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Analysis of Failures after Negative Second-Look in Patients with Advanced Ovarian Cancer: An Italian Multicenter Study
GYNECOLOGIC ONCOLOGY ARTICLE NO.
68, 150 –155 (1998)
GO974890
Analysis of Failures after Negative Second-Look in Patients with Advanced Ovarian Cancer: An Italian Multicenter Study Angiolo Gadducci, M.D.,*,1 Enrico Sartori, M.D.,† Tiziano Maggino,‡ Paolo Zola, M.D.,§ Fabio Landoni, M.D.,¶ Antonio Fanucchi, M.D.,* Nicoletta Palai, M.D.,† Chiara Alessi, M.D.,‡ Anna Maria Ferrero, M.D.,§ Stefania Cosio, M.D.,* and Renza Cristofani, M.D.\ *Department of Gynecology and Obstetrics, University of Pisa; †Department of Gynecology and Obstetrics, University of Brescia; ‡Department of Gynecology and Obstetrics, University of Padova; §Department of Gynecology and Obstetrics, University of Torino; ¶Department of Gynecology and Obstetrics, III Branch of the University of Milano (Monza); and \Department of Public Health and Biostatistics and CNR Institute of Clinical Physiology, Pisa, Italy Received May 8, 1997
ovarian cancer patients, ranging from 79.0% in stage I to 57.0% in stage II, 22.5% in stage III, and 8.4% in stage IV. Among patients with advanced malignancy, tumor stage [2–9], residual disease after initial surgery [3–7, 9 –15], tumor grade [3– 6, 9, 12], and histological type [4, 9, 15–18] are the clinicopathological variables influencing the response rate to chemotherapy and survival rate. The standard therapeutic strategy in advanced ovarian cancer includes cytoreductive surgery followed by platinum-based chemotherapy, achieving an objective response in 60 – 80% and a pathological complete response in 25–30% of cases [19 –23]. A negative second-look is associated with an improved survival, but the long-term prognostic significance of surgical reassessment after chemotherapy is still unclear since a high proportion of complete responders will subsequently develop recurrent disease [5, 24 –29]. The aim of this Italian multicenter retrospective study was to assess the patterns of failures and the prognostic factors for recurrences in advanced ovarian cancer patients after a negative second-look.
This multicenter retrospective study is based on 192 patients with advanced ovarian cancer in pathological complete response at second-look surgery. Ninety-four (48.9%) patients developed recurrent disease after a median time of 18 months (range, 4 – 89 months) from surgical reassessment. The recurrence involved the pelvis in 45 (47.9%) cases, the abdomen in 42 (44.7%), the retroperitoneal lymph nodes in 13 (13.8%), and distant sites in 20 (21.2%). On the whole series, 5- and 7-year disease-free survival rates after negative second-look were 47.4 and 44.5%, respectively. By log-rank test the disease-free survival rate was related to FIGO stage (P 5 0.008), tumor grade (P 5 0.0021), size of residual disease after initial surgery (P 5 0.0038), and type of second-look (laparoscopy vs laparotomy, P 5 0.0061), but not to histological type and first-line chemotherapy. Cox proportional hazard model showed that tumor grade, size of residual disease, and type of second-look were independent prognostic variables for diseasefree survival. The risk ratio of relapse was 2.386 (95% CI, 1.140 – 4.990) for grade 2 and 3.118 (95% CI, 1.515– 6.416) for grade 3 compared to grade 1 disease. For patients with residual disease 1–2 cm and >2 cm the risk ratio was, respectively, 1.877 (95% CI, 1.117–3.156) and 2.156 (95% CI, 1.324 –3.511) compared to patients with residual disease <1 cm. The risk ratio was 1.826 (95% CI, 1.121–2.973) for patients who were submitted to a laparoscopic second-look compared to those who underwent a laparotomic reassessment. Poorly differentiated grade and large residual disease after initial surgery are the strongest prognostic variables for recurrence after a negative second-look. © 1998 Academic Press
MATERIAL AND METHODS
INTRODUCTION
The present investigation includes 192 patients with advanced ovarian cancer in pathological complete response at second-look surgery after initial laparotomy and first-line chemotherapy treated at the Departments of Obstetrics and Gynecology of the Universities of Brescia, Padova, Pisa, and Torino between 1980 and 1994. Second-look surgery consisted of laparoscopy in 34 patients and laparotomy in 158. A pathological complete response was defined as the disappearance of all tumor deposits with negative peritoneal washing and negative multiple random biopsies. The median age of the patients at diagnosis was 55 years (range, 30 –74 years). After initial surgery tumor stage and histological diagnosis of each case were determined according to FIGO criteria and the histological typing system of the
Ovarian cancer is the leading cause of death for gynecological malignancy. According to the International Federation of Gynecology and Obstetrics (FIGO) Annual Report 1991, the 5-year survival rate was 40.9% in the whole series of 11,596 1 To whom correspondence should be addressed at Department of Gynecology and Obstetrics, University of Pisa, Via Roma 56, Pisa, 56127, Italy. Fax: 39 50 553410.
0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
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jointly test the relative importance of variables as predictors of disease-free survival times. RESULTS
FIG. 1. Disease-free survival in patients with stage III–IV epithelial ovarian cancer after negative second-look surgery.
World Health Organization, respectively. Tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated. The histological material was reviewed by the same pathologist in each center. According to the FIGO classification, tumor stage was IIIa in 20 (10.4%) patients, IIIb in 40 (20.8%), IIIc in 123 (64.1%), and IV in 9 (4.7%). Histologically, 131 (68.2%) tumors were serous, 22 (11.5%) endometrioid, 18 (9.4%) undifferentiated, 11 (5.7%) mucinous, 5 (2.6%) clear cell, 4 (2.1%) mixed, and 1 (0.5%) was a malignant Brenner tumor. Tumor grade was G1 in 24 (12.5%) patients, G2 in 70 (36.5%), G3 in 87 (45.3%), and unspecified in 11 (5.7%). Residual disease after initial surgery was #1 cm in 87 (45.3%) patients, 1–2 cm in 49 (25.5%), and .2 cm in 56 (29.2%). First-line chemotherapy consisted of single-agent cisplatin or carboplatin in 18 (9.4%) patients, cisplatin- or carboplatin-based regimens in 162 (84.3%), and nonplatinum-based regimens in 12 (6.3%). In detail, platinum-based combination chemotherapy included cisplatin 1 cyclophosphamide in 55 patients, cisplatin 1 cyclophosphamide 1 doxorubicin or epirubicin in 98, cisplatin 1 taxol in 4, and carboplatin 1 cyclophosphamide 1 doxorubicin in 5. Further therapy after negative second-look was adopted in 115 (59.3%) cases without any common protocol and the choices of treatment were based mainly on personal preference. All patients were followed until they died or until June 1996.
After negative second-look, 77 (39.7%) patients received no further treatment, 3 (1.5%) underwent external abdomen–pelvic irradiation, 1 (0.5%) received intraperitoneal chromic phosphorus, and 111 (57.2%) received consolidation chemotherapy of different types. Eighty-seven (45.3%) patients are still alive with no clinical evidence of disease after a median time of 71 months (range, 4 –150 months) from second-look. Eleven (5.7%) patients died of intercurrent disease with no clinical evidence of recurrent tumor after a median time of 30 months (range, 5–111 months). Ninety-four (48.9%) patients developed recurrent disease after a median time of 18 months (range, 4 – 89 months). The recurrent disease involved the pelvis in 45 (47.9%) cases, the abdomen in 42 (44.7%), the retroperitoneal lymph nodes in 13 (13.8%), and distant sites in 20 (21.2%). The sites of distant relapses included brain (6 cases), liver (4 cases), extraabdominal lymph nodes (4 cases), lung (2 cases), spleen (2 cases), and bone (2 cases). On the whole series, 5- and 7-year disease-free survival rates after negative second-look were 47.4 and 44.5%, respectively (Fig. 1). By log-rank test the disease-free survival was related to FIGO stage (P 5 0.008) (Fig. 2), tumor grade (P 5 0.0021) (Fig. 3), size of residual disease (P 5 0.0038) (Fig. 4), and type of second-look (laparoscopy vs laparotomy, P 5 0.0061) (Fig. 5), but not to histological subtype and first-line chemotherapy (data not shown). With regard to therapy after negative secondlook, the 5- and 7-year disease-free survival rates following surgical reassessment were 43.7 and 40.6%, respectively, for the patients who received no further treatment, and 49.4 and 46.3%, respectively, for those who underwent consolidation chemotherapy (P 5 NS).
Statistical Methods The statistical package SAS, release 6.7, was used for computations. The cumulative probability of disease-free survival from second-look was estimated by the product-limit method. The log-rank test was used to compare the homogeneity of disease-free survival functions across strata defined by categories of prognostic variables. A multiple regression analysis based on the Cox proportional hazard model was used to
FIG. 2.
Disease-free survival in complete responders by FIGO stage.
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FIG. 3.
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Disease-free survival in complete responders by tumor grade.
Cox proportional hazard model showed that tumor grade, size of residual disease, and type of second-look were independent prognostic variables for disease-free survival (Table 1). The management of recurrent disease was no therapy in 5 (5.3%) patients, chemotherapy in 61 (65.9%), surgery plus chemotherapy in 17 (18.1%), surgery in 4 (4.2%), hormonotherapy in 4 (4.2%), surgery plus radiotherapy in 2 (2.1%) (recurrence in the retroperitoneal lymph nodes and pelvis, respectively), and radiotherapy in 1 (1.1%) (bone recurrence). Among the relapsing patients, 79 (84.0%) died after a median time of 21 months (range, 2–55 months) from recurrence, 11 (11.7%) are still alive with clinical evidence of disease after a median time of 15 months (range, 7–51 months), and 4 (4.3%) are still alive with no clinical evidence of disease after 8, 10, 60, and 84 months, respectively. Survival rate after recurrence is shown in Fig. 6.
FIG. 4. Disease-free survival in complete responders by residual disease after initial surgery.
FIG. 5. Disease-free survival in complete responders by type of secondlook surgery.
DISCUSSION The achievement of a pathological complete response has a favorable prognostic relevance for patients with advanced ovarian cancer. However a review of the literature shows that 19.5–71% of complete responders develop recurrent disease after a median time of 14 –32 months from second-look [5, 24 –34]. Most of these cases are expected to have a relapse within 2 years, but Podczaski et al. [34] reported that 10 (66.7%) of their 15 relapses arose after 24 months and 6 (40.0%) arose after 36 months. The clinical outcome of patients with relapsing disease is poor since salvage treatment is largely unsuccessful. Median survival after recurrence ranges between 11 and 32 months [26, 33, 34]. Pelvis and abdomen are the most frequent sites of recurrences after a negative second-look. In the 15 relapsing patients detected by Podratz et al. [25], the recurrent disease involved the pelvis in 2 (13%) cases, pelvis and abdomen in 2 (13%), pelvis, abdomen, and chest in 3 (20%), pelvic or para-aortic lymph nodes in 3 (20%), liver in 4 (27%), and pelvis and para-aortic lymph nodes in 1 (7%) case. All 15 recurrences analyzed by Bar-Am et al. [29] were limited to the pelvis and abdominal cavity. Rubin et al. [26] reported that tumor recurred in the abdomen in 10 (47.6%) patients, in the lungs in 3 (14.3%), in the pelvis in 2 (9.5%), in the liver in 2 (9.5%), in the vagina in 2 (9.5%), and in the supraclavicular lymph nodes in 2 (9.5%). In the present series, 48.9% of the 192 patients with stage III–IV ovarian cancer in pathological complete response had a recurrence after a median time of 18 months from second-look. Our data on times and sites of recurrences are consistent with the literature. It is noteworthy that less than 14% of failures were limited to retroperitoneal lymph nodes. It is well known that some clinicopathological variables have prognostic relevance for advanced ovarian cancer. As for the whole population of patients with advanced disease, FIGO stage was an independent prognostic variable for survival in
FAILURES AFTER NEGATIVE SECOND-LOOK
TABLE 1 Variables Predictive of Disease-Free Survival by Cox Proportional Hazard Model Variable
Risk ratio
95% Confidence limits
P value
RD 1–2 cm RD .2 cm G2 G3 SL
1.877 2.156 2.386 3.118 1.826
1.117–3.156 1.324–3.511 1.140–4.990 1.515–6.416 1.121–2.973
0.0174 0.0020 0.0209 0.0020 0.0155
Note. RD, residual disease after initial surgery; G2, moderately differentiated tumor; G3, poorly differentiated tumor; SL, type of second-look (laparoscopy versus laparotomy).
some studies [2, 4, 7] but not in others [3, 5, 6]. With regard to the subset of patients who achieved a pathological complete response, tumor stage was related to the recurrence rate in the series of Rubin et al. [26] (III versus IV, 32.4 versus 60%) but not in the experiences of Gershenson et al. [24], Mangioni et al. [32], and Chiara et al. [35]. Our results showed that diseasefree survival after negative second-look was related to FIGO stage at univariate (III versus IV, P 5 0.008) but not at multivariate analysis. Residual disease after initial surgery is the most important prognostic factor for advanced ovarian cancer. Even if there is no agreement in the literature about the optimal diameter of residual tumor, most authors have used the value of 2 cm as the limit to define subsets of patients with different prognoses [3, 4, 6, 7, 9, 11–15, 36, 37]. However, according to some authors, only residual masses ,1 cm are associated with improved survival [5, 11]. All the authors agree that residual disease after initial surgery is also related to the risk of recurrence in pathologically complete responders [24, 25, 32, 35]. In the series of Gershenson et al. [24], 5-year progression-free survival after negative second-look was 64 and 69%, respectively, for patients with tumor residuum .2 cm and #2 cm and 92% for those without macroscopic residuum. Podratz et al. [25] reported that tumor recurred in 21% of patients with residual disease #2 cm and in 50% of those with residual disease .2 cm. In the series of Chiara et al. [35], including 95 patients with advanced ovarian cancer who achieved a pathological complete response, tumor residuum after initial surgery was an independent parameter for progression-free survival (.2 cm vs #2 cm, relative risk 5 2.0, 95% CI 5 1.1–3.7, P 5 0.02). In the present series, the disease-free survival was related to the size of residual disease both at univariate and multivariate analysis. The prognostic relevance of histological type in advanced ovarian cancer has long been debated. Generally endometrioid carcinoma [9, 15, 38] has the best prognosis, whereas mucinous type [9, 15, 16] and clear cell type [9, 15, 18] are often associated with a poor clinical outcome. For instance in the study of Makar et al. [9], including 455 patients with stage III disease, endometrioid carcinomas had the best survival, and the
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relative risk of death was 1.543 for serous, 1.693 for mixed, 1.947 for undifferentiated, 4.394 for clear cell, and 6.969 for mucinous tumors (P , 0.001). The prognostic value of histological type in pathologically complete responders is less clear than in the whole population of patients with advanced ovarian cancer. Gershenson et al. [24] found that 5-year progressionfree survival after negative second-look was 32% for mixed tumors, 67% for undifferentiated, 73% for serous, and 100% for mucinous and endometrioid tumors. Conversely, the risk of recurrence after negative surgical reassessment was not related to histological type in other studies [26, 32, 35] as well as in our experience. Regarding the whole group of patients with advanced disease, tumor grade was an independent prognostic factor for survival in some series [4, 9, 12] but not in others [3, 5, 6]. On the other hand, all the authors suggest that tumor differentiation has a strong predictive value for the risk of recurrence after a negative second-look. Gershenson et al. [24] reported that 5-year progression-free survival was 63, 79, and 100%, respectively, for grade 3, 2, and 1 disease. Podratz et al. [25] observed that the frequency of recurrent disease increased progressively from 0 to 53% as tumor grade according to Broders’ classification increased from 1 to 4. Mangioni et al. [32] reported similar results. Rubin et al. [26] detected tumor recurrence in 14.3% of patients with grade 1, in 35.3% of those with grade 2, and in 64.7% of those with grade 3 disease. In the series of Chiara et al. [35], the relative risk of relapse was 4.9 (95% CI, 1.1–21.0) for grade 2 and 5.0 (95% CI, 1.1–21.9) for grade 3 compared to grade 1 disease (P 5 0.048). Our data showed that disease-free survival was related to tumor grade both at univariate and multivariate analysis. The impact of first-line chemotherapy on the risk of recurrence after negative second-look is still controversial [25, 26, 32, 35]. Podratz et al. [25] reported that tumor recurred in 45% of the 31 patients treated with cyclophosphamide and cisplatin and in none of the 13 patients who received hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin. Rubin et al. [26] found that
FIG. 6.
Survival of complete responders after recurrence.
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platinum-treated patients had a 50% (12/24) recurrence rate compared with 25% (8/32) in nonplatinum-treated patients. They suggested that with the use of platinum-based regimens a higher proportion of patients achieve the complete clinical response and become eligible for second-look. However, because platinumbased regimens are generally given for a shorter time than singleagent or nonplatinum combination regimens, patients are required to remain clinically disease-free for a shorter time before surgical reassessment. So the difference in recurrence rate after negative second-look in the platinum- versus nonplatinum-treated patients could be due to the natural selective effect of time in subsets of patients receiving chemotherapy regimens of different duration. Conversely, in the series of Mangioni et al. [32] survival of complete responders was not related to the type or duration of first-line chemotherapy. Moreover, the intraperitoneal administration of chromic phosphorus after negative second-look did not seem to increase patient survival. In the experience of Chiara et al. [35], the addition of doxorubicin to first-line platinum-based chemotherapy did not improve the clinical outcome of patients with negative surgical reassessment. In our study the disease-free survival was similar in patients who received single-agent cisplatin or carboplatin, cisplatin- or carboplatin-based regimens, or nonplatinum-based chemotherapy. Moreover, the disease-free survival was not significantly different between patients who underwent consolidation chemotherapy and those who received no further treatment after negative second-look. So the additional therapy did not seem to be very helpful. However, no conclusion can be drawn on this point, since the choices of treatment following negative surgical reassessment were based mainly on personal preference. In the series of Mangioni et al. [32] the survival of complete responders was not related to the type of second-look. Conversely, we found that the risk ratio of relapse was 1.826 (95% CI, 1.121–2.973) for patients who were submitted to a laparoscopic second-look compared to those who underwent a laparotomic reassessment. Both laparoscopic and laparotomic second-look had washings. These surgical procedures had similar numbers of peritoneal biopsies, whereas lymph node biopsies were more frequent in patients submitted to laparotomic reassessment. The higher recurrence rate after a negative laparoscopy might reflect the lower accuracy of this surgical approach in detecting subclinical persistent disease, since some areas can be hindered by adhesions and retroperitoneum cannot be adequately assessed. Data from the literature show that some pretreatment variables have prognostic relevance in predicting response to therapy, progression-free survival, and survival in the whole population of advanced ovarian cancer patients [35]. In agreement with other authors, our results confirm that residual disease after initial surgery and tumor grade retains its prognostic value in the group of patients who achieve a pathological complete response. The risk ratio of relapse was 2.386 (95% CI, 1.140 – 4.990) for grade 2 and 3.118 (95% CI, 1.515– 6.416) for grade 3 compared to grade 1 disease. For patients with residual disease 1–2 cm and .2 cm the risk ratio was, respectively,
1.877 (95% CI, 1.117–3.156) and 2.156 (95% CI, 1.324 – 3.511) compared to patients with residual disease ,1 cm. In conclusion, about half of the patients with advanced ovarian cancer in pathological complete response will develop recurrent disease. Poorly differentiated grade and large residual disease after initial surgery are the strongest prognostic variables for the risk of recurrence. There is a need for consolidation therapy in a subset of complete responders at high risk of relapse who should be enrolled in randomized clinical trials [32]. REFERENCES 1. Pettersson F (ed): Annual report on the results of treatment in gynecological cancer: Vol. 21. Int J Gynecol Obstet 36 (Suppl), 1–315, 1991 2. Alberts DS, Dahlberg S, Green SJ, Garcia D, Hanningan EV, O’Toole R, Stock-Novack D, Surwit EA, Malviya VK, Jolles CJ: Analysis of patient age as an independent prognostic factor for survival in a phase III study of cisplatin– cyclophosphamide versus carboplatin– cyclophosphamide in stages III (suboptimal) and IV ovarian cancer. Cancer 71:618 – 627, 1993 3. Pfisterer J, Kommoss F, Sauerbrei W, Renz H, du Bois A, KiechleSchwarz M, Pfleiderer A: Cellular DNA content and survival in advanced ovarian carcinoma. Cancer 74:2509 –2515, 1994 4. Kaern J, Trope` CG, Kristensen GB, Tveit KM, and Pettersen EO: Evaluation of deoxyribonucleic acid ploidy and S-phase fraction as prognostic parameters in advanced epithelial ovarian carcinoma: a prospective study. Am J Obstet Gynecol 170:479 – 487, 1994 5. Baker TR, Piver MS, and Hempling RE: Long term survival by cytoreductive surgery to less than 1 cm, induction weekly cisplatin and monthly cisplatin, doxorubicin, and cyclophosphamide therapy in advanced ovarian adenocarcinoma. Cancer 74:656 – 663, 1994 6. Bruzzone M, Gadducci A, Brunetti I, Mammoliti S, Iskra L, Chiara S, Catsafados E, Foglia G, Boccardo F, Ragni N, Conte PF: Prognostic factors affecting long term survival of advanced ovarian cancer (AOC) patients (pts): univariate and multivariate analysis at 12 years follow up. Proc Am Soc Clin Oncol 14:286, 1995 [Abstract 812] 7. Del Campo JM, Felip E, Rubio D, Vidal R, Bermejo B, Colomer R, and Zanon V: Long-term survival in advanced ovarian cancer after cytoreduction and chemotherapy treatment. Gynecol Oncol 53:27–32, 1994 8. Partridge EE, Gunter BC, Gelder MS, Alvarez RD, Soong SJ, Austin JM, Kilgore LC: The validity and significance of substages of advanced ovarian cancer. Gynecol Oncol 48:236 –241, 1993 9. Makar AP, Baekelandt M, Trope´ CG, Kristensen GB: The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer. Gynecol Oncol 56:175–180, 1995 10. Griffiths CT, Fuller AF: Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 58:131–142, 1978 11. Bertelsen K: Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecol Oncol 38:203–209, 1990 12. GICOG: Long-term results of a randomized trial comparing cisplatin with cisplatin and cyclophosphamide with cisplatin, cyclophosphamide, and adriamycin in advanced ovarian cancer. Gynecol Oncol 45:115–117, 1992 13. Hoskins PJ, O’Reilly S, Spinelli J, Fairey RN, Benedet JL, Swenerton KD: 10 year follow up of patients with advanced (stages III and IV) epithelial ovarian carcinoma (EOC) treated with cisplatin-based multimodality therapy at a single institution. Proc Am Soc Clin Oncol 11:228, 1992 [Abstract 724] 14. Hoskins WJ: Epithelial ovarian carcinoma: principles of primary surgery. Gynecol Oncol 55:S91–S96, 1994
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68, 150 –155 (1998)
GO974890
Analysis of Failures after Negative Second-Look in Patients with Advanced Ovarian Cancer: An Italian Multicenter Study Angiolo Gadducci, M.D.,*,1 Enrico Sartori, M.D.,† Tiziano Maggino,‡ Paolo Zola, M.D.,§ Fabio Landoni, M.D.,¶ Antonio Fanucchi, M.D.,* Nicoletta Palai, M.D.,† Chiara Alessi, M.D.,‡ Anna Maria Ferrero, M.D.,§ Stefania Cosio, M.D.,* and Renza Cristofani, M.D.\ *Department of Gynecology and Obstetrics, University of Pisa; †Department of Gynecology and Obstetrics, University of Brescia; ‡Department of Gynecology and Obstetrics, University of Padova; §Department of Gynecology and Obstetrics, University of Torino; ¶Department of Gynecology and Obstetrics, III Branch of the University of Milano (Monza); and \Department of Public Health and Biostatistics and CNR Institute of Clinical Physiology, Pisa, Italy Received May 8, 1997
ovarian cancer patients, ranging from 79.0% in stage I to 57.0% in stage II, 22.5% in stage III, and 8.4% in stage IV. Among patients with advanced malignancy, tumor stage [2–9], residual disease after initial surgery [3–7, 9 –15], tumor grade [3– 6, 9, 12], and histological type [4, 9, 15–18] are the clinicopathological variables influencing the response rate to chemotherapy and survival rate. The standard therapeutic strategy in advanced ovarian cancer includes cytoreductive surgery followed by platinum-based chemotherapy, achieving an objective response in 60 – 80% and a pathological complete response in 25–30% of cases [19 –23]. A negative second-look is associated with an improved survival, but the long-term prognostic significance of surgical reassessment after chemotherapy is still unclear since a high proportion of complete responders will subsequently develop recurrent disease [5, 24 –29]. The aim of this Italian multicenter retrospective study was to assess the patterns of failures and the prognostic factors for recurrences in advanced ovarian cancer patients after a negative second-look.
This multicenter retrospective study is based on 192 patients with advanced ovarian cancer in pathological complete response at second-look surgery. Ninety-four (48.9%) patients developed recurrent disease after a median time of 18 months (range, 4 – 89 months) from surgical reassessment. The recurrence involved the pelvis in 45 (47.9%) cases, the abdomen in 42 (44.7%), the retroperitoneal lymph nodes in 13 (13.8%), and distant sites in 20 (21.2%). On the whole series, 5- and 7-year disease-free survival rates after negative second-look were 47.4 and 44.5%, respectively. By log-rank test the disease-free survival rate was related to FIGO stage (P 5 0.008), tumor grade (P 5 0.0021), size of residual disease after initial surgery (P 5 0.0038), and type of second-look (laparoscopy vs laparotomy, P 5 0.0061), but not to histological type and first-line chemotherapy. Cox proportional hazard model showed that tumor grade, size of residual disease, and type of second-look were independent prognostic variables for diseasefree survival. The risk ratio of relapse was 2.386 (95% CI, 1.140 – 4.990) for grade 2 and 3.118 (95% CI, 1.515– 6.416) for grade 3 compared to grade 1 disease. For patients with residual disease 1–2 cm and >2 cm the risk ratio was, respectively, 1.877 (95% CI, 1.117–3.156) and 2.156 (95% CI, 1.324 –3.511) compared to patients with residual disease <1 cm. The risk ratio was 1.826 (95% CI, 1.121–2.973) for patients who were submitted to a laparoscopic second-look compared to those who underwent a laparotomic reassessment. Poorly differentiated grade and large residual disease after initial surgery are the strongest prognostic variables for recurrence after a negative second-look. © 1998 Academic Press
MATERIAL AND METHODS
INTRODUCTION
The present investigation includes 192 patients with advanced ovarian cancer in pathological complete response at second-look surgery after initial laparotomy and first-line chemotherapy treated at the Departments of Obstetrics and Gynecology of the Universities of Brescia, Padova, Pisa, and Torino between 1980 and 1994. Second-look surgery consisted of laparoscopy in 34 patients and laparotomy in 158. A pathological complete response was defined as the disappearance of all tumor deposits with negative peritoneal washing and negative multiple random biopsies. The median age of the patients at diagnosis was 55 years (range, 30 –74 years). After initial surgery tumor stage and histological diagnosis of each case were determined according to FIGO criteria and the histological typing system of the
Ovarian cancer is the leading cause of death for gynecological malignancy. According to the International Federation of Gynecology and Obstetrics (FIGO) Annual Report 1991, the 5-year survival rate was 40.9% in the whole series of 11,596 1 To whom correspondence should be addressed at Department of Gynecology and Obstetrics, University of Pisa, Via Roma 56, Pisa, 56127, Italy. Fax: 39 50 553410.
0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
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jointly test the relative importance of variables as predictors of disease-free survival times. RESULTS
FIG. 1. Disease-free survival in patients with stage III–IV epithelial ovarian cancer after negative second-look surgery.
World Health Organization, respectively. Tumors were graded as well (G1), moderately (G2), or poorly (G3) differentiated. The histological material was reviewed by the same pathologist in each center. According to the FIGO classification, tumor stage was IIIa in 20 (10.4%) patients, IIIb in 40 (20.8%), IIIc in 123 (64.1%), and IV in 9 (4.7%). Histologically, 131 (68.2%) tumors were serous, 22 (11.5%) endometrioid, 18 (9.4%) undifferentiated, 11 (5.7%) mucinous, 5 (2.6%) clear cell, 4 (2.1%) mixed, and 1 (0.5%) was a malignant Brenner tumor. Tumor grade was G1 in 24 (12.5%) patients, G2 in 70 (36.5%), G3 in 87 (45.3%), and unspecified in 11 (5.7%). Residual disease after initial surgery was #1 cm in 87 (45.3%) patients, 1–2 cm in 49 (25.5%), and .2 cm in 56 (29.2%). First-line chemotherapy consisted of single-agent cisplatin or carboplatin in 18 (9.4%) patients, cisplatin- or carboplatin-based regimens in 162 (84.3%), and nonplatinum-based regimens in 12 (6.3%). In detail, platinum-based combination chemotherapy included cisplatin 1 cyclophosphamide in 55 patients, cisplatin 1 cyclophosphamide 1 doxorubicin or epirubicin in 98, cisplatin 1 taxol in 4, and carboplatin 1 cyclophosphamide 1 doxorubicin in 5. Further therapy after negative second-look was adopted in 115 (59.3%) cases without any common protocol and the choices of treatment were based mainly on personal preference. All patients were followed until they died or until June 1996.
After negative second-look, 77 (39.7%) patients received no further treatment, 3 (1.5%) underwent external abdomen–pelvic irradiation, 1 (0.5%) received intraperitoneal chromic phosphorus, and 111 (57.2%) received consolidation chemotherapy of different types. Eighty-seven (45.3%) patients are still alive with no clinical evidence of disease after a median time of 71 months (range, 4 –150 months) from second-look. Eleven (5.7%) patients died of intercurrent disease with no clinical evidence of recurrent tumor after a median time of 30 months (range, 5–111 months). Ninety-four (48.9%) patients developed recurrent disease after a median time of 18 months (range, 4 – 89 months). The recurrent disease involved the pelvis in 45 (47.9%) cases, the abdomen in 42 (44.7%), the retroperitoneal lymph nodes in 13 (13.8%), and distant sites in 20 (21.2%). The sites of distant relapses included brain (6 cases), liver (4 cases), extraabdominal lymph nodes (4 cases), lung (2 cases), spleen (2 cases), and bone (2 cases). On the whole series, 5- and 7-year disease-free survival rates after negative second-look were 47.4 and 44.5%, respectively (Fig. 1). By log-rank test the disease-free survival was related to FIGO stage (P 5 0.008) (Fig. 2), tumor grade (P 5 0.0021) (Fig. 3), size of residual disease (P 5 0.0038) (Fig. 4), and type of second-look (laparoscopy vs laparotomy, P 5 0.0061) (Fig. 5), but not to histological subtype and first-line chemotherapy (data not shown). With regard to therapy after negative secondlook, the 5- and 7-year disease-free survival rates following surgical reassessment were 43.7 and 40.6%, respectively, for the patients who received no further treatment, and 49.4 and 46.3%, respectively, for those who underwent consolidation chemotherapy (P 5 NS).
Statistical Methods The statistical package SAS, release 6.7, was used for computations. The cumulative probability of disease-free survival from second-look was estimated by the product-limit method. The log-rank test was used to compare the homogeneity of disease-free survival functions across strata defined by categories of prognostic variables. A multiple regression analysis based on the Cox proportional hazard model was used to
FIG. 2.
Disease-free survival in complete responders by FIGO stage.
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FIG. 3.
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Disease-free survival in complete responders by tumor grade.
Cox proportional hazard model showed that tumor grade, size of residual disease, and type of second-look were independent prognostic variables for disease-free survival (Table 1). The management of recurrent disease was no therapy in 5 (5.3%) patients, chemotherapy in 61 (65.9%), surgery plus chemotherapy in 17 (18.1%), surgery in 4 (4.2%), hormonotherapy in 4 (4.2%), surgery plus radiotherapy in 2 (2.1%) (recurrence in the retroperitoneal lymph nodes and pelvis, respectively), and radiotherapy in 1 (1.1%) (bone recurrence). Among the relapsing patients, 79 (84.0%) died after a median time of 21 months (range, 2–55 months) from recurrence, 11 (11.7%) are still alive with clinical evidence of disease after a median time of 15 months (range, 7–51 months), and 4 (4.3%) are still alive with no clinical evidence of disease after 8, 10, 60, and 84 months, respectively. Survival rate after recurrence is shown in Fig. 6.
FIG. 4. Disease-free survival in complete responders by residual disease after initial surgery.
FIG. 5. Disease-free survival in complete responders by type of secondlook surgery.
DISCUSSION The achievement of a pathological complete response has a favorable prognostic relevance for patients with advanced ovarian cancer. However a review of the literature shows that 19.5–71% of complete responders develop recurrent disease after a median time of 14 –32 months from second-look [5, 24 –34]. Most of these cases are expected to have a relapse within 2 years, but Podczaski et al. [34] reported that 10 (66.7%) of their 15 relapses arose after 24 months and 6 (40.0%) arose after 36 months. The clinical outcome of patients with relapsing disease is poor since salvage treatment is largely unsuccessful. Median survival after recurrence ranges between 11 and 32 months [26, 33, 34]. Pelvis and abdomen are the most frequent sites of recurrences after a negative second-look. In the 15 relapsing patients detected by Podratz et al. [25], the recurrent disease involved the pelvis in 2 (13%) cases, pelvis and abdomen in 2 (13%), pelvis, abdomen, and chest in 3 (20%), pelvic or para-aortic lymph nodes in 3 (20%), liver in 4 (27%), and pelvis and para-aortic lymph nodes in 1 (7%) case. All 15 recurrences analyzed by Bar-Am et al. [29] were limited to the pelvis and abdominal cavity. Rubin et al. [26] reported that tumor recurred in the abdomen in 10 (47.6%) patients, in the lungs in 3 (14.3%), in the pelvis in 2 (9.5%), in the liver in 2 (9.5%), in the vagina in 2 (9.5%), and in the supraclavicular lymph nodes in 2 (9.5%). In the present series, 48.9% of the 192 patients with stage III–IV ovarian cancer in pathological complete response had a recurrence after a median time of 18 months from second-look. Our data on times and sites of recurrences are consistent with the literature. It is noteworthy that less than 14% of failures were limited to retroperitoneal lymph nodes. It is well known that some clinicopathological variables have prognostic relevance for advanced ovarian cancer. As for the whole population of patients with advanced disease, FIGO stage was an independent prognostic variable for survival in
FAILURES AFTER NEGATIVE SECOND-LOOK
TABLE 1 Variables Predictive of Disease-Free Survival by Cox Proportional Hazard Model Variable
Risk ratio
95% Confidence limits
P value
RD 1–2 cm RD .2 cm G2 G3 SL
1.877 2.156 2.386 3.118 1.826
1.117–3.156 1.324–3.511 1.140–4.990 1.515–6.416 1.121–2.973
0.0174 0.0020 0.0209 0.0020 0.0155
Note. RD, residual disease after initial surgery; G2, moderately differentiated tumor; G3, poorly differentiated tumor; SL, type of second-look (laparoscopy versus laparotomy).
some studies [2, 4, 7] but not in others [3, 5, 6]. With regard to the subset of patients who achieved a pathological complete response, tumor stage was related to the recurrence rate in the series of Rubin et al. [26] (III versus IV, 32.4 versus 60%) but not in the experiences of Gershenson et al. [24], Mangioni et al. [32], and Chiara et al. [35]. Our results showed that diseasefree survival after negative second-look was related to FIGO stage at univariate (III versus IV, P 5 0.008) but not at multivariate analysis. Residual disease after initial surgery is the most important prognostic factor for advanced ovarian cancer. Even if there is no agreement in the literature about the optimal diameter of residual tumor, most authors have used the value of 2 cm as the limit to define subsets of patients with different prognoses [3, 4, 6, 7, 9, 11–15, 36, 37]. However, according to some authors, only residual masses ,1 cm are associated with improved survival [5, 11]. All the authors agree that residual disease after initial surgery is also related to the risk of recurrence in pathologically complete responders [24, 25, 32, 35]. In the series of Gershenson et al. [24], 5-year progression-free survival after negative second-look was 64 and 69%, respectively, for patients with tumor residuum .2 cm and #2 cm and 92% for those without macroscopic residuum. Podratz et al. [25] reported that tumor recurred in 21% of patients with residual disease #2 cm and in 50% of those with residual disease .2 cm. In the series of Chiara et al. [35], including 95 patients with advanced ovarian cancer who achieved a pathological complete response, tumor residuum after initial surgery was an independent parameter for progression-free survival (.2 cm vs #2 cm, relative risk 5 2.0, 95% CI 5 1.1–3.7, P 5 0.02). In the present series, the disease-free survival was related to the size of residual disease both at univariate and multivariate analysis. The prognostic relevance of histological type in advanced ovarian cancer has long been debated. Generally endometrioid carcinoma [9, 15, 38] has the best prognosis, whereas mucinous type [9, 15, 16] and clear cell type [9, 15, 18] are often associated with a poor clinical outcome. For instance in the study of Makar et al. [9], including 455 patients with stage III disease, endometrioid carcinomas had the best survival, and the
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relative risk of death was 1.543 for serous, 1.693 for mixed, 1.947 for undifferentiated, 4.394 for clear cell, and 6.969 for mucinous tumors (P , 0.001). The prognostic value of histological type in pathologically complete responders is less clear than in the whole population of patients with advanced ovarian cancer. Gershenson et al. [24] found that 5-year progressionfree survival after negative second-look was 32% for mixed tumors, 67% for undifferentiated, 73% for serous, and 100% for mucinous and endometrioid tumors. Conversely, the risk of recurrence after negative surgical reassessment was not related to histological type in other studies [26, 32, 35] as well as in our experience. Regarding the whole group of patients with advanced disease, tumor grade was an independent prognostic factor for survival in some series [4, 9, 12] but not in others [3, 5, 6]. On the other hand, all the authors suggest that tumor differentiation has a strong predictive value for the risk of recurrence after a negative second-look. Gershenson et al. [24] reported that 5-year progression-free survival was 63, 79, and 100%, respectively, for grade 3, 2, and 1 disease. Podratz et al. [25] observed that the frequency of recurrent disease increased progressively from 0 to 53% as tumor grade according to Broders’ classification increased from 1 to 4. Mangioni et al. [32] reported similar results. Rubin et al. [26] detected tumor recurrence in 14.3% of patients with grade 1, in 35.3% of those with grade 2, and in 64.7% of those with grade 3 disease. In the series of Chiara et al. [35], the relative risk of relapse was 4.9 (95% CI, 1.1–21.0) for grade 2 and 5.0 (95% CI, 1.1–21.9) for grade 3 compared to grade 1 disease (P 5 0.048). Our data showed that disease-free survival was related to tumor grade both at univariate and multivariate analysis. The impact of first-line chemotherapy on the risk of recurrence after negative second-look is still controversial [25, 26, 32, 35]. Podratz et al. [25] reported that tumor recurred in 45% of the 31 patients treated with cyclophosphamide and cisplatin and in none of the 13 patients who received hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin. Rubin et al. [26] found that
FIG. 6.
Survival of complete responders after recurrence.
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platinum-treated patients had a 50% (12/24) recurrence rate compared with 25% (8/32) in nonplatinum-treated patients. They suggested that with the use of platinum-based regimens a higher proportion of patients achieve the complete clinical response and become eligible for second-look. However, because platinumbased regimens are generally given for a shorter time than singleagent or nonplatinum combination regimens, patients are required to remain clinically disease-free for a shorter time before surgical reassessment. So the difference in recurrence rate after negative second-look in the platinum- versus nonplatinum-treated patients could be due to the natural selective effect of time in subsets of patients receiving chemotherapy regimens of different duration. Conversely, in the series of Mangioni et al. [32] survival of complete responders was not related to the type or duration of first-line chemotherapy. Moreover, the intraperitoneal administration of chromic phosphorus after negative second-look did not seem to increase patient survival. In the experience of Chiara et al. [35], the addition of doxorubicin to first-line platinum-based chemotherapy did not improve the clinical outcome of patients with negative surgical reassessment. In our study the disease-free survival was similar in patients who received single-agent cisplatin or carboplatin, cisplatin- or carboplatin-based regimens, or nonplatinum-based chemotherapy. Moreover, the disease-free survival was not significantly different between patients who underwent consolidation chemotherapy and those who received no further treatment after negative second-look. So the additional therapy did not seem to be very helpful. However, no conclusion can be drawn on this point, since the choices of treatment following negative surgical reassessment were based mainly on personal preference. In the series of Mangioni et al. [32] the survival of complete responders was not related to the type of second-look. Conversely, we found that the risk ratio of relapse was 1.826 (95% CI, 1.121–2.973) for patients who were submitted to a laparoscopic second-look compared to those who underwent a laparotomic reassessment. Both laparoscopic and laparotomic second-look had washings. These surgical procedures had similar numbers of peritoneal biopsies, whereas lymph node biopsies were more frequent in patients submitted to laparotomic reassessment. The higher recurrence rate after a negative laparoscopy might reflect the lower accuracy of this surgical approach in detecting subclinical persistent disease, since some areas can be hindered by adhesions and retroperitoneum cannot be adequately assessed. Data from the literature show that some pretreatment variables have prognostic relevance in predicting response to therapy, progression-free survival, and survival in the whole population of advanced ovarian cancer patients [35]. In agreement with other authors, our results confirm that residual disease after initial surgery and tumor grade retains its prognostic value in the group of patients who achieve a pathological complete response. The risk ratio of relapse was 2.386 (95% CI, 1.140 – 4.990) for grade 2 and 3.118 (95% CI, 1.515– 6.416) for grade 3 compared to grade 1 disease. For patients with residual disease 1–2 cm and .2 cm the risk ratio was, respectively,
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