GYNECOLOGY &OBSTETRICS

International Journal of Gynecology & Obstetrics 56 (1997) 147-1.53

Article

Multivariate

analysis of prognostic factors in patients with ovarian cancer stage I and II

K. Tanakaa, A. Tokunagab, N. Sudo, T. Takahashid, K. Matsui

S. Kodama+*,

Department of Obstetrics and Gynecology Ndgata University School OfMedicine, Niigata, Japan bDepartment of Obstehics and Gynecology, Niigata City Hospital, Niigata, Japan Nagaoka Red Cross Hospital, Niigata, Japan De artment of Obstehics and Gynecology, gDepartment of Obstetks and Gynecology, Niigata Cancer Center, Niigata, Japan eKashiwazaki Public Health Center, Niigata, Japan
Received 11 April 1996; revised 20 September 1996; accepted 30 September 1996

Abstract Objective: To evaluate prognostic factors such as surface capsular invasion, rupture of the capsule and intraperitoneal cytology in patients with stage I or II ovarian cancer. Method: Multivariate analysis was performed using 11 clinicopathologic prognostic factors obtained from 183 cases of stage I and II ovarian cancer, which had been surgically treated between 1983 and 1993. Results: Significant prognostic factors determined by the Kaplan-Meier method were rupture and invasion of the capsule in stage II ovarian cancer. Multivariate analysis showed that spontaneous rupture of the capsule was the only significant factor, and intrapelvic cytology was an important factor without significance. Although capsular rupture caused by the surgeon showed poor prognosis by the Kaplan-Meier method, no significance was observed for this factor by multivariate analysis. Conclusion: Multivariate analysis showed that capsular rupture caused by the surgeon did not affect the prognosis in stage I and II ovarian cancer. 0 1997 International Federation of Gynecology and Obstetrics Keywords:

Multivariate

analysis; Prognostic

factor; Ovarian cancer

1. Introduction The prognosis of stage I and II epithelial ovarian cancer is poor when positive cytodiagnosis of ascites or peritoneal washings, or tumor surface

invasion is present [l]. According to the International Federation of Gynecology and Obstetrics

(FIG01 classification system in 1987 [2], patients

showing a rupture of the ovarian capsule, surface capsular invasion, and positive cytology of ascites or peritoneal washings are staged as Ic or 11~.

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Rupture of the tumor capsule is subclassified into spontaneous rupture at the time of laparotomy or rupture caused by the surgeon. This subclassifiand Obstetrics

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cation of stages I and II may help to clarify the effect of ruptures on prognosis. Some studies have found differences in the prognosis of stage I or II ovarian cancer cases between those with and those without capsular rupture [3-71, but others have observed no differences [8-121. This inconsistency may be because some of the studies did not include intraperitoneal cytology and the histological diagnosis of tumor capsule invasion as criteria, and because the treatment contents differed. To determine whether capsular rupture is a significant prognostic factor, several other factors such as the histological type, surgical procedure, the presence or absence of radiotherapy, and the chemotherapy protocol should also be evaluated. Separate analyses of individual factors of stage I and II ovarian cancer are inadequate; in this respect, multivariate analysis is required [13,141. In the present study, we compared prognostic factors, mainly capsular findings, of stage I and II ovarian carcinomas by multivariate analysis, to determine those that would have the most influence on recurrence.
2. Materials and methods

A total of 183 patients with epithelial ovarian cancer including 130 with stage I cancer and 53 with stage II cancer were operated on at four institutions between 1983 and 1993. The clinical stage was classified according to the FIG0 classification system, and the histological classification was performed according to the World Health Organization (WHO) classification system in 1973 1151. The condition of the ovarian tumor capsule was classified as (a) the absence of rupture, (b> spontaneous rupture at the time of laparotomy, or (c) rupture caused by the surgeon. The presence or absence of surface capsular invasion was histologically confirmed. The results of the cytodiagnosis of ascites or intraperitoneal washings were classified as negative or positive. In some cases examination of the cytodiagnosis was not performed. After surgery, multiple drug chemotherapy was performed with FCAP or CAP; FCAP was comprised of 350 mg/m of 5-fluorouracil, 40 mg/m of adriamycin (ADM), 350 mg/m2 of cyclophosphamide (CPA) and 50 mg/m2 of cisplatin

(CDDP); and CAP was comprised of 400 mg/m2 of CPA, 40 mg/m2 of ADM and 6070 mg/m2 of CDDP. Five courses of chemotherapy at 3-week intervals were administered to the patients with stage IIc cancer, and three courses were administered to all others. Concerning the surgical procedure, hysterectomy was performed in 158 patients, bilateral salpingo-oophorectomy in 159 patients, unilateral salpingo-oophorectomy in 24, and omentectomy in 136. In patients with stage Ia cancer who strongly desired a future pregnancy, the ovary on the affected side alone was resected. As for lymph node dissection, pelvic nodes were dissected in 60 patients, paraaortic nodes in 1, and both pelvic and paraaortic nodes in 56. Dissection was not performed in 66 patients. The outcomes of all patients were evaluated on December 31, 1994. The cumulative survival rate was calculated by the Kaplan-Meier method. Comparisons of survival curves were done using the Cox-Mantel test. By multivariate analysis, the degree of influence of each factor on the prognosis was determined from a multiple logistic model [16]. The prognostic factors were evaluated as significant or not according to the P values. In all analyses, the significance level was set at 0.05.
3. Results 3.1. Incidence according to stages and histological types (Table 1)

In this study, stage Ic cancer was observed in 86 patients (47%), and stage IIc in 46 (25%). Concerning the histological type, the serous type was observed in 59 patients (32%), mutinous type in 45 (25%), clear cell type in 38 (21%), and the endometrioid type in 37 (20%).
3.2. ClinicalJindings 2) and 5-year survival rates (Table

The 5-year survival rate for each prognostic factor is shown in Table 2.
3.2.1. Clinical stage and j-year survival rates

The median follow-up period was 48 months for stage I and 45 months for stage II patients.

S. Kodama Table 1 Histology Histology

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149

and clinical

stage Clinical Ia stage Ib 1 0 0 2 0 3

IC

Total IIa 1 1 0 1 0 3 IIb 3 0 0 1 0 4 IIC 18 5 10 9 4 46 59 45 38 37 4 183

Serous Mutinous Clear cell Endometrioid Undifferentiated Total

9 15 8 9 0 41

27 24 20 15 0 86

Table 2 Clinical characteristics Clinical characteristics

and 5-year

survival

of the study patients Stage II 5-year survival No. of cases 5-year survival

Stage I No. of cases

Clinical Total t
C

stage 130 41 3 84 66 19 45 95.7% 100.0% 100.0% 93.1% 100.0% 94.4% 78.4% 53 3 4 46 14 12 27 11 42 21 23 22 6 11 10 4 53 0 12 21 20 hysterectomy; BSO, bilateral 81.0% 100.0% 100.0% 78.4% lOO.o%* lOO.o%* 66.4%* P < 0.01

Capsular rupture No Spontaneous Surgical Capsular invasion No Yes Wol%Y Negative Positive Histology Serous Mutinous Endometrioid Clear cell Undifferentiated Operation TAH + BSO us0 Lymphadenectomy No Pelvic Pelvic and paraaorta

108 22 79 32 37 39 26 28 0 102 28 54 39 37 TAH,

96.9% 89.3% 95.7% 92.8% 92.0% 100.0% 100.0% 92.7%

lOO.o%* 76.4%* I < 0.01 100.0% 84.3%

85.6% 75.0% 90.9% 66.7% 100.0% 82.4%

94.5% 100.0% 93.8% 97.2% 100.0% total abdominal

81.8% 72.4% 100.0% salpingo-oophorectomy;

* Significantly different from other values withasterisks. USO, unilateral salpingo-oophorectomy.

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The 5-year survival rate for stage I patients was 100% in the 41 patients with stage Ia and 3 with stage Ib, but 93% in the 86 patients with stage Ic. The 5-year survival rate for stage II patients was 100% in the 3 patients with stage IIa and 4 with stage IIb but 78% in the 46 with stage 11~.
3.2.2. Condition of the capsule and j-year survival rates

In the stage I group, all 66 patients without capsular rupture survived for 5 years at the least. However, the 5-year survival rate was 94% in the 19 patients with spontaneous rupture of the capsule and 78% in the 45 patients with capsular rupture caused pL the surgeon. In the stage II group, all 14 patients without capsular rupture and the 12 showing spontaneous rupture survived at least 5 years. However, the 5-year survival rate was 66% in the 27 patients whose rupture was caused by the surgeon. The prognosis was good in patients with stage IIc cancer showing spontaneous capsular rupture at the time of laparotomy. This may have been because early emergency surgery was performed due to clinical symptoms such as torsion of the pedicle and abdominal pain. In stage Ic, there was no significant differences between patients with rupture caused by surgeon and those with spontaneous rupture.
3.2.3. S&ace capsular invasion and j-year survival rates

with a rupture made during surgery showed surface capsular invasion and positive cytology. One patient showing negative cytology and the absence of capsular infiltration died of capsular rupture caused by the surgeon. In this patient, dissection of the pelvic and paraaortic lymph nodes was not performed, and recurrence was observed in the paraaortic lymph nodes. In the 7 patients in stage II who died of the tumor, spontaneous rupture was already observed at the time of laparotomy, and surface capsular invasion was present histologically.
3.3. Multivariate analysis (Table 3)

Since the number of patients with stage I cancer who died of cancer (4) was too small for multivariate analysis, the 7 patients who died of stage II cancer were combined with them for analysis. As shown in Table 3, the significant prognostic factor was spontaneous capsular rupture at the time of laparotomy (P= 0.01805). Positive cytology of ascites or intraperitoneal washings was a poor prognostic factor without significance. Nor were rupture during the operation or the histological type associated with the prognosis. Concerning the association between the surgical content and prognosis, preservative treatment did not affect the prognosis. 4. Discussion According to the FIG0 stage classification of ovarian cancer, cases showing tumor surface invasion, rupture of the tumor capsule, and positive results of the cytology of ascites or intraperitoneal washings are subclassified as stage Ic or 11~. For evaluation of the ovarian capsular rupture as a prognostic factor, capsular rupture is classified into spontaneous rupture and rupture caused by the surgeon. Whether capsular rupture affects the prognosis has been discussed, but no conclusion has yet been reached [l]. This is because of the prognostic factors of malignant ovarian tumors, cytopathological factors have been studied less than the surgical procedure and additional adjuvant treatment such as postoperative chemotherapy or radiotherapy. Chemotherapy

The 5-year survival rate in the absence of capsular infiltration was 97% for stage I and 100% for stage II. In contrast, the 5-year survival rate in the presence of capsular infiltration was 89% for stage I and 76% for stage II.
3.2.4. Cytology and j-year survival rates

The 5-year survival rate in the absence of negative malignant cells was 96% for stage I and 100% for stage II, and in the presence of positive malignant cells, it was 93% for stage I and 84% for stage II.
3.2.5. Cancerous deaths and prognostic factors

Four of the rupture caused

patients in stage Ic and 7 in stage IIc died tumor. In stage I, spontaneous capsular was observed in 1 patient and rupture by the surgeon in 3. One of the 3 patients

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Table 3 Multivariate Factors

analysis of ovarian cancer stage I and II Beta coefficient - 0.8369708 -0.2211956 - 0.2851097 -0.6051115 - 0.7475106 0.3076645 0.5253263 0.1586243 0.5477389 0.2260383 0.6951056
P

value

Rupture of capsule Spontaneous Surgical Surface capsular invasion Intrapelvic cytology Histology Serous Mutinous Endometrioid Clear cell Preservative operation Lymphadenectomy Pelvic Pelvic and paraaortic
*P < 0.05.

0.01805* 0.57123 0.93219 0.07110 0.90864 0.64018 0.44388 0.78251 0.21340 0.94269 0.10528

with cisplatin [17,18] has improved the prognosis of stage I ovarian cancer; the 5-year survival rate was reported to be 91% [19], and in our present study was 96%. Therefore, some of the conditions in the tumor capsule associated with the prognosis, lose their importance as prognostic factors with improvement in the treatment results. Some studies have suggested that capsular rupture caused by the surgeon affects the prognosis of ovarian cancer. Purola et al. [3] reported a 5-year survival rate of 80% for stage I cancer patients and a lower survival rate in the 20 patients with surgical capsular rupture (60%) than in the 27 without capsular rupture (83%). Similarly, Williams et al. [5] reported a 5-year survival rate of 98% in 58 patients with stage I cancer without capsular rupture and 43% in 7 with surgical capsular rupture. De la Custa et al. [7] recently reported poor prognoses in patients with ruptures made during surgery. However, in their study, no postoperative treatment was give in 45% of the patients incurring a capsular rupture during surgery, and their survival rate was 80%. This may have been associated with the poor prognosis. Conversely, there are some studies suggesting that capsular rupture does not affect the prognosis. Munnel [9] found that the 5-year survival rate

was 71% in the 99 patients with stage Ia or Ib cancer according to the former FIG0 classification, and among them, the rate was 81% in the 27 patients with capsular rupture during surgery. Of the 27 patients, 21 treated by postoperative radiotherapy showed a 5-year survival rate of 67%, and all of the remaining 6 not treated by postoperative radiotherapy survived. Parker et al. [lo] reported 5-year survival rates for stage I cancer of 60% and 59% in 27 patients without capsular rupture and 20 with capsular rupture at surgery, respectively, suggesting no effects of capsular rupture. To evaluate the importance of capsular rupture, analysis should be also done with respect to results of the cytodiagnosis of ascites or intraperitoneal washings, and the presence or absence of surface capsular invasion. However, many of the extant studies deal with considerably old cases. The chemotherapy in these studies differs from that used in recent studies, and the presence or absence of surface capsular invasion was not described. Therefore, whether capsular rupture during the operation affects the prognosis is difficult to evaluate. Sevelda et al. [12] performed bilateral salpingo-oophorectomy, hysterectomy, omentectomy, and pelvic lymph node dissection in combination with postoperative irradiation (83% in re-

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ported cases) in patients with stage Ia or Ib cancer and observed no difference in outcomes between the patients with and those without capsular rupture (76% in both). However, it was unclear whether radiotherapy or chemotherapy mainly with cisplatin was the more effective postoperative therapy. The .5-year survival rate in patients with stage I cancer treated by chemotherapy was reported to be 93% by Piver [18], showing improvement. Capsular rupture has been an important prognostic factor, but its importance is considered to be lost with the improvement in the prognosis of ovarian cancer due to advances in treatment. Independent piognostic factors can be analyzed by multivariate analysis. Dembo [13] performed multivariate analysis of prognostic factors in stage I ovarian cancer and reported a 5-year survival rate of 70% after postoperative radiotherapy performed in more than 50% of his patients. Finn [14] performed a similar analysis and reported 5-year survival rate of 70% after postoperative chemotherapy mainly with an alkylating agent given to 35% of his patients. Neither study noted significant differences according to rupture during surgery, capsular infiltration, or the histological type. In our multivariate analysis, chemotherapy with multiple drugs including cisplatin was administered to all patients, and the 5-year survival rate for the stage I patients was 96% (4 patients in stage Ic died). Therefore, an analysis of prognostic factors in only the stage I patients could not be performed. When the patients in stage II were added to those in stage I, spontaneous capsular rupture (P = 0.01805) and positive results of intraperitoneal cytodiagnosis (P = 0.07110) were closely associated with the prognosis. Analysis of the type of surgery revealed a 5-year survival rate of 100.0% in patients who underwent dissection of the paraaortic and pelvic lymph nodes. Multivariate analysis also showed a good P value without significance suggesting the close association of dissection of the paraaortic and pelvic lymph nodes with the prognosis. One patient with stage Ia cancer showing negative cytology and the absence of surface capsular invasion died of recurrence. However, in this patient, no dissection of the pelvic or paraaortic lymph

nodes was performed and recurrence was observed in the paraaortic lymph nodes. It was speculated that paraaortic lymph node metastasis had occurred subclinically at the first laparotomy. Taken together, the results of the present study suggest that capsular rupture caused by the surgeon does not directly affect the prognosis of ovarian cancer when postoperative combined chemotherapy with cisplatin is performed.
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