Intraperitoneal radioactive phosphorus (32P) versus observation after negative second-look laparotomy for stage III ovarian carcinoma: a randomized trial of the Gynecologic Oncology Group.

PURPOSE: The objectives of this prospective randomized study of consolidation therapy were to evaluate recurrence-free survival (RFS), overall survival (OS), and the morbidity of intraperitoneal (IP) chromic phosphate suspension (32P) therapy in patients with stage III epithelial ovarian carcinoma who have no detectable evidence of disease at the second-look laparotomy (SLL) procedure after primary chemotherapy. PATIENTS AND METHODS: In a multi-institution clinical cooperative trial, 202 eligible patients with a negative SLL were randomly selected to receive either 15 mCi IP 32P (n = 104) or no further therapy (NFT; n = 98). RESULTS: With a median follow-up of 63 months in living patients, 68 patients in the IP 32P group (65%) and 63 patients in the NFT group (64%) have developed tumor recurrence. The relative risk of recurrence is 0.90 (IP 32P to NFT) (90% confidence interval [CI], 0.68 to 1.19). The 5-year RFS rate is 42% and 36% for the IP 32P and NFT groups, respectively; the difference is not statistically significant (log-rank test, P =.27). There was no statistically significant difference in OS (P =.19). The relative risk of death is 0.85 (IP 32P to NFT) (90% CI, 0.62 to 1.16). Sixteen patients (8%) experienced grade 3 or 4 adverse effects, with eight in each respective group. CONCLUSION: Intraperitoneal chromic phosphate did not decrease the risk of relapse or improve survival for patients with stage III epithelial ovarian cancer after a negative SLL. Despite complete pathologic remission at SLL after initial surgery and platinum-based chemotherapy, 61% of stage III ovarian cancer patients had tumor recurrence within 5 years of negative SLL. This indicates a need for more effective initial therapy and further studies of consolidation therapy.     

Intraperitoneal chromic phosphate therapy after second-look laparotomy for ovarian cancer

Between 1973 and 1985, 118 patients in clinical remission after initial surgery and postoperative chemotherapy for epithelial ovarian carcinoma underwent second-look laparotomy at the University of North Carolina. No evidence of disease (NED) was found in 57 of these patients; 43 patients received 15 mCi of radioactive chromic phosphate (32P) suspension given intraperitoneally in the immediate postoperative period. In 29 other patients, only microscopic or minimal residual disease (nodules less than 2 cm in size) was found, seven received 32P alone, ten received 32P and further chemotherapy, and 12 received chemotherapy alone. The 4-year postsecond-look survival of the patients with NED at second-look was 89% for those receiving 32P and 67% for those who had not. The respective figures for patients with minimal residual disease at second-look are 59% versus 22%. Irrespective of treatment, a group at high risk for failure after negative second-look laparotomy has been identified; those with an initial International Federation of Gynecology and Obstetrics (FIGO) stage greater than I and histologic grade greater than 1. A comparison of our data with 18 previously published series, indicates that use of postsecond-look intraperitoneal 32P can improve the progression-free interval, and possibly overall survival, of patients with NED or minimal residual disease without adding significant complications.     

Long-term results of a cisplatin-containing combination chemotherapy regimen for the treatment of advanced ovarian carcinoma

Sixty-two patients with advanced ovarian adenocarcinoma (stages III and IV) and without prior chemotherapy or radiotherapy were treated with a four-drug combination consisting of cyclophosphamide, hexamethylmelamine, 5-fluorouracil (5-FU), and cisplatin (Chex-UP). All patients were evaluable for toxicity and response, and survivors have been observed for a minimum of 48 months. The overall response rate to Chex-UP chemotherapy was 69%, with 12 patients (19%) achieving a pathologically confirmed complete remission (CR) as documented by a negative second-look laparotomy. Seven of the twelve patients (58%) who achieved a surgically confirmed CR were randomized to six cycles of intraperitoneal (IP) 5-FU. There have been seven relapses in patients who had a negative second-look laparotomy, but only four of the patients died from recurrent ovarian cancer. The median duration of remission following a negative second-look laparotomy was 53 months, while the median duration of survival has not been reached and will exceed 7.5 years. Seventeen patients (27%) achieved a clinical CR with chemotherapy but were found to have residual disease at second-look laparotomy. The median survival for these patients was 29 months, which was statistically inferior to that achieved for those patients with a negative second-look laparotomy (P less than .002), and only one patient is alive after 4 years. All patients who either achieved a partial response (PR) to therapy (14 of 62; 23%) or did not respond to therapy (19 of 62; 31%) died of ovarian cancer by 24 months. Thus, prolonged survival is associated with a surgically confirmed CR to induction therapy with Chex-UP. However, only a minority of advanced-stage ovarian cancer patients (15%) are alive 4 years after initiation of treatment with this regimen.     

Prognosis of surgically determined complete responders in advanced ovarian cancer

From January 1971 through December 1981, 246 patients with advanced (Stages III and IV) epithelial ovarian cancer underwent second-look laparotomy at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Eighty-five of these patients had a complete response (negative second-look laparotomy) following treatment with a variety of chemotherapeutic regimens. Three patients had also received irradiation. Patients were analyzed according to pretreatment characteristics (age, FIGO stage, ascites, pleural effusion, histologic grade, tumor type, type of surgery, residual tumor diameter, initial clinical status) and by the number of biopsy specimens taken at second-look laparotomy. The probability of recurrence and the length of survival following a negative second-look laparotomy are statistically related to these characteristics. Twenty of the 85 patients (24%) developed recurrent disease 5 to 32 months after laparotomy. The estimated 2- and 5-year survival rates are 99% and 85%, respectively. Patients who achieve a surgically determined complete response have an excellent chance for long-term survival.     

Isolated incisional metastases after intraperitoneal radioactive chromic phosphate therapy for ovarian carcinoma

Two women developed apparently isolated recurrences of ovarian carcinoma involving prior incisions after receiving intraperitoneal radioactive chromic phosphate (P-32) adjuvant therapy for early epithelial ovarian carcinoma. Both are alive without evidence of disease at second-look laparotomy after surgical resection of the abdominal wall metastases and cisplatin-based combination chemotherapy. Mechanisms of cutaneous and incisional implantation metastases are discussed. Adjuvant therapy with intraperitoneal P-32 is unable to provide systemic therapy for occult metastatic disease. The favorable outcome in these cases probably reflects limited tumor burden at the time of recurrence and stands in stark contrast to other cases of soft tissue recurrences of ovarian carcinoma reported previously.     

Microscopic disease at second-look laparotomy in advanced ovarian cancer

During the 11-year interval from January 1971 to January 1982, 50 of 246 patients with advanced (Stage III and IV) epithelial ovarian carcinoma at second-look laparotomy had biopsy or cytologic evidence of persistent microscopic carcinoma. The stage and grade profile include 46 Stage III and 4 Stage IV patients: 4 borderline, 9 grade 1, 20 grade 2 and 17 grade 3 patients. Following second-look laparotomy, 4 patients received no further therapy, 45 received chemotherapy, and 1 received external radiation. No patient was lost to follow-up, and the median interval off therapy was 24 months. Progressive or recurrent disease has manifest in 12 (24%). No recurrences have developed either in patients younger than age 40 or in patients with grade 1 tumors. Two patients died of leukemia, 1 died of heart disease, and 35 (70%) are alive with no evidence of disease. In patients developing recurrence, the median progression-free interval was 17.5 months, with a range of 6 to 46 months. The median interval of survival following disease progression was 7 months. There was no evidence of progression at 2 years and 5 years in 81% and 70% of patients, respectively. The uncorrected 2- and 5-year survival rates were 96% and 71%, respectively. The 5-year survival rates for grades 1, 2, and 3 were 100%, 79%, and 36%, respectively. Other variables analyzed include number of positive foci, residual tumor volume at initial surgery, cytologic findings at second-look laparotomy, type of chemotherapy, and number of courses of chemotherapy before second-look laparotomy. In summary, patients with only microscopic evidence of disease at second-look surgery have a good probability for extended survival.     

Intraperitoneal cisplatin chemotherapy versus abdominopelvic irradiation in ovarian carcinoma patients after second-look laparotomy

The current study compares the outcome within 3 years after diagnosis in two groups of histologically confirmed Stage II-IV ovarian carcinoma patients in complete clinical remission with minimal or no residual disease at second-look laparotomy, performed after completion of cisplatin-based combination chemotherapy. One group (n = 18) received after reexploration abdominopelvic irradiation (RT group), the other, diagnosed during a later period (n = 19), received three courses of intraperitoneal cisplatin chemotherapy with systemic thiosulfate protection (IP group). The two groups were comparable with regard to age, stage at diagnosis, histologic category, grade of differentiation, size of residual tumor after the initial operation, and rate of negative second-look laparotomy. The overall survival probability after diagnosis was significantly better in the IP group, the maximal difference being observed at 36 months: 76.6% versus 44.4% in the RT group (P = 0.04). This difference was mainly evident in patients with a negative second-look laparotomy in whom the respective survival probabilities were 100% versus 70% (P = 0.04). Survival was significantly shorter (P less than 0.01) in patients with a positive second-look, and there was a nonsignificant trend for better survival in the IP group. Significantly improved probability of progression-free interval after diagnosis was also found in the IP group, the maximal difference being observed at 22 months: 78.3% as compared to 50.9% in the RT group (P = 0.04). This difference was again limited to patients with negative second-look, the respective values being 100% versus 60% (P = 0.05). Our retrospective data suggest an apparent advantage to intraperitoneal cisplatin treatment in these patients which should be further explored for definite evaluation.     

Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.     

A reassessment of the role of second-look laparotomy in advanced ovarian cancer

Thirty-nine patients with stage III and IV epithelial ovarian cancer who underwent second-look laparotomy (SLL) at New York University Medical Center and 11 eligible patients who did not undergo reexploration were retrospectively studied with follow-up from 24 to 105 months after diagnosis. Sixteen patients (41%) were found to have macroscopic disease, six (15%) microscopic tumor, and 17 (44%) no disease at SLL. Five of 22 patients who received further therapy based on positive SLL findings have remained without clinical evidence of disease 17 to 65 months after SLL. Nine of 17 patients with negative SLL, in whom treatment was stopped, recurred 8 to 52 months after SLL, five in extraperitoneal sites only. Five of 11 patients not undergoing SLL recurred 16 to 39 months after diagnosis, four intraperitoneally. There was no significant difference in survival between the second-look and no second-look groups for the period of study. Clinical trials are needed to determine if SLL influences longer-term survival and if continued treatment is indicated in a high-risk subgroup despite negative SLL. The value of SLL is limited by the efficacy of second line therapy. The role of routine SLL outside an investigational setting is questioned.     

Survival with intraperitoneal cisplatin in advanced ovarian cancer after second-look laparotomy.

We studied survival in 36 patients with Stage III/IV ovarian cancer who received intraperitoneal high-dose cisplatin (200 mg/m2) alone or in combination with cytarabine (2 g), after intravenous (i.v.) cisplatin-based chemotherapy followed by second-look laparotomy. Complete responders were scheduled for three courses of IP chemotherapy, and others for six. Eight patients (22%) did not complete treatment (6 catheter failures and 2 renal failures). Peritoneal cytology remained positive in 6 patients (17%). Median overall and progression-free survival after second-look laparotomy were 44 and 37 months, respectively, for 13 complete responders to i.v. chemotherapy; 24 months and 11 months for patients with residual tumors less than 2 cm (17 cases); 15 and 12 months with tumors greater than 2 cm (6 cases). There was a significant difference in overall (p = 0.05) and progression-free (p = 0.001) survival between complete responders to i.v. chemotherapy and patients whose tumor was less than 2 cm. We find no evidence that high-dose cisplatin-based intraperitoneal chemotherapy given after second-look laparotomy will enhance survival in advanced ovarian cancer with zero or minimal residual disease.     

Consolidation radiation therapy following cytoreductive surgery, chemotherapy and second-look laparotomy for epithelial ovarian carcinoma: long-term follow-up.

BACKGROUND: From 1979-1987, 139 stage IC-IV ovarian cancer patients who had undergone cytoreductive surgery received 6-11 cycles of cisplatin and adriamycin. STUDY DESIGN: Eighty-four clinically complete responders underwent second-look laparotomy, and 60 of them received consolidation abdominal irradiation. The patients were then followed for a median follow-up of 39 months. RESULTS: Five- and 10-year actuarial survival for all patients was 43% and 24%, for no residuum at primary surgery, 80% and 35%, for residual tumor <2 cm, 45% and 35%, and for residual tumor >2 cm, 20% and 4%. Median survival for stage III-IV patients negative at second-look laparotomy was 72 months in irradiated compared to 25 months in non-irradiated patients (P = 0.14) and 77 months in irradiated patients with microscopic disease at second-look laparotomy. Median survival in patients with macroscopic disease at second-look laparotomy was 23.5 months if irradiated compared to 18 months if not (P = 0.05). CONCLUSIONS: Consolidation whole abdominal irradiation in advanced stages of ovarian cancer may be of value in patients with negative or microscopic disease at second-look laparotomy. Unfortunately, despite the initial survival advantage observed in irradiated patients, owing to late recurrences there was no significant difference in their long-term survival probability.     

Survival after negative second-look laparotomy

Complete pathological responses, as defined by multiple negative intraperitoneal biopsies at second-look laparotomy, were recorded in 22 of 120 patients with epithelial ovarian cancer. Patients had been previously treated with either high-dose single agent cisplatinum (19) or total abdominal and pelvic irradiation (3). Nine of 21 (43%) evaluable patients developed recurrent disease after 'negative' second-look laparotomy. The median time to relapse was 15 months (3-19) and the median survival after relapse, 4 months (1-6). One patient remains alive with evidence of disease.     

Critical reassessment of second-look exploratory laparotomy for epithelial ovarian carcinoma. Minimal diagnostic and therapeutic value in patients with persistent cancer.

From 1979 to 1984, 88 women with epithelial ovarian cancer were treated with surgery and chemotherapy, achieved a clinical complete response, and then had "second-look" exploratory laparotomy to assess the pathologic status of their disease. Persistent cancer was found in 50 (57%) patients: 34 of 50 (68%) had gross tumor, which was larger than 2 cm in 12 (24%) and smaller than 2 cm in 22 (44%), and 16 (32%) had microscopic disease. Salvage therapy was as follows for these patients: whole abdominal irradiation, 29 (58%); chemotherapy, 17 (34%); intraperitoneal chromic phosphate, 1 (2%); and no further therapy, 3 (6%). With a follow-up time of 4 to 8 years, 7 (14%) patients are alive without evidence of cancer, 7 (14%) are alive with disease, 35 (70%) are dead of disease, and 1 (2%) has died of treatment complications. At 5 years, the relapse-free rate was 18% and the survival rate was 25%. Seventy-two parameters of suspected prognostic significance and 64 potential sites of tumor involvement were correlated with survival in a univariate analysis. The factors favorably affecting survival included the following: lower grade; microscopic tumor versus gross disease at second-look laparotomy; removal of the uterus; removal of the omentum; pelvic and paraaortic lymph node biopsy; negative results of a right diaphragm biopsy; and radiation therapy at Stanford University Medical Center, Stanford, California. There was no survival advantage for whole abdomen irradiation compared with chemotherapy or for the patients who had their disease successfully debulked at second-look laparotomy. The above factors and others were evaluated by multivariate regression. The best model (P = 0.000004) for predicting survival included largest tumor mass (P = 0.0002), operative blood loss (P = 0.002), perioperative blood transfusion (P = 0.003), and grade (P = 0.004). The detection of persistent ovarian cancer by second-look exploratory laparotomy should identify a subgroup of patients whose conditions can be salvaged by a second-line therapy. Unfortunately, that subgroup is small (8%) and an effective salvage therapy remains to be identified.     

Intraperitoneal chemotherapy versus no treatment in patients with ovarian carcinoma who are in complete clinical remission.

BACKGROUND. The optimal management of patients with ovarian carcinoma who are in complete clinical remission after completion of postoperative cisplatin-based chemotherapy has not been established. METHODS. In this study, the outcomes of two groups of such patients were compared. One group of 25 patients underwent a second-look laparotomy and subsequently received three courses of intraperitoneal chemotherapy (IP group). The other group of 12 patients was not reexplored and received no additional treatment (NT group). RESULTS. A trend for better survival in the IP group was found compared with the NT group. There was no difference in the duration of the progression-free interval. CONCLUSIONS. More effective treatment for the consolidation of complete clinical remission in patients with ovarian carcinoma is needed.     

Results of second-look laparotomy with extensive dissection of retroperitoneal lymph node in ovarian cancer patients

　Objective To evaluate retrospectively the results of extensive lymphadenectomy during second-look laparotomy on patients with ovarian cancer. Methods A total of 63 patients with ovarian malignancies received second-look laparotomy (SLL). Retroperitoneal lymph nodes, including pelvic and para-aortic lymph nodes below the level of left renal vein, were extensively dissected. Results Of the 63 patients, residual tumor was found in 24 (38.0%) on SLL. The frequency of residual tumor was positively correlated with the clinical stage and with the amount of tumor left after initial debulking but not with degree of differentiation of tumor cells. Lymph node metastasis(LNM) was pathologically confirmed in 19 cases (30.2%), of which no residual tumor was found in 8 patients. Tumor recurred in only 4 of the 39 patients (10.3%) with negative SLL. The overall 3- and 5-year survival rate were 75.0% and 68.0%, respectively. Conclusion Extensive retroperitoneal lymph node dissection was recommended during SLL. It favored a decrease in recurrence rate in ovarian cancer patients negative on SLL.     

Predictors of recurrent disease after negative second-look laparotomy for epithelial ovarian cancer

Twenty-four patients with epithelial ovarian cancer who had negative second-look laparotomy (SLL) were assessed in regard to recurrent disease. Four patients showed recurrence 11-36 months after negative SLL. All four patients had advanced stage and grade III tumors, with two having residual tumors greater than 1 cm in diameter after initial laparotomy. We believe that patients with advanced stage and high-grade tumors should receive some kind of treatment after negative SLL.     

Evaluation of the second-look laparotomy in the management of carcinoma of the ovary

One hundred and thirty four patients had a second-look laparotomy in the course of management of cancer of the ovary. Patients were stratified according to four indications: (1) resection of the residual tumor following chemotherapy or radiation therapy, (2) evaluation of the disease with intent to stop chemotherapy and assess signs of recurrence or persistence, (3) restaging, and (4) surgical indication. The first group consisted of 35 patients. In 20 of 35 patients in this group, complete removal of the residual tumor (residual less than or equal to 2 cm) was possible, and the survival curves indicated that removal of the residual tumor during the second-look laparotomy improved the survival rate. The second group consisted of 77 patients. No evidence of disease was found in 44 of the 77 patients in this group. Four patients with negative second-look laparotomy developed recurrences, and three patients died from the disease. The third group consisted of seven patients. In one of seven patients in this group, the stage was modified after second-look laparotomy.     

The role of second-look laparotomy in the long-term survival in ovarian cancer

Background: To elucidate the role of second-look laparotomy in themanagement of ovarian cancer patients, we retrospectively reviewed ourexperience with this procedure in epithelial ovarian cancer patients.Patients and methods: The hospital records of 617 patients with advancedovarian cancer were reviewed. The 308 patients who underwent second-looklaparotomy were followed from four to 18 years with a median follow-up of 12years after start of primary chemotherapy.Results: Patients who achieved pathological complete response (PCR),microscopic partial response (PPR mic.), macroscopic partial response (PPRmac.), stable disease (PSD), and progressive disease (PPD) at second-looklaparotomy had a median survival time of 149, 39.5, 24, 14, and eight months,respectively. Secondary surgical cytoreduction could be performed only in 101patients with macroscopic persistent disease. The group of all patients withsecondary tumor debulking had no survival advantage compared with the groupof patients with PPR mac., PSD, and PPD, unable to have secondarycytoreduction. Patients left with no tumor after second-look laparotomy didnot survive as long as patients who achieved PCR and PPR mic. at second-looklaparotomy. Factors prolonging survival after second-look laparotomy includedyounger age, good pre-treatment performance status, smaller primary residualtumor size, longer interval between start of chemotherapy and second-looklaparotomy, and the pathologically proven CR or PR mic.Conclusion: Second-look laparotomy appears to have a minor role in theroutine management of ovarian cancer patients, especially in the context ofthe limited effectiveness of second-line therapy. This procedure should belimited to clinical treatment protocols to determine effectiveness of newagents.     

Cisplatin-containing versus cisplatin-free adjuvant chemotherapy in ovarian carcinoma. Results after second-look laparotomy

In 1980, second-look laparotomy was introduced simultaneously into the treatment regimen for ovarian carcinoma at the two main referral centers of northern Spain. First-line chemotherapy after initial surgery was, however, different at both hospitals. At one of them (Bilbao), a combination involving the use of cisplatin was employed (cyclophosphamide 600 mg/m2, Adriamycin 45 mg/m2, and cisplatin 80 mg/m2 i.v. on day 1), whereas the patients of the other hospital were treated mainly with single-agent chemotherapy (melphalan 0.2 mg/kg p.o. on days 1-5) and never with a cisplatin combination as first-line therapy in any case. In all, 92 patients (42 stage I, 14 stage II, 33 stage III, and 3 stage IV) could be treated during the study period with optimal surgery (complete tumor excision or largest residual tumor less than 2 cm in diameter). This was followed by adjuvant chemotherapy for 12-18 months in all cases, except for 18 patients with a stage Ia borderline or G1 tumor. The latter were merely kept under observation until their second-look laparotomy after 1 year of negative follow-up. All of the 74 patients who received adjuvant chemotherapy, of whom 36 with cisplatin and 38 without, were clinically disease free after at least twelve courses of treatment and had a second-look laparotomy performed. This was positive in 33.3% of the cases after cisplatin-containing therapy and in 26.3% of the cases after cisplatin-free therapy. This difference is not statistically significant. The mean follow-up period after negative second-look was 34 months. The long-term results of both patient groups were comparable as far as rate of positive second-look laparotomies and survival rate, overall and stage for stage are concerned. The use of cisplatin did not result in any significant therapeutic improvement. It was uniformly bad tolerated by the patients and carried higher cost, since all patients had to be hospitalized for treatment.