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Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential
ORIGINAL RESEARCH
Response and Survival in Patients With Progressive or Recurrent Serous Ovarian Tumors of Low Malignant Potential Marta A. Crispens, MD, Diane Bodurka, MD, Michael Deavers, MD, Karen Lu, MD, Elvio G. Silva, MD, and David M. Gershenson, MD OBJECTIVE: To evaluate the response to therapy and survival of patients with progressive or recurrent serous ovarian tumors of low malignant potential. METHODS: Fifty-three patients with progressive or recurrent serous ovarian tumors of low malignant potential were identified. Response was assessed and progressionfree and overall survival were analyzed. The influence of clinicopathologic factors on survival was determined. RESULTS: In 49 patients with known histology of progression or recurrence, 36 (73%) had low-grade serous carcinoma, and 13 (27%) had serous ovarian tumors of low malignant potential. Forty-five patients received nonsurgical therapy and had an evaluable response. There were six (13%) patients with a complete response and six (13%) patients with a partial response. The median time to first progression or recurrence was 5.6 years. Median survival from diagnosis of first recurrence was 7.7 years. Median survival from initial diagnosis was 21 years. Nineteen (36%) patients are dead of tumor. Patients who recurred with low-grade serous carcinoma were more likely to die of tumor than those with serous ovarian tumors of low malignant potential (47% versus 0%, P ⴝ .045). Optimal cytoreduction was associated with improved survival (P ⴝ .007). CONCLUSION: Patients with progressive or recurrent serous ovarian tumors of low malignant potential have a long interval from diagnosis to progression and from progression to death, resulting in extended overall survival. Recurrence as low-grade serous carcinoma and failure to achieve optimal secondary cytoreduction were adverse prognostic factors. There were few responses to nonsurgical therapy. (Obstet Gynecol 2002;99:3–10. © 2002 by the American College of Obstetricians and Gynecologists.)
Serous ovarian tumors of low malignant potential were originally described by Taylor in 1929 as a group of From the Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, Illinois; and the Departments of Gynecologic Oncology, and Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
epithelial tumors which demonstrated a relatively good prognosis when compared with other ovarian cancers.1 This favorable prognosis has been confirmed by a number of studies, which have shown an overall 10-year survival rate of 83–91%.2– 4 Even patients with stage III disease appear to have a relatively good outcome, with survival rates ranging from 50 – 86%.4 – 6 The treatment of serous ovarian tumors of low malignant potential remains controversial. Surgery alone is curative in stage I disease.4 – 8 Most women are treated with abdominal hysterectomy and bilateral salpingooophorectomy. However, patients with serous ovarian tumors of low malignant potential tend to be younger than those with frankly invasive carcinoma, and preservation of fertility is frequently an issue.9 Several reports have demonstrated the safety of unilateral salpingo-oophorectomy for patients with stage I disease.5,6,8 Other studies have suggested that ovarian cystectomy alone may be adequate therapy.10,11 For patients with advanced stage disease, surgical cytoreduction remains the primary therapy. The role of postoperative chemotherapy in this tumor type is unclear.3,7,12–16 Because recurrences are rare, little is known about the nature and therapy of recurrent disease. The purpose of this study was to review the clinical course of patients seen at our institution with serous ovarian tumors of low malignant potential who developed progressive or recurrent disease.
MATERIALS AND METHODS All patients with the diagnosis of serous ovarian tumors of low malignant potential seen at the University of Texas M.D. Anderson Cancer Center from 1956 to 1997 were identified using institutional databases, and their medical records were retrospectively reviewed. Sixty-one patients with progressive or recurrent tumor were identified. Of these, the medical records of 53 patients
VOL. 99, NO. 1, JANUARY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/02/$22.00 PII S0029-7844(01)01649-0
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Figure 1. This hematoxylin-eosin-stained photomicrograph demonstrates the characteristics of a serous ovarian tumor of low malignant potential. These tumors are characterized by stratification of the epithelial lining of the papillae, formation of microscopic papillary projections or tufts, often detached, arising from the epithelial lining of the papillae, varying degrees of nuclear atypia, and absence of frank stromal invasion. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
were found to contain evaluable information. These 53 patients comprise the study group. Although all cases were reviewed histologically at the time of initial referral, histopathologic review of all primary tumors and recurrent tumor, when available, was performed by one of the authors (EGS). Pathologic material was available for review from recurrent tumors in 49 of 53 cases. In two cases, progression or recurrence was documented by cytologic evaluation of ascites or pleural fluid. In two other cases, clinical criteria alone were used to diagnose progression or recurrence. Serous ovarian tumors of low malignant potential were defined by the following pathologic criteria: 1) stratification of the epithelial lining of the papillae; 2) formation of microscopic papillary projections or tufts, often detached, arising from the epithelial lining of the papillae; 3) varying degrees of nuclear atypia; and 4) absence of frank stromal invasion (Figure 1). Low-grade serous carcinoma is an invasive serous neoplasm with mild to moderate nuclear atypia. The nuclei are generally regular from area to area, and up to ten mitotic figures per ten high-power fields may be present. Although the architectural pattern may vary, the most common one contains uniform, thin papillae. Psammoma bodies are found in the majority of these tumors (Figure 2). Peritoneal implants were classified as either noninvasive or invasive. Noninvasive peritoneal implants were glandular or papillary proliferations with cell detachments. Cellular atypia, psammoma bodies, and desmoplastic fibrosis were present in some cases.17 Invasive
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peritoneal implants were lesions similar to noninvasive implants but with epithelial cells infiltrating the stroma.18 Treatment was at the discretion of the attending physician. Not all therapy was administered at our institution. All patients had primary surgery. Surgical staging of these tumors was determined retrospectively according to criteria of the 1985 classification system of the International Federation of Gynecology and Obstetrics based on careful review of surgical notes and pathology review.19 For purposes of staging, only documented sites of resection or biopsy were used. Extent of residual disease was determined based on descriptions in written and dictated surgical reports and on clinical evaluation of patients in the early postoperative period. Detailed information concerning postoperative therapy, second-look surgery, and treatment for progression or recurrence was abstracted. Response to therapy was also determined retrospectively. In all cases, it was based upon the evaluation of measurable disease, either by physical exam or radiographic criteria. Standard definitions were used to evaluate response to therapy. A complete response was defined as the complete disappearance of all clinically measurable disease. A partial response was defined as a 50% or greater decrease in the size of all measurable lesions. Progressive disease was defined as a 50% or greater increase in the size of any measurable lesion or the appearance of any new lesion. Stable disease was defined as a change in measurable disease too small to meet the requirements for a partial response or progres-
Figure 2. This hematoxylin-eosin-stained photomicrograph demonstrates the characteristics of a low-grade serous carcinoma. These tumors are invasive serous neoplasms with mild to moderate nuclear atypia. The nuclei are generally regular from area to area, and up to 10 mitotic figures per 10 high-power fields may be present. The architectural pattern may vary. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
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sive disease and the appearance of no new lesions for a period of at least 8 weeks. Statistical analysis was performed using GraphPad Prism 2.0 (GraphPad Software, Inc., San Diego, CA). Survival was analyzed by the method of Kaplan and Meier. The effect of clinicopathologic variables on survival was evaluated using the log rank test. The relationship between survival and age, type of peritoneal implant, and secondary cytoreductive surgery was determined by the 2 test or Fisher exact test, as appropriate. A P value of ⱕ.05 was considered statistically significant. RESULTS Table 1 summarizes the patient characteristics at initial diagnosis. The mean age of the 53 patients at diagnosis was 37 (range 20 – 61 years). The majority of the patients were white (85%). Most patients had their initial diagnosis in the 1970s or 1980s. The majority of patients (56%) had stage III disease, and 24% were unstaged. The most common initial surgical procedure was abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Two patients were treated with ovarian cystectomy alone. Over half of the patients (58%) had no gross residual disease at the completion of their primary surgery. Thirty-five patients had peritoneal implants at the time of initial surgery. Twenty-three patients (66%) had noninvasive implants, and 12 (34%) had invasive implants. Forty patients received some form of postoperative therapy. The most common postoperative treatment was platinum-based chemotherapy, which was administered to 21 patients. Six patients had progression of disease on primary therapy, and 47 recurred 6 or more months after completion of primary therapy. The median time to first progression or recurrence was 5.6 years (range 0.25– 22.3 years). Table 2 summarizes the site of first progression or recurrence. Most patients recurred within the peritoneal cavity. Of the nine patients who recurred in a residual ovary, four were treated with surgery alone, four were treated with surgery followed by chemotherapy, and one was treated with surgery followed by abdominopelvic radiotherapy. Only one of these patients is dead, and she died of unknown causes. Six of these patients are alive without evidence of disease, and two are alive with disease. Forty-nine patients had surgical or biopsy documentation of a least one episode of progression or recurrence. In these 49 patients, the histology of the progression or recurrence was serous ovarian tumor of low malignant potential in 13 (27%) and low-grade serous carcinoma in 36 (73%). Two patients had progression or recurrence
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Table 1. Characteristics at Initial Diagnosis of Patients With Progressive or Recurrent Serous Ovarian Tumors of Low Malignant Potential (n ⫽ 53) Characteristic Age at initial diagnosis (y) 20–29 30–39 40–49 50–59 ⱖ60 Race White Black Hispanic Other Decade of diagnosis 1941–1950 1951–1960 1961–1970 1971–1980 1981–1990 1991–1997 FIGO stage Ib Ic IIa IIc IIIa IIIb IIIc Unstaged Type of initial surgery TAH USO BSO Cystectomy Omentectomy Gross residual disease None ⱕ2 cm ⬎2 cm Unknown Peritoneal implants None Noninvasive Invasive Unknown Postoperative therapy* None Platinum-based chemotherapy Nonplatinum-based chemotherapy External beam radiotherapy† Other‡
Number of patients (%) 16 (30) 19 (36) 12 (23) 4 (7) 2 (4) 45 (85) 4 (7) 2 (4) 2 (2) 1 (2) 2 (4) 5 (9) 11 (21) 30 (57) 4 (7) 1 (2) 1 (2) 6 (11) 2 (4) 10 (19) 16 (30) 4 (7) 13 (24) 41 (77) 13 (24) 38 (72) 2 (4) 32 (60) 31 (58) 12 (23) 2 (4) 8 (15) 4 (7) 23 (43) 12 (23) 14 (26) 13 21 10 12 4
FIGO ⫽ International Federation of Gynecologists and Obstetricians; TAH ⫽ total abdominal hysterectomy; USO ⫽ unilateral salpingooophorectomy; BSO ⫽ bilateral salpingo-oophorectomy. * Some patients received more than one modality of adjuvant postoperative therapy. † External beam whole pelvic radiotherapy in four, whole abdominal radiotherapy in seven, and local radiotherapy in one. ‡ One patient each treated with intraperitoneal P32, intraperitoneal Au198, leuprolide, and bacille Calmette-Gue´rin.
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Table 2. Site of Initial Progression or Recurrence of Serous Ovarian Tumors of Low Malignant Potential
Site Ovary Pelvic mass (other than ovary) Upper abdomen/ascites Lymph nodes Cervical/supraclavicular Para-aortic Inguinal Chest (lung, pleura, mediastinum, chest wall)† Bone Brain‡ Liver§ Pancreas§ Unknown
Number of patients* 9 23 18 4 2 2 8 1 1 1 1 3
* Patient may have had initial progression or recurrence documented at more than one site. † Four patients with pleural disease, three patients with pulmonary nodules, two patients with mediastinal disease, and one patient with metastatic disease to the chest wall. ‡ The patient with metastatic disease to the brain also had pulmonary nodules. § The same patient had metastatic disease to the liver and pancreas.
documented by cytology of ascites or pleural fluid. In two other patients, clinical criteria alone (physical examination, radiologic studies, or increasing serum CA-125) were used to diagnose progression or recurrence. The pathology of progression or recurrence was a significant predictor of survival, with patients who progressed or recurred as low-grade serous carcinoma (17 of 36, 47%) being more likely to die of disease than those who progressed or recurred as serous ovarian tumor of low malignant potential (zero of 13, 0%) (P ⫽ .045). Figure 3 shows the Kaplan-Meier survival curves for patients progressing or recurring as low-grade serous carcinoma compared with those progressing or recurring as serous ovarian tumors of low malignant potential. Thirty-five patients underwent 48 secondary surgical procedures for progression or recurrence. For each patient, the best surgical result was correlated with her outcome. Table 3 summarizes residual disease at the conclusion of surgical cytoreduction for progression or recurrence. The surgical outcome was a significant predictor of survival. Patients who had greater than 2-cm residual disease (suboptimal cytoreduction) at the completion of surgery were significantly more likely to die of disease than patients who had less than or equal to 2-cm residual disease (optimal cytoreduction) (P ⫽ .007). The Kaplan-Meier survival curves for survival of patients undergoing optimal versus suboptimal cytoreductive surgery is shown in Figure 4. There was no influence of age at diagnosis or type of peritoneal implant on survival.
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Figure 3. Kaplan-Meier curve demonstrating a significantly better survival for patients with serous ovarian tumors of low malignant potential recurring as serous tumors of low malignant potential (SLMP) (n ⫽ 13), compared with those recurring as low-grade serous carcinomas (LGSC) (n ⫽ 36). The comparison of the survival curves was performed using the log rank test. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
Of the 53 patients in this study with progressive or recurrent serous ovarian tumors of low malignant potential, 49 received one or more nonsurgical treatment regimens. Of these 49 patients, 45 were evaluable for response to treatment. Twenty-seven patients received more than one nonsurgical therapy during their treatment for progression or recurrence. The median number of regimens received was two (range 1–7). Forty-two patients received cytotoxic chemotherapy, 21 patients received hormonal therapy, and six patients were treated with radiotherapy. Cytotoxic chemotherapeutic agents used, either alone or in combination, included cisplatin, carboplatin, paclitaxel, actinomycin-D, chlorambucil, cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil, hexamethylmelamine, methotrexate, melphalan, thiotepa, topotecan, and vinorelbine. Hormonal agents used, either alone or in combination, included ethinyl estradiol, flutamide, leuprolide, medroxyprogesterone acetate, megestrol, tamoxifen, and testosterone. RadiotherTable 3. Outcomes for Patients With Recurrent or Progressive Serous Ovarian Tumors of Low Malignant Potential Who Underwent Secondary Cytoreductive Surgery
Surgical result
Number of patients
Number dead of disease (%)
No gross residual Optimal (ⱕ2 cm) Suboptimal (⬎2 cm) Unknown
10 7 10 8
1 (10) 1 (14) 6 (60) 1 (12)
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Figure 4. Kaplan-Meier curve demonstrating that patients with recurrent or progressive serous ovarian tumors of low malignant potential, who can be optimally cytoreduced to less than or equal to 2-cm maximal residual disease at secondary surgery (n ⫽ 7), have statistically significantly improved survival compared with patients whose tumors suboptimally cytoreduced to greater than 2-cm maximal residual disease (n ⫽ 10). Survival comparisons were performed using the log rank test. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
apeutic modalities used included local radiotherapy to a site of recurrence, whole pelvic radiotherapy, and whole abdominal radiotherapy. There were six of 45 (13%) patients who had complete responses and six of 45 (13%) patients who had partial responses. No patient had a response to more than one nonsurgical treatment regimen. Of the responses, six of 12 (50%) were to platinum-based chemotherapy regimens, three of 12 (25%) were to paclitaxel, one of 12 (8%) was to combination cyclophosphamide, hexamethylmelamine, 5-fluorouracil, and methotrexate chemotherapy, one of 12 (8%) was to leuprolide, and one of 12 (8%) was to whole pelvic radiotherapy. Details regarding response data are presented in Table 4.
There were 21 of 45 (47%) patients who had stable disease to one or more nonsurgical treatment regimens. Stable disease to platinum-based chemotherapy occurred in 11 patients, to paclitaxel in one patient, to nonplatinum, nonpaclitaxel chemotherapy in five patients, to hormonal therapy in eight patients, and to radiotherapy in three patients. The median duration of stable disease was 12 months (range 3–77.5 months). At the time of analysis, 14 of the 53 patients (26%) were alive and without evidence of disease, 16 (30%) were alive with disease, 19 (36%) were dead of disease, three (6%) were dead of unknown cause, and one (2%) was dead of other causes. The median survival from diagnosis of progression or recurrence was 7.7 years (range 0.5–18.8 years). The median survival from initial diagnosis was 21 years (range 0.75–34.3 years). DISCUSSION This study spans a period of approximately 41 years from 1956 to 1997. Although the International Federation of Gynecology and Obstetrics did not officially recognize the existence of tumors of “low potential malignancy” until 1971,20 and the World Health Organization did not recognize these tumors as separate entities until 1973,21 we were able to identify patients who had these tumors before 1971 by a complete pathology review of all patients with serous ovarian tumors presenting to our institution. The length of observation may be a concern because detection, treatment, and outcome have certainly changed significantly during this period. However, such a long length of observation is necessary to understand the natural history of a tumor whose median time to recurrence and median survival are long. We have observed a median time to first progression/
Table 4. Responders Among Patients With Recurrent or Persistent Serous Ovarian Tumors of Low Malignant Potential Patient
Therapy
Response
Disease status
Survival from recurrence (y)
1 2 3 4 5 6 7 8 9 10 11 12
PAC PAC Carbo/CTX CTX/HMM/5-FU/MTX Paclitaxel Paclitaxel Carbo/CTX Carbo/CTX Carbo/leuprolide/tamoxifen Paclitaxel Leuprolide Pelvic XRT
CR CR CR CR CR CR PR PR PR PR PR PR
AWD AWD AWD DOD NED AWD AWD AWD AWD DCU DOD DCU
16.0 7.9 6.2 2.3 4.0 4.6 8.3 4.4 8.6 3.1 5.6 7.7
PAC ⫽ cisplatin, doxorubicin, cyclophosphamide; Carbo ⫽ carboplatin; CTX ⫽ cyclophosphamide; HMM ⫽ hexamethylmelamine; 5-FU ⫽ 5-fluorouracil; MTX ⫽ methotrexate; XRT ⫽ radiotherapy; CR ⫽ complete response; PR ⫽ partial response; AWD ⫽ alive with disease; DOD ⫽ dead of disease; NED ⫽ alive, no evidence of disease; DCU ⫽ dead, cause unknown.
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recurrence of 5.6 years and a median survival from initial diagnosis of 21 years. Studies of this indolent disease must necessarily include protracted observation periods. Serous ovarian tumors of low malignant potential have a better prognosis than their frankly invasive counterparts. However, over a 10-year follow-up period, approximately 10 –15% of patients will relapse.2– 4 A number of potential risk factors for recurrence have been evaluated in previous studies. The two that appear consistently to be adverse prognostic factors at diagnosis are stage and residual disease at the completion of primary surgery.5,6,8,17,18,22–24 Patients with stage I ovarian serous borderline tumors have a relapse rate of approximately 1%, whereas patients with stages II–IV have a relapse rate in the range of 20%. This finding may be at least partially related to the ability to achieve optimal cytoreduction. In a long-term, follow-up study of patients with serous ovarian tumors of low malignant potential, Leake et al noted that in patients with stages II and III disease, mortality was 8% in patients with no residual disease at the completion of primary surgery as compared with 31% in patients with residual disease.6 Bostwick et al also noted that the inability to completely excise all visible tumor at the time of initial diagnosis or at the time of recurrence carried an increased risk of persistent or recurrent neoplasm.5 This study demonstrates that residual disease at the completion of secondary cytoreduction is an important prognostic factor for patients with recurrent serous ovarian tumors of low malignant potential. Only 12% of patients whose tumor was optimally cytoreduced died of their disease compared with 60% of those whose tumor was suboptimally cytoreduced. Aggressive surgical debulking of patients with persistent or recurrent disease would appear to be the best available treatment for serous ovarian tumors of low malignant potential, particularly in light of their relatively poor response to nonsurgical therapy. The other factor we identified, which had a statistically significant influence on survival, was the histology of the recurrence. Patients whose recurrence was lowgrade serous carcinoma had a significantly worse outcome than those whose recurrence consisted of serous ovarian tumor of low malignant potential. To our knowledge, this is the largest series detailing the histology of recurrence in patients with serous ovarian tumors of low malignant potential. We were able to identify only 17 patients from seven previous reports in which the histology of the recurrence was described.2,3,7,22,24 –26 Whether such disease represents a true recurrence or a new primary tumor remains unclear. Future clonality studies hopefully will elucidate the biology of this phenomenon. For the
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patient, however, such a distinction may be merely academic. Previous reports have detailed the safety of conservative surgery with resultant preservation of fertility for young patients with stage I serous ovarian tumors of low malignant potential.5,6,8,10,11,27 In this study, nine patients were identified who had recurred within the residual ovary after conservative surgery of serous ovarian tumor of low malignant potential. Not all of these patients were completely staged. Six (67%) of these patients are alive without evidence of disease, two (22%) are alive with disease, and one (11%) is dead of an unknown cause. Most, if not all, of these lesions probably consisted of new primary tumors rather than recurrent tumors. Again, future clonality studies will resolve this issue. These findings are consistent with those described in previous reports and are not inconsistent with the concept of conservative surgery for stage I disease confirmed by comprehensive surgical staging in women desiring to maintain fertility. Very little information exists regarding the chemosensitivity of serous ovarian tumors of low malignant potential. A few previous studies have provided detailed information on the effectiveness of postoperative chemotherapy in the treatment of primary serous ovarian tumors of low malignant potential with peritoneal implants.3,15,16 Fort et al15 described their experience with postoperative therapy. Nineteen patients were observed to have residual disease after primary surgery for serous ovarian tumors of low malignant potential. Subsequent therapy included alkylating agent chemotherapy, multiagent chemotherapy frequently including cisplatin, pelvic irradiation, or pelvic irradiation plus alkylating agent chemotherapy. Of these patients, 12 (63%) were found to have negative second-look laparotomies. In a subsequent report from the same institution, Barakat et al16 observed surgical complete responses in ten of 16 patients (62%) with serous ovarian tumors of low malignant potential who were treated with platinum-based chemotherapy. In a study from our institution, we found that 80% of 20 women who had macroscopic residual disease at initial surgery responded to chemotherapy— eight complete responders, eight partial responders, and four nonresponders—as evidenced by second-look surgical findings.3 Of course, in all these reports, residual disease may represent unresected peritoneal implants— either noninvasive or invasive—rather than the primary ovarian tumor. Our findings do not demonstrate a significant response to nonsurgical therapy among patients with persistent or recurrent disease. We observed a 13% clinical complete response rate and a 13% clinical partial response rate. Half of the responses occurred in patients
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who received platinum-based regimens, and another 25% of responses occurred in patients receiving paclitaxel alone. However, the number of patients responding to any therapy is small. With current information, it would seem reasonable to recommend either carboplatin, paclitaxel, or both for nonsurgical treatment of progressive or recurrent serous ovarian tumors of low malignant potential that recur as low-grade serous carcinomas. Hormonal therapy with either tamoxifen or leuprolide has been shown to have, at best, a 10 –15% response rate in the treatment of invasive epithelial ovarian carcinoma.28 –31 There are also case reports that describe complete serologic and clinical responses to either tamoxifen or leuprolide in patients with advanced stage serous ovarian tumors of low malignant potential.32,33 However, the present study did not confirm the efficacy of hormonal therapy alone for progressive or recurrent serous ovarian tumors of low malignant potential; only a single partial response to leuprolide was observed. One or more episode of stable disease was observed in almost half of patients. Stable disease was noted to platinum-based chemotherapy in 11 patients, to paclitaxel in one patient, to nonplatinum, nonpaclitaxel chemotherapy in five patients, to hormonal therapy in eight patients, and to radiotherapy in three patients. The significance of stable disease in patients whose tumor may inherently have an indolent course is uncertain. In summary, recurrent serous ovarian tumors of low malignant potential have an indolent course, as evidenced by long median survival time, and respond poorly to available systemic treatment. Recurrence of these tumors as low-grade serous carcinoma is a significant adverse prognostic factor. Secondary cytoreductive surgery appears to be beneficial, as patients whose disease was optimally cytoreduced had a significantly better survival than those whose disease could not be optimally cytoreduced. Major challenges for the future include defining the clonality of these so-called recurrent lesions and identifying more effective therapies.
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review of 81 cases with an assessment of the impact of treatment. Int J Radiat Oncol Biol Phys 1992;22:867–74. 5. Bostwick DG, Tazelaar HD, Ballon SC, Hendrickson MR, Kempson RL. Ovarian epithelial tumors of borderline malignancy: A clinical and pathologic study of 109 cases. Cancer 1986;58:2052– 64. 6. Leake JF, Currie JL, Rosenshein NB, Woodruff JD. Longterm follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 1992;47:150 – 8. 7. Kliman L, Rome RM, Fortune DW. Low malignant potential tumors of the ovary: A study of 76 cases. Obstet Gynecol 1986;68:338 –34. 8. Barnhill DR, Kurman RJ, Brady MF, Omura GA, Yordan E, Given FT, et al. Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: A Gynecologic Oncology Group study. J Clin Oncol 1995; 13:2752– 6. 9. Aure JC, Hoey K, Kolstad P. Clinical and histologic studies of ovarian carcinoma. Long-term follow-up of 990 cases. Obstet Gynecol 1971;37:1–9. 10. Tazelaar HD, Bostwick DG, Ballon SC, Hendrickson MR, Kempson RL. Conservative treatment of borderline ovarian tumors. Obstet Gynecol 1985;66:417–22. 11. Lim-Tan SK, Gajiga HE, Scully RE. Ovarian cystectomy for serous borderline tumors: A follow-up study of 35 cases. Obstet Gynecol 1988;72:775– 81. 12. Rice LW, Berkowitz RS, Mark SD, Yavner DL, Lage JM. Epithelial ovarian tumors of borderline malignancy. Gynecol Oncol 1990;39:195– 8. 13. Nation JG, Krepart GV. Ovarian carcinoma of low malignant potential: Staging and treatment. Am J Obstet Gynecol 1986;154:290 –3. 14. Chambers JT, Merino MJ, Kohorn EL, Schwartz PE. Borderline ovarian tumors. Am J Obstet Gynecol 1988; 159:1088 –94. 15. Fort GM, Pierce VK, Saigo PE, Hoskins WJ, Lewis JL. Evidence for the efficacy of adjuvant therapy in epithelial tumors of low malignant potential. Gynecol Oncol 1989; 32:269 –72. 16. Barakat RR, Benjamin I, Lewis JL, Saigo RE, Curtin JP, Hoskins WJ. Platinum-based chemotherapy for advancedstage serous ovarian carcinoma of low malignant potential. Gynecol Oncol 1995;59:390 –3. 17. Gershenson DM, Silva EG, Tortolero-Luna G, Levenback C, Morris M, Tornos C. Serous borderline tumors of the ovary with noninvasive peritoneal implants. Cancer 1998; 83:2157– 63. 18. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian serous borderline tumors with invasive peritoneal implants. Cancer 1998;82:1096 –103. 19. Staging announcement: FIGO Cancer Committee. Gynecol Oncol 1986;25:383–5. 20. International Federation of Gynaecology and Obstetrics.
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Address reprint requests to: Marta A. Crispens, MD, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, PO Box 19640, Springfield, IL 627949640; E-mail: [email protected]. Received January 30, 2001. Received in revised form August 29, 2001. Accepted September 6, 2001.
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Response and Survival in Patients With Progressive or Recurrent Serous Ovarian Tumors of Low Malignant Potential Marta A. Crispens, MD, Diane Bodurka, MD, Michael Deavers, MD, Karen Lu, MD, Elvio G. Silva, MD, and David M. Gershenson, MD OBJECTIVE: To evaluate the response to therapy and survival of patients with progressive or recurrent serous ovarian tumors of low malignant potential. METHODS: Fifty-three patients with progressive or recurrent serous ovarian tumors of low malignant potential were identified. Response was assessed and progressionfree and overall survival were analyzed. The influence of clinicopathologic factors on survival was determined. RESULTS: In 49 patients with known histology of progression or recurrence, 36 (73%) had low-grade serous carcinoma, and 13 (27%) had serous ovarian tumors of low malignant potential. Forty-five patients received nonsurgical therapy and had an evaluable response. There were six (13%) patients with a complete response and six (13%) patients with a partial response. The median time to first progression or recurrence was 5.6 years. Median survival from diagnosis of first recurrence was 7.7 years. Median survival from initial diagnosis was 21 years. Nineteen (36%) patients are dead of tumor. Patients who recurred with low-grade serous carcinoma were more likely to die of tumor than those with serous ovarian tumors of low malignant potential (47% versus 0%, P ⴝ .045). Optimal cytoreduction was associated with improved survival (P ⴝ .007). CONCLUSION: Patients with progressive or recurrent serous ovarian tumors of low malignant potential have a long interval from diagnosis to progression and from progression to death, resulting in extended overall survival. Recurrence as low-grade serous carcinoma and failure to achieve optimal secondary cytoreduction were adverse prognostic factors. There were few responses to nonsurgical therapy. (Obstet Gynecol 2002;99:3–10. © 2002 by the American College of Obstetricians and Gynecologists.)
Serous ovarian tumors of low malignant potential were originally described by Taylor in 1929 as a group of From the Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, Illinois; and the Departments of Gynecologic Oncology, and Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
epithelial tumors which demonstrated a relatively good prognosis when compared with other ovarian cancers.1 This favorable prognosis has been confirmed by a number of studies, which have shown an overall 10-year survival rate of 83–91%.2– 4 Even patients with stage III disease appear to have a relatively good outcome, with survival rates ranging from 50 – 86%.4 – 6 The treatment of serous ovarian tumors of low malignant potential remains controversial. Surgery alone is curative in stage I disease.4 – 8 Most women are treated with abdominal hysterectomy and bilateral salpingooophorectomy. However, patients with serous ovarian tumors of low malignant potential tend to be younger than those with frankly invasive carcinoma, and preservation of fertility is frequently an issue.9 Several reports have demonstrated the safety of unilateral salpingo-oophorectomy for patients with stage I disease.5,6,8 Other studies have suggested that ovarian cystectomy alone may be adequate therapy.10,11 For patients with advanced stage disease, surgical cytoreduction remains the primary therapy. The role of postoperative chemotherapy in this tumor type is unclear.3,7,12–16 Because recurrences are rare, little is known about the nature and therapy of recurrent disease. The purpose of this study was to review the clinical course of patients seen at our institution with serous ovarian tumors of low malignant potential who developed progressive or recurrent disease.
MATERIALS AND METHODS All patients with the diagnosis of serous ovarian tumors of low malignant potential seen at the University of Texas M.D. Anderson Cancer Center from 1956 to 1997 were identified using institutional databases, and their medical records were retrospectively reviewed. Sixty-one patients with progressive or recurrent tumor were identified. Of these, the medical records of 53 patients
VOL. 99, NO. 1, JANUARY 2002 © 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/02/$22.00 PII S0029-7844(01)01649-0
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Figure 1. This hematoxylin-eosin-stained photomicrograph demonstrates the characteristics of a serous ovarian tumor of low malignant potential. These tumors are characterized by stratification of the epithelial lining of the papillae, formation of microscopic papillary projections or tufts, often detached, arising from the epithelial lining of the papillae, varying degrees of nuclear atypia, and absence of frank stromal invasion. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
were found to contain evaluable information. These 53 patients comprise the study group. Although all cases were reviewed histologically at the time of initial referral, histopathologic review of all primary tumors and recurrent tumor, when available, was performed by one of the authors (EGS). Pathologic material was available for review from recurrent tumors in 49 of 53 cases. In two cases, progression or recurrence was documented by cytologic evaluation of ascites or pleural fluid. In two other cases, clinical criteria alone were used to diagnose progression or recurrence. Serous ovarian tumors of low malignant potential were defined by the following pathologic criteria: 1) stratification of the epithelial lining of the papillae; 2) formation of microscopic papillary projections or tufts, often detached, arising from the epithelial lining of the papillae; 3) varying degrees of nuclear atypia; and 4) absence of frank stromal invasion (Figure 1). Low-grade serous carcinoma is an invasive serous neoplasm with mild to moderate nuclear atypia. The nuclei are generally regular from area to area, and up to ten mitotic figures per ten high-power fields may be present. Although the architectural pattern may vary, the most common one contains uniform, thin papillae. Psammoma bodies are found in the majority of these tumors (Figure 2). Peritoneal implants were classified as either noninvasive or invasive. Noninvasive peritoneal implants were glandular or papillary proliferations with cell detachments. Cellular atypia, psammoma bodies, and desmoplastic fibrosis were present in some cases.17 Invasive
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peritoneal implants were lesions similar to noninvasive implants but with epithelial cells infiltrating the stroma.18 Treatment was at the discretion of the attending physician. Not all therapy was administered at our institution. All patients had primary surgery. Surgical staging of these tumors was determined retrospectively according to criteria of the 1985 classification system of the International Federation of Gynecology and Obstetrics based on careful review of surgical notes and pathology review.19 For purposes of staging, only documented sites of resection or biopsy were used. Extent of residual disease was determined based on descriptions in written and dictated surgical reports and on clinical evaluation of patients in the early postoperative period. Detailed information concerning postoperative therapy, second-look surgery, and treatment for progression or recurrence was abstracted. Response to therapy was also determined retrospectively. In all cases, it was based upon the evaluation of measurable disease, either by physical exam or radiographic criteria. Standard definitions were used to evaluate response to therapy. A complete response was defined as the complete disappearance of all clinically measurable disease. A partial response was defined as a 50% or greater decrease in the size of all measurable lesions. Progressive disease was defined as a 50% or greater increase in the size of any measurable lesion or the appearance of any new lesion. Stable disease was defined as a change in measurable disease too small to meet the requirements for a partial response or progres-
Figure 2. This hematoxylin-eosin-stained photomicrograph demonstrates the characteristics of a low-grade serous carcinoma. These tumors are invasive serous neoplasms with mild to moderate nuclear atypia. The nuclei are generally regular from area to area, and up to 10 mitotic figures per 10 high-power fields may be present. The architectural pattern may vary. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
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sive disease and the appearance of no new lesions for a period of at least 8 weeks. Statistical analysis was performed using GraphPad Prism 2.0 (GraphPad Software, Inc., San Diego, CA). Survival was analyzed by the method of Kaplan and Meier. The effect of clinicopathologic variables on survival was evaluated using the log rank test. The relationship between survival and age, type of peritoneal implant, and secondary cytoreductive surgery was determined by the 2 test or Fisher exact test, as appropriate. A P value of ⱕ.05 was considered statistically significant. RESULTS Table 1 summarizes the patient characteristics at initial diagnosis. The mean age of the 53 patients at diagnosis was 37 (range 20 – 61 years). The majority of the patients were white (85%). Most patients had their initial diagnosis in the 1970s or 1980s. The majority of patients (56%) had stage III disease, and 24% were unstaged. The most common initial surgical procedure was abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Two patients were treated with ovarian cystectomy alone. Over half of the patients (58%) had no gross residual disease at the completion of their primary surgery. Thirty-five patients had peritoneal implants at the time of initial surgery. Twenty-three patients (66%) had noninvasive implants, and 12 (34%) had invasive implants. Forty patients received some form of postoperative therapy. The most common postoperative treatment was platinum-based chemotherapy, which was administered to 21 patients. Six patients had progression of disease on primary therapy, and 47 recurred 6 or more months after completion of primary therapy. The median time to first progression or recurrence was 5.6 years (range 0.25– 22.3 years). Table 2 summarizes the site of first progression or recurrence. Most patients recurred within the peritoneal cavity. Of the nine patients who recurred in a residual ovary, four were treated with surgery alone, four were treated with surgery followed by chemotherapy, and one was treated with surgery followed by abdominopelvic radiotherapy. Only one of these patients is dead, and she died of unknown causes. Six of these patients are alive without evidence of disease, and two are alive with disease. Forty-nine patients had surgical or biopsy documentation of a least one episode of progression or recurrence. In these 49 patients, the histology of the progression or recurrence was serous ovarian tumor of low malignant potential in 13 (27%) and low-grade serous carcinoma in 36 (73%). Two patients had progression or recurrence
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Table 1. Characteristics at Initial Diagnosis of Patients With Progressive or Recurrent Serous Ovarian Tumors of Low Malignant Potential (n ⫽ 53) Characteristic Age at initial diagnosis (y) 20–29 30–39 40–49 50–59 ⱖ60 Race White Black Hispanic Other Decade of diagnosis 1941–1950 1951–1960 1961–1970 1971–1980 1981–1990 1991–1997 FIGO stage Ib Ic IIa IIc IIIa IIIb IIIc Unstaged Type of initial surgery TAH USO BSO Cystectomy Omentectomy Gross residual disease None ⱕ2 cm ⬎2 cm Unknown Peritoneal implants None Noninvasive Invasive Unknown Postoperative therapy* None Platinum-based chemotherapy Nonplatinum-based chemotherapy External beam radiotherapy† Other‡
Number of patients (%) 16 (30) 19 (36) 12 (23) 4 (7) 2 (4) 45 (85) 4 (7) 2 (4) 2 (2) 1 (2) 2 (4) 5 (9) 11 (21) 30 (57) 4 (7) 1 (2) 1 (2) 6 (11) 2 (4) 10 (19) 16 (30) 4 (7) 13 (24) 41 (77) 13 (24) 38 (72) 2 (4) 32 (60) 31 (58) 12 (23) 2 (4) 8 (15) 4 (7) 23 (43) 12 (23) 14 (26) 13 21 10 12 4
FIGO ⫽ International Federation of Gynecologists and Obstetricians; TAH ⫽ total abdominal hysterectomy; USO ⫽ unilateral salpingooophorectomy; BSO ⫽ bilateral salpingo-oophorectomy. * Some patients received more than one modality of adjuvant postoperative therapy. † External beam whole pelvic radiotherapy in four, whole abdominal radiotherapy in seven, and local radiotherapy in one. ‡ One patient each treated with intraperitoneal P32, intraperitoneal Au198, leuprolide, and bacille Calmette-Gue´rin.
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Table 2. Site of Initial Progression or Recurrence of Serous Ovarian Tumors of Low Malignant Potential
Site Ovary Pelvic mass (other than ovary) Upper abdomen/ascites Lymph nodes Cervical/supraclavicular Para-aortic Inguinal Chest (lung, pleura, mediastinum, chest wall)† Bone Brain‡ Liver§ Pancreas§ Unknown
Number of patients* 9 23 18 4 2 2 8 1 1 1 1 3
* Patient may have had initial progression or recurrence documented at more than one site. † Four patients with pleural disease, three patients with pulmonary nodules, two patients with mediastinal disease, and one patient with metastatic disease to the chest wall. ‡ The patient with metastatic disease to the brain also had pulmonary nodules. § The same patient had metastatic disease to the liver and pancreas.
documented by cytology of ascites or pleural fluid. In two other patients, clinical criteria alone (physical examination, radiologic studies, or increasing serum CA-125) were used to diagnose progression or recurrence. The pathology of progression or recurrence was a significant predictor of survival, with patients who progressed or recurred as low-grade serous carcinoma (17 of 36, 47%) being more likely to die of disease than those who progressed or recurred as serous ovarian tumor of low malignant potential (zero of 13, 0%) (P ⫽ .045). Figure 3 shows the Kaplan-Meier survival curves for patients progressing or recurring as low-grade serous carcinoma compared with those progressing or recurring as serous ovarian tumors of low malignant potential. Thirty-five patients underwent 48 secondary surgical procedures for progression or recurrence. For each patient, the best surgical result was correlated with her outcome. Table 3 summarizes residual disease at the conclusion of surgical cytoreduction for progression or recurrence. The surgical outcome was a significant predictor of survival. Patients who had greater than 2-cm residual disease (suboptimal cytoreduction) at the completion of surgery were significantly more likely to die of disease than patients who had less than or equal to 2-cm residual disease (optimal cytoreduction) (P ⫽ .007). The Kaplan-Meier survival curves for survival of patients undergoing optimal versus suboptimal cytoreductive surgery is shown in Figure 4. There was no influence of age at diagnosis or type of peritoneal implant on survival.
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Figure 3. Kaplan-Meier curve demonstrating a significantly better survival for patients with serous ovarian tumors of low malignant potential recurring as serous tumors of low malignant potential (SLMP) (n ⫽ 13), compared with those recurring as low-grade serous carcinomas (LGSC) (n ⫽ 36). The comparison of the survival curves was performed using the log rank test. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
Of the 53 patients in this study with progressive or recurrent serous ovarian tumors of low malignant potential, 49 received one or more nonsurgical treatment regimens. Of these 49 patients, 45 were evaluable for response to treatment. Twenty-seven patients received more than one nonsurgical therapy during their treatment for progression or recurrence. The median number of regimens received was two (range 1–7). Forty-two patients received cytotoxic chemotherapy, 21 patients received hormonal therapy, and six patients were treated with radiotherapy. Cytotoxic chemotherapeutic agents used, either alone or in combination, included cisplatin, carboplatin, paclitaxel, actinomycin-D, chlorambucil, cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil, hexamethylmelamine, methotrexate, melphalan, thiotepa, topotecan, and vinorelbine. Hormonal agents used, either alone or in combination, included ethinyl estradiol, flutamide, leuprolide, medroxyprogesterone acetate, megestrol, tamoxifen, and testosterone. RadiotherTable 3. Outcomes for Patients With Recurrent or Progressive Serous Ovarian Tumors of Low Malignant Potential Who Underwent Secondary Cytoreductive Surgery
Surgical result
Number of patients
Number dead of disease (%)
No gross residual Optimal (ⱕ2 cm) Suboptimal (⬎2 cm) Unknown
10 7 10 8
1 (10) 1 (14) 6 (60) 1 (12)
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Figure 4. Kaplan-Meier curve demonstrating that patients with recurrent or progressive serous ovarian tumors of low malignant potential, who can be optimally cytoreduced to less than or equal to 2-cm maximal residual disease at secondary surgery (n ⫽ 7), have statistically significantly improved survival compared with patients whose tumors suboptimally cytoreduced to greater than 2-cm maximal residual disease (n ⫽ 10). Survival comparisons were performed using the log rank test. Crispens. Recurrent Serous Ovarian Tumors. Obstet Gynecol 2002.
apeutic modalities used included local radiotherapy to a site of recurrence, whole pelvic radiotherapy, and whole abdominal radiotherapy. There were six of 45 (13%) patients who had complete responses and six of 45 (13%) patients who had partial responses. No patient had a response to more than one nonsurgical treatment regimen. Of the responses, six of 12 (50%) were to platinum-based chemotherapy regimens, three of 12 (25%) were to paclitaxel, one of 12 (8%) was to combination cyclophosphamide, hexamethylmelamine, 5-fluorouracil, and methotrexate chemotherapy, one of 12 (8%) was to leuprolide, and one of 12 (8%) was to whole pelvic radiotherapy. Details regarding response data are presented in Table 4.
There were 21 of 45 (47%) patients who had stable disease to one or more nonsurgical treatment regimens. Stable disease to platinum-based chemotherapy occurred in 11 patients, to paclitaxel in one patient, to nonplatinum, nonpaclitaxel chemotherapy in five patients, to hormonal therapy in eight patients, and to radiotherapy in three patients. The median duration of stable disease was 12 months (range 3–77.5 months). At the time of analysis, 14 of the 53 patients (26%) were alive and without evidence of disease, 16 (30%) were alive with disease, 19 (36%) were dead of disease, three (6%) were dead of unknown cause, and one (2%) was dead of other causes. The median survival from diagnosis of progression or recurrence was 7.7 years (range 0.5–18.8 years). The median survival from initial diagnosis was 21 years (range 0.75–34.3 years). DISCUSSION This study spans a period of approximately 41 years from 1956 to 1997. Although the International Federation of Gynecology and Obstetrics did not officially recognize the existence of tumors of “low potential malignancy” until 1971,20 and the World Health Organization did not recognize these tumors as separate entities until 1973,21 we were able to identify patients who had these tumors before 1971 by a complete pathology review of all patients with serous ovarian tumors presenting to our institution. The length of observation may be a concern because detection, treatment, and outcome have certainly changed significantly during this period. However, such a long length of observation is necessary to understand the natural history of a tumor whose median time to recurrence and median survival are long. We have observed a median time to first progression/
Table 4. Responders Among Patients With Recurrent or Persistent Serous Ovarian Tumors of Low Malignant Potential Patient
Therapy
Response
Disease status
Survival from recurrence (y)
1 2 3 4 5 6 7 8 9 10 11 12
PAC PAC Carbo/CTX CTX/HMM/5-FU/MTX Paclitaxel Paclitaxel Carbo/CTX Carbo/CTX Carbo/leuprolide/tamoxifen Paclitaxel Leuprolide Pelvic XRT
CR CR CR CR CR CR PR PR PR PR PR PR
AWD AWD AWD DOD NED AWD AWD AWD AWD DCU DOD DCU
16.0 7.9 6.2 2.3 4.0 4.6 8.3 4.4 8.6 3.1 5.6 7.7
PAC ⫽ cisplatin, doxorubicin, cyclophosphamide; Carbo ⫽ carboplatin; CTX ⫽ cyclophosphamide; HMM ⫽ hexamethylmelamine; 5-FU ⫽ 5-fluorouracil; MTX ⫽ methotrexate; XRT ⫽ radiotherapy; CR ⫽ complete response; PR ⫽ partial response; AWD ⫽ alive with disease; DOD ⫽ dead of disease; NED ⫽ alive, no evidence of disease; DCU ⫽ dead, cause unknown.
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recurrence of 5.6 years and a median survival from initial diagnosis of 21 years. Studies of this indolent disease must necessarily include protracted observation periods. Serous ovarian tumors of low malignant potential have a better prognosis than their frankly invasive counterparts. However, over a 10-year follow-up period, approximately 10 –15% of patients will relapse.2– 4 A number of potential risk factors for recurrence have been evaluated in previous studies. The two that appear consistently to be adverse prognostic factors at diagnosis are stage and residual disease at the completion of primary surgery.5,6,8,17,18,22–24 Patients with stage I ovarian serous borderline tumors have a relapse rate of approximately 1%, whereas patients with stages II–IV have a relapse rate in the range of 20%. This finding may be at least partially related to the ability to achieve optimal cytoreduction. In a long-term, follow-up study of patients with serous ovarian tumors of low malignant potential, Leake et al noted that in patients with stages II and III disease, mortality was 8% in patients with no residual disease at the completion of primary surgery as compared with 31% in patients with residual disease.6 Bostwick et al also noted that the inability to completely excise all visible tumor at the time of initial diagnosis or at the time of recurrence carried an increased risk of persistent or recurrent neoplasm.5 This study demonstrates that residual disease at the completion of secondary cytoreduction is an important prognostic factor for patients with recurrent serous ovarian tumors of low malignant potential. Only 12% of patients whose tumor was optimally cytoreduced died of their disease compared with 60% of those whose tumor was suboptimally cytoreduced. Aggressive surgical debulking of patients with persistent or recurrent disease would appear to be the best available treatment for serous ovarian tumors of low malignant potential, particularly in light of their relatively poor response to nonsurgical therapy. The other factor we identified, which had a statistically significant influence on survival, was the histology of the recurrence. Patients whose recurrence was lowgrade serous carcinoma had a significantly worse outcome than those whose recurrence consisted of serous ovarian tumor of low malignant potential. To our knowledge, this is the largest series detailing the histology of recurrence in patients with serous ovarian tumors of low malignant potential. We were able to identify only 17 patients from seven previous reports in which the histology of the recurrence was described.2,3,7,22,24 –26 Whether such disease represents a true recurrence or a new primary tumor remains unclear. Future clonality studies hopefully will elucidate the biology of this phenomenon. For the
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patient, however, such a distinction may be merely academic. Previous reports have detailed the safety of conservative surgery with resultant preservation of fertility for young patients with stage I serous ovarian tumors of low malignant potential.5,6,8,10,11,27 In this study, nine patients were identified who had recurred within the residual ovary after conservative surgery of serous ovarian tumor of low malignant potential. Not all of these patients were completely staged. Six (67%) of these patients are alive without evidence of disease, two (22%) are alive with disease, and one (11%) is dead of an unknown cause. Most, if not all, of these lesions probably consisted of new primary tumors rather than recurrent tumors. Again, future clonality studies will resolve this issue. These findings are consistent with those described in previous reports and are not inconsistent with the concept of conservative surgery for stage I disease confirmed by comprehensive surgical staging in women desiring to maintain fertility. Very little information exists regarding the chemosensitivity of serous ovarian tumors of low malignant potential. A few previous studies have provided detailed information on the effectiveness of postoperative chemotherapy in the treatment of primary serous ovarian tumors of low malignant potential with peritoneal implants.3,15,16 Fort et al15 described their experience with postoperative therapy. Nineteen patients were observed to have residual disease after primary surgery for serous ovarian tumors of low malignant potential. Subsequent therapy included alkylating agent chemotherapy, multiagent chemotherapy frequently including cisplatin, pelvic irradiation, or pelvic irradiation plus alkylating agent chemotherapy. Of these patients, 12 (63%) were found to have negative second-look laparotomies. In a subsequent report from the same institution, Barakat et al16 observed surgical complete responses in ten of 16 patients (62%) with serous ovarian tumors of low malignant potential who were treated with platinum-based chemotherapy. In a study from our institution, we found that 80% of 20 women who had macroscopic residual disease at initial surgery responded to chemotherapy— eight complete responders, eight partial responders, and four nonresponders—as evidenced by second-look surgical findings.3 Of course, in all these reports, residual disease may represent unresected peritoneal implants— either noninvasive or invasive—rather than the primary ovarian tumor. Our findings do not demonstrate a significant response to nonsurgical therapy among patients with persistent or recurrent disease. We observed a 13% clinical complete response rate and a 13% clinical partial response rate. Half of the responses occurred in patients
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who received platinum-based regimens, and another 25% of responses occurred in patients receiving paclitaxel alone. However, the number of patients responding to any therapy is small. With current information, it would seem reasonable to recommend either carboplatin, paclitaxel, or both for nonsurgical treatment of progressive or recurrent serous ovarian tumors of low malignant potential that recur as low-grade serous carcinomas. Hormonal therapy with either tamoxifen or leuprolide has been shown to have, at best, a 10 –15% response rate in the treatment of invasive epithelial ovarian carcinoma.28 –31 There are also case reports that describe complete serologic and clinical responses to either tamoxifen or leuprolide in patients with advanced stage serous ovarian tumors of low malignant potential.32,33 However, the present study did not confirm the efficacy of hormonal therapy alone for progressive or recurrent serous ovarian tumors of low malignant potential; only a single partial response to leuprolide was observed. One or more episode of stable disease was observed in almost half of patients. Stable disease was noted to platinum-based chemotherapy in 11 patients, to paclitaxel in one patient, to nonplatinum, nonpaclitaxel chemotherapy in five patients, to hormonal therapy in eight patients, and to radiotherapy in three patients. The significance of stable disease in patients whose tumor may inherently have an indolent course is uncertain. In summary, recurrent serous ovarian tumors of low malignant potential have an indolent course, as evidenced by long median survival time, and respond poorly to available systemic treatment. Recurrence of these tumors as low-grade serous carcinoma is a significant adverse prognostic factor. Secondary cytoreductive surgery appears to be beneficial, as patients whose disease was optimally cytoreduced had a significantly better survival than those whose disease could not be optimally cytoreduced. Major challenges for the future include defining the clonality of these so-called recurrent lesions and identifying more effective therapies.
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review of 81 cases with an assessment of the impact of treatment. Int J Radiat Oncol Biol Phys 1992;22:867–74. 5. Bostwick DG, Tazelaar HD, Ballon SC, Hendrickson MR, Kempson RL. Ovarian epithelial tumors of borderline malignancy: A clinical and pathologic study of 109 cases. Cancer 1986;58:2052– 64. 6. Leake JF, Currie JL, Rosenshein NB, Woodruff JD. Longterm follow-up of serous ovarian tumors of low malignant potential. Gynecol Oncol 1992;47:150 – 8. 7. Kliman L, Rome RM, Fortune DW. Low malignant potential tumors of the ovary: A study of 76 cases. Obstet Gynecol 1986;68:338 –34. 8. Barnhill DR, Kurman RJ, Brady MF, Omura GA, Yordan E, Given FT, et al. Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: A Gynecologic Oncology Group study. J Clin Oncol 1995; 13:2752– 6. 9. Aure JC, Hoey K, Kolstad P. Clinical and histologic studies of ovarian carcinoma. Long-term follow-up of 990 cases. Obstet Gynecol 1971;37:1–9. 10. Tazelaar HD, Bostwick DG, Ballon SC, Hendrickson MR, Kempson RL. Conservative treatment of borderline ovarian tumors. Obstet Gynecol 1985;66:417–22. 11. Lim-Tan SK, Gajiga HE, Scully RE. Ovarian cystectomy for serous borderline tumors: A follow-up study of 35 cases. Obstet Gynecol 1988;72:775– 81. 12. Rice LW, Berkowitz RS, Mark SD, Yavner DL, Lage JM. Epithelial ovarian tumors of borderline malignancy. Gynecol Oncol 1990;39:195– 8. 13. Nation JG, Krepart GV. Ovarian carcinoma of low malignant potential: Staging and treatment. Am J Obstet Gynecol 1986;154:290 –3. 14. Chambers JT, Merino MJ, Kohorn EL, Schwartz PE. Borderline ovarian tumors. Am J Obstet Gynecol 1988; 159:1088 –94. 15. Fort GM, Pierce VK, Saigo PE, Hoskins WJ, Lewis JL. Evidence for the efficacy of adjuvant therapy in epithelial tumors of low malignant potential. Gynecol Oncol 1989; 32:269 –72. 16. Barakat RR, Benjamin I, Lewis JL, Saigo RE, Curtin JP, Hoskins WJ. Platinum-based chemotherapy for advancedstage serous ovarian carcinoma of low malignant potential. Gynecol Oncol 1995;59:390 –3. 17. Gershenson DM, Silva EG, Tortolero-Luna G, Levenback C, Morris M, Tornos C. Serous borderline tumors of the ovary with noninvasive peritoneal implants. Cancer 1998; 83:2157– 63. 18. Gershenson DM, Silva EG, Levy L, Burke TW, Wolf JK, Tornos C. Ovarian serous borderline tumors with invasive peritoneal implants. Cancer 1998;82:1096 –103. 19. Staging announcement: FIGO Cancer Committee. Gynecol Oncol 1986;25:383–5. 20. International Federation of Gynaecology and Obstetrics.
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Address reprint requests to: Marta A. Crispens, MD, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, PO Box 19640, Springfield, IL 627949640; E-mail: [email protected]. Received January 30, 2001. Received in revised form August 29, 2001. Accepted September 6, 2001.
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