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Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage i ovarian clear cell carcinoma
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Gynecologic Oncology 88 (2003) 394 –399
www.elsevier.com/locate/ygyno
Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage I ovarian clear cell carcinoma Chih-Ming Ho,a,* Tsai-Yen Chien,a Bor-Yuan Shih,a and Shih-Hung Huangb a
Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106, Taiwan b Department of Pathology, Cathay General Hospital, Taipei 106, Taiwan Received 27 June 2002
Abstract Objective. The aim was to determine the benefits of lymphadenectomy and paclitaxel plus carboplatin chemotherapy for stage I ovarian clear cell carcinoma (defined as intra-abdominal disease confined to the ovaries). Methods. Twenty patients with stage I pure clear cell carcinoma of the ovary diagnosed between 1991 and 2001 were divided into two groups: Group A (12 patients, 1997–2001) underwent complete surgical staging including bilateral salpingo-oophorectomy, hysterectomy, omentectomy, and pelvic and para-aortic lymphadenectomy, followed by paclitaxel and carboplatin chemotherapy. Group B (8 patients, 1991–1996) underwent bilateral salpingo-oophorectomy, hysterectomy, and omentectomy without lymphadenectomy, followed by cisplatin-based chemotherapy. The survival of the two groups was compared. The clinical characteristics of the two groups were evaluated for age distribution, grade, substage, preoperative CA-125, presence or absence of endometriosis, and maximal tumor diameter. Results. The estimated 4-year survival rate was 76.9%. The clinical characteristics of the two groups were similar, except for lymphadenectomy and regimen of chemotherapy. With a median follow-up of 36 months (range: 11–130 months), one of 12 patients in Group A had recurrence in comparison with 6 of 8 patients in Group B (P ⫽ 0.004). The estimated 3-year recurrence-free survival and 4-year overall survival for Group A was significantly greater than that for Group B (91.7 vs 33.3%, P ⫽ 0.014; 100 vs 50%, P ⫽ 0.014). Median time to recurrence was 8 months. Conclusion. Complete surgical staging, including pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy, appeared to be capable of improving survival of patients with stage I ovarian clear cell carcinoma. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Ovarian cancer; Clear cell carcinoma; Lymphadenectomy; Chemotherapy
Introduction Clear cell carcinoma has been recognized as a distinct histological entity in the World Health Organization classification of ovarian tumor since 1973 [1]. Clear cell carcinoma constitutes 5–10% of surface epithelial ovarian cancer [2], and up to 60% of the patients with clear cell carcinoma have stage I disease [3]. Patients with stage I ovarian cancer * Corresponding author. Gynecologic Cancer Center, Cathay General Hospital, 280 Section 4 Jen-Ai Road, Taipei 106, Taiwan. Fax: ⫹886-287731988. E-mail address: [email protected] (C.-M. Ho).
usually have favorable prognoses. Nonetheless, patients with clear cell carcinoma have poorer prognoses than do those with other pathological types of epithelial ovarian carcinoma [4,5]. A significant proportion of women (20 – 50%) with stage I clear cell ovarian carcinoma have recurrences and die of their malignancies [4]. The earliest reports on survival in patients with clear cell ovarian carcinoma were possibly biased by limited staging information as well as by the inclusion of patients with mixed histological types of epithelial ovarian adenocarcinoma, including clear cell carcinoma [6,7]. More recent studies remain inconclusive in regard to survival in patients
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(02)00156-7
C.-M. Ho et al. / Gynecologic Oncology 88 (2003) 394 –399
with pure clear cell carcinoma, despite improved histological criteria and staging accuracy [8 –10]. Recent trends in the clinical management of early stage ovarian cancer include increased attention to surgical staging with pelvic and para-aortic lymphadenectomy and general acceptance of paclitaxel plus platinum-based adjuvant chemotherapy. The introduction of cisplatin in the late 1970s markedly changed the postoperative management of ovarian cancer patients. Nonetheless, the results and value of these newer efforts and therapies applied to clear cell carcinoma are as yet undetermined [4,9 –11]. Since 1997, we have performed aortic and pelvic lymphadenectomy, along with optimal cytoreduction at initial surgery, for early stage clear cell carcinoma patients who received paclitaxel plus carboplatin adjuvant chemotherapy. We wondered whether the patients with stage I clear cell ovarian carcinoma (intra-abdominal disease confined to the ovaries) receiving lymphadenectomy and paclitaxel plus carboplatin benefited from improved survival compared to those who did not undergo lymphadenectomy and platinum-based chemotherapy.
Materials and methods Twenty-two patients with stage I clear cell carcinoma of the ovary diagnosed between 1991 and 2001 were identified from tumor registry of Cathay General Hospital. During this period, 154 patients with epithelial ovarian cancer were treated at Cathay General Hospital and staged based on the FIGO classification. Data were collected from medical records and clinical follow-up visits. Among those patients, 34 were originally diagnosed with clear cell carcinoma, and the histological slides were reviewed by one of the authors. Tumors were classified as clear cell adenocarcinoma if typical clear or hobnail cells were present in a papillary, solid, or tubulocystic pattern. All clear cell tumors were considered to be high-grade tumors [12]. After exclusion of 2 patients with admixtures of other histological types and 12 patients with advanced clear cell carcinoma, 20 patients with stage I pure clear cell carcinoma of the ovary (intraabdominal disease confined to the ovaries) were included for study. Twelve patients (Group A), who were treated from 1997 to 2001, underwent total hysterectomy, bilateral salpingooophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy as their initial operation. They all received postoperative chemotherapy combing paclitaxel 175 mg/m2 and carboplatin chemotherapy, with an area under the curve (AUC) equal to 5. They received six cycles of chemotherapy every 3 weeks. Eight patients (Group B) who were treated from 1991 to 1996, underwent total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy without pelvic and para-aortic lymphadenectomy as their initial operation. They received adjuvant chemotherapy containing a platinum compound, mainly cisplatin, epirubi-
395
cin, and cyclophosphamide (PAC) or cisplatin and cyclophosphamide (CP). Doses of the drugs used were epirubicin 60 mg/m2, cyclophosphamide 50 mg/m2, cisplatin 50 mg/m2 or cisplatin 75 mg/m2, and cyclophosphamide 750 mg/m2. They also received six courses of chemotherapy every 3 weeks. Exploration for regional lymph nodes included systemic lymphadenectomy, removal of palpable nodes, or all lymphatic tissue surrounding the retroperitoneal vessels, in the absence of clinically obvious disease. Para-aortic lymph node dissection was performed from the bifurcation of the aorta to the origin of the renal vessels. Pelvic node dissection was done from the common, external and internal iliac, and obturator vessels to the femoral ring. An average of 36 lymph nodes were removed (range: 5– 49 nodes), including 27 pelvic nodes (range: 12– 49 nodes) and 9 para-aortic nodes (range: 5–24 nodes). The clinical characteristics of the two groups were evaluated for age distribution, grade, substage, preoperative CA-125, presence or absence of endometriosis, maximal tumor diameter, surgical procedure and postoperative chemotherapy. Follow-up was accomplished by contacting patients or primary physicians or by reviewing medical records and tumor registry files. Patients were usually monitored as follows: years 1 and 2, physical examination, serum CA125 estimation every 3 months, computed tomography (CT) scan of abdomen and pelvis or ultrasound (US) of the abdomen and pelvis every 6 months; years 3 through 5, physical examination and serum CA-125 estimation every 6 months and CT of the abdomen and pelvis or US of the abdomen and pelvis annually; and years 6 through 10, physical examination and serum CA-125 estimation annually, CT or US only if clinically indicated. More frequent assessments or investigations were performed as clinically indicated. Patient populations were compared using Fisher’s exact test and the Wilcoxon rank sum test. Survival time was considered the primary outcome measure and was measured from the date of diagnosis to the date of death or until last contact. Survival curves were generated using the method of Kaplan–Meier. Differences in survival curves were calculated using the log rank test.
Results A total of 20 patients with pure stage I clear cell carcinoma of the ovary were entered into the study. The mean age was 56 years (range: 37–59 years), and the median follow-up duration was 36 months (range: 11–130 months). No patient was lost to follow-up. Three patients had stage Ia disease, and 17 patients had stage Ic disease. Three of 17 (18%) patients with stage Ic had capsule tumor invasion, while the remaining 14 patients (82%) had tumor rupture during surgery. The clinical char-
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Table 1 Characteristics of Group A and Group B patients Treatment
Stage Ia Ic Age (mean ⫾ SD) (years) Pre-op CA-125 (median) (U/ml) (mean ⫾ SD) (U/ml) Endometriosis Absent Present Maximal tumor diameter (cm) a b
Group A (n ⫽ 12)
Group B (n ⫽ 8)
1 (8.3%) 11 (91.7%) 56.05 ⫾ 9.07 71.0 376.8 ⫾ 876.4
2 (25.0%) 6 (75.0%) 55.12 ⫾ 7.05 22.7 69.0 ⫾ 98.4
7 (58.3%) 5 (41.7%) 14.7 ⫾ 5.7
3 (37.5%) 5 (62.5%) 11.5 ⫾ 3.1
P value
0.54a 0.51b 0.08b 0.65a 0.19b
Based on Fisher’s Exact test. Based on Wilcoxon rank sum test.
acteristics of two groups were similar, except for surgical procedure (with or without lymphadenectomy) and regimen of chemotherapy (paclitaxel– carboplatin vs PAC or CP) (Table 1). The median survival of all patients had not yet been reached. The estimated 4-year survival rate was 76.9%. The estimated 3-year recurrence-free survival for Group A was significantly greater than that of Group B (91.7 vs 33.3%, P ⫽ 0.014) (Fig. 1). The estimated 4-year overall survival for Group A was also significantly greater than that for Group B (100 vs 50%, P ⫽ 0.014, based on the log rank test) (Fig. 2). Seven of 20 patients (35%) relapsed, including 67% (2/3) with stage Ia and 29% (5/17) with stage Ic disease. One of the 12 patients in Group A relapsed in comparison with 6 of 8 patients in Group B (P ⫽ 0.004, Fisher’s exact test). The median time from diagnosis to recurrence was 8 months (range: 4 – 42 months), including 42 and 36 months for stage
Ia, and 13, 8, 7, 6, and 4 months for five stage Ic tumors. The median time from recurrence to death was 3 months (range: 1–13 months). The sites of recurrence included the para-aortic lymph nodes (1) in Group A, and in Group B, the sites of recurrence were pelvis (3), pelvis and abdomen (1), lung (1), and lung and liver (1). One of the three patients with capsule tumor invasion relapsed, while 4 of 14 patients (29%) without capsule invasion relapsed (P value was not significant). None of the 12 patients who underwent lymphadenectomy had retroperitoneal node metastases; nonetheless, 1 patient in Group A, who underwent complete lymphadenectomy, relapsed with metastasis to the retroperitoneal nodes 4 months after surgery. One patient with stage Ia disease in Group B had a recurrence in the pelvis 42 months after diagnosis. She has remained alive without evidence of disease, for more than 5 years after successful debulking surgery followed by paclitaxel and cisplatin chemotherapy. Table 2 presents data of patients who had recurrences. Due to the small sample size, further analysis could not be done. Discussion Clear cell carcinoma represents approximately 6% of ovarian cancers and represents 8 –10% of invasive epithelial cancers [10]. A literature survey revealed that up to 60% of reported patients had stage I disease at diagnosis [6,9]. Several studies report platinum-based regimens to achieve 5-year survival rates of greater than 90% even in high-risk, stage I ovarian cancer such as grade 3 tumors or stage Ic disease [13,14]. Clear cell tumors are reported to be associated with a poorer outcome, are often referred to as highrisk stage I tumors, and consequently are assigned an unfavorable prognosis. Five-year survival in stage I clear cell carcinoma is poor, varying from 50 to 73% [8,9]. Montag et
Fig. 1. Kaplan–Meier estimated recurrence-free survival of patients with stage I pure clear cell carcinoma.
C.-M. Ho et al. / Gynecologic Oncology 88 (2003) 394 –399
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Fig. 2. Kaplan–Meier estimated overall survival of patients with stage I pure clear cell carcinoma.
al. reported a survival rate for stage I clear cell carcinoma of 55%, with frequent distant metastases and lymph node involvement upon recurrence [15]. Most of their reported patients did not undergo lymphadenectomy. The frequency of lymph node involvement in apparent limited stage disease ovarian cancer is around 16% (13–24%) [16]. The true incidence of lymph node metastasis in apparent limited stage clear cell carcinoma is unclear. Lymph node metastasis was significantly increased with recurrent clear cell carcinoma when compared with serous adenocarcinoma [9]. Jenison et al. recommended that pelvic and para-aortic node sampling be performed in clear cell carcinoma patients with early stage disease during the primary operation [9]. Many authors and the FIGO recommend comprehensive surgical staging in early ovarian cancer [17–19]. Retroperitoneal lymph node dissection (RPLND) aims to achieve the following advantages: proper staging of disease, prediction of patient prognosis, and improvement of patient survival. It has not been clarified whether removal of the affected nodes and prophylactic RPLND would improve the survival rates of patients with ovarian carcinoma. Onda et al. reported that the presence of positive lymph nodes might
be of little relevance to the survival of patients with an intraperitoneal tumor limited to the pelvis, as long as systemic aortic and pelvic lymphadenectomy is performed [20]. Pertu et al. reported that lymph node metastases, some less than 2 mm in diameter, occurred in an appreciable percentage of patients with intra-abdominal disease confined to the ovaries. In their report, recurrences in the group that had not undergone lymphadenectomy included the retroperitoneal lymph nodes in 7 of 8 patients; only two of these patients had recurrences located exclusively in the lymph nodes, although most recurrences were intra-abdominal. In contrast, only 2 of 7 patients who underwent lymphadenectomy had recurrences in the retroperitoneal lymph nodes. In our study, none of the 12 patients in Group A who underwent lymphadenectomy had lymph node metastasis; only one patient had recurrence in the retroperitoneal nodes 4 months after lymphadenectomy. A plausible explanation for this might be that micrometastases already existed somewhere in retroperitoneal nodes, which were not completely removed. Lymph node metastases are relatively refractory and difficult to eradicate by chemotherapy [21]. It is not
Table 2 Recurrences in Stage I clear cell carcinoma patients Group
B B B B B B A
Substage
Ia Ia Ic Ic Ic Ic Ic
Recurrence Percentage
Months
Treatment
Sites
2/3 (67%)
42 36 13 8 7 6 4
Paclitaxel ⫹ cisplatin Refused Refused Paclitaxel Paclitaxel ⫹ carboplatin Refused Lyposomal doxorubicin ⫹ extended field radiotherapy
Pelvis Pelvis Pelvis Lung, liver Pelvis, abdomen Lung Para-aortic lymph nodes
5/17 (29%)
Note. NED, no evidence of disease; DOD, died of disease.
Status
Months of follow-up after recurrence
NED DOD DOD DOD DOD DOD NED
88 13 2 3 3 4 6
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surprising that these metastases could not be killed completely by paclitaxel and carboplatin. It is possible that lymph node metastases cause a persistent subperitoneal lymphangiosis, macroscopically undetectable, which is responsible for intra-abdominal recurrences. This might be a biologically plausible rationale for why systemic lymphadenectomy could decrease the risk of intra-abdominal recurrences indirectly. We postulate that the percentage of retroperitoneal relapses can be reduced by systemic lymphadenectomy, and the incidence of intra-abdominal and distant recurrences in clear cell carcinoma patients can be diminished by paclitaxel and carboplatin chemotherapy. We believe this is why we saw a survival benefit in our subset of 12 patients who underwent systemic lymphadenectomy and received paclitaxel plus carboplatin chemotherapy. Only a few articles address the outcome of surgical stage I clear cell carcinoma of the ovary. Behbakht et al. reported recurrence in 37% of surgically staged stage I patients (10/27) with clear cell carcinoma of ovary. With a median follow-up of 40 months, 93% of stage I patients were alive, 20% with disease. Half of those patients had received paclitaxel plus platinum-based chemotherapy [22]. Kennedy et al. reported that the 5-year progression-free survival for patients with stage I disease was 61%, and the 5-year overall survival for patients with stage I disease was 73% [8]. In our study, 60% (12/20) of patients underwent complete surgical staging. With a median follow-up of 36 months, 35% (7/20) of patients had recurrence. The estimated 4-year survival rate was 77%. Only one of the 12 patients in Group A who underwent complete surgical staging and paclitaxel plus carboplatin adjuvant chemotherapy had a recurrence. The estimated 4-year survival rate was 100%, in contrast to 50% for those who did not undergo this regimen. Due to such a good outcome in Group A, we emphasize the importance of complete surgical staging and the potential benefits of paclitaxel and carboplatin for improving survival in stage I patients with clear cell ovarian carcinoma. Among patients who did not undergo complete lymphadenectomy in Group B, some may have had lymph node metastases and, thus, should have been restaged into stage IIIc disease, although they were classified in stage I. This might have had a detrimental effect on survival rate. Although recurrence sites in Group B patients were mainly located in the pelvis, abdomen, and distant organs, some might coexist with lymph node recurrences, which could not be detected by imaging studies. Silent retroperitoneal lymphatic spread is always overshadowed by extensive intraperitoneal implantation in the majority of ovarian cancer patients with recurrence. Lymph node metastases not eradicated by chemotherapy can cause the development of a network for subperitoneal lymphangiosis, which might be responsible for intraperitoneal persistent disease. Kennedy et al. reported poor survival of 6 patients with stage Ic cancers. Four of the 6 patients in their study died of their neoplasms, while 2 lived with evidence of their cancer
[10]. Kennedy et al. were unable to demonstrate improved survival of patients treated with cisplatin-based chemotherapy compared to other studies [10]. In our study, 17 of 20 patients with stage I clear cell carcinoma had stage Ic disease. Of these, 29% (5/17) had recurrence. Fourteen of 17 patients (82%) had their tumors rupture during surgery. This is in contrast to Jenison et al., who reported that 93% of patients with stage Ic had intraoperative rupture of their tumors, and only 27% of those patients survived 5 years [9]. The greater tendency for tumor rupture intraoperatively was probably due to large tumor size as well as adherence promoted by endometriosis to peritoneum. In our study, 67% (2/3) of patients with stage Ia also had recurrence. This high recurrence rate in early disease may be related to chemoresistance. The median time to recurrence was short (8 months), which is similar to another Japanese report [23]. These findings suggest the susceptibility of clear cell carcinoma to frequent and early recurrence, which may be one of reasons for the poor prognoses of patients with clear cell carcinoma. Thus, it is suggested that clear cell carcinoma generally lacks sensitivity to conventional platinum-based chemotherapy such as PAC or CP [23]. In support of this conclusion, an in vitro study by Gorai et al. indicated that clear cell carcinoma cells exhibited resistance to cisplatin [24]. Combination chemotherapy consisting of a platinum analog and paclitaxel show higher efficacy for survival than a platinum analog and cyclophosphamide for advanced ovarian cancer [25]. Moreover, combination chemotherapy consisting of a platinum analog and paclitaxel has been established as standard chemotherapy for ovarian cancer. Nonetheless, platinum-containing regimens have low sensitivity for clear cell adenocarcinoma of the ovary [11,26]. Although paclitaxel was effective in clear cell carcinoma cell lines in vitro [27], as yet, no data have appeared on the efficacy of paclitaxel-containing regimens for survival in clear cell carcinoma. To the best of our knowledge, ours is the first report to address complete surgical staging and paclitaxel plus carboplatin for improving survival in stage I clear cell carcinoma patients. Although we retrospectively studied data from a small number of patients, we feel that it is worth pointing out that there is a potential benefit of paclitaxel– carboplatin regimens for stage I clear cell carcinoma patients in comparison to regimens reported in the literature [4,6,15,22,23]. Unfortunately, due to the small number of cases, further analysis could not be done. A large-scale, multi-institutional, prospective, randomized trial (paclitaxel plus carboplatin vs conventional platinum-based chemotherapy) should be conducted to confirm our observation.
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C.-M. Ho et al. / Gynecologic Oncology 88 (2003) 394 –399 [2] Russell P, Bannatyne P. Surgical pathology of the ovaries. New York: Churchill Livingstone, 1989. [3] Russell P. Surface epithelial-stromal tumors of the ovary. In: Kurman RJ, editor. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer, 1995. p. 752– 62. [4] O’Brien MER, Schofield JB, Tan S, Fryatt I, Fisher C, Wiltshaw E. Clear cell epithelial ovarian cancer (mesonephroid): bad prognosis only in early stages. Gynecol Oncol 1993;49:250 – 4. [5] Omura GA, Brady MF, Homesley HD, Yordan E, Major FJ, Buchsbaum HJ, et al. Long-term follow-up prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991;9:1138 –50. [6] Aure JC, Hoeg K, Kolstad P. Mesonephroid tumors of the ovary; clinical and histopathologic studies. Obstet Gynecol 1971;37:860 –7. [7] Fine G, Clarke HD, Horn RC. Mesonephroma of the ovary: a clinical, morphological, and histogenetic appraisal. Cancer 1973;31:389 – 410. [8] Kennedy AW, Markman M, Biscotti CV, Emery JD, Rybicki LA. Survival probability in ovarian clear cell adenocarcinoma. Gynecol Oncol 1999;74:108 –14. [9] Jenison EL, Montag AG, Griffiths CT, Welch WR, Lavin PT, Greer J. Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma. Gynecol Oncol 1989;32:65–71. [10] Kennedy AW, Biscotti CV, Hart WR, Webster KH. Ovarian clear cell adenocarcinoma. Gynecol Oncol 1989;32:342–9. [11] Goff BA, Sainz de la Cuesta R, Muntz HG, Fleischhacker D, Ek M, Rice LW, et al. Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease. Gynecol Oncol 1996;60:412–7. [12] Kennedy AW, Biscotti CV, Hart WR, Tuason LJ. Histologic correlates of progression-free interval and survival in ovarian clear cell adenocarcinoma. Gynecol Oncol 1993;50:334 – 8. [13] Dottino P, Plaxe S, Cohen C. A phase II trial of adjuvant cisplatin and doxorubicin in stage I epithelial ovarian cancer. Gynecol Oncol 1991; 43:203–5. [14] Piver S, Malfetano J, Baker T, Hempling R. Five-year survival for stage Ic and stage I grade 3 epithelial ovarian cancer treated with cisplatin-based chemotherapy. Gynecol Oncol 1992;46:357– 60. [15] Montag AG, Jenison EL, Griffiths CT, Welch WR, Lavin PT, Knapp RC. Clear cell carcinoma: a clinicopathologic analysis of 44 cases. Int J Gynecol Pathol 1989;8:85–96. [16] Poncheville L, Perrotin F, Lefrancq T, Lansac J, Body G. Does para-aortic lymphadenectomy have a benefit in the treatment of ovar-
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Gynecologic Oncology 88 (2003) 394 –399
www.elsevier.com/locate/ygyno
Evaluation of complete surgical staging with pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy for improvement of survival in stage I ovarian clear cell carcinoma Chih-Ming Ho,a,* Tsai-Yen Chien,a Bor-Yuan Shih,a and Shih-Hung Huangb a
Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106, Taiwan b Department of Pathology, Cathay General Hospital, Taipei 106, Taiwan Received 27 June 2002
Abstract Objective. The aim was to determine the benefits of lymphadenectomy and paclitaxel plus carboplatin chemotherapy for stage I ovarian clear cell carcinoma (defined as intra-abdominal disease confined to the ovaries). Methods. Twenty patients with stage I pure clear cell carcinoma of the ovary diagnosed between 1991 and 2001 were divided into two groups: Group A (12 patients, 1997–2001) underwent complete surgical staging including bilateral salpingo-oophorectomy, hysterectomy, omentectomy, and pelvic and para-aortic lymphadenectomy, followed by paclitaxel and carboplatin chemotherapy. Group B (8 patients, 1991–1996) underwent bilateral salpingo-oophorectomy, hysterectomy, and omentectomy without lymphadenectomy, followed by cisplatin-based chemotherapy. The survival of the two groups was compared. The clinical characteristics of the two groups were evaluated for age distribution, grade, substage, preoperative CA-125, presence or absence of endometriosis, and maximal tumor diameter. Results. The estimated 4-year survival rate was 76.9%. The clinical characteristics of the two groups were similar, except for lymphadenectomy and regimen of chemotherapy. With a median follow-up of 36 months (range: 11–130 months), one of 12 patients in Group A had recurrence in comparison with 6 of 8 patients in Group B (P ⫽ 0.004). The estimated 3-year recurrence-free survival and 4-year overall survival for Group A was significantly greater than that for Group B (91.7 vs 33.3%, P ⫽ 0.014; 100 vs 50%, P ⫽ 0.014). Median time to recurrence was 8 months. Conclusion. Complete surgical staging, including pelvic and para-aortic lymphadenectomy and paclitaxel plus carboplatin chemotherapy, appeared to be capable of improving survival of patients with stage I ovarian clear cell carcinoma. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Ovarian cancer; Clear cell carcinoma; Lymphadenectomy; Chemotherapy
Introduction Clear cell carcinoma has been recognized as a distinct histological entity in the World Health Organization classification of ovarian tumor since 1973 [1]. Clear cell carcinoma constitutes 5–10% of surface epithelial ovarian cancer [2], and up to 60% of the patients with clear cell carcinoma have stage I disease [3]. Patients with stage I ovarian cancer * Corresponding author. Gynecologic Cancer Center, Cathay General Hospital, 280 Section 4 Jen-Ai Road, Taipei 106, Taiwan. Fax: ⫹886-287731988. E-mail address: [email protected] (C.-M. Ho).
usually have favorable prognoses. Nonetheless, patients with clear cell carcinoma have poorer prognoses than do those with other pathological types of epithelial ovarian carcinoma [4,5]. A significant proportion of women (20 – 50%) with stage I clear cell ovarian carcinoma have recurrences and die of their malignancies [4]. The earliest reports on survival in patients with clear cell ovarian carcinoma were possibly biased by limited staging information as well as by the inclusion of patients with mixed histological types of epithelial ovarian adenocarcinoma, including clear cell carcinoma [6,7]. More recent studies remain inconclusive in regard to survival in patients
0090-8258/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0090-8258(02)00156-7
C.-M. Ho et al. / Gynecologic Oncology 88 (2003) 394 –399
with pure clear cell carcinoma, despite improved histological criteria and staging accuracy [8 –10]. Recent trends in the clinical management of early stage ovarian cancer include increased attention to surgical staging with pelvic and para-aortic lymphadenectomy and general acceptance of paclitaxel plus platinum-based adjuvant chemotherapy. The introduction of cisplatin in the late 1970s markedly changed the postoperative management of ovarian cancer patients. Nonetheless, the results and value of these newer efforts and therapies applied to clear cell carcinoma are as yet undetermined [4,9 –11]. Since 1997, we have performed aortic and pelvic lymphadenectomy, along with optimal cytoreduction at initial surgery, for early stage clear cell carcinoma patients who received paclitaxel plus carboplatin adjuvant chemotherapy. We wondered whether the patients with stage I clear cell ovarian carcinoma (intra-abdominal disease confined to the ovaries) receiving lymphadenectomy and paclitaxel plus carboplatin benefited from improved survival compared to those who did not undergo lymphadenectomy and platinum-based chemotherapy.
Materials and methods Twenty-two patients with stage I clear cell carcinoma of the ovary diagnosed between 1991 and 2001 were identified from tumor registry of Cathay General Hospital. During this period, 154 patients with epithelial ovarian cancer were treated at Cathay General Hospital and staged based on the FIGO classification. Data were collected from medical records and clinical follow-up visits. Among those patients, 34 were originally diagnosed with clear cell carcinoma, and the histological slides were reviewed by one of the authors. Tumors were classified as clear cell adenocarcinoma if typical clear or hobnail cells were present in a papillary, solid, or tubulocystic pattern. All clear cell tumors were considered to be high-grade tumors [12]. After exclusion of 2 patients with admixtures of other histological types and 12 patients with advanced clear cell carcinoma, 20 patients with stage I pure clear cell carcinoma of the ovary (intraabdominal disease confined to the ovaries) were included for study. Twelve patients (Group A), who were treated from 1997 to 2001, underwent total hysterectomy, bilateral salpingooophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy as their initial operation. They all received postoperative chemotherapy combing paclitaxel 175 mg/m2 and carboplatin chemotherapy, with an area under the curve (AUC) equal to 5. They received six cycles of chemotherapy every 3 weeks. Eight patients (Group B) who were treated from 1991 to 1996, underwent total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy without pelvic and para-aortic lymphadenectomy as their initial operation. They received adjuvant chemotherapy containing a platinum compound, mainly cisplatin, epirubi-
395
cin, and cyclophosphamide (PAC) or cisplatin and cyclophosphamide (CP). Doses of the drugs used were epirubicin 60 mg/m2, cyclophosphamide 50 mg/m2, cisplatin 50 mg/m2 or cisplatin 75 mg/m2, and cyclophosphamide 750 mg/m2. They also received six courses of chemotherapy every 3 weeks. Exploration for regional lymph nodes included systemic lymphadenectomy, removal of palpable nodes, or all lymphatic tissue surrounding the retroperitoneal vessels, in the absence of clinically obvious disease. Para-aortic lymph node dissection was performed from the bifurcation of the aorta to the origin of the renal vessels. Pelvic node dissection was done from the common, external and internal iliac, and obturator vessels to the femoral ring. An average of 36 lymph nodes were removed (range: 5– 49 nodes), including 27 pelvic nodes (range: 12– 49 nodes) and 9 para-aortic nodes (range: 5–24 nodes). The clinical characteristics of the two groups were evaluated for age distribution, grade, substage, preoperative CA-125, presence or absence of endometriosis, maximal tumor diameter, surgical procedure and postoperative chemotherapy. Follow-up was accomplished by contacting patients or primary physicians or by reviewing medical records and tumor registry files. Patients were usually monitored as follows: years 1 and 2, physical examination, serum CA125 estimation every 3 months, computed tomography (CT) scan of abdomen and pelvis or ultrasound (US) of the abdomen and pelvis every 6 months; years 3 through 5, physical examination and serum CA-125 estimation every 6 months and CT of the abdomen and pelvis or US of the abdomen and pelvis annually; and years 6 through 10, physical examination and serum CA-125 estimation annually, CT or US only if clinically indicated. More frequent assessments or investigations were performed as clinically indicated. Patient populations were compared using Fisher’s exact test and the Wilcoxon rank sum test. Survival time was considered the primary outcome measure and was measured from the date of diagnosis to the date of death or until last contact. Survival curves were generated using the method of Kaplan–Meier. Differences in survival curves were calculated using the log rank test.
Results A total of 20 patients with pure stage I clear cell carcinoma of the ovary were entered into the study. The mean age was 56 years (range: 37–59 years), and the median follow-up duration was 36 months (range: 11–130 months). No patient was lost to follow-up. Three patients had stage Ia disease, and 17 patients had stage Ic disease. Three of 17 (18%) patients with stage Ic had capsule tumor invasion, while the remaining 14 patients (82%) had tumor rupture during surgery. The clinical char-
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Table 1 Characteristics of Group A and Group B patients Treatment
Stage Ia Ic Age (mean ⫾ SD) (years) Pre-op CA-125 (median) (U/ml) (mean ⫾ SD) (U/ml) Endometriosis Absent Present Maximal tumor diameter (cm) a b
Group A (n ⫽ 12)
Group B (n ⫽ 8)
1 (8.3%) 11 (91.7%) 56.05 ⫾ 9.07 71.0 376.8 ⫾ 876.4
2 (25.0%) 6 (75.0%) 55.12 ⫾ 7.05 22.7 69.0 ⫾ 98.4
7 (58.3%) 5 (41.7%) 14.7 ⫾ 5.7
3 (37.5%) 5 (62.5%) 11.5 ⫾ 3.1
P value
0.54a 0.51b 0.08b 0.65a 0.19b
Based on Fisher’s Exact test. Based on Wilcoxon rank sum test.
acteristics of two groups were similar, except for surgical procedure (with or without lymphadenectomy) and regimen of chemotherapy (paclitaxel– carboplatin vs PAC or CP) (Table 1). The median survival of all patients had not yet been reached. The estimated 4-year survival rate was 76.9%. The estimated 3-year recurrence-free survival for Group A was significantly greater than that of Group B (91.7 vs 33.3%, P ⫽ 0.014) (Fig. 1). The estimated 4-year overall survival for Group A was also significantly greater than that for Group B (100 vs 50%, P ⫽ 0.014, based on the log rank test) (Fig. 2). Seven of 20 patients (35%) relapsed, including 67% (2/3) with stage Ia and 29% (5/17) with stage Ic disease. One of the 12 patients in Group A relapsed in comparison with 6 of 8 patients in Group B (P ⫽ 0.004, Fisher’s exact test). The median time from diagnosis to recurrence was 8 months (range: 4 – 42 months), including 42 and 36 months for stage
Ia, and 13, 8, 7, 6, and 4 months for five stage Ic tumors. The median time from recurrence to death was 3 months (range: 1–13 months). The sites of recurrence included the para-aortic lymph nodes (1) in Group A, and in Group B, the sites of recurrence were pelvis (3), pelvis and abdomen (1), lung (1), and lung and liver (1). One of the three patients with capsule tumor invasion relapsed, while 4 of 14 patients (29%) without capsule invasion relapsed (P value was not significant). None of the 12 patients who underwent lymphadenectomy had retroperitoneal node metastases; nonetheless, 1 patient in Group A, who underwent complete lymphadenectomy, relapsed with metastasis to the retroperitoneal nodes 4 months after surgery. One patient with stage Ia disease in Group B had a recurrence in the pelvis 42 months after diagnosis. She has remained alive without evidence of disease, for more than 5 years after successful debulking surgery followed by paclitaxel and cisplatin chemotherapy. Table 2 presents data of patients who had recurrences. Due to the small sample size, further analysis could not be done. Discussion Clear cell carcinoma represents approximately 6% of ovarian cancers and represents 8 –10% of invasive epithelial cancers [10]. A literature survey revealed that up to 60% of reported patients had stage I disease at diagnosis [6,9]. Several studies report platinum-based regimens to achieve 5-year survival rates of greater than 90% even in high-risk, stage I ovarian cancer such as grade 3 tumors or stage Ic disease [13,14]. Clear cell tumors are reported to be associated with a poorer outcome, are often referred to as highrisk stage I tumors, and consequently are assigned an unfavorable prognosis. Five-year survival in stage I clear cell carcinoma is poor, varying from 50 to 73% [8,9]. Montag et
Fig. 1. Kaplan–Meier estimated recurrence-free survival of patients with stage I pure clear cell carcinoma.
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Fig. 2. Kaplan–Meier estimated overall survival of patients with stage I pure clear cell carcinoma.
al. reported a survival rate for stage I clear cell carcinoma of 55%, with frequent distant metastases and lymph node involvement upon recurrence [15]. Most of their reported patients did not undergo lymphadenectomy. The frequency of lymph node involvement in apparent limited stage disease ovarian cancer is around 16% (13–24%) [16]. The true incidence of lymph node metastasis in apparent limited stage clear cell carcinoma is unclear. Lymph node metastasis was significantly increased with recurrent clear cell carcinoma when compared with serous adenocarcinoma [9]. Jenison et al. recommended that pelvic and para-aortic node sampling be performed in clear cell carcinoma patients with early stage disease during the primary operation [9]. Many authors and the FIGO recommend comprehensive surgical staging in early ovarian cancer [17–19]. Retroperitoneal lymph node dissection (RPLND) aims to achieve the following advantages: proper staging of disease, prediction of patient prognosis, and improvement of patient survival. It has not been clarified whether removal of the affected nodes and prophylactic RPLND would improve the survival rates of patients with ovarian carcinoma. Onda et al. reported that the presence of positive lymph nodes might
be of little relevance to the survival of patients with an intraperitoneal tumor limited to the pelvis, as long as systemic aortic and pelvic lymphadenectomy is performed [20]. Pertu et al. reported that lymph node metastases, some less than 2 mm in diameter, occurred in an appreciable percentage of patients with intra-abdominal disease confined to the ovaries. In their report, recurrences in the group that had not undergone lymphadenectomy included the retroperitoneal lymph nodes in 7 of 8 patients; only two of these patients had recurrences located exclusively in the lymph nodes, although most recurrences were intra-abdominal. In contrast, only 2 of 7 patients who underwent lymphadenectomy had recurrences in the retroperitoneal lymph nodes. In our study, none of the 12 patients in Group A who underwent lymphadenectomy had lymph node metastasis; only one patient had recurrence in the retroperitoneal nodes 4 months after lymphadenectomy. A plausible explanation for this might be that micrometastases already existed somewhere in retroperitoneal nodes, which were not completely removed. Lymph node metastases are relatively refractory and difficult to eradicate by chemotherapy [21]. It is not
Table 2 Recurrences in Stage I clear cell carcinoma patients Group
B B B B B B A
Substage
Ia Ia Ic Ic Ic Ic Ic
Recurrence Percentage
Months
Treatment
Sites
2/3 (67%)
42 36 13 8 7 6 4
Paclitaxel ⫹ cisplatin Refused Refused Paclitaxel Paclitaxel ⫹ carboplatin Refused Lyposomal doxorubicin ⫹ extended field radiotherapy
Pelvis Pelvis Pelvis Lung, liver Pelvis, abdomen Lung Para-aortic lymph nodes
5/17 (29%)
Note. NED, no evidence of disease; DOD, died of disease.
Status
Months of follow-up after recurrence
NED DOD DOD DOD DOD DOD NED
88 13 2 3 3 4 6
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surprising that these metastases could not be killed completely by paclitaxel and carboplatin. It is possible that lymph node metastases cause a persistent subperitoneal lymphangiosis, macroscopically undetectable, which is responsible for intra-abdominal recurrences. This might be a biologically plausible rationale for why systemic lymphadenectomy could decrease the risk of intra-abdominal recurrences indirectly. We postulate that the percentage of retroperitoneal relapses can be reduced by systemic lymphadenectomy, and the incidence of intra-abdominal and distant recurrences in clear cell carcinoma patients can be diminished by paclitaxel and carboplatin chemotherapy. We believe this is why we saw a survival benefit in our subset of 12 patients who underwent systemic lymphadenectomy and received paclitaxel plus carboplatin chemotherapy. Only a few articles address the outcome of surgical stage I clear cell carcinoma of the ovary. Behbakht et al. reported recurrence in 37% of surgically staged stage I patients (10/27) with clear cell carcinoma of ovary. With a median follow-up of 40 months, 93% of stage I patients were alive, 20% with disease. Half of those patients had received paclitaxel plus platinum-based chemotherapy [22]. Kennedy et al. reported that the 5-year progression-free survival for patients with stage I disease was 61%, and the 5-year overall survival for patients with stage I disease was 73% [8]. In our study, 60% (12/20) of patients underwent complete surgical staging. With a median follow-up of 36 months, 35% (7/20) of patients had recurrence. The estimated 4-year survival rate was 77%. Only one of the 12 patients in Group A who underwent complete surgical staging and paclitaxel plus carboplatin adjuvant chemotherapy had a recurrence. The estimated 4-year survival rate was 100%, in contrast to 50% for those who did not undergo this regimen. Due to such a good outcome in Group A, we emphasize the importance of complete surgical staging and the potential benefits of paclitaxel and carboplatin for improving survival in stage I patients with clear cell ovarian carcinoma. Among patients who did not undergo complete lymphadenectomy in Group B, some may have had lymph node metastases and, thus, should have been restaged into stage IIIc disease, although they were classified in stage I. This might have had a detrimental effect on survival rate. Although recurrence sites in Group B patients were mainly located in the pelvis, abdomen, and distant organs, some might coexist with lymph node recurrences, which could not be detected by imaging studies. Silent retroperitoneal lymphatic spread is always overshadowed by extensive intraperitoneal implantation in the majority of ovarian cancer patients with recurrence. Lymph node metastases not eradicated by chemotherapy can cause the development of a network for subperitoneal lymphangiosis, which might be responsible for intraperitoneal persistent disease. Kennedy et al. reported poor survival of 6 patients with stage Ic cancers. Four of the 6 patients in their study died of their neoplasms, while 2 lived with evidence of their cancer
[10]. Kennedy et al. were unable to demonstrate improved survival of patients treated with cisplatin-based chemotherapy compared to other studies [10]. In our study, 17 of 20 patients with stage I clear cell carcinoma had stage Ic disease. Of these, 29% (5/17) had recurrence. Fourteen of 17 patients (82%) had their tumors rupture during surgery. This is in contrast to Jenison et al., who reported that 93% of patients with stage Ic had intraoperative rupture of their tumors, and only 27% of those patients survived 5 years [9]. The greater tendency for tumor rupture intraoperatively was probably due to large tumor size as well as adherence promoted by endometriosis to peritoneum. In our study, 67% (2/3) of patients with stage Ia also had recurrence. This high recurrence rate in early disease may be related to chemoresistance. The median time to recurrence was short (8 months), which is similar to another Japanese report [23]. These findings suggest the susceptibility of clear cell carcinoma to frequent and early recurrence, which may be one of reasons for the poor prognoses of patients with clear cell carcinoma. Thus, it is suggested that clear cell carcinoma generally lacks sensitivity to conventional platinum-based chemotherapy such as PAC or CP [23]. In support of this conclusion, an in vitro study by Gorai et al. indicated that clear cell carcinoma cells exhibited resistance to cisplatin [24]. Combination chemotherapy consisting of a platinum analog and paclitaxel show higher efficacy for survival than a platinum analog and cyclophosphamide for advanced ovarian cancer [25]. Moreover, combination chemotherapy consisting of a platinum analog and paclitaxel has been established as standard chemotherapy for ovarian cancer. Nonetheless, platinum-containing regimens have low sensitivity for clear cell adenocarcinoma of the ovary [11,26]. Although paclitaxel was effective in clear cell carcinoma cell lines in vitro [27], as yet, no data have appeared on the efficacy of paclitaxel-containing regimens for survival in clear cell carcinoma. To the best of our knowledge, ours is the first report to address complete surgical staging and paclitaxel plus carboplatin for improving survival in stage I clear cell carcinoma patients. Although we retrospectively studied data from a small number of patients, we feel that it is worth pointing out that there is a potential benefit of paclitaxel– carboplatin regimens for stage I clear cell carcinoma patients in comparison to regimens reported in the literature [4,6,15,22,23]. Unfortunately, due to the small number of cases, further analysis could not be done. A large-scale, multi-institutional, prospective, randomized trial (paclitaxel plus carboplatin vs conventional platinum-based chemotherapy) should be conducted to confirm our observation.
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