Value of lymph node assessment in ovarian cancer: Status of the art at the end of the second millennium.

Available data on the incidence and the clinical value of lymph node assessment in ovarian cancer are reported. In early ovarian cancer, positive nodes are found in 4-25% of patients. Serous adenocarcinoma and poorly differentiated tumors are characterized by the highest incidence of node metastases. Five-year survival for stage IIIC disease with only retroperitoneal spread is clearly better than for stage IIIC with intraperitoneal dissemination. In advanced ovarian cancer, the rate of node involvement ranges from 55 to 75%. The percentage of positive nodes is significantly related to the amount of residual tumor after cytoreductive surgery, and node status seems to be an important prognostic factor for survival. Although data from retrospective studies advocate a therapeutic effect for systematic lymphadenectomy, results from prospective randomized trials are warranted. After chemotherapy a high percentage of patients (range, 25-77%) are found to have metastatic nodes. In particular, at second-look laparotomy, positive nodes are detected in 17-40% of patients who have no intraperitoneal disease.

Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma.

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m(2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.

Systematic pelvic and paraaortic lymphadenectomy at second-look laparotomy for ovarian cancer.

A retrospective review of the medical records of all ovarian cancer patients admitted to our institution from January 1974 to December 1993 was performed. A total of 58 consecutive patients who underwent systematic pelvic and paraaortic lymphadenectomy during second-look surgery was found. Node metastases were found in 15 of 58 patients (25.8%). No significant correlation was found between the variables of disease (e.g., stage of the disease at diagnosis, histology, grade, residual tumor after the first cytoreductive surgery, and the type of chemotherapy administered) and node status at second-look. Node metastases were found in 8 of 45 (17.7%) patients with absence of intraperitoneal disease, compared with 7 of 11 (63.6%) patients with intraabdominal residual disease (P < 0.02). There was no difference in 5-year survival for patients with absence of residual tumor in the peritoneal cavity as well as in the retroperitoneum (5-year survival 80%) and for patients with retroperitoneal disease only (5-year survival 77%). On the contrary, a highly significant difference in survival (P < 0.001) was observed between these two groups of patients and those who had intraabdominal residual tumor. Twelve of 45 (26.6%) patients have recurred. FIGO stage, grade, and residual disease after primary surgery were determinant in predicting recurrence. Notably, no relation emerged between relapse rate and the node status at second-look.

Systematic pelvic and paraaortic lymphadenectomy for advanced ovarian cancer: prognostic significance of node metastases.

A retrospective study of 488 patients with untreated advanced ovarian cancer is presented. Systematic pelvic and paraaortic lymphadenectomy was performed in 248 cases (50.8%). Selective sampling and node biopsy was performed in 33 (6.7%) and 47 (9.6%) patients, respectively. Node metastases were found in 194 of 328 patients (59.1%). The incidence of metastatic nodes significantly increased with more advanced stages, with serous histology, and with a greater amount of residual tumor. Node status appeared to be related to pathology findings at second-look. A complete pathologic response was documented in 26 of 31 (83.8%) patients with negative nodes and in 38 of 59 (64.6%) with positive nodes at first surgery. Patients with negative nodes survived significantly longer (5-year survival, 46%; median, 60 months) than those who had node metastases (5-year survival, 25%; median, 36 months). Using multivariate analysis, lymph node status, together with the stage of disease and residual tumor, still had a significant impact on 5-year survival. Moreover, among patients with optimal cytoreduction, 5-year survival was 46% (median, 56 months) and 30% (median, 41 months) for patients who did and did not undergo lymphadenectomy, respectively (P = 0.05). Likewise, when suboptimal cytoreduction was considered, a median 5-year survival of 24 months was obtained in patients who underwent lymphadenectomy compared with 14 months in patients who did not (P < 0.005).

Combined preoperative chemoradiotherapy followed by radical surgery in locally advanced vulvar carcinoma. A pilot study.

BACKGROUND: Although for decades exenterative surgery has represented the standard treatment for patients with locally advanced vulvar cancer, combined approaches, including preoperative radiation with or without chemotherapy, are now considered the treatment of choice. We report the results of a pilot study on concurrent chemoradiotheraphy followed by radical surgery for patients with locally advanced squamous cell carcinomas of the vulva. METHODS: Thirty-one patients with squamous cell carcinoma of the vulva were treated with two courses of combination chemotherapy mitomycin C, 15 mg/m2 intravenously (i.v.) on Day 1, and 5-fluorouracil, 750 mg/m2 i.v., in continuous 24-hour infusion on Days 1 to 5. Inguinal and pelvic lymph node chains and the vulva were irradiated (starting on the same day as the chemotherapy) up to a total dose of 36 Gy. After a 2-week interval, a second course of chemoradiotherapy was given (18 Gy on the vulvar region only). After 2 weeks, patients underwent radical surgery. RESULTS: An objective response was observed in 22 of 24 primary cases (91.6%) and in 7 of 7 recurrent cases. All but two unresponsive patients underwent radical surgery. The postoperative morbidity rate was 65% (19 of 29 patients), and the mortality rate was 13.8% (4 of 29 patients). Five of nine patients (55%) with biopsy-proven inguinal lymph node metastases showed no residual lymph node disease in the surgical specimen. The recurrence rate was 31.8% and the medial follow-up time was 34 months. CONCLUSIONS: Chemoradiotherapy seems to be effective for squamous cell carcinoma of the vulva. If treatment-related morbidity could be decreased, such a combined approach might offer a new perspectives for a conservative treatment of locally advanced vulvar cancer.

An intensive treatment with mitoxantrone and ifosfamide in second-line therapy of epithelial ovarian cancer.

AIMS AND BACKGROUND: Both mitoxantrone (DHAD) and ifosfamide (IFO) have given promising results when administered as single agents in advanced ovarian cancer pretreated with platinum compounds. The aim of this I.T.M.O. group pilot trial was to evaluate, in a selected population of ovarian cancer patients, the efficacy and tolerability of the following intensive second-line regimen: DHAD, 12 mg/m2 i.v., day 1; IFO, 4,000 mg/m2 i.v., days 1 and 2; Mesna, 800 mg/m2 i.v. t.i.d., days 1 and 2. Filgrastim (5 micrograms/kg/day i.m.) was given from day 6 to day 19 to reduce the expected neutropenia. Cycles were repeated every 21 days. METHODS: Nineteen platinum-pretreated patients were enrolled and 14 were evaluated for tumor response; the disease of 5 patients was not measurable clinically or radiologically. RESULTS: Seven responses were observed (3 CRs), with a median response duration of 5 months. The median time to treatment failure and overall survival for all 19 patients was respectively 8 and 13 months. Anemia was observed in all of the treated patients (grade 3-4 in 9 cases). Only 6 of the 19 patients ended the five planned cycles of chemotherapy without any delay. CONCLUSIONS: Although DHAD plus IFO induced a considerable number of objective responses, the limited response duration time to treatment failure, and overall survival as well as the reported side effects suggest that this is not a recommended regimen for the palliative treatment of ovarian cancer patients undergoing second-line chemotherapy.

Surgical staging for epithelial ovarian tumors of low malignant potential.

From January 1975 to December 1991, 34 patients with a diagnosis of epithelial ovarian tumors of low malignant potential (LMP) were admitted to the Istituto Nazionale Tumori of Milan. Eighteen of them (group 1) underwent complete staging laparotomy and retroperitoneal para-aortic and pelvic lymphadenectomy, as for ovarian cancer. In the remaining 16 cases (group 2), the surgical treatment ranged from unilateral oophorectomy to incomplete staging procedure. In group 1, nine patients (50%) were found to have retroperitoneal nodal involvement. In group 2, all patients had stage I disease. Patients were followed up for 20-222 months (mean 108, median 86). There were two recurrences in group 2 (after 5 years) and none in group 1 (NS). Currently all patients are alive and disease free. Nine of 18 group 1 patients were upstaged to stage III on the basis of lymph node involvement only. However, at least in this retrospective series, lymph node metastases did not affect prognosis or survival.

High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer.

BACKGROUND: On the basis of preliminary results achieved with a high-dose cisplatin regimen including glutathione as chemoprotector, the efficacy and toxicity of the new regimen was further evaluated in a larger series of patients with advanced ovarian cancer (stage III and IV). PATIENTS AND METHODS: The study included patients with bulky or extensive residual disease after primary laparotomy or with bulky inoperable tumor masses. A total of 79 patients were treated with up to five courses of high-dose cisplatin (40 mg/m2 daily in normal saline, for four days) plus glutathione (2500 mg as a short-term infusion before cisplatin), together with cyclophosphamide (600 mg/m2 as an i.v. bolus on day 4). A standard i.v. hydration consisting of a total of 2000 ml of fluids without diuretics was employed. RESULTS: All eligible patients, who received a total of 345 courses, were assessed for response and toxicity and 52 received the planned five courses of the protocol. Forty-five patients (57%) achieved complete clinical responses and 20 (25%) had partial remissions for an overall response rate of 82%. The response rate was critically dependent on tumor size before chemotherapy. Thirty-eight of 45 patients who had complete clinical responses underwent second-look laparotomy, and 29 had pathological complete responses (37%). Seventeen of these 29 patients subsequently relapsed (median disease-free interval, 12 months; range, 6-45). With a median follow-up time of 44 months, the median survival for the 79 analyzed cases was 40 months. The toxicity of the regimen was moderate. Nausea/vomiting was the most severe acute toxicity. Myelotoxicity was acceptable, with severe leukopenia and thrombocytopenia (grade 4) occurring in 8% and 3% of patients, respectively. Nephrotoxicity was minimal with a transient increase (to < 2 mg/dL) in serum creatinine in only 6 patients (8%). Peripheral neurotoxicity and ototoxicity were the most significant long-term toxicities. The severity of these side effects (grade 3 WHO neurotoxicity occurred in only 4% of patients) was apparently less than has been reported with other high-dose cisplatin regimens. Neurotoxicity required discontinuation of therapy in three patients after four courses. Most affected patients had complete or partial recovery of symptoms with time. DISCUSSION: The efficacy and tolerability of the regimen confirm the feasibility of this new approach including glutathione in order to increase cisplatin dose intensity. The superiority of this regimen over standard induction therapy should be confirmed in randomized trials.

A preoperative single course of high-dose cisplatin and bleomycin with glutathione protection in bulky stage IB/II carcinoma of the cervix.

One course of preoperative chemotherapy including high-dose cisplatin (40 mg/m2 daily for 5 consecutive days) with glutathione protection and bleomycin (15 mg on days 2, 8 and 9) was administered to 27 patients with bulky operable cervical carcinoma (stage IB/II) in a pilot study. In all patients the tumor diameter was greater than 4 cm. Surgery (radical hysterectomy with pelvic and para-aortic lymphadenectomy) was planned within one month of chemotherapy. In 27 evaluable patients, nausea/vomiting was the most pronounced side effect. Significant (but transient) increases in serum transaminases were detected in 19 patients. Electrolyte imbalance (hypokalemia) was detected in 6 patients (one with hypocalcemia). These reversible effects were not associated with other signs of renal toxicity. Objective clinical responses were observed in 21 patients, 18 of them partial and 3 complete responders (pathologically confirmed in 2). Radical hysterectomy with pelvic and para-aortic lymphadenectomy was performed with no particular complications. The shrinking of bulky tumor made the operation easier, especially in parametrial resections. High-dose cisplatin chemotherapy prior to surgery is feasible with acceptable toxicity. The encouraging results of this study warrant further investigations to define the role of neoadjuvant therapy.

A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma.

Glutathione (GSH) is a sulfur-containing nucleophile that protects against cisplatin-induced renal toxicity without reducing the antitumor activity of the cytotoxic agent. To document further the clinical role of GSH in improving the outcome of cisplatin-containing regimens, the feasibility of the GSH/cisplatin combination using a low-volume hydration protocol was evaluated in untreated ovarian cancer patients. Twelve patients at stage III (minimal residual disease) and 23 with localized disease at high risk for recurrence were treated with cisplatin (90 mg/m2, i.v. in 250 ml of normal saline over 30 min) and cyclophosphamide (600 mg/m2 i.v.) every 3 weeks. GSH (5 g in 200 ml of normal saline) was administered by a short-term infusion (15 min) prior to cisplatin. The hydration protocol consisted of 1 liter of fluids without diuretics. The treatment was well tolerated; no nephrotoxic or neurotoxic manifestations were observed. The renal excretion of cisplatin (23%) at 24 hours following infusion was lower than expected using a standard i.v. hydration protocol. No reduction of renal elimination of cisplatin could be detected in subsequent courses, thus suggesting a minimal degree of impairment in renal function. In the series of evaluable patients (11) with stage III disease, 9 had complete pathological response. In the series of patients with no clinically detectable disease initially, all were disease-free at treatment completion. Taken together with previous observations, these results support the view that the use of GSH is a successful approach in the attempt to optimize cisplatin treatment, providing a new modality of drug administration for out-patient treatment.

Cisplatin and cyclophosphamide in advanced ovarian carcinoma: activity and toxicity of an ambulatory regimen.

Chemotherapy with cisplatin (CDDP, 90 mg/m2) and cyclophosphamide (CTX, 600 mg/m2) was administered to 54 consecutive patients with advanced epithelial ovarian cancer (37 stage III and 17 stage IV). In 51 patients, surgery was performed prior to chemotherapy. Of the 37 stage III patients, 13 had only minimal residual disease after surgical debulking. The overall response rate was 69%, with 44% patients achieving clinical (cCR; n = 2) or pathological (pCR; n = 20) complete response. Median follow-up and overall survival time was 26 months, and median CR duration was 30 months. CR was achieved in 6 of 14 patients (43%) who were partial responders after five cycles of chemotherapy and had continued treatment for three to five more cycles. Severe bone marrow toxicity or renal function impairment was never observed, but eight patients presented peripheral signs of dose-related neurotoxicity. These findings indicate that CDDP and CTX in combination are an effective treatment for patients with advanced ovarian carcinoma, and can be administered with tolerable toxicity. In selected cases, prolonged chemotherapy administration can result in durable complete remissions.

Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer.

Recent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i.v. on day 4). The treatment was repeated every 3-4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i.v. over 15 min, with a standard i.v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2-3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosuppression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4-5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

Randomized comparison of cyclophosphamide, doxorubicin and cisplatin (CAP) versus cyclophosphamide and doxorubicin (CA) for the treatment of advanced ovarian cancer (ADOVCA). A EORTC Gynecological Cancer Cooperative Group Study.

The possible advantage of adding cisplatin (P) to cyclophosphamide (C) + adriamycin (A) in the management of stages III and IV ovarian cancer of epithelial origin was tested in a trial in which 149 patients were randomized to receive, after initial surgery, either CAP (C = 600 mg/sqm, A = 45 mg/sqm, P = 50 mg/sqm) or CA (C = 600 mg/sqm, A = 45 mg/sqm) every 4 weeks for 6 to 12 cycles, at which time follow-up laparotomoy was to be performed in responding or clinically disease-free patients. Fifteen patients were not included in the final analysis and the remaining 134 patients were considered fully or partially evaluable and are used in analysis of response and survival. The complete and partial response rates were 45.6% in the CAP arm and 45.4% in the CA arm, but the CAP regimen is of special importance in patients with bulky disease. Median survival CAP = 24 m and CA = 24.2 m), time to progression and survival was found not significantly different when CAP and CA were compared. However, more patients in the CA regimen had no macroscopic disease left after surgery than in CAP regimen (11 versus 6) and more patients in the CAP arm dose reductions and schedule delays than in the CA arm (61.1% versus 38.2%).

Pelvic and para-aortic lymphadenectomy in cancer of the ovary.

The role of the lymphadenectomy in ovarian carcinoma is widely discussed. The natural history of disease, its tendency to spread to peritoneal cavity and the lack of any reported series of careful node dissections undertaken during surgical exploration has made it difficult to establish the real significance of nodal metastatization and the optimal therapeutic approach for patients with positive nodes. At the Istituto Nazionale Tumori, Milan, 341 patients with ovarian carcinoma have been subjected to lymph node dissection. In 253 cases in which lymphadenectomy has been carried out during first surgery, the lymphonodal diffusion has been evaluated by stage, grading and histology. The incidence of lymphonodal metastases increased with the diffusion of the primitive tumour and this is particularly evident for the serous adenocarcinoma. From our data (as shown in our series of 173 cases Stage III with peritoneal and retroperitoneal diffusion) the lymphonodal involvement has to be considered as a negative prognostic factor, influencing survival in a statistically significant way. In the 88 patients subjected to radical lymphadenectomy during second-look surgery, after chemotherapy, a smaller percentage of positive nodes was observed as compared to untreated cases but, on the other hand, we documented a portion of positive nodes not sterilized by sistemic therapy. All this data confirm the necessity to perform radical lymphadenectomy not only as a staging procedure (because of low sensitivity of lymphangiography) but also as a therapeutic one for some patients.

Therapeutic and staging operations for endometrial carcinomas.

A staging error can lead to a treatment failure in the management of patients with malignant diseases. The actual progression of endometrial carcinoma was postoperatively examined in twenty patients with clinical stage II disease classified by FIGO (International Federation of Gynecology and Obstetrics) criteria. In seven of 20 patients (35%), extrauterine lesions were revealed at surgery. These seven stage-up tumors included three grade 3 endometrioid cancers, three uterine papillary serous carcinomas (UPSC) and one grade 2 endometrioid tumor with deep myometrial invasion. The sites of the extrauterine lesions were determined. The grade 2 cancer was associated with parametrial invasions and positive pelvic lymph nodes. One grade 3 endometrioid tumor and two UPSCs had positive periaortic lymph nodes. Omental involvements were revealed in one grade 3 cancer and two UPSCs, indicating that the pattern of spreading of endometrial cancer with a malignant histology is similar to the spreading of ovarian cancer. Since the both endometrium and ovarian surface epithelium have a common histologic origin in the early embryonic stage, a similar biological characteristics of these tumors are suggested. From the results, it is recommended that a radical hysterectomy with periaortic lymph node dissection, omentectomy and peritoneal washing cytology be performed for endometrial cancer with a malignant histology or deep myometrial invasion to obtain the actual staging which is necessary for maximal curative potential.

A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity.

A total of 16 consecutive patients (15 with ovarian cancer and 1 with unknown adenocarcinoma) were treated with a standard regimen including cisplatin and cyclophosphamide or with the same regimen in combination with reduced glutathione as potential protective agent against cisplatin nephrotoxicity, in a non-randomized study. Reduced glutathione (1500 mg/m2) was administered prior to each cisplatin administration (90 mg/m2) to seven patients for a maximum of five consecutive courses. A standard hydration protocol without diuretics was used. The patients received a total of 33 courses with glutathione. Glutathione was well tolerated, since it did not produce appreciable side effects. Cisplatin and glutathione combination did not produce unexpected toxicity. Two patients treated with standard regimen without glutathione developed a transient nephrotoxicity. The severity of myelosuppression was reduced following glutathione administration. Moreover, the therapeutic efficacy was not impaired by glutathione pretreatment.

Germ cell tumors of the ovary: the experience of the National Cancer Institute of Milan. I. Dysgerminoma.

The experience of the Istituto Nazionale Tumori of Milan on dysgerminoma is presented. Between 1970 and December of 1982, 25 patients were treated with a unique protocol which considered surgery and radiotherapy with different schedules according to the extension of the disease. With this treatment protocol all 13 patients at Stage I were alive and free of disease with a median follow-up of 77 months. Of 12 patients at Stage III (10 retroperitoneal and 2 retroperitoneal and peritoneal) 4 relapsed. The 5-year relapse-free survival of Stage III patients was 61.4% and the overall survival 89.5%. Amenorrhea due to radiation dose absorbed by the contralateral shielded ovary was found in 7.7%. The excellent results in Stage I patients were balanced by the unsatisfactory results in Stage III patients. A more aggressive treatment and the knowledge of other prognostic factors seem necessary.