Gynecology_Novak

Gynecology_Novak. Some authors suggested that selected patients with suboptimal stage III and stage IV disease and those with large volume ascites and pleural effusions should have chemotherapy prior to debulking surgery. A series performed by Schwartz et al. suggested that these patients treated with neoadjuvant or cytoreductive chemotherapy had survival that was comparable to those patients treated in the same institution with debulking surgery followed by conventional chemotherapy (218). It is accepted that two or three cycles of chemotherapy before cytoreductive surgery may be helpful in patients with massive ascites and large pleural effusions. The chemotherapy may “dry up” the effusions, improve the patient’s performance status, and decrease postoperative morbidity, particularly chest morbidity (219,220).


Gynecology_Novak

Gynecology_Novak. The EORTC completed a large randomized trial in 718 patients with advanced ovarian cancer comparing initial surgery followed by six cycles of carboplatin and paclitaxel with three cycles of neoadjuvant chemotherapy followed by surgical debulking and another three cycles of chemotherapy. The study found that the progression-free survival was identical in both arms (12 months) and similarly the overall survival (30 months) was the same in both arms (221). The morbidity of surgery was significantly less in patients receiving neoadjuvant chemotherapy, suggesting that in selected patients with very advanced (stages IIIC and IV) ovarian cancer two to three cycles of neoadjuvant chemotherapy prior to surgical debulking is a reasonable option.


Gynecology_Novak

Gynecology_Novak. Inhibition of angiogenesis with drugs such as bevacizumab demonstrated activity and benefit in women with recurrent ovarian cancer. There is evidence in other tumor types such as breast cancer and colon cancer that the addition of bevacizumab to chemotherapy increases response rates, progression-free survival, and survival in some studies (222–224). Two large randomized trials (GOG 218 and ICON7) investigating the impact of the addition of bevacizumab to standard carboplatin and paclitaxel in patients with advanced ovarian cancer were completed (225,226). GOG 218 is a phase III three-arm randomized double-blind placebo-controlled trial. Patients in arm one received six cycles of carboplatin and paclitaxel and placebo starting with the second cycle and continuing for 16 additional cycles after the completion of chemotherapy. Patients in arm two received six cycles of chemotherapy with bevacizumab starting with cycle two and administered with chemotherapy followed by 16 cycles of


Gynecology_Novak

Gynecology_Novak. after the completion of chemotherapy. Patients in arm two received six cycles of chemotherapy with bevacizumab starting with cycle two and administered with chemotherapy followed by 16 cycles of placebo, and in arm three patients received bevacizumab starting with cycle two of chemotherapy and then received 16 additional cycles after the completion of chemotherapy. This study was designed to investigate the benefit of bevacizumab in combination with chemotherapy and as a maintenance therapy. The bevacizumab was administered at a does of 15 mg/kg, starting with the second cycle of chemotherapy, to decrease the risk of gastrointestinal perforation, which is a rare complication of this agent in the setting of its use in colorectal cancer. The results of GOG 218 reported a modest improvement of 3.8 months in progression-free survival in patients randomized to receive bevacizumab in combination with carboplatin and paclitaxel every 3 weeks and then as a maintenance therapy every 3 weeks


Gynecology_Novak

Gynecology_Novak. of 3.8 months in progression-free survival in patients randomized to receive bevacizumab in combination with carboplatin and paclitaxel every 3 weeks and then as a maintenance therapy every 3 weeks for an additional 16 cycles for a total of 15 months’ treatment (225). The toxicity of bevacizumab was acceptable and the risk of bowel perforation very low (below 2%). The study did not find any improvement in overall survival, but follow-up is required. The ICON7 study is similar to the GOG study, although it is a two-arm study of carboplatin and paclitaxel plus or minus bevacizumab 7.5 mg/kg administered every 3 weeks with chemotherapy for six cycles and then as maintenance therapy for 12 additional cycles. The ICON7 results were presented and reported a statistically significant, yet modest, 1.7-month improvement in median progression-free survival in the experimental arm (226). The results of these studies support a role of bevacizumab in combination with chemotherapy in patients with


Gynecology_Novak

Gynecology_Novak. 1.7-month improvement in median progression-free survival in the experimental arm (226). The results of these studies support a role of bevacizumab in combination with chemotherapy in patients with advanced ovarian cancer. However, the cost of bevacizumab is very high and the improvement in progressive-free survival is short.


Gynecology_Novak

Gynecology_Novak. For the treatment of advanced-stage epithelial ovarian cancer, the following is recommended (Table 37.4): Combination chemotherapy or intravenous carboplatin and paclitaxel or intraperitoneal cisplatin and paclitaxel (using the GOG 172 protocol) are the treatments of choice for patients with advanced disease. The advantages and disadvantages of the intravenous versus intraperitoneal routes of administration of these drugs should be discussed with the patient. The recommended doses and schedule for intravenous chemotherapy are: carboplatin (starting dose AUC = 5–6), and paclitaxel (175 mg/m2), every 3 weeks for six to eight cycles, or the dose-dense regimen of carboplatin AUC 6 every 3 weeks for six cycles and weekly paclitaxel 80 mg/m2 (217).


Gynecology_Novak

Gynecology_Novak. The recommended doses and schedule for intraperitoneal chemotherapy are paclitaxel 135 mg/m2 intravenous on day 1, followed by cisplatin 75 to 100 mg/m2 intraperitoneal on day 2, followed by paclitaxel 60 mg/m2 intraperitoneal on day 8, every 3 weeks for Table 37.4 Combination Chemotherapy for Advanced Epithelial Ovarian Cancer: Recommended Regimens Doxorubicin, liposomal 35–50 IV 3–4 Topotecan 1.0–1.25 IV 1 4.0 IV 3 (daily × 3–5 days) Etoposide 50 PO 3, days 14–21 ∗Bevacizumab 7.5–15 mg/kg can be added to any of these regimens. aExcept for carboplatin dosing, where AUC—area under the curve—dose calculated by using Calvert formula (Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–1756).bDrugs that can be substituted for paclitaxel if hypersensitivity to that drug occurs; the number of treatments administered as tolerated.


Gynecology_Novak

Gynecology_Novak. six cycles, as tolerated. (Many centers modified the dose of cisplatin to 75 mg/m2 rather than 100 mg/m2 to reduce toxicity. Others substitute carboplatin (AUC 6) for cisplatin in the regimen.) The impact on outcome of these pragmatic modifications is unknown. Bevacizumab 7.5–15 mg/kg can be added to any of these intravenous or intraperitoneal chemotherapy regimens. In patients who cannot tolerate combination chemotherapy, single-agent, intravenously administered carboplatin (AUC 5–6) can be given. In patients who have a hypersensitivity to paclitaxel or carboplatin, an alternative active drug can be substituted (e.g., docetaxel, nanoparticle paclitaxel, cisplatin). In the case of carboplatin hypersensitivity, desensitization could be attempted.


Gynecology_Novak

Gynecology_Novak. The treatment of all patients with advanced-stage disease is approached in a similar manner, with modifications based on the overall status and general health of the patient and the extent of residual disease present at the time treatment is initiated. Maintenance of Complete Clinical Response to First-Line Chemotherapy Because as many as 80% of women with advanced-stage disease who completely respond to their first-line chemotherapy will ultimately relapse, several trials were conducted that administer a drug to these patients immediately following their primary treatment in an effort to decrease the relapse rate.


Gynecology_Novak

Gynecology_Novak. Paclitaxel In a study conducted by the GOG and SWOG, 277 women with advanced ovarian cancer who had a complete clinical remission to first-line chemotherapy were randomized to receive 3 or 12 cycles of additional single-agent paclitaxel (175 or 135 mg/m2 every 28 days) (227). Patients were excluded if they developed grade 2 or 3 neurotoxicity during their initial chemotherapy. Because of cumulative toxicity, the mean number of actual cycles of paclitaxel received by the group assigned to receive 12 cycles was 9. The treatment-related grade 2 to 3 neuropathy was more common with longer treatment, 24% versus 14% of patients, respectively.


Gynecology_Novak

Gynecology_Novak. The study closed after a median follow-up of only 8.5 months, and an interim analysis showed a significant 7-month prolongation in median progression-free survival (28 versus 21 months) with 9 versus 3 months of consolidation paclitaxel. There was no difference in median overall survival and this study has not changed practice. The rate of disease progression increased significantly after maintenance therapy was discontinued, which suggested that long-term survival was not likely to be improved. It is improbable that a survival benefit will appear with longer follow-up, because patients assigned to three cycles were given the option of receiving an additional nine courses of paclitaxel after the study was discontinued (228). Another placebo-controlled, randomized trial using two formulations of paclitaxel is being conducted by the GOG.


Gynecology_Novak

Gynecology_Novak. Topotecan Four additional treatment courses of topotecan were administered to patients following six cycles of carboplatin and paclitaxel in two randomized trials, one conducted in Italy and the other in Germany (229,230). In the larger trial conducted in Germany, 1,059 evaluable patients were randomly assigned to six cycles of paclitaxel (175 mg/m2 over 3 hours) and carboplatin (AUC 5) with (537 patients) or without (522 patients) four additional cycles of topotecan (1.25 mg/m2 intravenous days 1 to 5 every 3 weeks) (230). In the Italian trial, 273 women were randomly assigned to receive four additional cycles (137 patients) of topotecan at a dose of 1 mg/m2 on days 1 to 5 every 3 weeks or no further chemotherapy (136 patients) (229). Preliminary reports suggest no significant differences in either progression-free or overall survival in patients who received four to six cycles of consolidation topotecan.


Gynecology_Novak

Gynecology_Novak. Cisplatin In a randomized clinical trial of intraperitoneal cisplatin for consolidation versus observation, there was no difference in survival between the treatment arms (231). Biologic Therapies As noted above, the use of the monoclonal antibody (MonAb) bevacizumab with first-line carboplatin and paclitaxel chemotherapy followed by maintenance bevacizumab for a year was associated with a modest improvement in progression-free survival, (225,226). Patients and their physicians may consider maintenance therapy with bevacizumab as delivered in GOG 218 and ICON7. There are a number of ongoing trials addressing the role of oral angiogenesis inhibitors as maintenance therapy after completion of first-line therapy in women with advanced ovarian cancer.


Gynecology_Novak

Gynecology_Novak. Studies MonAbs directed toward CA125 (OvaRex) and toward the HMFG (human milk fat globulin) tumor–associated antigens were conducted (232–234). In a randomized, placebo-controlled trial of intravenous oregovomab (anti-CA125 MonAb) as maintenance therapy, Berek et al. reported that oregovomab did not demonstrate a survival advantage as a maintenance therapy (233). A randomized trial of an intraperitoneally administered yttrium-labeled antimucin (HMFG) MonAb versus placebo was not associated with an improved overall survival after a negative second-look laparoscopy (234).


Gynecology_Novak

Gynecology_Novak. Treatment Assessment Many patients who undergo optimal cytoreductive surgery and subsequent chemotherapy for epithelial ovarian cancer have no evidence of disease at the completion of treatment. Tumor markers and radiologic assessments are too insensitive to exclude the presence of subclinical disease. Historically, a second-look surgery was performed to evaluate these patients, but was abandoned, as there is no evidence of a meaningful benefit to patients (132,235– 244).


Gynecology_Novak

Gynecology_Novak. The level of CA125, a surface glycoprotein associated with m¨ullerian epithelial tissues, is elevated in about 80% of patients with epithelial ovarian cancers, particularly those with nonmucinous tumors (245–247). The levels frequently become undetectable after the initial surgical resection and one or two cycles of chemotherapy. Carcinoembryonic antigen (CEA) levels are often elevated in patients with ovarian cancer, and the test is too nonspecific and insensitive to be used in the management of these patients, apart from patients with a mucinous cancer of the ovary (48).


Gynecology_Novak

Gynecology_Novak. Levels of CA125 were correlated with findings at second-look operations. Elevated levels are useful in predicting the presence of disease, but negative levels are an insensitive determinant of the absence of disease. In a prospective study, the predictive value of a positive test was 100%; if the level of CA125 was elevated (>35 U/mL), disease was always detectable in patients at the second-look procedure (245). The predictive value of a negative test was only 56%; if the level was less than 35 U/mL, disease was present in 44% of the patients at the time of the second-look surgery. A literature review suggests that an elevated CA125 level predicts persistent disease at second-look surgery in 97% of the cases, but the CA125 level is not sensitive enough to exclude subclinical disease in many patients (246).


Gynecology_Novak

Gynecology_Novak. Serum CA125 levels can be used during chemotherapy to follow those patients whose levels were positive at the initiation of therapy (245). The change in level correlates with response. Those patients with persistently elevated levels after three cycles of treatment probably have persistent disease. When levels rise after treatment, almost invariably treatment has failed, and continuation of the current regimen is futile. A retrospective study determined that a doubling of the CA125 level from its nadir in those patients with a persistently elevated level accurately predicts disease progression (247).


Gynecology_Novak

Gynecology_Novak. Radiologic tests assess response in patients with measurable lesions at the start of therapy. In patients who have no or minimal residual disease following cytoreductive surgery, the value of these tests is limited, but they may be useful in follow-up, especially to document the site of recurrence. Ascites can be readily detected, but quite large omental metastases can be missed on CT scan in patients with recurrent disease (248). If liver enzyme levels are abnormal, the liver can be evaluated with a CT scan or ultrasonography. A positive CT scan and fine-needle aspiration (FNA) cytology indicating tumor persistence could document persistent or recurrent disease, but the false-negative rate of a CT scan is about 45% (249). Positron-emission tomography (PET) alone, or with CT imaging, may help detect relapse, although the relative value of adding PET is not established. There appears to be a higher false-positive rate with PET compared with CT (106,107). MRI can be used as an


Gynecology_Novak

Gynecology_Novak. may help detect relapse, although the relative value of adding PET is not established. There appears to be a higher false-positive rate with PET compared with CT (106,107). MRI can be used as an alternative to CT in patients with allergies to the contrast medium (105).


Gynecology_Novak

Gynecology_Novak. Secondary cytoreduction may be defined as an attempt at cytoreductive surgery at some stage following completion of first-line chemotherapy (250–253). Patients with progressive disease on chemotherapy are not suitable candidates for secondary cytoreduction, but patients with recurrent disease are occasionally candidates for surgical excision of their disease. Tumor resection under these circumstances should be restricted to those who have a disease-free interval of at least 12, but preferably 24, months or those in whom it is expected that all macroscopic disease can be resected, regardless of the disease-free interval (250–258). Complete resection is possible when there are only one or two isolated recurrences in patients without diffuse carcinomatosis (258).


Gynecology_Novak

Gynecology_Novak. The majority of women who relapse will be offered more chemotherapy with the likelihood of benefit related to the initial response and the duration of response. The goals of treatment include improving control of disease-related symptoms, maintaining or improving quality of life, delaying time to progression, and possibly prolonging survival, particularly in women with platinum-sensitive recurrences. Many active chemotherapy agents (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) and targeted agents (bevacizumab) are available, and the choice of treatment is based on many factors including likelihood of benefit, potential toxicity, and patient convenience.


Gynecology_Novak

Gynecology_Novak. Women who relapse later than 6 months after primary chemotherapy are classified as platinum-sensitive and usually receive further platinum-based chemotherapy with response rates ranging from 27% to 65% and a median survival of 12 to 24 months (259–263). Patients who relapse within 6 months of completing first-line chemotherapy are classified as platinum-resistant and have a median survival of 6 to 9 months and a 10% to 30% likelihood of responding to chemotherapy. Patients who progress while on treatment are classified as having platinum-refractory disease. Objective response rates to chemotherapy in patients with platinum-refractory ovarian cancer are low—less than 20% (264).


Gynecology_Novak

Gynecology_Novak. The potential adverse effects associated with chemotherapy in trials in women with recurrent ovarian cancer are well documented and should not be underestimated. The three most commonly used drugs are paclitaxel, topotecan, and liposomal doxorubicin (265–291). The reported adverse effects associated with paclitaxel were alopecia in 62% to 100%, neurotoxicity (any grade) in 5% to 42% of patients, and severe leukopenia in 4% to 24% of patients. Topotecan is associated with significantly greater myelosuppression than liposomal doxorubicin or paclitaxel and is observed in 49% to 76% of patients. Liposomal doxorubicin is associated with palmer-planter erythrodysesthesia (PPE) of any grade in over 50% of patients and is severe in 23%. Severe stomatitis is reported in up to 10% of patients (265–268).


Gynecology_Novak

Gynecology_Novak. Platinum-Sensitive Disease The use of combination platinum plus paclitaxel chemotherapy versus a single-agent platinum was tested in two multinational randomized phase III trials and a randomized phase II study (292,293). In a report of the ICON4 and AGO-OVAR-2.2 (AGO Studiengruppe Ovarialkarzinom) trials, 802 women with platinum-sensitive ovarian cancer, who relapsed after being treatment free for at least 6 to 12 months were randomized to platinum-based chemotherapy (72% carboplatin or cisplatin alone; 17% CAP; 4% carboplatin plus cisplatin; and 3% cisplatin plus doxorubicin)or paclitaxel plus platinum-based chemotherapy (80% paclitaxel plus carboplatin; 10% paclitaxel plus cisplatin; 5% paclitaxel plus both carboplatin and cisplatin; and 4% paclitaxel alone) (292). The AGO-OVAR-2.2 trial did not accrue its planned number of patients. In both trials, a significant proportion of the patients did not receive paclitaxel as part of their initial chemotherapeutic regimen. Combining the


Gynecology_Novak

Gynecology_Novak. did not accrue its planned number of patients. In both trials, a significant proportion of the patients did not receive paclitaxel as part of their initial chemotherapeutic regimen. Combining the trials for analysis, there was a significant survival advantage for the paclitaxel-containing therapy (HR = 0.82) with a median follow-up of 42 months. The absolute 2-year survival advantage was 7% (57% versus 50%), and there was a 5-month improvement in median survival (29 versus 24 months). Progression-free survival was better with the paclitaxel regimen (HR = 0.76); there was a 10% difference in 1-year progression-free survival (50% versus 40%) and a 3-month prolongation in median progression-free survival (13 versus 10 months). The toxicities were comparable, except for a significantly higher incidence of neurologic toxicity and alopecia in the paclitaxel group, while myelosuppression was significantly greater with the non-paclitaxel-containing regimens. These data support the slight


Gynecology_Novak

Gynecology_Novak. incidence of neurologic toxicity and alopecia in the paclitaxel group, while myelosuppression was significantly greater with the non-paclitaxel-containing regimens. These data support the slight advantage of a second-line regimen containing both paclitaxel and a platinum agent compared with platinum-based therapy alone in patients who have not received paclitaxel in their primary chemotherapeutic regimen.


Gynecology_Novak

Gynecology_Novak. There were two randomized trials comparing carboplatin alone to carboplatin and gemcitabine or liposomal doxorubicin (294,295). There was a higher response rate with the combination therapy and a longer progression-free survival, but the studies were not powered to look at overall survival. In the Gynecologic Oncology Intergroup (GCIG) study comparing carboplatin and gemcitabine with carboplatin alone, the response rate was 47.2% for the combination and 30.9% for carboplatin, with the progression-free survival being 8.6 months and 5.8 months, respectively (294). A large GCIG study (CALYPSO) compared carboplatin and liposomal doxorubicin (CD) with carboplatin and paclitaxel (CP) in 976 patients (296). The progression-free survival for the CD arm was statistically superior to CP arm with a median progression-free survival of 11.3 months versus 9.4 months, respectively. Overall survival data are not yet available. The CD arm was better tolerated with less severe toxicities, and this


Gynecology_Novak

Gynecology_Novak. a median progression-free survival of 11.3 months versus 9.4 months, respectively. Overall survival data are not yet available. The CD arm was better tolerated with less severe toxicities, and this combination is now widely used (296).


Gynecology_Novak

Gynecology_Novak. Platinum-Resistant and Refractory Disease Patients with platinum-refractory and resistant ovarian cancer are treated with chemotherapy and may have a number of lines of therapy depending on response and performance status. In platinum-refractory patients (i.e., those progressing on treatment), response rates to second-line chemotherapy are less than 10% and the median survival is short, around 3 to 5 months (260–264). The management of women who are platinum-resistant (i.e., progressing within 6 months of completion of chemotherapy) is difficult and “non-cross-resistant agents” are selected, but there does not appear to be one best treatment. Single-agent therapy is typically used because combination regimens are associated with more toxicity without any apparent additional benefit. High response rates of 48% to 64% were reported with dose-dense weekly carboplatin (AUC4) plus paclitaxel (90 mg/m2), and this deserves more study (297). There are a variety of potentially active drugs:


Gynecology_Novak

Gynecology_Novak. response rates of 48% to 64% were reported with dose-dense weekly carboplatin (AUC4) plus paclitaxel (90 mg/m2), and this deserves more study (297). There are a variety of potentially active drugs: paclitaxel, docetaxel, topotecan, liposomal doxorubicin, gemcitabine, oral etoposide, tamoxifen, and bevacizumab are the most frequently used. Other agents include vinorelbine and newer drugs such as trabectedin.


Gynecology_Novak

Gynecology_Novak. The results of a study comparing topotecan with liposomal doxorubicin demonstrate the low response rates and poor prognosis among women with platinum-resistant ovarian cancer (265). There were two randomized trials comparing liposomal doxorubicin with either topotecan or paclitaxel. In a study of 237 women who relapsed after receiving one platinum-containing regimen, 117 of whom (49.4%) had platinum-refractory disease, liposomal doxorubicin 50 mg/m2 over 1 hour every 4 weeks was compared with topotecan 1.5 mg/m2/day for 5 days every 3 weeks (265). The two treatments had a similar overall response rate (20% versus 17%), time to progression (22 versus 20 weeks), and median overall survival (66 versus 56 weeks). The myelotoxicity was significantly lower in the liposomal doxorubicin-treated patients than with those receiving topotecan. In a second study comparing liposomal doxorubicin with single-agent paclitaxel in 214 platinum-treated patients who had not received prior taxanes, the


Gynecology_Novak

Gynecology_Novak. patients than with those receiving topotecan. In a second study comparing liposomal doxorubicin with single-agent paclitaxel in 214 platinum-treated patients who had not received prior taxanes, the overall response rates for liposomal doxorubicin and paclitaxel were 18% versus 22%, respectively, and median survival durations were 46 and 56 weeks, respectively, and these were not significantly different (266). In practice, most patients are treated with a starting dose of 40 mg/m2 of liposomal doxorubicin every 4 weeks, because of the toxicity associated with the higher dose and the need to dose reduce when 50 mg/m2 is used. In a subset analysis of platinum-resistant patients, the median time to progression ranged from 9.1 to 13.6 weeks for topotecan and liposomal doxorubicin, respectively. The median survival (p = 0.455) was 35.6 weeks for pegylated liposomal doxorubicin and 41.3 weeks for topotecan. Objective response rates were recorded in 6.5% of patients who received topotecan and


Gynecology_Novak

Gynecology_Novak. The median survival (p = 0.455) was 35.6 weeks for pegylated liposomal doxorubicin and 41.3 weeks for topotecan. Objective response rates were recorded in 6.5% of patients who received topotecan and in 12.3% of those who received pegylated liposomal doxorubicin (p = 0.118). It is not known whether the treatment improved symptoms control or quality of life because this was not specifically addressed.


Gynecology_Novak

Gynecology_Novak. In another randomized trial in 195 patients with platinum-resistant ovarian cancer, patients were randomized to receive either liposomal doxorubicin (PLD) or gemcitabine (298). In the gemcitabine and PLD groups, median progression-free survival was 3.6 versus 3.1 months; median overall survival was 12.7 versus 13.5 months; overall response rate was 6.1% versus 8.3%; and in the subset of patients with measurable disease, overall response rate was 9.2% versus 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea or vomiting, fatigue, and neutropenia.


Gynecology_Novak

Gynecology_Novak. Some researchers attempted to treat patients with non-platinum drugs to prolong the platinum-free interval, hoping that would allow the tumor to become platinum-sensitive during the interval use of non-cross-resistant agents. The rationale for this approach is the belief that the platinum-free interval is equivalent to the treatment-free interval, and before the availability of other active drugs, these two terms were synonymous. There are no data to support the hypothesis that the interposition of another drug can produce an increased platinum sensitivity as a result of a longer interval since the last platinum treatment.


Gynecology_Novak

Gynecology_Novak. Single-agent paclitaxel shows objective responses in 20% to 30% in phase II trials of women with platinum-resistant ovarian cancer (269–274). The main toxicities are fatigue and peripheral neuropathy. Weekly paclitaxel is active, and the toxicity, especially myelosuppression, is less than with the every 3-week regimens. In a study of 53 women with platinum-resistant ovarian cancer, weekly paclitaxel (80 mg/m2 over 1 hour) had an objective response of 25% in patients with measurable disease, and 27% of patients without measurable disease had a 75% decline in serum CA125 levels (269). Docetaxel has some activity in these patients (299–301). The GOG studied 60 women with platinum-resistant ovarian or primary peritoneal cancer (301). Although there was a 22% objective response rate, the median response duration was only 2.5 months, and therapy was complicated by severe neutropenia in three-quarters of the patients.


Gynecology_Novak

Gynecology_Novak. Topotecan Topotecan is an active second-line treatment for patients with platinum-sensitive and platinum-resistant disease (277–291). In a study of 139 women receiving topotecan 1.5 mg/m2 daily for 5 days, response rates were 19% and 13% in patients with platinum-sensitive and platinum-resistant disease, respectively (287). The predominant toxicity of topotecan is hematologic, especially neutropenia. With the 5-day dosing schedule, approximately 70% to 80% of patients have severe neutropenia, and 25% have febrile neutropenia with or without infection. In some studies, regimens of 5 days produce better response rates than regimens of shorter duration, but in others, reducing the dose to 1.0 mg/m2 per day for 3 days is associated with similar response rates but lower toxicity (280,290). In a study of 31 patients, one-half of whom were platinum refractory, topotecan 2 mg/m2 per day for 3 days every 21 days had a 32% response rate (285). Continuous infusion topotecan (0.4 mg/m2 per day


Gynecology_Novak

Gynecology_Novak. a study of 31 patients, one-half of whom were platinum refractory, topotecan 2 mg/m2 per day for 3 days every 21 days had a 32% response rate (285). Continuous infusion topotecan (0.4 mg/m2 per day for 14 to 21 days) had a 27% to 35% objective response rate in platinum-refractory patients (284). Weekly topotecan administered at a dose of 4 mg/m2 per week for 3 weeks with a week off every month produced a response rate similar to the 5-day regimen with considerably less toxicity, and this is the preferred dose schedule in the recurrent setting (290).


Gynecology_Novak

Gynecology_Novak. Oral topotecan, not available in the United States, results in similar response rates with less hematologic toxicity (286). The intravenous and oral formulations of topotecan were compared in a randomized trial of 266 women as a third-line regimen after an initial platinum-based regimen (291). Compared with intravenous topotecan (1.5 mg/m2 daily for 5 days every 3 weeks), oral topotecan (2.3 mg/m2 per day for 5 days every 3 weeks) produced a similar response rate (13% versus 20%), less severe myelosuppression, and only a slightly shorter median survival (51 versus 58 weeks).


Gynecology_Novak

Gynecology_Novak. Liposomal Doxorubicin Liposomal doxorubicin (Doxil in the United States and Caelyx in Europe), as noted above, has activity in platinum-and taxane-refractory disease (265–268,295). One of the most important side effects of liposomal doxorubicin is the hand-foot syndrome, also known as palmar-plantar erythrodysesthesia or acral erythema, which occurs in 20% of patients who receive 50 mg/m2 every 4 weeks (266). Most oncologists administer 40 mg/m2 and escalate only if there are no side effects. Liposomal doxorubicin has a low rate of alopecia. In a study of 89 patients with platinum-refractory disease, including 82 paclitaxel-resistant patients, liposomal doxorubicin (50 mg/m2 every 3 weeks) produced a response in 17% (1 complete and 14 partial responses) (268). In another study, an objective response of 26% was reported, although there were no responses in women who progressed during first-line therapy (265).


Gynecology_Novak

Gynecology_Novak. Gemcitabine Gemcitabine is associated with response rates of 20% to 50%, with 15% to 30% in patients who are platinum-resistant (302–306). The principal toxicities are myelosuppression and gastrointestinal. The drug is used in doublet combinations with cisplatin or carboplatin with acceptable responses and toxicities, and in the triplet combination with carboplatin and paclitaxel (304). Oral Etoposide The most common toxicities with oral etoposide are myelosuppression and gastrointestinal: grade 4 neutropenia is observed in about one-fourth of patients, and 10% to 15% have severe nausea and vomiting (307,308). A study of oral etoposide given for a prolonged treatment (50 mg/m2 daily for 21 days every 4 weeks) had a 27% response rate in 41 women with platinum-resistant disease, 3 of whom had durable complete responses (308). In 25 patients with platinum and taxane-resistant disease, 8 objective responses (32%) were reported.


Gynecology_Novak

Gynecology_Novak. Hormonal Therapy Tamoxifen is associated with CA125 response rates of 15% to 20% in small studies of patients with recurrent ovarian cancer (309–315). Aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane), which have activity in metastatic breast cancer, are being studied in relapsed ovarian cancer (316). One of the principal advantages of this class of agents is its very low toxicity (317).


Gynecology_Novak

Gynecology_Novak. Targeted Therapies Knowledge of molecular pathways within normal and malignant cells is leading to the development of cancer treatment agents with specific molecular targets. There is great potential in targeting angiogenesis, in particular vascular endothelial growth factor (VEGF), which plays a major role in the biology of epithelial ovarian cancer (318). There are three main approaches to target angiogenesis: the first is to target VEGF itself, the second to target the VEGF receptor, and the third is to inhibit tyrosine kinase activation and downstream signaling with small molecules that work at the intracellular level.


Gynecology_Novak

Gynecology_Novak. Bevacizumab is the first targeted agent to show significant single agent activity in ovarian cancer. It is a humanized monoclonal antibody that targets angiogenesis by binding to VEGF-A, thereby blocking the interaction of VEGF with its receptor. There are a number of phase II studies reported using bevacizumab in patients with platinum-sensitive and platinum-resistant ovarian cancer with response rates ranging from 16% to 22% in both platinum-sensitive and -refractory patients (319). Up to 40% of patients had stabilization of disease for at least 6 months. A study of low-dose metronomic chemotherapy with 50 mg of cyclophosphamide daily and bevacizumab 10 mg/kg intravenously every 2 weeks showed significant activity in a study of 70 patients with recurrent ovarian cancer (320). The primary end point was progression-free survival at 6 months. The probability of being alive and progression free at 6 months was 56%. A partial response was achieved in 17 patients (24%). Median time to


Gynecology_Novak

Gynecology_Novak. end point was progression-free survival at 6 months. The probability of being alive and progression free at 6 months was 56%. A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. This comes with toxicity. The side effects of bevacizumab are well recognized and include hypertension, fatigue, proteinuria, gastrointestinal perforation or fistula, and uncommonly, vascular thrombosis and central nervous system ischemia, pulmonary hypertension, and bleeding and wound healing complications. The most common side effects are hypertension that is grade 3 in 7% of patients and is usually treatable. The most concerning side effect is bowel perforation and the study by Cannistra et al. was stopped after recruiting 44 patients because of an 11% incidence of perforation of the bowel (321).


Gynecology_Novak

Gynecology_Novak. It was suggested that the bowel perforation complication could be avoided by carefully screening patients. Simpkins et al. limited bevacizumab treatment to patients without clinical symptoms of bowel obstruction or evidence of rectosigmoid involvement on pelvic examination or bowel involvement on CT scan (322). Their study included 25 patients with platinum-resistant ovarian cancer who were heavily pretreated, and they observed a response rate of 28% and no bowel perforations or any other grade 3 or 4 toxicities were reported. This highlights the importance of patient selection and suggests that increased experience with these agents will result in less toxicity. VEGF Trap functions as a soluble decoy receptor soaking up ligand before it can interact with its receptor and is being evaluated in phase II trials in patients with recurrent ovarian cancer. There are other oral agents that target angiogenesis through tyrosine kinase inhibition that are in clinical trial (323).


Gynecology_Novak

Gynecology_Novak. Radiation Therapy Whole-abdominal radiation therapy given as a treatment for recurrent or persistent disease is associated with a high morbidity and is not used. The principal problem associated with this approach is the development of acute and chronic intestinal morbidity. As many as 30% of patients treated with this approach develop intestinal obstruction, which necessitated exploratory surgery with potential morbidity (324). Intestinal Obstruction Patients with epithelial ovarian cancer often develop intestinal obstruction, either at the time of initial diagnosis or in association with recurrent disease (325–340). Obstruction may be related to a mechanical blockage or to carcinomatous ileus.


Gynecology_Novak

Gynecology_Novak. The intestinal blockage can be corrected in most patients whose obstruction appears at initial diagnosis. The decision to perform an exploratory procedure to ease intestinal obstruction in patients with recurrent disease is more difficult. For patients whose life expectancy is very short (e.g., less than 2 months), surgical relief of the obstruction is not indicated (325–330). In those patients with a longer projected lifespan, features predicting a reasonable likelihood of correcting the obstruction include young age, good nutritional status, and the absence of rapidly accumulating ascites (326).


Gynecology_Novak

Gynecology_Novak. For most patients with recurrent ovarian cancer and intestinal obstruction, initial management should include proper radiographic documentation of the obstruction, hydration, correction of any electrolyte disturbances, parenteral alimentation, and intestinal intubation. For some patients, the obstruction may be alleviated by this conservative approach. A preoperative upper gastrointestinal radiographic series and a barium enema will define possible sites of obstruction.


Gynecology_Novak

Gynecology_Novak. If exploratory surgery is deemed appropriate, the type of operation to be performed will depend on the site and the number of obstructions. Multiple sites of obstruction are not uncommon in patients with recurrent epithelial ovarian cancer. More than one-half of the patients have small bowel obstruction, one-third have colonic obstruction, and one-sixth have both (327–331). If the obstruction is principally contained in one area of the bowel (e.g., the terminal ileum), this area can be either resected or bypassed, depending on what is easier to accomplish safely. Intestinal bypass is less morbid than resection, and in patients with progressive cancer, the survival time after these two operations is the same (332–337).


Gynecology_Novak

Gynecology_Novak. If multiple obstructions are present, resection of several segments of intestine is usually not indicated, and intestinal bypass and/or colostomy should be performed. A gastrostomy may be useful in this circumstance, and this can usually be placed percutaneously (336,339). Surgery for bowel obstruction in patients with ovarian cancer carries an operative mortality of about 10% and a major complications rate of about 30% (325–337). The need for multiple reanastomoses and prior radiation therapy increase the morbidity, which consists primarily of sepsis and enterocutaneous fistulae. The median survival ranges from 3 to 12 months, although about 20% of such patients survive longer than 12 months (337–340).


Gynecology_Novak

Gynecology_Novak. Survival The prognosis for patients with epithelial ovarian cancer is related to several clinical variables. Survival analyses based on prognostic variables are presented (1,3,30,123–127). Including patients at all stages, patients younger than 50 years of age have a 5-year survival rate of about 40%, compared with about 15% for patients older than 50 years. The 5-year survival rate for carefully and properly staged patients with stage I disease is as high as 94%, for stage II is 73%, for stage III or IV 28% (1). The 5-year survival rate for stage IIIA is 41%, for stage IIIB about 25%, for stage IIIC 23%, and for stage IV disease 11% (Fig. 37.16). An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database reveals a trend toward improved survival for ovarian cancer in the United States. In this cohort, the survival for stage I was 93%, for stage II 70%, for stage III 37%, and for stage IV 25% (341).


Gynecology_Novak

Gynecology_Novak. Survival of patients with borderline tumors is excellent, with stage I lesions having a 98% 15year survival (30). When all stages of borderline tumors are included, the 5-year survival rate is about 86% to 90%. Patients with stage III disease with microscopic residual disease at the start of treatment have a 5-year survival rate of about 40% to 75%, compared with about 30% to 40% for those with optimal disease and only 5% for those with suboptimal disease (126,127,149). Patients whose Karnofsky index (KI) is low (<70) have a significantly shorter survival than those with a KI greater than 70 (30).


Gynecology_Novak

Gynecology_Novak. Figure 37.16 Survival of patients with epithelial ovarian cancer by substage. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:491, adapted with permission from Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. In Twenty-sixth annual report of the results of treatment of gynaecological cancer. Int J Gynecol Oncol 2006;95(suppl 1):S161–S192. Compared with epithelial ovarian cancers, other malignant tumors of the ovary are uncommon.


Gynecology_Novak

Gynecology_Novak. Compared with epithelial ovarian cancers, other malignant tumors of the ovary are uncommon. Nonepithelial malignancies of the ovary account for about 10% of all ovarian cancers (2,3,342). Nonepithelial ovarian cancers include malignancies of germ cell origin, sex cord– stromal cell origin, metastatic carcinomas to the ovary, and a variety of extremely rare ovarian cancers (e.g., sarcomas). Although there are similarities in the presentation, evaluation, and management of these patients, the tumors have unique qualities that require a special approach (2,342–345).


Gynecology_Novak

Gynecology_Novak. Germ Cell Malignancies Germ cell tumors are derived from the primordial germ cells of the ovary. Their incidence is about one-tenth the incidence of malignant germ cell tumors of the testis, so most of the advances in the management of these tumors are extrapolations from experience with the corresponding testicular tumors. Although malignant germ cell tumors can arise in extragonadal sites such as the mediastinum and the retroperitoneum, most germ cell tumors arise in the gonad from undifferentiated germ cells. The variation in the site of these cancers is explained by the embryonic migration of the germ cells from the caudal part of the yolk sac to the dorsal mesentery before their incorporation into the sex cords of the developing gonads (2,3,342). Table 37.5 Histologic Typing of Ovarian Germ Cell Tumors 1. Primitive germ cell tumors 3. Monodermal teratoma and somatic-type A. Dysgerminoma tumors associated with dermoid cysts B. Yolk sac tumor A. Thyroid tumor


Gynecology_Novak

Gynecology_Novak. A. Dysgerminoma tumors associated with dermoid cysts B. Yolk sac tumor A. Thyroid tumor C. Embryonal carcinoma 1. Struma ovarii D. Polyembryoma a. Benign E. Non-gestational choriocarcinoma b. Malignant F. Mixed germ cell tumor B. Carcinoid 2. Biphasic or triphasic teratoma C. Neuroectodermal tumor A. Immature teratoma D. Carcinoma B. Mature teratoma E. Melanocytic 1. Solid F. Sarcoma 2. Cystic G. Sebaceous tumor a. Dermoid cyst H. Pituitary-type tumor b. Fetiform teratoma (homunculus) I. Others Adapted from Tavassoll FA, Devllee P, eds. World Health Organization classification of tumours. Pathology and genetics of tumors of the breast and female organs. Lyon: IARC Press, 2003. substances in tumors is correlated, a classification of germ cell tumors emerges (Fig. 37.17) (346).


Gynecology_Novak

Gynecology_Novak. substances in tumors is correlated, a classification of germ cell tumors emerges (Fig. 37.17) (346). In this scheme, embryonal carcinoma (a cancer composed of undifferentiated cells) synthesizes both hCG and AFP, and this lesion is the progenitor of several other germ cell tumors (346–348). More differentiated germ cell tumors, such as the endodermal sinus tumor, which secretes AFP, and the choriocarcinoma, which secretes hCG, are derived from the extraembryonic tissues; the immature teratomas derived from the embryonic cells have lost the ability to secrete these substances. Pure germinomas do not secrete these markers.


Gynecology_Novak

Gynecology_Novak. Epidemiology Although 20% to 25% of all benign and malignant ovarian neoplasms are of germ cell origin, only about 3% of these tumors are malignant (2,3). Germ cell malignancies account for fewer than 5% of all ovarian cancers in Western countries. Germ cell malignancies represent up to 15% of ovarian cancers in Asian and African American societies, where epithelial ovarian cancers are much less common. In the first two decades of life, almost 70% of ovarian tumors are of germ cell origin, and one-third of these are malignant (2,3,342). Germ cell cancers are seen in the third decade, but thereafter they become quite rare.


Gynecology_Novak

Gynecology_Novak. In contrast to the slower-growing epithelial ovarian tumors, germ cell malignancies grow rapidly and are characterized by subacute pelvic pain related to capsular distention, hemorrhage, or necrosis. The rapidly enlarging pelvic mass may produce pressure symptoms on the bladder or rectum, and menstrual irregularities may occur in menarcheal patients. Some young patients misinterpret the early symptoms of a neoplasm as those of pregnancy, which can lead to a delay in the diagnosis. Acute symptoms associated with torsion or rupture of the adnexa can develop. These symptoms may be confused with acute appendicitis. In more advanced cases, ascites may develop, and the patient can have abdominal distention (336).


Gynecology_Novak

Gynecology_Novak. Primordial germ cell Germinoma: dysgeminomaAFP (−)hCG (−) Embryonalcarcinoma AFP (+)hCG (+) Trophoblast Yolk sac Extraembryonicdifferentation Immature teratoma AFP (−)hCG (−) Embryonicdifferentation Choriocarcinoma AFP (−)hCG (+) Endodermal sinus tumor AFP (+)hCG (−) Mature teratoma AFP (−)hCG (−) Figure 37.17 Relationship between types of pure malignant tumors. Germ cell tumors and their secreted marker substances. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2010:511, with permission.


Gynecology_Novak

Gynecology_Novak. For a patient with a palpable adnexal mass, the evaluation can proceed as outlined. Some patients with germ cell tumors will be premenarcheal and may require examination under anesthesia. If the lesions are principally solid or a combination of solid and cystic, as might be noted on an ultrasonographic evaluation, a neoplasm is probable and a malignancy is possible (see Fig. 14.8 and Chapter 14). During the remainder of the physical examination, effort should be directed to searching for signs of ascites, pleural effusion, and organomegaly.


Gynecology_Novak

Gynecology_Novak. Adnexal masses measuring 2 cm or larger in premenarcheal girls or 8 cm or larger in other premenopausal patients will usually require surgical exploration. For young patients, blood tests should include serum hCG and AFP and LDH. A CT scan of the chest is important because germ cell tumors can metastasize to the lungs or mediastinum. A karyotype should be obtained preoperatively for all premenarcheal girls, particularly those with dysgerminomas, because of the propensity of these tumors to arise in dysgenetic gonads (343,349). A preoperative CT scan or MRI may document the presence and extent of retroperitoneal lymphadenopathy or liver metastases; however, because these patients require surgical exploration, preoperative imaging is not usually required. If postmenarcheal patients have predominantly cystic lesions up to 8 cm in diameter, they may be observed or given oral contraceptives for two menstrual cycles (350). CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer


Gynecology_Novak

Gynecology_Novak. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer Figure 37.18 Dysgerminoma of the ovary. Note that the lesion is principally solid with some cystic areas and necrosis. to 3% of all ovarian cancers, but they represent as many as 5% to 10% of ovarian cancers in patients younger than 20 years. Seventy-five percent of dysgerminomas occur between the ages of 10 and 30 years, 5% occur before the age of 10 years, and they rarely occur after 50 years of age (2,3,336). Because these malignancies occur in young women, 20% to 30% of ovarian malignancies associated with pregnancy are dysgerminomas. Germinomas are found in both sexes and may arise in gonadal or extragonadal sites.


Gynecology_Novak

Gynecology_Novak. Germinomas are found in both sexes and may arise in gonadal or extragonadal sites. The latter include the midline structures from the pineal gland to the mediastinum and the retroperitoneum. Histologically, they represent abnormal proliferations of the basic germ cell. In the ovary, the germ cells are encapsulated at birth (the primordial follicle), and the unencapsulated or free cells die. If either of the latter processes fails, it is possible that the germ cell could free itself of its normal control and multiply indiscriminately. The size of dysgerminomas varies widely, but they are usually 5 to 15 cm in diameter (2,3). The capsule is slightly bosselated, and the consistency of the cut surface is ﬂeshy and pale tan to gray-brown in color (Fig. 37.18).


Gynecology_Novak

Gynecology_Novak. The histologic characteristics of the dysgerminoma are very distinctive. The large round, ovoid, or polygonal cells have abundant, clear, very-pale–staining cytoplasm, large and irregular nuclei, and prominent nucleoli (Fig. 37.19). Mitotic figures are seen in varying numbers, although they are usually numerous. Another characteristic feature is the arrangement of the elements in lobules and nests separated by fibrous septa, which are often extensively infiltrated with lymphocytes, plasma cells, and granulomas with epithelioid cells and multinucleated giant cells. When necrosis is extensive, the lesion may be confused with tuberculosis. Dysgerminomas may contain syncytiotrophoblastic giant cells and may be associated with precocious puberty or virilization. The presence of these cells does not seem to alter the behavior of the Figure 37.19 Dysgerminoma of ovary. Primitive germ cells are divided into clusters and lobules by fibrous septa rich in lymphocytes.


Gynecology_Novak

Gynecology_Novak. Figure 37.19 Dysgerminoma of ovary. Primitive germ cells are divided into clusters and lobules by fibrous septa rich in lymphocytes. tumor (2,3). The presence of calcifications should prompt a search for a possible underlying gonadoblastoma. Because the dysgerminoma is a germ cell tumor and parthenogenesis (stimulation of the basic germ cell to atypical division) is the accepted genesis for the more immature teratomas, it is logical that these two tumors may coexist. Choriocarcinoma, endodermal sinus tumor, and other extraembryonal lesions may be associated with the dysgerminoma.


Gynecology_Novak

Gynecology_Novak. Approximately 5% of dysgerminomas are discovered in phenotypic women with abnormal gonads (2,349,351). This malignancy can be associated with patients who have pure gonadal dysgenesis (46,XY, bilateral streak gonads), mixed gonadal dysgenesis (45,X/46,XY, unilateral streak gonad, contralateral testis), and the androgen insensitivity syndrome (46,XY, testicular feminization). For premenarcheal patients with a pelvic mass, the karyotype should be determined (see Chapter 29). For most patients with gonadal dysgenesis, dysgerminomas arise in gonadoblastomas, which are benign ovarian tumors that are composed of germ cells and sex cord stroma. If gonadoblastomas are left in situ in patients with gonadal dysgenesis, more than 50% will develop into ovarian malignancies (351).


Gynecology_Novak

Gynecology_Novak. About 65% of dysgerminomas are stage I (i.e., confined to one or both ovaries) at diagnosis (2,3,352–356). About 85% to 90% of stage I tumors are confined to one ovary; 10% to 15% are bilateral. Dysgerminoma is the only germ cell malignancy that has this significant rate of bilaterality. Other germ cell tumors are rarely bilateral. For patients whose contralateral ovary is preserved, disease can develop in 5% to 10% of the retained gonads over the next 2 years (2). This figure includes those not given additional therapy and patients with gonadal dysgenesis.


Gynecology_Novak

Gynecology_Novak. In the 25% of patients who are diagnosed initially with metastatic disease, the tumor commonly spreads via the lymphatic system. It can spread hematogenously or by direct extension through the capsule of the ovary with exfoliation and dissemination of cells throughout the peritoneal surfaces. Metastases to the contralateral ovary may be present when there is no other evidence of spread. An uncommon site of metastatic disease is bone; when metastasis to this site occurs, the lesions are principally in the lower vertebrae. Metastases to the lungs, liver, and brain are often in patients with longstanding or recurrent disease. Metastasis to the mediastinum and supraclavicular lymph nodes is usually a late manifestation of disease (352,353).


Gynecology_Novak

Gynecology_Novak. The treatment of patients with early dysgerminoma is primarily surgical, including resection of the primary lesion and proper surgical staging. Chemotherapy is administered to patients with metastatic disease. Because the disease principally affects girls and young women, special consideration must be given to the preservation of fertility and use of chemotherapy whenever possible. An algorithm for the management of ovarian dysgerminoma is presented in Figure 37.20.


Gynecology_Novak

Gynecology_Novak. Surgery The minimal surgical operation for ovarian dysgerminoma is a unilateral oophorectomy (354). If there is a desire to preserve fertility, as there almost always is, the contralateral ovary, fallopian tube, and uterus should be left in situ, even in the presence of metastatic disease, because of the sensitivity of the tumor to chemotherapy. If fertility need not be preserved, it may be appropriate to perform a total abdominal hysterectomy and bilateral salpingo-oophorectomy for patients with advanced disease (356). For patients whose karyotype analysis reveals a Y chromosome, both ovaries should be removed, although the uterus may be left in situ for possible future embryo transfer (351). Whereas cytoreductive surgery is of unproved value, bulky disease that can be readily resected (e.g., an omental cake) should be removed during the initial operation.


Gynecology_Novak

Gynecology_Novak. In patients in whom the neoplasm appears on inspection to be confined to the ovary, a careful staging operation should be undertaken to determine the presence of any occult metastatic disease. All peritoneal surfaces should be inspected and palpated, and any suspicious lesions should be sampled for biopsy. Unilateral pelvic lymphadenectomy and careful palpation and biopsy of enlarged para-aortic nodes are particularly important parts of the staging. These tumors often metastasize to the para-aortic nodes around the renal vessels. Dysgerminoma is the only germ cell tumor that tends to be bilateral, excisional biopsy of any suspicious masses is desirable (354–356). If a small contralateral tumor is found, it may be possible to resect it and preserve some normal ovary.


Gynecology_Novak

Gynecology_Novak. Many patients with a dysgerminoma will have a tumor that is apparently confined to one ovary and will be referred after unilateral salpingo-oophorectomy without surgical staging. The options for such patients are (i) repeat laparotomy for surgical staging, (ii) regular pelvic and abdominal CT scans, or (iii) adjuvant chemotherapy. Because these are rapidly growing tumors, the preference is to perform regular surveillance. Tumor markers (LDH, AFP, and β-hCG) should be monitored in case occult mixed germ cell elements are present. Radiation Therapy Dysgerminomas are very sensitive to radiation therapy, and doses of 2,500 to 3,500 cGy may be curative, even for gross metastatic disease. Loss of fertility is a problem with radiation therapy, and radiation is rarely used as first-line treatment ().


Gynecology_Novak

Gynecology_Novak. Chemotherapy There is very good evidence to demonstrate the effectiveness of platinum-based chemotherapy, which is regarded as the treatment of choice (356–367). The obvious advantage is the preservation of fertility (368). The most frequently used chemotherapeutic regimen for germ cell tumors is BEP (bleomycin, etoposide, and cisplatin), EP or EC (etoposide and carboplatin) (356–373) (Table 37.6). The GOG studied three cycles of the EC regimen, consisting of etoposide (120 mg/m2 intravenously on days 1, 2, and 3 every 4 weeks) and carboplatin (400 mg/m2 intravenously on day 1 every 4 weeks) for patients with completely resected ovarian dysgerminoma, stage IB, IC, II, or III (364). The results showed a sustained disease-free remission rate of 100%.


Gynecology_Novak

Gynecology_Novak. For patients with advanced, incompletely resected germ cell tumors, the GOG studied cisplatinbased chemotherapy in two consecutive protocols (357,358). In the first study, patients received four cycles of vinblastine (12 mg/m2 every 3 weeks), bleomycin (20 units/m2 intravenously every week for 12 weeks), and cisplatin (20 mg/m2 per day intravenously for 5 days every 3 weeks). Patients with persistent or progressive disease at second-look laparotomy were treated


Gynecology_Novak

Gynecology_Novak. CT scan or ultrasound of pelvis and abdomen q 2 mos × first 6 mos q 3 mos × next 6 mos q 6 mos × second yr Dysgerminoma Apparently confined to ovary(s)  Unilateral oophorectomy  Inspect contralateral ovary Surgical staging performed No metastatic disease Documented occult metastatic disease Small focus in contralateral ovary ?Second-look Metastatic disease  Unilateral salpingo oophorectomy  Remove readily resectable metastases BEP × 4–6 cycles BEP × 4 cycles BEP × 4 cycles BEP × 4 cycles Surgical staging not performed Resect focus with ovarian preservation If cytologic or histologic evidence of relapse ?Second-look  Observation  Physical examination every 2 months for first 12 months  CT scan at 6 and 12 months Figure 37.20 Management of dysgerminoma of the ovary. BEP = bleomycin, etoposide, and cisplatin; CT = computed tomo-gram. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:515, with


Gynecology_Novak

Gynecology_Novak. bleomycin, etoposide, and cisplatin; CT = computed tomo-gram. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:515, with permission. 1398


Gynecology_Novak

Gynecology_Novak. Table 37.6 Combination Chemotherapy for Germ Cell Tumors of the Ovary Bleomycin 15 units/m2/week × 5; then on day 1 of course 4 Etoposide 100 mg/m2/day × 5 days every 3 weeks Cisplatin 20 mg/m2/day × 5 days, or 100 mg/m2/day × 1 day Vinblastine 0.15 mg/kg days 1 and 2 every 3 weeks Bleomycin 15 units/m2/week × 5; then on day 1 of course 4 Cisplatin 100 mg/m2 on day 1 every 3 weeks Vincristine 1–1.5 mg/m2 on day 1 every 4 weeks Actinomycin D 0.5 mg/day × 5 days every 4 weeks Cyclophosphamide 150 mg/m2/day × 5 days every 4 weeks a All doses given intravenously.


Gynecology_Novak

Gynecology_Novak. with six cycles of VAC (vincristine, actinomycin D, and cyclophosphamide). In the second trial, patients received three cycles of BEP initially, followed by consolidation with VAC, which was later discontinued in patients with dysgerminomas (358). The VAC consolidation after BEP is no longer used. A total of 20 evaluable patients with stages III and IV dysgerminoma were treated in these two protocols, and 19 were alive and free of disease after 6 to 68 months (median = 26 months). Fourteen of these patients had a second-look laparotomy, and all findings were negative. Another study at M. D. Anderson Cancer Center used BEP in 14 patients with residual disease, and all patients were free of disease during long-term follow-up (361). These results demonstrate that patients with advanced-stage, incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy. The standard regimen is three to four cycles of BEP, depending on assigned


Gynecology_Novak

Gynecology_Novak. incompletely resected dysgerminoma have an excellent prognosis when treated with cisplatin-based combination chemotherapy. The standard regimen is three to four cycles of BEP, depending on assigned risk based on the data from testicular cancers (372,373).


Gynecology_Novak

Gynecology_Novak. About 75% of recurrences occur within the first year after initial treatment, the most common sites being the peritoneal cavity and the retroperitoneal lymph nodes (2,335,336). These patients should be treated with chemotherapy, although radiation may be appropriate in selected patients. Patients with recurrent disease who had no therapy other than surgery should be treated with chemotherapy. If prior chemotherapy with BEP was given, there are a number of second-line options including TIP (paclitaxel, iphosphamide, cisplatin) or VIP (vinblastine, iphosphamide, cisplatin) (Table 35.7), and consideration should be given to the use of high-dose chemotherapy in selected patients. Patients with recurrent disease should be managed in specialized centers. Radiation therapy is effective for this disease, with the major disadvantage being loss of fertility if pelvic and abdominal irradiation is required. Because dysgerminomas tend to occur in young patients, they may coexist with pregnancy.


Gynecology_Novak

Gynecology_Novak. Because dysgerminomas tend to occur in young patients, they may coexist with pregnancy. When a stage IA cancer is found, the tumor can be removed intact and the pregnancy continued. For patients with more advanced disease, continuation of the pregnancy depends on the gestational age of the fetus. Chemotherapy can be given in the second and third trimesters in the same dosages as given for the nonpregnant patient without apparent detriment to the fetus (368). For patients whose initial disease is stage Ia (i.e., a unilateral encapsulated dysgerminoma), unilateral oophorectomy alone results in a 5-year disease-free survival rate of greater than 95% (355). The features associated with a higher tendency to recur, include lesions larger than Table 37.7 POMB-ACE Chemotherapy for Germ Cell Tumors of the Ovary


Gynecology_Novak

Gynecology_Novak. IV, intravenous. The sequence of treatment schedules is two courses of POMB followed by ACE. POMB is then alternated with ACE until patients are in biochemical remission as measured by human chorionic gonadotropin (hCG) and α-fetoprotein (AFP), placental alkaline phosphatase (PLAP), and lactate dehydrogenase (LDH). The usual number of courses of POMB is three to five. Following biochemical remission, patients alternate ACE with OMB until remission has been maintained for approximately 12 weeks. The interval between courses of treatment is kept to the minimum (usually 9 to 11 days). If delays are caused by myelosuppression after courses of ACE, the first 2 days of etoposide are omitted from subsequent courses of ACE. From Newlands ES, Southall PJ, Paradinas FJ, et al. Management of ovarian germ cell tumours. In: Williams CJ, Kaikorian JG, Green MR, et al., eds. Textbook of uncommon cancer. New York: John Wiley and Sons, 1988:47, with permission.


Gynecology_Novak

Gynecology_Novak. 10 to 15 cm in diameter, age younger than 20 years, and a microscopic pattern that includes numerous mitoses, anaplasia, and a medullary pattern (2,346). Surgery for advanced disease followed by pelvic and abdominal radiation resulted in a 5-year survival rate of 63% to 83%, for this same group of patients cure rates of 85% to 90% are reported with the use of VBP (vinblastine, bleomycin, cisplatin), BEP,or EC combination chemotherapy and radiation is infrequently indicated (356–376).


Gynecology_Novak

Gynecology_Novak. Immature Teratomas Immature teratomas contain elements that resemble tissues derived from the embryo. Immature teratomatous elements may occur in combination with other germ cell tumors as mixed germ cell tumors. The pure immature teratoma accounts for fewer than 1% of all ovarian cancers, but it is the second most common germ cell malignancy and accounts for 10% to 20% of all ovarian malignancies seen in women younger than 20 years (2). About 50% of pure immature teratomas of the ovary occur in women between the ages of 10 and 20 years, and they rarely occur in postmenopausal women. Of fundamental importance in the understanding of the teratoma is recognition of the maturation of the various elements. If maturation continues along normal lines, the mature or adult teratoma results, and the prognosis is excellent. Conversely, abnormal maturation of these elements can result in an immature teratoma that has metastatic potential.


Gynecology_Novak

Gynecology_Novak. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer Figure 37.21 Ovarian teratoma. This tumor contains both mature and immature neural elements with a neural tube-like structure near its center. Teratomas containing immature elements, although relatively rare, were recognized more often as pathologists became more alert to their presence (Fig. 37.21). Among the tumors with embryonal elements, those containing neural tissues demonstrate the ability to mature.


Gynecology_Novak

Gynecology_Novak. Semiquantification of immature neuroepithelium correlates with survival in ovarian immature teratoma and is the basis for grading of these tumors (377–379). Those with less than one low power field (X 4) of immature neuroepithelium on the slide with the greatest amount of such tissue (grade 1) have a survival of at least 95%, whereas greater amounts of immature neuroepithelium (grades 2 and 3) appear to have a lower overall survival (approximately 85%) (379). This may not apply to immature teratomas of the ovary in children because they have a good outcome with surgery alone, regardless of the degree of immaturity (380,381). The significant inter-and intraobserver difficulty with a three-tier system led some authorities to recommend the two-tier grading system in use, with immature teratomas categorized as either low grade or high grade (377). Immature ovarian teratomas may be associated with gliomatosis peritonei, a favorable prognostic finding if composed of completely mature


Gynecology_Novak

Gynecology_Novak. teratomas categorized as either low grade or high grade (377). Immature ovarian teratomas may be associated with gliomatosis peritonei, a favorable prognostic finding if composed of completely mature tissues; reports using molecular methods indicate these glial implants are not tumor derived but represent teratomainduced metaplasia of pluripotent m¨ullerian stem cells in the peritoneum (382,383).


Gynecology_Novak

Gynecology_Novak. Somatic malignant change in benign cystic teratomas was recorded as occurring in 0.5% to 2% of cases, usually in patients older than 40 years of age (377). The most common malignancy developing in the initially benign teratoma is squamous cell carcinoma. Other neoplasms were reported (e.g., adenocarcinomas, melanomas, which may arise from the skin or retinal anlage, and sarcomas, including leiomyosarcomas and mixed mesodermal tumors) (2). Carcinomas may arise from any of the epithelial elements. The preoperative evaluation and differential diagnosis of immature teratomas are the same as for other germ cell tumors. Some of these lesions will contain calcifications similar to those of mature teratomas, which can be detected by a radiograph of the abdomen or by ultrasonography. Rarely they are associated with the production of steroid hormones and can be accompanied by sexual pseudoprecocity (342). Tumor markers are negative unless a mixed germ cell tumor is present.


Gynecology_Novak

Gynecology_Novak. Surgery In a premenopausal patient whose lesion appears to be confined to a single ovary, unilateral oophorectomy and surgical staging should be performed. For a postmenopausal patient, a total abdominal hysterectomy and bilateral salpingo-oophorectomy may be performed. Contralateral involvement is rare, and routine resection or wedge biopsy of the contralateral ovary is unnecessary (3,378,379). Any lesions on the peritoneal surfaces should be sampled and submitted for histologic evaluation. The most frequent site of dissemination is the peritoneum and, much less commonly, the retroperitoneal lymph nodes. Blood-borne metastases to organ parenchyma, such as the lungs, liver, or brain, are uncommon. When present, they are usually seen in patients with late or recurrent disease and most often in tumors that are poorly differentiated (i.e., grade 3).


Gynecology_Novak

Gynecology_Novak. It is unclear whether debulking of metastatic implants enhances the response to combination chemotherapy (384–390). Unlike epithelial lesions, immature teratomas are chemosensitive. Because cure depends on the prompt delivery of chemotherapy, any surgical resection that is potentially morbid and could delay chemotherapy should be resisted. Chemotherapy Patients with IA, grade 1 tumors have an excellent prognosis, and no adjuvant therapy is required. For patients whose tumors are stage IA, grade 2 or 3, adjuvant chemotherapy should be used (359–361,374,375–378). Chemotherapy is indicated for patients who have ascites, regardless of tumor grade. The standard approach is BEP. The most frequently used combination chemotherapeutic regimen was VAC, but this regimen is no longer used (359,360,391–397).


Gynecology_Novak

Gynecology_Novak. The GOG is prospectively studying three courses of BEP therapy for patients with completely resected stages I, II, and III ovarian germ cell tumors (359,360,397). Overall, the toxicity is acceptable, and 91 of 93 patients whose nondysgerminomatous tumors were treated are clinically free of disease. The BEP regimen, which is standard of care for testicular cancer, is also the most appropriate chemotherapy regimen for nondysgerminomatous germ cells tumors of the ovary. As these tumors can progress rapidly, treatment should be initiated as soon as possible after surgery, preferably within 7 to 10 days (398).


Gynecology_Novak

Gynecology_Novak. The switch from VBP to BEP was prompted by the experience in patients with testicular cancer, in which the replacement of vinblastine with etoposide was associated with a better therapeutic index (i.e., equivalent efficacy and lower morbidity), especially less neurologic and gastrointestinal toxicity. The use of bleomycin seems to be important for this group of patients. In a randomized study of three cycles of etoposide plus cisplatin with or without bleomycin (EP versus BEP) in 166 patients with germ cell tumors of the testes, the BEP regimen had a relapse-free survival rate of 84% compared with 69% for the EP regimen (p = 0.03) (372). Cisplatin may be slightly better than carboplatin in the setting of metastatic germ cell tumors. One hundred ninety-two patients with germ cell tumors of the testes were entered into a study of four cycles of etoposide plus cisplatin (EP) versus four cycles of etoposide plus carboplatin (EC). There were three relapses with the EP regimen versus seven


Gynecology_Novak

Gynecology_Novak. the testes were entered into a study of four cycles of etoposide plus cisplatin (EP) versus four cycles of etoposide plus carboplatin (EC). There were three relapses with the EP regimen versus seven with the EC regimen, although the overall survival of the two groups is identical thus far (373). In view of these results, BEP is the preferred treatment regimen for patients with gross residual disease and has replaced the VAC regimen for patients with completely resected disease.


Gynecology_Novak

Gynecology_Novak. It is unclear whether adjuvant chemotherapy is indicated or required for all patients with resected immature teratomas. Several reports support the successful management of these patients with surgery alone and close surveillance (390,399). In the largest series, an Intergroup study from the Pediatric Oncology Group and the Children’s Cancer Group, 73 children with immature teratoma (44 of ovarian origin) underwent surgery followed by surveillance. With a median follow-up of 35 months, the overall 3-year event-free survival rates for all patients and those with ovarian teratomas were 93% and 100%, respectively. Thirteen of the 44 girls with an immature ovarian teratoma had microscopic foci of yolk sac tumor in the teratoma; one developed recurrent disease and was successfully treated with cisplatin-based chemotherapy. Of note, 82% of the tumors were grade 1 or 2; however, 92% of those with foci of yolk sac tumor were grade 2or3.


Gynecology_Novak

Gynecology_Novak. The need for a second-look operation was questioned (375,376). It seems not to be justified in patients who received chemotherapy in an adjuvant setting, because chemotherapy in these patients is effective. Second-look laparotomy in patients with macroscopic residual disease at the start of chemotherapy may be of value in selected patients, as some patients may have residual mature teratoma and are at risk of growing teratoma syndrome, a rare complication of immature teratomas (400,401). Cancers can arise at a later date in residual mature teratoma. It is important to resect any residual mass and exclude persistent disease because further chemotherapy may be indicated. The principles of surgery are based on the much larger experience of surgery in males with residual masses following chemotherapy for germ cell tumors with a component of immature teratoma (402). Mathew et al. reported their experience of laparotomy in assessing the nature of postchemotherapy residue in ovarian germ


Gynecology_Novak

Gynecology_Novak. for germ cell tumors with a component of immature teratoma (402). Mathew et al. reported their experience of laparotomy in assessing the nature of postchemotherapy residue in ovarian germ cell tumors. Sixty-eight patients completed combination chemotherapy with cisplatin regimes, and 35 had radiological residual masses. Twenty-nine of these 35 patients underwent laparotomy and 3 patients had viable tumor, 7 immature teratomas, 3 mature teratoma, and 16 only necrosis or fibrosis. None of the patients with dysgerminoma, embryonal carcinoma, absence of teratoma element in the primary tumor, and radiological residual mass of less than 5 cm had viable tumor, whereas all patients with tumors containing the teratoma component initially had residual tumor, strengthening the case for surgery in patients with immature teratoma and any residual mass (403,404).


Gynecology_Novak

Gynecology_Novak. The most important prognostic feature of the immature teratoma is the grade of the lesion (2,370). The stage of disease and the extent of tumor at the initiation of treatment have an impact on the curability of the lesion. Overall, the 5-year survival rate for patients with all stages of pure immature teratomas is 70% to 80%, and it is 90% to 95% for patients with surgically staged, stage I lesions (374,377,386). Endodermal Sinus Tumors Endodermal sinus tumors (EST) are referred to as yolk sac carcinomas because they are derived from the primitive yolk sac (2, 3). These lesions are the third most frequent malignant germ cell tumors of the ovary. ESTs occur in patients with a median age of 16 to 18 years (2,3,405). About one-third of the patients are premenarcheal at the time of diagnosis. Abdominal or pelvic pain is the most frequent initial symptom, occurring in about 75% of patients, whereas an asymptomatic pelvic mass is documented in 10% of patients (343).


Gynecology_Novak

Gynecology_Novak. The gross appearance of an EST is soft grayish-brown. Cystic areas caused by degeneration or necrosis are present in these rapidly growing lesions. The capsule is intact in most cases. The EST is unilateral in 100% of cases; thus, biopsy of the opposite ovary is contraindicated. The association of such lesions with gonadal dysgenesis must be appreciated, and chromosomal analysis should be performed preoperatively in premenarcheal patients (3).


Gynecology_Novak

Gynecology_Novak. The association of such lesions with gonadal dysgenesis must be appreciated, and chromosomal analysis should be performed preoperatively in premenarcheal patients (3). Microscopically, the characteristic feature is the endodermal sinus, or Schiller-Duval body (Fig. 37.22). The cystic space is lined with a layer of ﬂattened or irregular endothelium into which projects a glomerulus-like tuft with a central vascular core. These structures vary throughout the tumor, and the reticular, myxoid elements simulate undifferentiated mesoblast. The lining of the papillary infolding and the cavity is irregular, with an occasional cell containing clear, glassy cytoplasm, simulating the hobnail appearance of the epithelium in clear cell tumors. The association of EST with dysgerminoma must be emphasized if diagnosis and therapy are to be optimal (2,3).


Gynecology_Novak

Gynecology_Novak. Most EST lesions secrete AFP and, rarely, they may elaborate detectable alpha-1 antitrypsin (AAT). AFP can be demonstrated in the tumor by means of the immunoperoxidase technique. There is a good correlation between the extent of disease and the level of AFP, although discordance is observed. The serum level of these markers, particularly AFP, is useful in monitoring the patient’s response to treatment (405–409). Figure 37.22 Endodermal sinus tumor of the ovary. Note the classic Schiller-Duval body with its central vessel and mantle of endoderm. Rare Germ Cell Tumors of the Ovary


Gynecology_Novak

Gynecology_Novak. Figure 37.22 Endodermal sinus tumor of the ovary. Note the classic Schiller-Duval body with its central vessel and mantle of endoderm. Rare Germ Cell Tumors of the Ovary Surgery The treatment of the EST consists of surgical exploration, unilateral salpingooophorectomy, and a frozen section for diagnosis. The addition of a hysterectomy and contralateral salpingo-oophorectomy does not alter outcome (407). Any gross metastases should be removed, if possible, but thorough surgical staging is not indicated because all patients need chemotherapy. At surgery, the tumors tend to be solid and large, ranging in size from 7 to 28 cm (median, 15 cm) in the GOG series (397). Bilaterality does not occur, and the other ovary is involved with metastatic disease only when there are other metastases in the peritoneal cavity. Most patients have early-stage disease: 71%, stage I; 6%, stage II; and 23%, stage III (409).


Gynecology_Novak

Gynecology_Novak. Chemotherapy All patients with ESTs are treated with either adjuvant or therapeutic chemotherapy. Before the routine use of combination chemotherapy for this disease, the 2year survival rate was only about 25%. After the introduction of the VAC regimen, this rate improved to 60% to 70%, indicating the chemosensitivity of most of these tumors (392,393). With conservative surgery and adjuvant chemotherapy, fertility can be preserved as with other germ cell tumors. Cisplatin-containing combination chemotherapy with three to four cycles of BEP should be used as primary chemotherapy for EST. The GOG protocols used three to four treatment cycles given every 3 weeks (397,410).


Gynecology_Novak

Gynecology_Novak. Embryonal carcinoma of the ovary is an extremely rare tumor that is distinguished from a choriocarcinoma of the ovary by the absence of syncytiotrophoblastic and cytotrophoblastic cells. The patients are very young; ages ranged between 4 and 28 years (median, 14 years) in two series (411). Older patients were reported (412). Embryonal carcinomas may secrete estrogen, with the patient exhibiting symptoms and signs of precocious pseudopuberty or irregular bleeding (2). The clinical picture is otherwise similar to that of the EST. The primary lesions tend to be large, and about two-thirds are confined to one ovary at the time of diagnosis. These lesions frequently secrete AFP and hCG, which are useful for following the response to subsequent therapy (408). The treatment of embryonal carcinomas is the same as for the EST (i.e., a unilateral oophorectomy followed by combination chemotherapy with BEP) (360,397). Choriocarcinoma of the Ovary


Gynecology_Novak

Gynecology_Novak. Choriocarcinoma of the Ovary Pure nongestational choriocarcinoma of the ovary is an extremely rare tumor. Histologically, it has the same appearance as gestational choriocarcinoma metastatic to the ovaries (413). Most patients with this cancer are younger than 20 years. The presence of hCG can be useful in monitoring the patient’s response to treatment. In the presence of high hCG levels, isosexual precocity occurs in about 50% of patients whose lesions appear before menarche (413,414). There are only a few limited reports on the use of chemotherapy for nongestational choriocarcinomas, but complete responses were reported with the MAC (methotrexate, actinomycin D, and cyclophosphamide) regimen used in a manner described for gestational trophoblastic disease (379) (see Chapter 39). Alternatively, the BEP regimen can be used. The prognosis of ovarian choriocarcinomas is poor, with most patients having metastases to organ parenchyma at the time of diagnosis.


Gynecology_Novak

Gynecology_Novak. Polyembryoma of the ovary is another extremely rare tumor, which is composed of embryoid bodies. This tumor replicates the structures of early embryonic differentiation (i.e., the three somatic layers: endoderm, mesoderm, and ectoderm) (2,346). The lesion tends to occur in very young, premenarcheal girls with signs of pseudopuberty and elevated AFP and hCG levels. Anecdotally, the VAC chemotherapeutic regimen is reported to be effective (346,415). Mixed Germ Cell Tumors Mixed germ cell malignancies of the ovary contain two or more elements of the lesions described above. In one series, the most common component of a mixed malignancy was dysgerminoma, which occurred in 80%, followed by EST in 70%, immature teratoma in 53%, choriocarcinoma in 20%, and embryonal carcinoma in 16% (415). The most frequent combination was a dysgerminoma and an EST. The mixed lesions may secrete either AFP, hCG, or both or neither of these markers, depending on the components.


Gynecology_Novak

Gynecology_Novak. These lesions should be managed with combination chemotherapy, preferably BEP. The serum marker, if positive initially, may become negative during chemotherapy, but this finding may reﬂect regression of only a particular component of the mixed lesion. Therefore, for these patients, a second-look laparotomy may be indicated to determine the precise response to therapy if macroscopic disease was present at initiation of chemotherapy. The most important prognostic features are the size of the primary tumor and the relative size of its most malignant component (416). For stage IA lesions smaller than 10 cm, survival is 100%. Tumors composed of less than one-third EST, choriocarcinoma, or grade 3, immature teratoma have an excellent prognosis, but it is less favorable when these components constitute most of the mixed lesions. Late Effects of Treatment of Malignant Germ Cell Tumors of the Ovary


Gynecology_Novak

Gynecology_Novak. Late Effects of Treatment of Malignant Germ Cell Tumors of the Ovary Although there are substantial data regarding late effects of cisplatin-based therapy in men with testicular cancer, sparse information is available for women with ovarian germ cell tumors. Among the adverse events from chemotherapy reported in men are renal and gonadal dysfunction, neurotoxicity, cardiovascular toxicity, and secondary malignancies.


Gynecology_Novak

Gynecology_Novak. An important cause of infertility in patients with ovarian germ cell tumors is unnecessary bilateral salpingo-oophorectomy and hysterectomy. Although temporary ovarian dysfunction or failure is common with platinum-based chemotherapy, most women will resume normal ovarian function, and childbearing is usually preserved (349,355). In one representative series of 47 patients treated with combination chemotherapy for germ cell malignancies, 91.5% resumed normal menstrual function, and there were 14 healthy live births and no birth defects (370). Factors such as older age at initiation of chemotherapy, greater cumulative drug dose, and longer duration of therapy all have an adverse effect on future gonadal function. An important cause of late morbidity and mortality in patients receiving chemotherapy for germ cell tumors is the development of secondary tumors. Etoposide in particular was implicated in the development of treatment-related leukemias (417,418).


Gynecology_Novak

Gynecology_Novak. The chance of developing treatment-related leukemia following etoposide is dose related. The incidence of leukemia is approximately 0.4% to 0.5% (representing a 30-fold increased likelihood) in patients receiving a cumulative etoposide dose of less than 2,000 mg/m2, compared with as much as 5% (representing a 336-fold increased likelihood) in those receiving more than 2,000 mg/m2 (417). In a typical three-or four-cycle course of BEP, patients receive a cumulative etoposide dose of 1,500 or 2,000 mg/m2, respectively. Despite the risk of secondary leukemia, risk-benefit analyses concluded that etoposidecontaining chemotherapy regimens are beneficial in advanced germ cell tumors; one case of treatment-induced leukemia would be expected for every 20 additionally cured patients who receive BEP as compared with platinum, vincristine, bleomycin (PVB). The risk–benefit balance for low-risk disease, or for high-dose etoposide in the salvage setting, is less clear (418).


Gynecology_Novak

Gynecology_Novak. Sex cord–stromal tumors of the ovary account for about 5% to 8% of all ovarian malignancies (2,3,342,343,419–425). This group of ovarian neoplasms is derived from the sex cords and the ovarian stroma or mesenchyme. The tumors usually are composed of various combinations of elements, including the “female” cells (i.e., granulosa and theca cells) and “male” cells (i.e., Sertoli and Leydig cells), and morphologically indifferent cells. A classification of this group of tumors is presented in Table 37.8. Table 37.8 Sex Cord–Stromal and Steroid Cell Tumors 1. A. Granulosa cell tumor B. Tumors in thecoma-fibroma group 1. 2. 3. 2. Androblastomas; Sertoli-Leydig cell tumors A. Well-differentiated 1. 2. 3. B. Moderately differentiated C. Poorly differentiated (sarcomatoid) D. With heterologous elements 3. 4. Sex cord tumor with annular tubules 5. Sex cord-stromal tumors, unclassified 6. A. Stromal luteoma B. Leydig cell tumor C. Steroid cell tumor, not otherwise classified


Gynecology_Novak

Gynecology_Novak. 4. Sex cord tumor with annular tubules 5. Sex cord-stromal tumors, unclassified 6. A. Stromal luteoma B. Leydig cell tumor C. Steroid cell tumor, not otherwise classified Granulosa-stromal cell tumors include granulosa cell tumors, thecomas, and fibromas. The granulosa cell tumor is a low-grade malignancy; rarely, thecomas and fibromas have morphologic features of malignancy and may be referred to as fibrosarcomas. Granulosa cell tumors, which secrete estrogen, are seen in women of all ages. They are found in prepubertal girls in 5% of cases; the remainder are found in women throughout their reproductive and postmenopausal years (422). Granulosa cell tumors are bilateral in only 2% of patients.


Gynecology_Novak

Gynecology_Novak. Granulosa cell tumors range from a few millimeters to 20 cm or more in diameter. The tumors are rarely bilateral and have a smooth, lobulated surface. The solid portions of the tumor are granular, frequently trabeculated, and yellow or gray-yellow in color. After clear cell carcinoma, the granulosa-theca cell tumor is probably the most inaccurately diagnosed tumor of the female gonad. Of 477 ovarian tumors from the Emil Novak Ovarian Tumor Registry diagnosed initially as granulosa-theca cell tumors, almost 15% were reclassified after histologic review. Lesions misdiagnosed as granulosa cell tumors included primary or metastatic carcinomas, teratoid tumors, and poorly differentiated mesothelial tumors (419).


Gynecology_Novak

Gynecology_Novak. The classic adult granulosa cell is round or ovoid with scant cytoplasm. The nucleus contains compact, finely granular chromatin and is either euchromatic or hypochromatic (3). “Coffee bean” grooved nuclei are characteristic; mitotic figures may be present, but numerous mitotic figures should prompt consideration for poorly differentiated or undifferentiated carcinoma. In the most common variety, the adult granulosa cells show a tendency to arrange themselves in small clusters or rosettes around a central cavity, so there is a resemblance to primordial follicles (i.e., Call-Exner bodies) (Fig. 37.23). The stroma is similar to the theca and may be luteinized. In children and adolescents, the granular cell tumors are often cystic, contain luteinized cells, and can be associated with precocious puberty. Juvenile granulosa cell tumors, so named because of their tendency to occur in younger patients, feature rounder, more hyperchromatic nuclei and may contain numerous mitotic figures. The


Gynecology_Novak

Gynecology_Novak. puberty. Juvenile granulosa cell tumors, so named because of their tendency to occur in younger patients, feature rounder, more hyperchromatic nuclei and may contain numerous mitotic figures. The presence of large, irregular follicle spaces is an additional distinguishing feature of the juvenile granulosa cell tumor. The adult granulosa cell tumor tends to occur in older women and the juvenile tumor in children and young women, but the diagnosis is not based on age of presentation, but on histology. Adult granulosa cell tumors, but not juvenile granulose cell tumors, harbor a somatic mutation in the FOXL2 gene (426).


Gynecology_Novak

Gynecology_Novak. Figure 37.23 Granulosa cell tumor of the ovary. Note the classic Call-Exner bodies with a minimal stromal component in this tumor of folliculoid pattern. (Arrow points to an example.) Granulosa cell tumors, which secrete estrogen, are seen in women of all ages. They are found in prepubertal girls in 5% of cases (typically the juvenile form); the remainder are distributed throughout the reproductive and postmenopausal years (422– 425). They are bilateral in only 2% of patients.


Gynecology_Novak

Gynecology_Novak. Of the rare prepubertal lesions, 75% are associated with sexual pseudoprecocity because of the estrogen secretion (422). Most reproductive-age patients have menstrual irregularities or secondary amenorrhea, and, frequently, cystic hyperplasia of the endometrium. Abnormal uterine bleeding is often the initial symptom for postmenopausal women. The estrogen secretion in these patients can be sufficient to stimulate the development of endometrial cancer. Low-grade endometrial cancer occurs in association with granulosa cell tumors in at least 5% of cases, and 25% to 50% are associated with endometrial hyperplasia (2,413,419–422,426). The other symptoms and signs of granulosa cell tumors are nonspecific and the same as most ovarian malignancies. Ascites is present in about 10% of cases, and, rarely, a pleural effusion is present (419–422). Granulosa tumors tend to be hemorrhagic; occasionally, they rupture and produce a hemoperitoneum.


Gynecology_Novak

Gynecology_Novak. Adult granulosa cell tumors are usually stage I at diagnosis, but may recur 5 to 30 years after initial diagnosis (421). Most juvenile granulosa cell tumors are clinically benign; only about 10% recur and when they do so, it is generally within 5 years of the initial diagnosis. The tumors may spread hematogenously, and metastases can develop in the lungs, liver, and brain years after initial diagnosis. When adult granulosa cell tumors do recur, they can progress rapidly. Malignant thecomas are extremely rare, and their signs and symptoms, management, and outcome are similar to those of the granulosa cell tumors (419). Inhibin is secreted by some granulosa cell tumors and is a useful marker for the disease (427–431). An elevated serum inhibin level in a premenopausal woman presenting with amenorrhea and infertility is suggestive of a granulosa cell tumor (432).


Gynecology_Novak

Gynecology_Novak. The treatment of granulosa cell tumors depends on the age of the patient and the extent of disease. For most patients, surgery alone is sufficient primary therapy; radiation and chemotherapy are reserved for the treatment of recurrent or metastatic disease (422–429,433–436).


Gynecology_Novak

Gynecology_Novak. Surgery Because granulosa cell tumors are bilateral in only about 2% of patients, a unilateral salpingo-oophorectomy is appropriate therapy for stage IA tumors in children or in women of reproductive age (420). At the time of laparotomy, if a granulosa cell tumor is identified by frozen section, a staging operation is performed, including an assessment of the contralateral ovary. If the opposite ovary appears enlarged, it should be sampled for biopsy. For perimenopausal and postmenopausal women for whom ovarian preservation is not important, a hysterectomy and bilateral salpingo-oophorectomy should be performed. For premenopausal patients in whom the uterus is left in situ, an endometrial biopsy should be performed because of the possibility of a coexistent adenocarcinoma of the endometrium (422).


Gynecology_Novak

Gynecology_Novak. Radiation Therapy There is no evidence to support the use of adjuvant radiation therapy for granulosa cell tumors, although pelvic irradiation may help to palliate isolated pelvic recurrences (422,434).


Gynecology_Novak

Gynecology_Novak. Chemotherapy There is no evidence that adjuvant chemotherapy will prevent recurrence of disease (436–439). Metastatic lesions and recurrences were treated with a variety of antineoplastic drugs. Although the data are inconclusive, BEP or carboplatin and paclitaxel are used in selected patients with stage III or IV tumors or recurrent disease (433). In a GOG study, 37% (14 of 30) patients treated with BEP had a negative second-look laparotomy, and these patients had a median time to progression of 24.4 months (440). Granulosa cell tumors are potentially hormonally responsive, with about 30% of granulosa tumors expressing estrogen receptors and almost 100% expressing progesterone receptors. Hormonal agents such as progestins or luteinizing hormone-releasing hormone agonists are used to treat these patients because they are often elderly (441–445). There are case reports of durable response to aromatase inhibitors in patients with metastatic granulosa cell tumors who received multiple


Gynecology_Novak

Gynecology_Novak. these patients because they are often elderly (441–445). There are case reports of durable response to aromatase inhibitors in patients with metastatic granulosa cell tumors who received multiple prior treatment (443). Small clinical series and case reports indicated that luteinizing hormone-releasing hormone agonists had a 50% response rate in 13 patients, while 4 of 5 patients in the literature responded to a progestational agent. Two case series reported durable responses in a total of six patients receiving aromatase inhibitors among those who progressed on or were intolerant of chemotherapy (442–445).


Gynecology_Novak

Gynecology_Novak. Adult granulosa cell tumors have a prolonged natural history and a tendency toward late relapse, reﬂecting their low-grade biology. Ten-year survival rates of about 90% are reported, with 20-year survival rates dropping to 75% (420–422,432,433). Most histologic types have the same prognosis, but patients with the more poorly differentiated diffuse or sarcomatoid type tend to do worse (419). The DNA ploidy of the tumors is correlated with survival. Holland et al. reported DNA aneuploidy in 13 of 37 patients (35%) with primary adult granulosa cell tumors (437). The presence of residual disease is the most important predictor of progression-free survival, but DNA ploidy is an independent prognostic factor. Patients with residual-negative DNA diploid tumors had a 10-year progression-free survival of 96%.