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A. Hassan - Ovarian cancer - Guidelines and clinical case presentation (2-3 cases)
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A. Hassan - Ovarian cancer - Guidelines and clinical case presentation (2-3 cases)

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  • 1. Dr. Adnan Hassan, MD, FACOG Dept. Of Obstetrics and Gynecology Jordan hospital Consultant in Obstetrics, Gynecology, and Gynecologic Oncology American Board
  • 2.
    • Ovarian cancer is the ninth most common cancer in western women. It ranks fifth as the cause of cancer death in women.
    • A woman’s risk of getting ovarian cancer in her life time is 1 in 71 and the risk of death from ovarian cancer is 1 in 95.
    • There are large variations in the incidence of ovarian cancer in different areas of the world. In the United States 21500 new cases each year, and in the European union, there were 42700 new cases in 2004.
  • 3.
    • Half of the women with ovarian cancer are 60 years or older
    • Obesity, talcum powder use and fertility drugs
    • Poor reproductive history, early menarche and late menopause
    • Genetic predisposition: Women who carry BRCA1 and BRCA2 mutations have an estimated lifetime risk of 60-85% of developing breast cancer and 26-54% of developing ovarian cancer for BRCA1 and 10-23% for BRCA2
    • The factors associated with a decreased risk of ovarian cancer are the use of oral contraceptives, breast feeding, bilateral tubal ligation, hysterectomy, and prophylactic oophorectomy
  • 4.
    • Approximately, 90% of primary malignant ovarian tumors are epithelial carcinomas arising from the ovarian surface epithelium or mullerian derivatives
    • WHO classification of ovarian epithelial tumors recognizes six major histological types (serous, mucinous, endometrioid, clear cell, transitional, and squamous)
    • Tumors of each type are subdivided into three categories (malignant, benign, and intermediate). The latter are known as tumors of borderline malignancy or low malignant potential and atypical proliferative tumors
  • 5.
    • Mucinous tumors consist of two subgroups; the so-called endocervical-like mucinous tumors, usually in the borderline category and the intestinal type, which is most common
    • It is very important to differentiate between metastatic carcinoma from the gastrointestinal tract, pancreas and cervix and primary ovarian mucinous tumor
    • Approximately, 80-85% of all ovarian carcinomas are serous. Up to 95% of patients with FIGO stage III-IV disease have serous carcinoma, while FIGO stage I serous carcinoma are very uncommon
    • Recent pathological and molecular studies suggest that the secretory epithelium cells of the fallopian tube may be site of origin for high grade serous ovarian tumors in the hereditary ovarian cancer
  • 6.
    • The subclassification proposed by Kurman, based on pathology and genetics consists of two groups designated type I and type II.
    • Type I tumors include those that arise from well characterized precursor lesion, especially borderline tumors (mucinous, endometrioid, and clear cell), while others are slowly growing neoplasms (low grade serous carcinoma).
    • Type I tumors show a number of different mutations including KRAS, BRAT, PTEN, and B-Catenin and are relatively stable.
    • Type ll tumors are high grade, biologically aggressive tumors that do not have a recognized precursor lesion and are thought to arise de novo from coelomic epithelium. In this group high grade serous and transitional carcinoma, malignant mixed mesodermal tumor, and undifferentiated carcinoma
    • Type II tumors show genetic instability and TP53 mutation, while the mutations characteristic of type I tumors are not detected, Hereditary cancers with BRCA1 and BRCA2 mutations belong to type II tumors
  • 7.
    • The most frequent symptoms are abdominal discomfort or vague abdominal pain, abdominal fullness, bowel habits changes, dyspepsia and bloating. The presence of a pelvic mass is suggestive of ovarian cancer.
    • In advanced stage disease patients most often have abdominal distension related to ascites and tumor masses. Shortness of breath due to pleural effusion in stage IV disease is also reported. Enlarged inguinal and supra clavicular nodes may be found in some cases.
    • CA-125 is used as a tumor marker in the primary assessment of adnexal masses. False positive results may result from several conditions, in particular those associated with peritoneal inflammation such as endometriosis, uterine fibroid, PID, menstruation, benign ovarian cysts, and other causes of ascites. The specificity of the test was 98.5% for women over 50 years and was lower 94.5% for women younger than 50.
    • Transvaginal ultrasound is helpful in the evaluation of a pelvic mass. Features suggestive of ovarian cancer include the presence of a complex mass with solid and cystic components, associated with internal echoes and septations, ascites, and evidence of peritoneal and omental masses.
  • 8.
    • Surgical staging requires a laparotomy by a midline incision for adequate exposure and careful examination of the abdominal cavity according to FIGO guidelines.
    • If disease appears confined to the ovary, staging procedure includes washings from the diaphragm, right and left side of the abdomen and pelvis. Biopsy of the peritoneum of the diaphragm, paracolic gutters, and pelvis. TAH BSO, infra-colic omentectomy, appendectomy, and complete or selective para-aortic and pelvic lymphadenectomy.
    • In an apparent early stage disease, after proper staging, the cancer will be upstaged in at least 25% of patients.
    • In the case of advanced disease, retroperitoneal lymphadenectomy is not routinely performed and the prognostic benefits remain controversial, but resection of enlarged nodes is essential.
  • 9.
    • Stage I Growth limited to the ovaries
    • IA Growth limited to one ovary; no ascites present containing malignant cells.
    • No tumour on the external surface; capsule intact
    • IB Growth limited to both ovaries; no ascites present containing malignant cells.
    • No tumour on the external surfaces; capsules intact
    • IC Tumour either stage IA or IB, but with tumour on surface of one or both ovaries, or with capsule ruptured,
    • or with ascites present containing malignant cells, or with positive peritoneal washings
    • Stage II Growth involving one or both ovaries with pelvic extension
    • IIA Extension and/or metastases to the uterus and/or tubes
    • IIB Extension to other pelvic tissues
    • IIC Tumour either stage IIA or IIB, but with tumour on surface of one or both ovaries, or with capsule(s) ruptured,
    • or with ascites present containing malignant cells, or with positive peritoneal washings
    • Stage III Tumour involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or
    • positive regional lymph nodes. Superficial liver metastases equal stage III. Tumour is limited to the true pelvis,
    • but with histologically proven malignant extension to small bowel or omentum
    • IIIA Tumour grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic
    • seeding of abdominal peritoneal surfaces, or histologic proven extension to small bowel or mesentery
    • IIIB Tumour of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal
    • peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
    • IIIC Peritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodes
    • Stage IV Growth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be
    • positive cytology to allot a case to stage IV. Parenchymal liver metastasis equals stage IV
  • 10.
    • In patients with disease apparently confined to the pelvis, surgical staging is essential. Peritoneal washings and peritoneal biopsies, TAH BSO, omentectomy, appendectomy, and retropritoneal lymph nodes dissection should be performed.
    • In selected patients who desire to preserve their fertility, unilateral salpingo-oophorectomy should be performed after proper counseling.
    • Laparoscopy may be used, but large studies evaluating disease free interval and OS after laparoscopy compared to laparotomy is needed
    • Adjuvant chemotherapy for early stage ovarian cancer remains controversial topic. A recent meta-analysis of large prospective clinical trials showed that chemotherapy is more beneficial than observation in patients with early stage disease. Six cycles of single agent carboplatin is recommended
  • 11.
    • The standard treatment of advanced ovarian cancer is cytoreductive surgery followed by six courses of platinum/paclitaxel chemotherapy. Nowadays, optimal cytoreduction with survival advantages is cytoreduction to no visible lesion.
    • Patients with optimal cytoreduction had a median survival of 39 months compared to that of 17 months of patients with suboptimal disease.
    • If initial maximal cytoreduction is not carried out, interval debulking surgery (IDS) should be done after three cycles of chemotherapy, followed by three more cycles of the same chemotherapy after surgery
  • 12.
    • A retrospective analysis of 360 patients with stage IV, who underwent primary surgery followed by six cycles of platinum/paclitaxel showed that patients with microscopic residual disease had the best outcome, where as patients with 0.1-1.0 cm residual disease and patients with 1.0-5.0 cm had similar OS and PFS.
  • 13.
    • Since 1996, the combination of cisplatin plus paclitaxel has been the standard treatment. Subsequently, cisplatin was replaced by carboplatin in view of the GOG 114 results in which carboplatin compared with cisplatin showed equivalent outcome with less toxicity
    • To improve long term survival, a third drug was added. The addition of gemcitabine or liposomal doxorubicin to carboplatin and paclitaxel. There was no statistically significant superiority or clinically useful benefit associated with the three drug regimen compared with the control group.
    • The standard number of chemotherapy cycles is six. Three randomized trials analyzed the impact of the number of chemotherapy cycles on OS. None of these studies demonstrated a difference in median survival, but longer duration was associated with more toxicity, especially neuropathy.
  • 14.
    • The intraperitoneal chemotherapy (IP) administration of chemotherapy offers the possibility of targeting therapy to the site of disease while minimizing systemic toxicities.
    • The results of the GOG 172 study showed that IP therapy added to IV therapy was associated with longer survival in patients with optimal debulking as compared with IV chemotherapy (65.6 versus 49.7 months) of median survival. However, the study raised concern about IP toxicity and tolerability, since less than half of the patients completed the planned treatment (42% of 205 patients).
  • 15.
    • History, physical and pelvic examination every 3 months during the first 2 years, every 4 months during the third year and every 6 months after that or until recurrence is documented.
    • Serum assay of CA-125 during chemotherapy is used to evaluate the response to the treatment. It is also used for the follow up of responders after the completion of chemotherapy.
    • At the ASCO 2009, the results of a large phase III randomized study, evaluating whether there were clinical benefits from the early start of chemotherapy based on the increased CA-125 antigen versus a delay of treatment up to the onset of clinical manifestations of the disease. The study involved 527 patients in complete remission after first line platinum- based chemotherapy and with normal CA-125 level.
    • With a median follow up of 49 months and 351 deaths, there were no evidence of difference in the OS between immediate and delayed treatment. Quality of life was lower with early treatment group because of chemotherapy toxicity especially neuropathy.
    • PET-CT scan is superior to CT scan in detecting site of tumor recurrence. PET-CT allows a more accurate selection of cases potentially candidates for secondary surgery.
  • 16.
    • Appropriate salvage therapy is based on the timing and nature of recurrence and the extent of prior chemotherapy.
    • Surgical resection should be considered in patients with prolonged treatment free survival (e.g. >24 months), especially with isolated recurrence and good general condition. A recent meta-analysis showed that the most important predictor of survival is complete cytoreduction. Surgery to relieve bowel obstruction may be feasible in selected patients with ovarian cancer,
    • Patients who progress during treatment with platinum are considered platinum refractory disease. Patients who develop recurrence within six months of first line platinum chemotherapy are considered to have platinum resistant disease and those with an interval > 6 months , platinum sensitive disease.
  • 17.
    • Six courses of gemcitabine and carboplatin versus carboplatin alone. PFS in combination group was 8.6 months compared 5.8 months in single agent. Response rate was 47.2 months in the combination and 30.9 in the single agent, but no statistically significant difference in the OS was observed.
    • A multicenter phase III study presented in ASCO meeting comparing efficacy and safety of carboplatin and pegylated liposomal doxorubicin and carboplatin-paclitaxel in 976 relapsed platinum sensitive ovarian cancer patients.
    • The trial showed PFS 11.3 months in carboplatin-pegylated liposomal doxorubicin versus 9.4 in carboplatin-paclitaxel with lower rate of toxicity. Carboplatin-pegylated liposomal doxorubicin could become the standard chemotherapy in patients with recurrent ovarian cancer.

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