Prognostic factors in ovarian carcinoma in complete histologic remission at second-look surgery

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1 Int J Gynecol Cancer 1999, 9, Prognostic factors in ovarian carcinoma in complete histologic remission at second-look surgery D. HAMID*, B. DUCLOS, J. C. BARATS, G. PREVOT, M. HUMMEL, J. J. BALDAUF**, P. BRETTES, C. GIRON*, F. MALOISEL*, B. LIOURE*, R. HERBRECHT*, B. AUDHUY, J. P BERGERAT, F. OBERLING* & P. DUFOUR* *Onco-Hematology Unit, Medical Oncology Unit, **Gynecology and Obstetrics I Unit, University Hospitals of Strasbourg, Hôpital de Hautepierre, Strasbourg, France; Onco-Hematology Unit, Center Hospital of Colmar, Colmar, France; Oncology and Radiotherapy Unit, Hasenrain Hospital, Mulhouse, France; Gynecological and Obstetrical Unit, Center Medico-Chirurgical and Obstétrical, Schiltigheim, France; Maternity, University Hospitals of Strasbourg, Strasbourg, France Abstract. Hamid D, Duclos B, Barats JC, Prevot G, Hummel M, Baldauf JJ, Brettes P, Giron C, Maloisel F, Lioure B, Herbrecht R, Audhuy B, Bergerat JP, Oberling F, Dufour P. Prognostic factors in ovarian carcinoma in complete histologic remission at second-look surgery. Int J Gynecol Cancer 1999;9: Prognosis of ovarian carcinoma in complete histologic remission (CHR) at second-look surgery is still controversial. In a series of 83 patients in CHR we studied retrospectively several prognostic factors (age, stage, histologic grade, histologic type, initial residual disease after surgery, CA 125 normalization period) to determine which patients present a high risk of relapsing after CHR and could be included in therapeutic protocols for consolidation treatment. Univariate analysis showed that the combination of CA 125 normalization < 8 weeks with absence of macroscopic tumoral residue after initial surgery permits the definition of a group with a very good prognosis, while for patients with CA 125 normalization period > 8 weeks and an initial macroscopic residual tumor, the prognosis is relatively poor (progression-free survival 100% vs. 47%, at 2 years P < 0.05). Using the Cox multivariate analysis, only the initial tumoral residue is of prognostic significance for progression-free survival; there is no prognostic significance for overall survival. The therapeutic strategy for ovarian cancer may be improved for patients in CHR after second-look surgery by determining those at high risk, making it possible to confine consolidation treatment trials to such a group. KEYWORDS: complete histologic remission, ovarian carcinoma, prognostic factors, second look. Address for correspondence: Pr P. Dufour, Service Oncohématologie, Hôpitaux Universitaires de Strasbourg, Strasbourg Cedex France. The decision to discontinue chemotherapy in patients with epithelial ovarian cancer who are in complete histologic remission (CHR) after second-look laparotomy is still controversial. Depending on prognostic factors, 13 50% of patients in CHR after second look will relapse (1 4). Several types of consolidation treatment, such as abdomino-pelvic radiotherapy, intraperitoneal chemotherapy, and intensive chemotherapy with autograft bone marrow transplant, have been proposed (5,6) to improve this outcome. Their ef IGCS

2 232 D. Hamid et al. fectiveness is not yet proved (7) and they are also associated with high morbidity (8). For these reasons, the identification of prognostic factors for relapse after CHR would make it possible to identify which patients could be included in a consolidation treatment trial. From this standpoint, we analyzed retrospectively different prognostic factors for progression-free survival (PFS) and overall survival (OS) in 83 patients in CHR at second look. Patients and methods Between January 1985 and October 1995, in a series of 165 patients presenting an ovarian tumor between s Ic and IV, 83 patients in CHR after second look were studied retrospectively in order to determine progression-free survival (PFS) and overall survival (OS), depending on a range of potential prognostic factors. The stage of disease was determined according to the International Federation of Gynecological Oncology (FIGO) classification and histologic grades according to Broder s classification. s were divided into two categories by order of frequency (serous and other). All 165 patients underwent the same therapeutic strategy. This consisted of initial surgery with maximal debulking consisting of total hysterectomy with a bilateral salpingo-oophorectomy, omentectomy, and systemic biopsies of the colo-parietal gutters, diaphragm surfaces and the pouch of Douglas followed by six cycles of chemotherapy in accordance with two protocols: before 1991, the CAP protocol associating cisplatin (100 mg/m 2 IV d 1), adriamycin (50 mg/m 2 IV, d 1), and cyclophosphamide (500 mg/m 2 IVd1) (one cycle every three weeks) and after 1991 the Carbo-endoxan protocol associating carboplatin (400 mg/m 2 IV, d 1) and cyclophosphamide (600 mg/m 2 IV, d 1) (one cycle every three weeks). The patients who responded to treatment (clinical amelioration, decrease of CA 125, shrinking of tomodensitometric lesions) underwent second-look laparotomy consisting of visual and manual inspection of the abdominal cavity, peritoneal washing with cytological examination, systematic biopsies of the coloparietal gutters, diaphragm surfaces, pouch of Douglas and all adhesions. A second attempt at resection of residual masses was also made at second-look when macroscopic lesions were observed. CHR was defined in accordance with the established criterion, namely the complete absence of residual disease after histologic examination of the different biopsies performed during second look. Eightythree patients meeting this criterion were included in our study. All the patients in CHR underwent continued therapy as laid down in the treatment protocol studied. The consolidation treatment in the case of patients under the age of 55 consisted of intensive chemotherapy with autologous bone marrow transplant (ABMT). Patients over the age of 55 or those refusing ABMT were given mitoxantrone intraperitoneal chemotherapy. For technical reasons several patients were given a different type of therapy, consisting of total abdomino-pelvic irradiation or consolidation chemotherapy. The median age was 55 years (18 80). We placed s I, II and IIIa in a first group of low tumoral mass without extra-pelvic macroscopic lesion (n = 39) and s IIIb, IIIc and IV in a second group of high tumoral mass presenting an extra-pelvic macroscopic lesion (n = 44). In 24 cases the grading was undeterminable. Fifty-four patients presented a residual tumoral mass smaller than 2 cm after initial surgery, 23 presented a tumoral mass larger than 2 cm, while five remained undetermined. Seventeen patients underwent an ABMT, 50 intraperitoneal chemotherapy with mitoxantrone, four abdomino-pelvic irradiation (45 grays), and a different kind of treatment was administered to 12 patients. After consolidation treatment, patients were taken off therapy and were followed up by means of trimestrial clinical examination and CA 125 dosage, chest X-ray every six months, and abdomino-pelvic ultrasonography every six months, possibly in association with an annual CT scan. Progression was defined by a positive iconography possibly documented by biopsies or, in a few cases, a new and persistent CA 125 level elevation. Prognostic factors We took as our basis six current prognostic factors (1 4) (9,10). Age FIGO staging Residual disease after initial surgery (< or > 2 cm) (RD). CA125 normalization period (checked every three weeks, regarded as normal when < 35 UI/ml) As the CA 125 test was introduced in our institution after 1990, we only performed this study in 59 patients.

3 Prognostic factors in ovarian carcinoma 233 Statistical analyses A univariate analysis was performed for each prognostic factor. Survival curves were calculated using Kaplan-Meier estimates. The log-rank test was used for testing differences between survival curves. A multivariate analysis of survival times was performed with the Cox proportional hazards model. PFS was the period between diagnosis and relapse, while OS was the time from diagnosis to death. Results Disease characteristics are shown in Table 1. The median patient follow-up was 42 months after primary diagnosis (range 8 132). OS at five years was 56.7% (confidence interval (CI) 95%: 49,3 64,1). PFS at five years was 37.8% (CI 95%: ) (Fig. 1). Forty-three patients relapsed (for sites see Table 2). 16.6% of relapses were outside the peritoneal cavity. In 19% of cases we observed only one new significant and persistent CA 125 increase which was considered as a relapse, and which was treated with salvage therapy. Univariate analysis In univariate analysis (Table 3), age < 55 years, RD < 2 cm, CA 125 normalization period < 8 weeks were favorable significant prognostic factors for PFS (P < 0.05) but not for OS. Table 1. Disease characteristics IC 5 IIA 5 IIB 7 IIC 5 IIIA 17 IIIB 32 IIIC 5 IV 7 Serous 63 Other ND a 24 >2 cm 23 <2 cm 55 ND 5 a ND, Not determined. Figure 1. Overall survival (solid line) and progression-free survival (dotted line) for all patients in CHR at second-look surgery Table 2. Multivariate analysis Using the Cox multivariate analysis only, RD < 2 cm was found to be a favorable significant prognostic factor for PFS (Table 4) but it did not improve OS (Table 5). Discussion Sites of relapse Sites of relapse Pelvis 9 (20.9%) Abdomen 15 (34.8%) Liver 4 (9.3%) Isolated elevation of CA (19%) Pleural and/or pulmonary 2 (5%) Retroperitoneal lymph nodes 5 (11.6%) The determination of prognostic factors for recurrence after CHR at second look is of considerable strategic importance in the treatment of ovarian cancer. Nearly 40% of patients in CHR eventually relapse, and it seems reasonable to offer them consolidation treatment (1 5). Furthermore, even if intraperitoneal chemotherapy, intensive chemotherapy with ABMT, or abdomino-pelvic irradiation apparently produce good results in terms of PFS (6 12), those results are based on experimental protocols only and their effectiveness must be verified by randomized studies comparing them with a wait and see attitude (13,14). Given the high morbidity associated with these different types of consolidation treatment, it seems more appropriate to propose them in the case of patients with a high risk of relapse in spite of CHR at second look. Second look has been performed because there is ample evidence

4 234 D. Hamid et al. Table 3. Variables Univariate analysis for PFS and OS n PFS at two years (%) p OS at two years (%) Age <55 years >55 years I+II+IIIA III B+III C+IV <2 cm , >2 cm Serous , Other CA125 normalization period <8 weeks >8 weeks ND a 28 a ND = Not determined p Table 4. Multivariate analysis censored at 2 years for progressive survival Prognostic factors Relative risk (RR) 95% CI p Age <55 years >55 years I+II+IIIA III B +III C+IV <2 cm >2 cm Serous Other CA125 normalization period <8 weeks >8 weeks of the superior sensitivity of a second look operation over clinical, biochemical, and radiologic detection techniques. CA 125 level, CT scan, and MRI have by this stage shown their limits when it comes to accurately predicting recurrences (1 4,9 11,15). To date, only a small number of studies concerning the evaluation of prognostic factors for relapse after CHR at second look have been published. In a limited series of 24 patients Ayhan et al. (16) observed that advanced staging (III, IV), with grade III, and residual tumor mass exceeding 1 cm after initial surgery, were significant prognostic factors for relapse. The authors concluded that consolidation treatment was advisable for these patients. In a series of 50 patients in CHR at second look, Podratz et al. (2) determined three significant parameters (P < 0.01) for PFS (age < 50 years, histologic type and residual mass after initial surgery). By the association of these parameters, the authors defined groups at high risk of relapse, with variable sensitivities and specificities, and likely to benefit from consolidation treatment. Chiara et al. (3) evaluated in 129 advanced ovarian cancer patients in macroscopic complete response at second look the impact of stage, histology, grade, re-

5 Prognostic factors in ovarian carcinoma 235 Table 5. Multivariate analysis censored at 2 years for overall survival Prognostic factors Relative risk (RR) 95% CI p Age <55 years >55 years I+II+IIIA III B +III C+ IV <2 cm >2 cm Serous Other CA125 normalization delay <8 weeks >8 weeks a ND ND ND a ND, Not determined sidual disease after initial surgery and disease status at second look on PFS and OS. After an observation period of 118 months, they found that stage, grade, residual disease and disease status at second look had a significant impact on both OS and PFS, whereas consolidation therapy did not influence survival. The authors concluded that advanced ovarian cancer patients with macroscopically complete remission at second look present a substantial risk of relapse even after aggressive treatment. Bolis et al. (15) analyzed the determinants of longterm survival in 140 patients (s III-IV ovarian cancer) with negative second look after primary surgery and chemotherapy. In addition to the usual prognostic factors (grade, stage, residual disease after initial surgery, age at diagnosis) the authors looked at the importance of lymph node status. Sixty-six percent of patients with RD less than 1 cm and positive lymph nodes had a 5-year survival probability compared with 85% of those with RD less than 1 cm and negative lymph nodes (P = 0.05). In a study of 458 ovarian cancer (stage III to IV) cases treated by primary cytoreductive surgery and chemotherapy, Hoskins et al. (17) also showed that primary cytoreductive surgery may have a beneficial effect on survival in patients with RD < 2 cm. For Lopez et al. (18) the most important prognostic factor adversely influencing time to relapse in a series of 117 patients with clinically complete remission is the presence of ascites at advanced tumor stage. Our study of 83 patients in CHR at second-look enabled us to highlight three important prognostic factors for PFS, namely age (P = 0.03), residual mass after initial surgery (P = 0.01), and CA 125 normalization period (P = 0.04). Neither staging nor grading appears to be significant in this evaluation (P < 0.05), although histologic grade is often cited in other trials as a prognostic factor for OS and PFS (19 24). The predictive value of staging for OS or for PFS varies from one publication to another (19). According to this study staging is almost significant for PFS (P = 0.06) but not quite. We think that it is not a significant prognostic element for PFS on the basis of our study, for reasons of group size. Histologic grading does not seem to be a prognostic factor (P = 0.22 for PFS, P = 0.16 for OS) as has been reported by other authors (25). The normalization period of CA 125 level is an important prognostic element for relapse at two years (P = 0.04). Other authors have tried to correlate the reduction of CA 125 levels to tumoral response to chemotherapy (26). A rapid and complete regression of tumor should be associated with a rapid decline in levels of the serum marker and might correlate with a favorable prognosis. According to a report by Van der Burg et al. (27), patients with a CA 125 half-life of 20 days or more had a 3.2-fold higher progression rate and shorter median time to progression. These results, together with those of our study, underline the importance of the CA 125 level normalization period as a potential prognostic factor for relapse even after negative second look. As indicated in several other trials, residual mass after initial surgery remains a parameter influencing OS and PFS and the importance of maximal surgical

6 236 D. Hamid et al. resection is no longer in doubt (9,25). We have noted in many other studies a clear correlation between the size of residual mass after surgery and the prognosis for patients (17,26 32). Podratz et al. (2) found that up to 63% of patients were alive at five years if initial surgery was maximum vs. only 11% if residual tumor mass was less than 2 cm and 4% if greater than 2 cm (P < 0.01). Like Podratz et al. (2), we tried to define high-risk groups by studying the association of these potential prognostic factors. It seems that the association of a CA 125 level normalization period shorter than eight weeks and the absence of macroscopic residual tumor after initial surgery indicate a good prognostic group. Nineteen of the patients studied who met these criteria had a 100% overall survival and progression-free survival at two years. A normalization delay in excess of eight weeks associated with a residual tumor mass after initial surgery greater than 2 cm isolates a poor prognostic group, however, with 78% of patients alive at two years and 55% in PFS (n = 19). We noted a significant statistical difference between these two groups in terms of PFS (P = 0.05) and OS (P < 0.05). Multivariate analysis apparently gives residual disease after initial surgery as the main prognostic factor for PFS (no relationship with OS). No prognostic factors for survival after CHR at second look have so far been identified by means of multivariate analysis. In our study 16.6% of relapses were outside the peritoneal cavity and in 19% of cases an isolated elevation of CA 125 was observed. These results, if confirmed with a larger cohort of patients, might cast doubt on the usefulness of treatment limited to the abdomen (intraperitoneal chemotherapy, abdomino-pelvic irradiation) as opposed to treatment by systemic chemotherapy. Conclusion The treatment strategy for ovarian cancer may be improved by the determination of high-risk groups in spite of CHR after second look, making it possible to decide when consolidation treatment is advisable. Patients with RD < 2 cm and CA 125 normalization period < 8 weeks have a good prognosis, and consolidation treatment is unnecessary in this subgroup. For patients with RD > 2 cm and CA 125 normalization period > 8 weeks, consolidation treatment is warranted, but the type of consolidation treatment is still controversial. We are doubtful, however, about the usefulness of consolidation treatment for patients who do not meet these criteria. As we observed a high relapse rate outside the abdominal cavity, systemic chemotherapy seems to be a more appropriate consolidation treatment for this high-risk group. More experience is needed to decide what criteria influence time to relapse and randomized trials must be carried out to provide evidence of benefit from consolidation treatment for CHR patients. Acknowledgments The authors are indebted to Marjorie Bettison for help in the preparation of the manuscript. References 1 Lund B, Wiliamson P. Prognostic factors for outcome of and survival after second-look laparotomy in patients with advanced ovarian carcinoma. Obstet Gynecol 1990; 76: Podratz KC, George D, Malkasian JR et al. Recurrent disease after negative second-look laparotomy in stage III and IV ovarian carcinoma. Gynecol Oncol 1988; 29: Chiara S, Lionetto R. Long term prognosis following macroscopic complete response at second-look laparotomy in advanced ovarian cancer patients treated with platinum-based chemotherapy. Eur J Cancer 1995; 31: Luesley DM, Chan KK, Lawton FG. Survival after negative second-look laparotomy. Eur J Surg Oncol 1989; 15: Fuks Z, Rizel S, Biran S. Chemotherapeutic and surgical induction of pathological complete remission and whole abdominal radiation for consolidation does not enhance the cure of stage III ovarian carcinoma. J Clin Oncol 1988; 6: Bruzzone M, Repetto L, Chiara S et al. Chemotherapy versus radiotherapy in the management of ovarian cancer patients with complete response or minimal residual disease at second-look. Gynecol Oncol 199l; 3: Dufour P, Bergerat JP, Liu KL et al. High dose melphalan and ABMT with or without radiotherapy as consolidation treatment for ovarian carcinoma in complete remission or with microscopic residual disease. Eur J Gynecol Oncol 1991; 12: Dembo AJ, Busch RS. Choice of post-operative therapy based on prognostic factors;. Int J Radiation Oncol Biol Phys 1982; 8: Van Oosterom AT. Complete remission at second-look laparotomy: Still a gold standard in ovarian cancer? Lancet 1986; 3: Podczaski E, Manetta A, Kaminski P et al. Survival of patients with ovarian epithelial carcinomas after secondlook laparotomy. Gynecol Oncol 1990; 36: Rubin S, Hoskins W, Saigo PE et al. Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecol Oncol 1991; 42: Dufour P, Maloisel F, Bergerat JP et al. Intraperitoneal

7 Prognostic factors in ovarian carcinoma 237 mitoxantrone as consolidation treatment for stage III ovarian carcinoma: a pilot study. Bull Cancer 1991; 72: Dufour P, Bergerat JP, Barats JC et al. Intraperitoneal mitoxantrone as consolidation treatment for patients with ovarian carcinoma in pathological complete remission. Cancer 1994; 73: Davis B, Goldhirsch A, Locker GW et al. Pathological data of prognostic significance for remission induction in advanced ovarian carcinoma;. J Cancer Clin Oncol 1984; 107: Bolis G, Villa A, Guarnerio P et al. Survival of women with advanced ovarian cancer and complete pathologic response at second-look laparotomy. Cancer 1996; 77: Ayhan A, Urman B, Yarali H et al. Predictors of recurrent disease after negative second look laparotomy for epithelial ovarian cancer. J Surg Oncol 1990; 44: Hoskins W, Mc Guire W, Brady M et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994; 170: Lopez RI, Paul J, Atkinson R. Prognostic factor analysis for patients with no evidence of disease after initial chemotherapy for advanced epithelial ovarian carcinoma. Int J Gynecol Cancer 1996; 6: Malkasian GD, Dukes DG, Webb MJ et al. Histology of epithelial tumors of the ovary clinical usefulness and prognostic significance of the histologic classification and grading. Semin Oncol 1975; 2: Hacker NF, Bereck J, Burnison S et al. Whole abdominal radiation as salvage therapy for epithelial ovarian cancer. Obstet Gynecol 1985; 65: Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Int Monogr 1975; 42: Varia M, Fowler W, Walton R. Intra-peritoneal phosphor 32 following second-look laparotomy for ovarian cancer. Int J Radiat Oncol Biol Phys 1983; 9: Vogl SE, Pagano M, Kagler BH et al. Cisplatin-based combination for advanced ovarian cancer. Cancer 1983; 51: Mc Guire W, Hoskins W, Brady M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: Gerhenson D, Copeland L, Wharton JT et al. Prognosis of surgically determined complete responders in advanced ovarian cancer. Cancer 1985; 55: Rustin GS, Genny JN, Nelstrop AE et al. Use of CA 125 to predict survival of patients with ovarian carcinoma. J Clin Oncol 1989; 7: Van der Burg ME, Lammes FB, Van Putten WLJ, et al. Ovarian cancer: the prognostic value of the serum halflife of CA 125 during induction chemotherapy. Gynecol Oncol 1988; 30: Piver MS, Baker TR. The potential for optimal (< 2 cm) cytoreductive surgery in advanced ovarian carcinoma at a tertiary medical center: a prospective study. Gynecol Oncol 1986; 24: Hoskins W, Rubin S, Dulaney E et al. Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 1989; 31: Piver MS, Lele S, Marchetti D. The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III-IV ovarian carcinoma. J Chir Oncol 1988; 6: Girling JC, Souter WP. Cytoreductive surgery in the primary management of advanced epithelial ovarian carcinoma: a topic for debate. Int J Gynecol Cancer 1996; 6: Brinkhius M, Lund B, Meijer GA, Baak JPA. Quantitative pathological variables as prognostic factors for overall survival in Danish patients with FIGO III ovarian cancer. Int J Gynecol Cancer 1996; 6: Accepted for publication March 26, 1999.