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The Role of Radiotherapy in the Management of Ovarian CancerArticle by: Nagendra Sai Koneru, M.D., Anthony Fyles, M.D., William Small Jr., M.D.What is Radiation Therapy?Radiation oncology is a branch of medicine that manipulates ionizing radiation to treat cancer and other benign diseases. The goal of radiation therapy is to eradicate cancer cells through the delivery of a measured dose of radiation to a precisely defined tissue volume, while attempting to minimize damage to any healthy surrounding tissue. In ovarian cancer radiation oncologists work closely with gynecologic oncologists, who are the primary surgical oncologists that treat ovarian cancer, and medical oncologists. Both medical and gynecologic oncologists deliver chemotherapy.Radiation kills cancer cells by damaging the DNA. Tumor cells often have impaired repair mechanisms that are normally found in healthy cells. Thus, tumor cells can be inherently sensitive to radiation effects. Damage to DNA can occur by direct interaction of radiation with a cell’s DNA or indirectly by the creation of free radicals that are produced by the interaction of radiation and water within the cell.Radiation oncologists use linear accelerators to deliver radiation to a patient. Linear accelerators are treatment machines that selectively create high-energy radiation beams which are then directed at a specific target. Epidemiology of Ovarian CancerThere are three primary types of ovarian cancer. Epithelial ovarian cancer comprises approximately 80%-90% of ovarian cancer and will be the subject of this review. Germ and stromal tumors represent the remaining 10-20%. There are numerous risk factors for ovarian cancer and can include lower number of pregnancies, nulliparity and infertility [3]. Oral contraceptive use has been shown to reduce the risk of ovarian cancer [4]. Women who have a family history of breast cancer or ovarian cancer are at increased risk. Gene mutations in BRCA1 and BRCA2 have been observed in many of these families. Hereditary non-polyposis colon cancer (HNPCC) is a genetic syndrome that has been associated with colon, endometrial and ovarian cancer.Detection/ScreeningRoutine screening for ovarian cancer has not been recommended because there have been no reliable markers for detecting early epithelial ovarian cancer [1,5] although routine gynecologic care should still be recommended. The tumor marker CA-125 has been found to be helpful in ovarian cancer screening. The combination of a pelvic exam, transvaginal ultrasound and a blood test for CA-125 can be offered for women who are symptomatic or at high risk [1,5].Clinical PresentationEpithelial ovarian cancer does not present with specific signs or symptoms. Patients most commonly present with abdominal distention, however, heartburn, nausea, and lower abdominal pain can also manifest [5].Ovarian cancer is often metastatic or spread beyond the ovaries at presentation and confined to the ovary in only 23% of cases [6]. The peritoneum is a multilayered membrane which lines the abdominal cavity, and supports and covers the organs within it. The most common route of spread is through the peritoneum (transperitoneal) and the disease is confined to the abdominal cavity in 85% of patients [6]. However, ovarian cancer may also spread through the blood or lymphatics.The Federation of International Gynecologists and Obstetrics (FIGO) has grouped ovarian cancer into four primary stages. Stage I disease is limited to the ovaries. Stage II involves tumor spread in the pelvis beyond the ovaries. Stage III involves spread outside the pelvis but confined within the abdominal cavity or inguinal nodes. Stage IV disease involves tumor in one or both ovaries with distant metastasis, such as the liver parenchyma or lungs. Microscopically the aggressiveness of the tumor is classified according to its grade, ranging from 1 to 3. Grade 1 shows the least aggressiveness, while grade 3 shows the most.Overall 5 year survival, including all stages for ovarian cancer, is 53% [1]. For early stage disease, the 5 year survival is 94.7%. For intermediate stage disease, the 5 year survival is 72% [1]. For late stage, the 5 year survival is 30.7% [1].TreatmentSurgery is the standard initial management of ovarian cancer [6]. Because of transperitoneal spread and the frequent appearance of upper abdominal disease, pre-treatment surgical staging is performed. Surgical staging involves partial omentectomy, visualization or the entire peritoneum, biopsy of any suspicious or palpable lesions, and cytologic examination of ascites or peritoneal washings from pelvis, paracolic gutters, and diaphragm [6].Studies have revealed that the amount of residual tumor volume after surgery may impact survival. As residual tumor volume increases, median survival decreases [6]. Cytoreductive surgery is thus recommended for maximum tumor removal [6]. For stage I, grade 1 disease, surgery alone has a 5% relapse rate and is often the only treatment modality used [6]. Patients with stage I disease with unfavorable prognostic factors, such as grade 2 or 3, and patients with stage II and III disease are often recommended to have surgery followed by intravenous (IV) carboplatin and paclitaxel chemotherapy, since there is often at least a 30% risk of recurrence [2]. Recent trials have shown that platinum-based adjuvant chemotherapy improved survival and recurrence-free survival in early-stage ovarian cancer [7]. Alternatively, intraperitoneal (IP) chemotherapy, which involves injecting chemotherapy directly into the abdomen, has gained recent attention and may be considered an alternative to IV chemotherapy in certain clinical situations [8]. Adjuvant abdominopelvic radiotherapy can also be used in selected patients [9].Rationale for Radiation TherapyEvidence that radiation therapy is an effective adjuvant therapy in certain stages and extents of ovarian cancer has been proven in several trials [6]. For early and intermediate stage disease, trials have shown that radiotherapy to the whole abdomen following surgery to be more effective than certain chemotherapy and pelvic radiation. Although there have been no randomized trials comparing platinum based chemotherapy to whole abdominal therapy, platinum based chemotherapy has largely supplanted the use of radiotherapy in the United States. However, radiotherapy does have a role in both cure and symptom control in patients with ovarian cancer.A Princess Margaret Hospital randomized trial of 147 patients compared pelvic radiotherapy alone or with chlorambucil chemotherapy to whole abdomen radiotherapy, in patients with stages I-III disease. After a 7 year follow-up, the 10-year difference in survival was significantly higher in the 76 patients treated with pelvis plus whole abdomen radiotherapy compared to the 71 patients treated with pelvic irradiation and chlorambucil (46% vs 31%, p=0.05) [10]. The survival benefit was only seen in patients with small macroscopic residual tumor

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