62 Stereotactic body radiosurgery for pelvic relapse of gynecologic malignancies.

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Clinical outcomes for stereotactic ablative radiotherapy in oligometastatic and oligoprogressive gynecological malignancies. Int J Gynecol Cancer 27 2 —8. Phase I trial of carboplatin and gemcitabine chemotherapy and stereotactic ablative radiosurgery for the palliative treatment of persistent or recurrent gynecologic cancer. Front Oncol Current clinical trials testing combinations of immunotherapy and radiation.

New Insights into the Pathogenesis of Ovarian Cancer: Oxidative Stress

Semin Radiat Oncol 25 1 — Radiotherapy: changing the game in immunotherapy. Trends Cancer 2 6 — Formenti SC. Is classical stereotactic radiotherapy the optimal partner for immunotherapy? Oncology 29 5 , , Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 4 — BMC Cancer Helical tomotherapy as a new treatment technique for whole abdominal irradiation.

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Radiother Oncol 1 — Poly-ADP-ribosylation in health and disease. Cell Mol Life Sci 62 7 —8. Ledermann JA. PARP inhibitors in ovarian cancer. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12 9 — Nature — N Engl J Med 2 — Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 22 — Biomarkers of response and resistance to DNA repair targeted therapies.

Clin Cancer Res 22 23 — Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer.