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    Aggressive variant uterine cancer Aggressive variant uterine cancer Document Transcript

    • Management of Aggressive Histologic Variants of Endometrial Carcinoma at the Tom Baker Cancer Centre between 1984 and 1994 Peter S. Craighead, FFRad(T), FRCPC,* Khalid Sait, M.D., FRCPC,† Gavin C. Stuart, M.D., FRCPC,† Keith Arthur, M.D., FRCPC,* Jill Nation, M.D., FRCPC,† Maire Duggan, M.D., FRCPC,‡ and Dianlin Guo, Ph.D. (Epidem)§ *Department of Radiation Oncology, †Department of Gynecologic Oncology, and §Department of Preventive Oncology and Epidemiology, Tom Baker Cancer Centre; and ‡Department of Pathology, Foothills Hospital and University of Calgary, 1331 29th Street NW, Calgary, Canada T3G 3A6 Received July 26, 1999 Objective. The aim of this study was to determine the patient characteristics and outcome of patients with aggressive histologic variants (AV) of endometrial carcinoma, including uterine papil- lary serous carcinoma (UPSC), uterine clear cell carcinoma (UCCC), and mixed type. Methods and materials. All cases with AV histological type of endometrial carcinoma from January 1984 to December 1994 at the Tom Baker Cancer Centre were identified using the Alberta Cancer Registry. Relevant data from the charts of these patients were entered into a study database (Microsoft Excel) and analyzed for presentation, demography, treatment parameters, and out- come of treatment. All pathology was reviewed at the time of diagnosis. Statistical analysis was performed using the S-plus statistics computer program. Univariate and multivariate analyses were used to assess independent prognostic factors using the Cox proportional hazards model. Results. A total of 103 patients with AV histological type were identified and analyzed; there were 61, 31, and 11 cases of UPSC, CCC, and mixed tumors, respectively. Sixty-three patients had Stage I, 11 had Stage II, 15 had Stage III, and 14 had Stage IV disease. The median age of patients was 67 years with a range of 36 to 86 years. Median follow-up was 60 months with a range of 36 to 156 months. The Cox proportional hazards model showed that lymphvascular space invasion and stage are the two independent prognostic factors affecting recurrence and survival. Forty six percent of all cases underwent surgery alone, 39% underwent treatment which included pelvic RT, and 17% underwent treat- ment which included chemotherapy. Pelvic recurrence was re- duced significantly by radiotherapy in Stages I, II, and III (19% recurrence with no RT vs 7% recurrence with RT, P < 0.005). Chemotherapy improved overall survival, but made little differ- ence in distant relapse rates. Conclusions. Stage Ia cases treated by surgery alone have a low risk of relapse and need not be offered adjuvant systemic therapy or pelvic radiation. Patients with Ib, Ic, II, and III have signifi- cantly lower pelvic failure rates if treated with pelvic radiation, but still have a high distant failure rate. Systemic therapy did not significantly improve distant relapse-free survival, but did extend overall survival. Stage IV patients usually died within 6 months with a few responding to systemic chemotherapy. These results suggest that there is a need for randomized trials for these patients. © 2000 Academic Press Key Words: uterine serous papillary carcinoma; endometrial carcinoma; adjuvant radiotherapy. INTRODUCTION Endometrial cancer is the most common female genital tract malignancy in North America and traditionally is regarded as having a good prognosis. The uterine papillary serous variant of endometrial cancer (UPSC) was first regarded as a distinct entity in 1982 [1]. Several retrospective reviews have sug- gested that UPSC is an aggressive variant of endometrial cancer, with a clinical course similar to that of epithelial ovarian cancer [2–6]. Carcangui and Chambers have shown that uterine clear cell (UCCC) and mixed variants which con- sist of greater than 75% UCCC or UPSC histology all exhibit an aggressive natural history, with similar patterns of relapse to UPSC [7]. For this reason many centers treat UPSC, UCCC, and mixed tumors as aggressive variants (AV), with ap- proaches that attempt to control potential pelvic and extrapel- vic disease. Since 1984 the Gynecologic Oncology Tumor Board at the Tom Baker Cancer Centre has recommended that all patients with AV undergo staging laparotomy to remove the uterus, fallopian tubes and ovaries and assess pelvic and paraortic nodes, omentum, and peritoneal cytology. A proportion did not undergo full staging because of comorbid illness. However, there has been less consensus on what adjuvant therapies to use postsurgery. The standard recommendation for surgical Stage Ia cases at this center has been observation. Surgically staged Ib, Ic, and II cases usually have been recommended for whole pelvic plus intracavitary radiotherapy (pelvic RT) after sur- gery. It was the recommendation that certain Stage II cases who did not undergo full staging and all Stage III cases be offered chemotherapy plus pelvic radiotherapy. This involved the ad- Gynecologic Oncology 77, 248–253 (2000) doi:10.1006/gyno.2000.5746, available online at http://www.idealibrary.com on 2480090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
    • ministration of four cycles of cisplatin, Adriamycin, and cy- clophosphamide (PAC), followed by pelvic RT and a further four cycles of PAC after RT. Stage IV patients were recom- mended for PAC chemotherapy at presentation only if they had low bulk or symptomatic disease and were able to tolerate this regime. Multiple claims of treatment success have been published in small uncontrolled series. Management in these series has ranged from observation to adjuvant pelvic RT in Stage I cases and from whole abdominal RT to chemotherapy in Stage II and III cases. A randomized study currently underway by the Gynecology Oncology Group (GOG) is comparing whole ab- dominal RT with systemic chemotherapy in higher risk UPSC cases. We performed this retrospective study in an attempt to increase our understanding of the clinical outcome of this disease, especially as it relates to a combination of UPSC, CCC, or mixed variants. We also assessed prognostic factors and audited compliance to the treatment guidelines. METHOD AND MATERIALS The demographics, details of pathology, treatment parame- ters, and results of treatment for patients with UPSC, UCCC, or mixed uterine carcinoma between 1984 and 1995 were ex- tracted from registry charts and entered into a database (see Table 1), excepting one case who also had adenosquamous carcinoma of the cervix. Only AV cases were included in this review. All cases had their pathology reviewed within the Gynecology Tumor Board Forum. Treatment Surgery. The preferred surgery included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, lymph node sampling, and peritoneal cytology assessment. Radiotherapy. Radiotherapy consisted of whole pelvic ra- diation to a dose of 45 Gy in 25 daily fractions, utilizing high energy photon therapy in a four-field arrangement to include the vaginal cuff as well as the obturator and internal/external iliac nodes bilaterally. This was followed 1 week later by a single low-dose-rate cesium insert to a vaginal surface dose of 20 Gy. Chemotherapy. In selected cases chemotherapy was deliv- ered using 50 mg/m2 cisplatin, 50 mg/m2 doxorubicin, and 600 mg/m2 cyclophosphamide intravenously every 3 weeks, to- gether with antiemetics and hydration for eight cycles. When administered in a sandwich approach, the pelvic radiotherapy was delivered between the fourth and fifth cycles. Statistical Analysis Statistical analysis was performed using the S-plus statistics program. Analysis of differences between baseline character- istics was performed using the Kruskall–Wallis rank sum test. The difference between proportions was tested using the ␹2 test. Survival estimates were calculated using the Kaplan– Meier method and the significance between survival tested using the log-rank test. Multivariate analysis was performed for overall survival and recurrence-free survival using the Cox proportional hazards model. RESULTS Between 1984 and 1994 there were 936 patients with endo- metrial cancer registered at the Tom Baker Cancer Centre, with 888 (95%) of them undergoing pathology review and tumor board discussion. One hundred four cases (11%) were shown TABLE 2 Sites of Recurrence Stage I Stages II and III Surgery (36 cases) S ϩ RT (27 cases) Surgery (5 cases) S ϩ RT (9 cases) S ϩ Chem (6 cases) S/Ch/RT (6 cases) No. of pts with recurrence 5 5 3 4 4 3 Pelvic recurrence 5/36 (14%) 1/27 (4%) 1/5 (20%) 1/8 (12.5%) 3/6 (50%) 1/6 (17%) Distant disease 4/36 (11%) 4/27 (15%) 2/5 (40%) 4/8 (50%) 1/6 (17%) 3/6 (50%) TABLE 1 Treatment Characteristics (Total ‫؍‬ 103 Cases) Stage I Ia Ib Ic II III IV Surgery only 36 18 14 4 2 3 6 Surgery and RT 27 5 12 10 5 3 1 Surgery ϩ ch 0 0 0 0 2 4 8 Surgery ϩ RT/ch 0 0 0 0 2 4 0 Total 63 23 26 14 11 14 15 Note. Surgery usually included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal cytology. In a proportion it included omentectomy and nodal assessment. RT, pelvic radiotherapy; Ch, systemic chemotherapy using cisplatin, doxorubicin, and cyclophosphamide. 249MANAGEMENT OF ENDOMETRIAL CARCINOMA VARIANTS
    • to have aggressive variants. One of these cases was also shown to have primary adenosquamous carcinoma of the cervix and was thus removed from survival analysis. Patient Characteristics The median age of patients was 67 years, with a range of 36 to 86 years. Nulliparity was evident in 63 cases, but there was no association between the development of this with exoge- nous estrogens, diabetes mellitus, hypertension, or obesity. Median follow-up was 60 months (range 36 to 156 months). There were 61, 31, and 11 cases of UPSC, UCCC, and mixed tumors, respectively. Division by stage showed 63 patients with Stage I, II with Stage II, 15 with Stage III, and 14 with Stage IV. There was no substantial difference between propor- tions of patients with different variants per stage. Treatment Results Table 1 shows treatment by stage. Forty-seven (46%) of all cases underwent surgery only, 42 cases (41%) underwent treat- ment which included pelvic RT, and 20 cases (19%) underwent treatment which included chemotherapy. In Stage Ia cases managed by postsurgery surveillance there was an 11% recur- rence rate, with all of these being either vault or pelvic in nature. Pelvic recurrence was reduced significantly by radio- therapy in Stages Ib/Ic, II, and III (24% of 29 pts treated without RT vs 13% of 36 pts who received RT, P Ͻ 0.001). Chemotherapy was associated with an improvement in overall survival but had little effect on pelvic control or distant relapse rates (see Table 2). Adherence to Guidelines (See Table 2) Sixty-five percent of the cases were treated according to the guidelines and 35% outside of them. Surgery alone was used appropriately in most Stage Ia and IV cases, and the majority of Stage Ib, Ic, and II cases (88%) were treated within the guidelines. There was adherence to the recommendation for RT with/without PAC in 64% of Stage II cases and for RT/PAC in 58% of Stage III patients. In Stage I to III cases there was a statistically significant reduction in local recurrence (8.5 vs 38%, P Ͻ 0.001), but a nonsignificant difference in distant disease (27 vs 34%, P ϭ 0.4) for those treated within and outside the guidelines. Other than in Stage Ia, where no reason was given why 20% of cases received radiotherapy, the major reason for failure to comply with recommendations was age/ poor performance status. Overall and Recurrence-Free Survival, Local Control, and Risk Factors (Tables 3 and 4 and Figs. 1–4) Stage IV patients [14] had a median survival of 4.5 months, with the difference between those who did not receive pallia- tive chemotherapy (2.48 months) against those who did (7.96 months) being significant (P ϭ 0.0046, log rank). Whether this is due to treatment or that only better performance status patients were given chemotherapy is difficult to determine. The remainder of the analysis was limited to Stage I to III cases. The Cox proportional hazards model for death showed in- creased stage, lymphvascular invasion (LVS), and the lack of chemotherapy to be significant predictive factors for death. Stages II, III, and IV had relative hazards of death of 3.9 (CI 1.1 to 14), 5.3 (CI 1.7 to 17), and 42 (CI 9.4 to 188) compared TABLE 3 Multivariate Analysis for Recurrence-Free Survival Coef Exp (coef) SE (coef) Z P LVS 1.59 4.912 0.480 3.315 0.00092 Staging s2 1.69 5.446 0.591 2.866 0.00420 Staging s3 1.93 6.873 0.619 3.116 0.00180 Chemotherapy Ϫ0.54 0.583 0.577 Ϫ0.936 0.35000 Radiation Ϫ1.19 0.306 0.485 Ϫ2.444 0.01500 TABLE 4 Multivariate Analysis for Overall Survival Coef Exp (coef) SE (coef) z P LVS 1.645 5.183 0.518 3.18 0.015 Staging s2 1.365 3.917 0.653 2.09 0.037 Staging s3 1.672 5.322 0.586 2.86 0.043 Staging s4 3.739 42.059 0.767 4.88 0.0000011 Chemotherapy Ϫ1.509 0.221 0.552 Ϫ2.74 0.0062 Radiation Ϫ0.523 0.593 0.515 Ϫ1.02 0.31 250 CRAIGHEAD ET AL.
    • with Stage I (P ϭ 0.0000011). The presence of LVS had a relative hazard of death of 5.2 (P Ͻ 0.0015, C.I. 1 to 14), and chemotherapy significantly reduced the relative risk (RR) of death to 0.22 (P Ͻ 0.034, CI 0.08 to 0.65). Thirty-five percent of Stage Ib to III cases (23 of 66) experienced relapse, with 72% of these having a form of extrapelvic component. A Cox model for recurrence-free sur- vival showed the presence of LVS to transfer a relative risk of recurrence of 4.9 (P Ͻ 0.00092, 1.9 to 12.6) and Stages II and III to have an RR of 5.4 and 6.9 compared with Stage I (P ϭ 0.0042). Radiotherapy had a relative risk of recurrence of 0.31 compared with no pelvic RT (P Ͻ 0.015, CI 0.11 to 0.79). DISCUSSION UPSC traditionally has been quoted as having a prevalence of approximately 2% of endometrial cancers, but little has been published on the prevalence of a combination of UPSC, UCCC, or mixed variants. These results show that they con- stituted 11% of malignant endometrial cases in our center, with UPSC being more common than the two other diagnoses (60 vs 40%). Age and other patient characteristics are comparable to other types of endometrial cancer. Because of small numbers we did not compare outcome data according to UPSC, UCCC, or mixed variant categories. Significant risk factors for survival within this series in- cluded increasing stage, lymphvascular invasion, and the lack of chemotherapy, which have been reported previously [6–8]. Of interest is the finding that pelvic RT significantly improved pelvic relapse-free rates in Stages Ib, Ic, II and III, making it an important consideration for patients in these stages. Given that patients in Stages I to III had significantly improved local control when managed within the guidelines, it is necessary for us to find ways of addressing lack of compliance. This may be partly addressed by offering vault brachytherapy alone in poor performance cases. The results for intermediate risk cases (Stages Ib, Ic, and II) support the use of radiotherapy postsurgery, but show that distant relapses remain a problem (14% in Stage I and 35% in Stage II). The use of pelvic RT has also been supported by the results of the Gynecology Oncology Group 99 protocol, which revealed a significant reduction in pelvic/vaginal recurrences with radiotherapy in normal endometrial subtypes [9]. Despite FIG. 2. Survival by treatment Log-rank test, P ϭ 0.000124. FIG. 1. Survival by staging Log-rank test, P Ͻ 0.000001. 251MANAGEMENT OF ENDOMETRIAL CARCINOMA VARIANTS
    • the reduction in pelvic recurrence rate with radiotherapy in the GOG 99 trial, there was no difference in overall survival, with a similar finding in our study. Several retrospective studies have recommended the use of whole abdominal radiotherapy (WART) in early UPSC, but have not provided sufficient data to determine where this could be applied safely [10–12]. We have not used this approach because of the high risk of distant relapse and the reasonable pelvic control achieved by pelvic RT. The benefit of WART is questionable in these patients, given the extra-abdominal re- lapse rates of 30%. No randomized trials comparing adjuvant treatments for UPSC or AV have yet to be reported. Our results have affirmed the use of observation only for Stage Ia cases treated by full staging laporotomy, with relapse occurring in only 11% of these cases. Although this could be reduced by vaginal brachy- therapy, approximately 60% of these would be salvageable by pelvic RT and/or surgery. This questions the need to apply adjuvant radiotherapy in this subgroup of patients. Several others have published excellent results for observation in Stage Ia UPSC cases [13, 14]. Although some centers treat all AV cases as if they were ovarian cancer, and therefore use adjuvant chemotherapy alone, our results suggest that chemotherapy needs to be sup- plemented by pelvic RT if pelvic control is to be optimized in Stages II and III [15]. From our experience it is recommended that Stage Ic and II cases whose tumors have lymphvascular space involvement and all Stage III cases be considered for systemic treatment plus pelvic RT, for they are at a reasonable risk of both local and distant relapse. Until a systemic approach that obviates local recurrences in a high proportion of cases can be found, it would be pertinent to continue this combination of modalities. Other studies show low response rates to systemic therapy in patients with macroscopic tumor and that the major benefit from chemotherapy appears to be in patients who have low- bulk disease [16–18]. Our results show that the use of chemo- therapy alone did not reduce the risk of relapse (either local or distant). However, it was associated with a small improvement in overall survival. This was probably related to most patients in our series treated with chemotherapy having advanced or bulky disease. FIG. 4. Recurrence-free survival by treatment (Stages I to III). Log-rank test, P ϭ 0.00043. FIG. 3. Recurrence-free survival by staging. Log-rank test, P ϭ 0.000174. 252 CRAIGHEAD ET AL.
    • Although the standard adjuvant and palliative systemic regime throughout North America has usually been PAC [16], our center now has changed to single-agent carboplatin. This was done because of the significant morbidity experienced on PAC in this older patient group and with evidence suggesting that carboplatin has efficacy in other Mu¨llerian tract malignancies. The morbidity of PAC included severe myelosuppression and emesis, which resulted in prolonged delays during treatment. We intend to con- duct an analysis after the first 25 patients on carboplatin to assess the control and morbidity rates associated with this approach. We await the results of studies assessing other systemic agents, but until such trials have been approved will continue to use systemic agent/s with the least toxicity. In conclusion, Stage Ia cases should not be offered adjuvant therapy routinely after surgery, since they have a low risk of relapse, most of which are in the pelvis. There is a definite local benefit to pelvic radiotherapy in intermediate-risk cases (Stages Ib, Ic and II) who have had comprehensive surgery. Finally, cases with lymphvascular invasion in Stages Ib, Ic, II and all Stage III cases are at a higher risk of both pelvic and distant relapse and should be considered for combined modality ther- apy. This should include surgery, chemotherapy, and pelvic radiotherapy, although the latter affects only pelvic control. This study does not support the use of such an approach for Stage Ib and Ic cases who don’t have LVS. We strongly recommend that multicenter clinical trials be performed, for we believe that it is only through this that we will be able to advance the treatment of this group of patients in the future. REFERENCES 1. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R: Uterine papil- lary serous carcinoma: a highly malignant form of endometrial adenocar- cinoma. Am J Surg Pathol 6:93–108, 1982 2. Goff BA, Kato D, Schmidt RA, Ek M, Ferry J, et al.: Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 54:264– 267, 1994 3. Dunton C, Gulnar G, McFarland M, Hernandez E: Uterine papillary serous carcinoma: a review. Obstet Gynecol Surv 46(2):97–102, 1991 4. Nicklin J, Copeland L: Endometrial papillary serous carcinoma: patterns of spread and treatment. Clin Obstet Gynecol 39(3):680–695, 1996 5. Sutton G, Brill L, Michael H, Stehman F, Ehrlich C: Malignant papillary lesions of the endometrium. Gynecol Oncol 27:294–304, 1987 6. Carcangui M, Chambers J: Uterine papillary serous carcinoma: a study of 108 cases with emphasis on the prognostic significance of associated endometrial carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecol Oncol 47:298–305, 1992 7. Carcangiu M, Chambers J: Early pathologic stage clear cell carcinoma and uterine papillary serous carcinoma of the endometrium: comparison of clinico pathological features and survival. Int J Gyn Pathol 14:30–38, 1995 8. Gitsch G, Friedhandler M, Wain GV, Hacker N: Uterine papillary serous carinoma: a clinical study. Cancer 75(9):2239–2243, May 1995 9. Roberts J, Brunetto V, Keys H, Zaino R, Spiros N, et al.: A phase III randomized study of surgery vs surgery plus adjuvant radiotherapy in intermediate risk endometrial carcinoma (GOG 99), Abstract 35, Proceed- ings of the Society of Gynecol Oncologists, 1998 10. Mallipeddi P, Kapp D, Teng N: Long term survival with adjuvant whole abdominopelvic irradiation for uterine papillary serous carcinoma. Cancer 71:3076–3081, 1993 11. Parkash L, Carcangui M. Uterine papillary serous carcinoma and radio- therapy. Cancer 69(2):494–501, 1992 12. Frank A, Tseng P, Haffty B, Papadopoulos DP, Kacinski B, et al.: Adjuvant whole abdominal radiation therapy in uterine papillary serous carcinoma. Cancer 68:1516–1519, 1991 13. Grice J, Ek M, Greer B, Koh WJ, Muntz H, et al.: Uterine papillary serous carcinoma: evaluation of long term survival in surgically staged patients. Gynecol Oncol 69:69–73, 1998 14. Aquino Parsons C, Lim P, Wong F, Milenberger M: Papillary serous and clear cell carcinoma limited to endometrial curettings in FIGO Stage Ia and Ib endometrial adenocarcinoma: treatment implications. Gynecol On- col 71:83–86, 1998 15. Christman E, Kapp D, Hendrickson M, Howes A, Ballon S: Therapeutic approaches to uterine papillary serous carcinoma: a preliminary report. Gynecol Oncol 26:228–235, 1987 16. Levenback C, Burke T, Silva E, Morris M, Gershenson D, et al.: Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin and cyclophosphamide (PAC). Gynecol Oncol 46:317–321, 1992 17. Rosenberg P, Boeryd B, Simonsen E: A new aggressive approach to high grade endometrial cancer of possible benefit to Stage I uterine papillary cancer. Gynecol Oncol 48:32–37, 1993 18. Price F, Chambers S, Carcangui ML, Kohorn E, Schwartz P, et al.: Intravenous cisplatin, doxorubicin, and cyclophosphamide in the treatment of uterine papillary serous carcinoma (UPSC). Gynecol Oncol 51:383– 389, 1993 253MANAGEMENT OF ENDOMETRIAL CARCINOMA VARIANTS