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Preoperative radiation therapy in clinical stage II endometrial carcinoma
GYNECOLOGIC
ONCOLOGY
45, 174-178 (1992)
Preoperative Radiation Therapy in Clinical Stage II Endometrial Carcinoma SUSANA. REISINGER,M.D.,*%’ ERIC B. STAROS,M.D. ,t RICK FELD, M.D. ,$ MOHAMMEDMOHIUDDIN,M.D. ,* AND GEORGEC. LEWIS,M.D.5 *Department of Radiation Oncology, TDepartment of Surgical Pathology, *Department of Diagnostic Radiology, and $Departmentof ObstetricsGynecology,
Thomas Jefferson
University
Hospital,
11th and Sansom Streets, Philadelphia,
Pennsylvania
19107
Received July 18, 1991
From 1980 to 1987, 30 patients with FIG0 clinical Stage II carcinoma of the endometium were treated with 5000 cGy preoperative pelvic radiation therapy at Thomas Jefferson University Hospital. Patients with gross cervical disease received additional intracavitary irradiation with a tandem and ovoids for a combined total dose of 7000 cGy to point A. All patients then underwent exploratory laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO). The S-year actuarial survival for the entire group was 69%. The S-year actuarial survival for the 8 patients with papillary serous, clear cell, and undifferentiated small cell carcinoma was 38%, with most patients failing in the upper abdomen. The 5-year actuarial survival for the remaining 22 patients was 82%. The only local failure occurred in the patient with an undifferentiated small cell carcinoma. Although preoperative pelvic radiation therapy together with TAH/BSO appears to offer excellent local control in all patients with Stage II endometrial carcinoma, additional treatment options should be considered for patients with papillary serous and clear cell histologies becauseof the poor survival and high failure rate in the upper abdomen. o 1~92 Academic press, I~C. INTRODUCTION
Cancer of the endometrium is the most common female genital malignancy, with a total of 33,000 new cancer cases projected in the United States for 1991 [l]. The majority of these newly diagnosed cases are Stage I, with cancer confined to the uterus, although approximately 10% of patients will present with Stage II disease [2], with cancer involving both the uterus and the cervix. The treatment of Stage II endometrial carcinoma remains a subject of debate. Recently there has been a trend toward surgical staging and then tailoring adjuvant treatment based on pathologic findings. This trend is further emphasized by ’ To whom reprint requests should be addressed.
the implementation of the new 1988 FIG0 staging system, which is again based on pathologic findings [3]. There will, however, be instances where clinical staging may play a role in the initial evaluation and treatment of a patient with Stage II endometrial cancer. Once involvement of the cervix is documented, treatment of the parametrium and pelvic wall is necessary. Radiation therapy is a useful modality for treatment of the parametrium and pelvic lymph nodes preoperatively. A TAH/BSO can then be considered adequate surgery as opposed to a more radical procedure. Preoperative radiation therapy also offers the theoretical advantage of decreasing the size of the uterus, thereby lowering the risk of tumor dissemination at the time of hysterectomy [4]. At Thomas Jefferson University Hospital, preoperative pelvic radiation therapy is routinely used in those patients with clinical Stage II endometrial carcinoma. There has been a scarcity of reports on preoperative external beam radiation therapy without the use of intracavitary irradiation for patients with Stage II carcinoma and microscopic involvement of the cervix. Most studies of Stage II endometrial carcinoma report on patients who were treated with both external beam radiation and intracavitary radiation therapy [5-131. Gagnon et al. [14] have reported the largest series of patients treated solely with preoperative external beam radiation therapy. Their series of 13 patients did not demonstrate an unusually high pelvic failure rate. This paper deals with 25 patients treated with 5000 cGy of preoperative external beam radiation therapy for microscopic cervical involvement, in addition to 5 patients with gross cervical involvement treated with external beam radiation therapy and intracavitary therapy. The purpose of this paper is also to further identify optimal candidates for preoperative pelvic radiation therapy based on histological subtypes.
174 0090-8258/92 $4.00 Copyright 0 1992by AcademicPress,Inc. All rights of reproductionin any form reserved.
STAGE II ENDOMETRIAL
175
CARCINOMA
METHODS AND MATERIALS
From January 1980 to January 1988, 30 patients with clinical Stage II endometrial carcinoma were evaluated and treated at Thomas Jefferson University Hospital. The patients were staged using the classification of the International Federation of Obstetricians and Gynecologists (FIGO) as outlined in 1971 [15]. All patients had histologically proven endometrial cancer. Cervical involvement was documented by all available evidence, including endocervical curettings, positive cervical biopsies, and gross disease of the cervix. Fifteen patients were classified as Stage II based on positive endocervical curettings, ten patients presented with positive cervical biopsies, and 5 patients presented with gross disease of the cervix. Further extent of disease workup included an intravenous pyelogram and barium enema in all patients. Cystoscopy and proctoscopy were optional. Since diagnostic imaging techniques were improving toward the latter half of the study, 12 patients underwent CT of the abdomen and pelvis. Three additional patients underwent pelvic sonography. Pathology from the 30 patients was retrospectively reviewed. Special effort was made to identify patients with papillary serous or clear cell carcinomas. Twenty-two patients had adenocarcinoma, adenosquamous carcinoma, or papillary carcinoma; these histologies have been designated favorable. Among the 16 patients with adenocarcinema there were 4 grade I tumors, 9 grade II tumors, and 3 grade III tumors. Five patients had papillary serous carcinoma, two patients had clear cell carcinoma, and one patient had an undifferentiated small cell carcinoma. All these histologies have been designated unfavorable. The pathologist was asked to exclude any patient who had only free-floating malignant cells in the endocervical curettings. Patients with cervical stromal invasion, cervical glandular involvement, or malignant cells intimately admixed with benign endocervical cells were included in the study. All patients who had no evidence of disease beyond the uterus and cervix underwent preoperative pelvic radiation therapy. For those patients designated Stage II, based on positive endocervical curettings or positive cervical biopsies with no gross disease, 5000 cGy of whole pelvic external beam radiation therapy was delivered, Patients with gross cervical disease received 4000-5000 cGy of whole pelvic external beam radiation therapy and intracavitary irradiation with a tandem and ovoids to bring the dose to point A to 7000 cGy. Treatment volumes included the whole pelvis using a four-field technique with an average field dimension of 15 x 14 cm for the anterior and posterior fields and an average field dimension of 15 x 12 cm for the opposed lateral fields. Approximately 4 weeks after completion of radiation
--c
Overall Survival
20 1
1
04. 0
8 12
"1'.
24
'. 36
1.. 40
' 60
MONTHS
FIG. 1. Five-year actuarial survival of all patients treated with preoperative radiation therapy.
therapy, all patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pelvic lymph node sampling was performed only when inspection revealed suspicious nodes because dissection in a previously irradiated pelvis can increase morbidity. However, 16 patients underwent a paraaortic lymph node sampling to include those nodes from the bifurcation of the aorta to the right renal vessel and 15 patients underwent peritoneal washings. The entire abdomen was also explored for any evidence of extrauterine disease. Follow-up was calculated from the date of diagnosis. All patients were followed for at least 2 years, with a median of 36 months. Actuarial survival rates were determined by the method of Kaplan and Meier [16]. Patients who died of intercurrent disease were censored at the time of death. RESULTS
The 5-year actuarial survival for the entire group was 69% (Fig. 1). The 5-year actuarial survival for the 22 patients with favorable histologies was 82% versus 38% for those patients with unfavorable histologies (Fig. 2). Follow-up revealed eventual treatment failure in eight patients, of whom five had a recurrence in the upper abdomen (Table 1). Three of these patients had papillary serous carcinoma, one had papillary carcinoma, and the fifth had clear cell carcinoma. Two patients had recurrences in extraabdominal sites. The only local failure occurred in a patient with an undifferentiated small cell carcinoma. Only one of five patients with gross cervical disease had a recurrence. This patient failed in a supraclavicular node.
176
REISINGER ET AL.
maining tumor is removed by total abdominal hysterectomy. Our series of 25 patients with microscopic cervical involvement alone included 1 pelvic failure in a patient with small cell carcinoma. We know of one other series where only preoperative pelvic external beam therapy was used, that of Gagnon et al. [14], whose 13 patients included 1 with vaginal failure. That report did not include survival results, however. A literature review shows that others have used preoperative pelvic external beam radiation therapy along Favorable Histologies with intracavitary radiation therapy with tandem and Unfavorable Histologies 20 ovoids [5-S, 10-13, 171. The rationale behind intracavitary radiation therapy is to treat the paracervical and paravaginal tissue to reduce the incidence of vaginal rea! currence. In our experience, external beam radiation ther0 12 24 38 48 60 apy alone appeared to prevent vaginal and pelvic reMONTHS currence in the absence of gross cervical disease. FIG. 2. Five-year actuarial survival of favorable histologies versus Furthermore, most series describe using 4000 cGy of pelunfavorable histologies. vic radiation therapy with additional intracavitary radiation therapy to bring the dose to the pelvic lymphatics Sixteen patients underwent paraaortic lymph node sam- to a total of 5000 cGy [5,13]. Indeed, Cox et al. [6] noted pling to include those nodes from the bifurcation of the more lateral failures in those patients with Stage II-III aorta to the right renal vessel and none were found to endometrial cancer who received less than 5000 cGy to have positive paraaortic lymph nodes. Peritoneal wash- the lateral pelvic wall. Our treatment philosophy calls for ings obtained in 15 patients showed that 1 patient with 5000 cGy of pelvic radiation therapy in order to treat the clear cell carcinoma had positive cytology. Two patients pelvic lymphatics. This approach is obviously more ecowith papillary serous carcinoma had disseminated intraab- nomical and easier for the patient. However, it is our dominal malignancy at the time of exploration. Exami- policy in those patients with gross cervical involvement nation of the uterus after radiation therapy revealed 12 to use intracavitary irradiation along with external beam patients with less than one-third myometrial invasion, 6 radiation therapy. This is because these patients are likely patients with greater than one-third myometrial invasion, to have tumor spread into the parametrium [18], necesand 5 patients with residual tumor in the cervix. In 7 sitating a higher dose of radiation therapy to that region. patients, the preoperative radiation therapy had totally No patient with gross cervical involvement in our series eradicated their disease with no evidence of tumor re- failed locally. Our survival results of 69% are consistent with those maining in the uterus. Twelve of the thirty patients underwent preoperative found in the literature. Ahmad et al. [2] recently sumCT. None of these patients had a previously positive CT marized the modern literature for Stage II endometrial or ultrasound, and surgery confirmed these negative findings in all but one patient, who was found to have disTABLE 1 seminated intraabdominal disease at the time of surgery. Initial Site of FailureStage II Endometrial Carcinoma Three additional patients underwent a sonography to deMicroscopic versus tect extrauterine extension. Their negative findings were Site of gross disease confirmed at surgery and all of them are alive and free Patient of the cervix initial failure Histology of disease.
I
DISCUSSION The treatment protocol for clinical Stage II endometrial carcinoma at Thomas Jefferson University Hospital calls for 5000 cGy of preoperative external beam pelvic radiation therapy for patients without gross cervical involvement. External beam pelvic radiation therapy is used to treat the pelvic lymphatics, parametrium, and upper vagina, and to reduce tumor bulk in the uterus. The re-
1 2
Gross Microscopic
Adenocarcinoma Papillary serous
Neck Abdomen at time of surgery
3 4 5
Microscopic Microscopic Microscopic
Papillary serous Papillary Papillary serous
Abdomen Abdomen Abdomen at time of surgery
6 I 8
Microscopic Microscopic Microscopic
Small cell Papillary Clear cell
Pelvis Lung Abdomen
STAGE II ENDOMETRIAL
carcinoma treated with a combination of radiation therapy and surgery. They found an average survival of 74% with a range of 44 to 91.2%. Eight of our patients did have papillary serous clear cell or undifferentiated small cell carcinoma. The 5-year actuarial survival for these 8 patients was 38%. When these 8 patients were excluded, the 5-year actuarial survival for the remaining 22 patients with favorable histologies was 82%. The revised 1988 FIG0 staging system is a surgical staging system. The obvious advantage of surgical staging is a more accurate assessment of the extent of disease. Treatment may then be tailored according to the surgical findings. However, preoperative radiation therapy can be a useful method of sterilizing the parametrium and pelvic lymph nodes, thereby decreasing the need for a more extensive operative procedure such as a radical hysterectomy and pelvic lymph node dissection. Also, many theoretical advantages for preoperative radiation have been proposed such as decreased risk of tumor dissemination at surgery, increased ease of operability due to diminution of the uterus and tumor size, prevention of vaginal recurrences, and treatment of well-oxygenated tissues [4]. Note that of our 30 patients, 12 patients underwent a CT and 3 patients underwent pelvic sonography. Since all patients had a careful workup as described above, this patient selection may account for the finding of no positive periaortic lymph nodes at the time of hysterectomy. Furthermore, only 2 of our patients had disseminated intraabdominal malignancy at the time of exploration. Both had papillary serous histologies; 1 had not had a preoperative CT and the other reportedly had a negative CT. Those patients who were noted to have abnormalities on preoperative CT were treated in a manner consistent with their disease spread and were not included in this study. It is our impression that accurate preoperative staging of patients with endometrial carcinoma is mandatory to select those patients who would benefit from preoperative pelvic radiation therapy. However, we do not recommend preoperative radiation therapy in patients with papillary serous or clear cell carcinoma. It has been noted that patients with papillary serous and clear cell histologies have a lower survival rate [9,10,19,20]. Others have reported a high incidence of pelvic and paraaortic lymph nodes in patients with clinical Stage I or Stage II papillary serous carcinoma [21-231. Furthermore, various authors have noted abdominal failures in patients with clinical Stage I [24-261. Operative staging also reveals more frequent advanced disease than clinicians tend to assume. Christman et al. [19] recorded that 5 of 10 patients required upstaging, with 4 of 7 patients having positive peritoneal washings. Chambers et al. [27] also noted that 50% of patients with clinical Stage I papillary serous car-
177
CARCINOMA
cinoma had pelvic or abdominal metastases at the time of surgery. Two of our patients with papillary serous carcinoma were found to have intraabdominal metastasesat the time of surgical exploration. As predicted by previous reports in the literature, four of our seven patients with papillary serous or clear cell histologies eventually had a relapse in the upper abdomen. This suggests that treatment of patients with clear cell or papillary serous histologies needs to be more comprehensive, with serious consideration of either chemotherapy or total abdominal radiation therapy after surgical exploration. In summary, preoperative pelvic radiation therapy with 5000 cGy of external beam irradiation for microscopic cervical involvement appears to provide excellent local control. Intracavitary treatment is reserved for patients with gross cervical disease. If preoperative pelvic radiation therapy is used, then all patients should be evaluated with a CT scan and/or possibly an MRI and ultrasound to select patients with extrauterine extension of disease who would require different treatment. Papillary serous and clear cell histologies should be identified. Tumors with these histologies tend to behave in an aggressive fashion, and limiting treatment to preoperative pelvic radiation therapy for these patients appears inadequate because of the strong likelihood of upper abdominal recurrence. REFERENCES 1. Cancer statistics 1990, Cu Cancer J. Clin. 41, 28 (1991). 2. Ahmad, K., Kim, Y. H., Deppe, G., Malone, J., Herskovic, A.,
3. 4
5.
6.
Ratanatharathron, V., Medina, A., and Malviya, V. Radiation therapy in stage II carcinoma of the endometrium, Cuncer 63,854-858 (1989). FIG0 stages-1988 revision, Gynecol. Oncol. 35, 125-127 (1989). Nolan, J. F., Dorough, M. E., and Anson, J. H. The value of preoperative radiation therapy in stage I carcinoma of the uterine corpus, Am. J. Obstet. Gynecol. 98, 663-674 (1967). Bruckman, J. E., Goodman, R. L., Murthy, A., and Marck, A. Combined irradiation and surgery in the treatment of stage II carcinoma of the endometrium, Cancer 42, 1146-1151 (1978). Cox, J. D., Komaki, R., Wilson, J. F., and Greenberg, M. Locally advanced adenocarcinoma of the endometrium: Results of irradiation with and without subsequent hysterectomy, Cancer 45, 715719 (1980).
7. Grigsby, P. W., Perez, C. A., Camel, H. M., Kao, M. S., and
Galakatos, A. E. Stage II carcinoma of the endometrium: Results of therapy and prognostic factors, Int. J. Radiat. Oncol. Biol. Phys. 13, 1653-1659 (1987). 8. Kinsella, T. J., Bloomer, W. D., Lavin, P. T., and Knapp, R. C. Stage II endometrial carcinoma: lo-year follow-up of combined radiation and surgical treatment, Gynecol. Oncol. 10, 290-297 (1980). 9. Kurman, R. J., and Scully, R. E. Clear cell carcinoma of the endometrium. An analysis of 21 cases, Cancer 37, 872-888 (1976). 10. Onsrud, M., Aalders, J., Abeler, V., and Taylor, P. Endometrial
178
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carcinoma with cervical involvement (Stage II): Prognostic factors and value of combined radiological-surgical treatment, Gynecol. Oncol. 13, 76-86 (1982).
11. Prempree, T., Patanaphan, V., and Salazar, 0. M. Influence of treatment and tumor grade on the prognosis of stage II carcinoma of the endometrium, Acta Radiol. Oncol. 21, 225-229 (1982). 12. Salazar, 0. M., Feldstein, M. L., DePapp, E. W., Bonfiglio, T. A., Keller, B. E., Rubin, P., and Rudolph, J. H. Endometrial carcinoma: Analysis of failures with special emphasis on the use of initial preoperative external pelvic radiation, ht. J. Radiat. Oncol. Biol. Phys. 2, 1101-1107 (1977). 13. Surwit, E. A., Fowler, W. C., Rogoff, E. E., Jelovsek, F., Parker, R. T., and Creasman, W. T. Stage II carcinoma of the endometrium, ht. J. Radiat. Oncol. Biol. Phys. 5, 123-126 (1979). 14. Gagnon, J. D., Moss, W. T., Gabourel, L. S., and Stevens, K. R. External irradiation in the management of stage II endometrial carcinoma. A logical approach, Cancer 44, 1247-1251 (1979). 15. American Joint Committee on Cancer Manual For Staging Of Cancer, Chicago, pp. 157-162 (1989). 16. Kaplan, E. W., and Meier, P. Non-parametric estimation from incomplete observations, J. Am. Statist. Assoc. 53, 457-481 (1958). 17. Larson, D. M., Copeland, L. J., Gallagher, S., Kong, J. P., Wharton, J. T., and Stringer, A. Stage II endometrial carcinoma, Cancer 61, 1528-1534 (1988). 18. Morrow, C. P., DiSaia, P. J., and Townsend, D. E. Current management of endometrial carcinoma, Obstet. Gynecol. 42, 399-406 (1973).
19. Christman, J. E., Kapp, D. S., Hendrickson, M. R., Howes, A. E., and Ballon, S. C. Therapeutic approaches to uterine papillary serous
ET AL.
carcinoma: A preliminary report, Gynecol. Oncol. 26, 228-235 (1987). 20. Fanning, J., Evans, M. C., Peters, A. J., Samuel M., Harmon, E. R., and Bates, J. S. Endometrial adenocarcinoma histologic subtypes: Clinical and pathologic profile, Gynecol. Oncol. 32,288-291 (1989). 21. Chen, S. S., and Lee, L. Retroperitoneal lymph node metastases in stage I carcinoma of the endometrium: Correlation with risk factors, Gynecol. Oncol. 16, 319-325 (1983). 22. Burrell, M. O., Franklin, E. W., and Powell, J. L. Endometrial cancer: Evaluation of spread and follow-up in one hundred eightnine patients with stage I or stage II disease, Am. J. Obstet. Gynecol. 144, 181-185 (1982). 23. Creasman, W. T., Morrow, C. P., Bundy, B. N., Homesley, H. D., Graham, J. E., and Heller, P. B. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study, Cancer 60, 2035-2041 (1987). 24. Eifel, P. J., Ross, J., Hendrickson, M., Cox, R. S., Kempson, R., and Martinez, A. Adenocarcinoma of the endometrium. Analysis of 256 cases with disease limited to the uterine corpus: Treatment comparisons, Cancer 52, 1926-1031 (1983). 25. Ramirez-Gonzalez, C. E., Adamsons, K., Mangual-Vazquez, T. Y., and Wallach, R. C. Papillary adenocarcinoma in the endometrium, Obstet. Gynecol. 70, 212-215 (1987). 26. Jeffrey, J. F., Krepart, G. V., and Lotocki, R. J. Papillary serous adenocarcinoma of the endometrium, Obstet. Gynecol. 67,670-674 (1986). 27. Chambers, J. T., Merino, M., Kohorn, E. I., Peschel, R. E., and Schwartz, P. E. Uterine papillary serous carcinoma, Obstet. Gynecol. 69, 109 (1987).
ONCOLOGY
45, 174-178 (1992)
Preoperative Radiation Therapy in Clinical Stage II Endometrial Carcinoma SUSANA. REISINGER,M.D.,*%’ ERIC B. STAROS,M.D. ,t RICK FELD, M.D. ,$ MOHAMMEDMOHIUDDIN,M.D. ,* AND GEORGEC. LEWIS,M.D.5 *Department of Radiation Oncology, TDepartment of Surgical Pathology, *Department of Diagnostic Radiology, and $Departmentof ObstetricsGynecology,
Thomas Jefferson
University
Hospital,
11th and Sansom Streets, Philadelphia,
Pennsylvania
19107
Received July 18, 1991
From 1980 to 1987, 30 patients with FIG0 clinical Stage II carcinoma of the endometium were treated with 5000 cGy preoperative pelvic radiation therapy at Thomas Jefferson University Hospital. Patients with gross cervical disease received additional intracavitary irradiation with a tandem and ovoids for a combined total dose of 7000 cGy to point A. All patients then underwent exploratory laparotomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO). The S-year actuarial survival for the entire group was 69%. The S-year actuarial survival for the 8 patients with papillary serous, clear cell, and undifferentiated small cell carcinoma was 38%, with most patients failing in the upper abdomen. The 5-year actuarial survival for the remaining 22 patients was 82%. The only local failure occurred in the patient with an undifferentiated small cell carcinoma. Although preoperative pelvic radiation therapy together with TAH/BSO appears to offer excellent local control in all patients with Stage II endometrial carcinoma, additional treatment options should be considered for patients with papillary serous and clear cell histologies becauseof the poor survival and high failure rate in the upper abdomen. o 1~92 Academic press, I~C. INTRODUCTION
Cancer of the endometrium is the most common female genital malignancy, with a total of 33,000 new cancer cases projected in the United States for 1991 [l]. The majority of these newly diagnosed cases are Stage I, with cancer confined to the uterus, although approximately 10% of patients will present with Stage II disease [2], with cancer involving both the uterus and the cervix. The treatment of Stage II endometrial carcinoma remains a subject of debate. Recently there has been a trend toward surgical staging and then tailoring adjuvant treatment based on pathologic findings. This trend is further emphasized by ’ To whom reprint requests should be addressed.
the implementation of the new 1988 FIG0 staging system, which is again based on pathologic findings [3]. There will, however, be instances where clinical staging may play a role in the initial evaluation and treatment of a patient with Stage II endometrial cancer. Once involvement of the cervix is documented, treatment of the parametrium and pelvic wall is necessary. Radiation therapy is a useful modality for treatment of the parametrium and pelvic lymph nodes preoperatively. A TAH/BSO can then be considered adequate surgery as opposed to a more radical procedure. Preoperative radiation therapy also offers the theoretical advantage of decreasing the size of the uterus, thereby lowering the risk of tumor dissemination at the time of hysterectomy [4]. At Thomas Jefferson University Hospital, preoperative pelvic radiation therapy is routinely used in those patients with clinical Stage II endometrial carcinoma. There has been a scarcity of reports on preoperative external beam radiation therapy without the use of intracavitary irradiation for patients with Stage II carcinoma and microscopic involvement of the cervix. Most studies of Stage II endometrial carcinoma report on patients who were treated with both external beam radiation and intracavitary radiation therapy [5-131. Gagnon et al. [14] have reported the largest series of patients treated solely with preoperative external beam radiation therapy. Their series of 13 patients did not demonstrate an unusually high pelvic failure rate. This paper deals with 25 patients treated with 5000 cGy of preoperative external beam radiation therapy for microscopic cervical involvement, in addition to 5 patients with gross cervical involvement treated with external beam radiation therapy and intracavitary therapy. The purpose of this paper is also to further identify optimal candidates for preoperative pelvic radiation therapy based on histological subtypes.
174 0090-8258/92 $4.00 Copyright 0 1992by AcademicPress,Inc. All rights of reproductionin any form reserved.
STAGE II ENDOMETRIAL
175
CARCINOMA
METHODS AND MATERIALS
From January 1980 to January 1988, 30 patients with clinical Stage II endometrial carcinoma were evaluated and treated at Thomas Jefferson University Hospital. The patients were staged using the classification of the International Federation of Obstetricians and Gynecologists (FIGO) as outlined in 1971 [15]. All patients had histologically proven endometrial cancer. Cervical involvement was documented by all available evidence, including endocervical curettings, positive cervical biopsies, and gross disease of the cervix. Fifteen patients were classified as Stage II based on positive endocervical curettings, ten patients presented with positive cervical biopsies, and 5 patients presented with gross disease of the cervix. Further extent of disease workup included an intravenous pyelogram and barium enema in all patients. Cystoscopy and proctoscopy were optional. Since diagnostic imaging techniques were improving toward the latter half of the study, 12 patients underwent CT of the abdomen and pelvis. Three additional patients underwent pelvic sonography. Pathology from the 30 patients was retrospectively reviewed. Special effort was made to identify patients with papillary serous or clear cell carcinomas. Twenty-two patients had adenocarcinoma, adenosquamous carcinoma, or papillary carcinoma; these histologies have been designated favorable. Among the 16 patients with adenocarcinema there were 4 grade I tumors, 9 grade II tumors, and 3 grade III tumors. Five patients had papillary serous carcinoma, two patients had clear cell carcinoma, and one patient had an undifferentiated small cell carcinoma. All these histologies have been designated unfavorable. The pathologist was asked to exclude any patient who had only free-floating malignant cells in the endocervical curettings. Patients with cervical stromal invasion, cervical glandular involvement, or malignant cells intimately admixed with benign endocervical cells were included in the study. All patients who had no evidence of disease beyond the uterus and cervix underwent preoperative pelvic radiation therapy. For those patients designated Stage II, based on positive endocervical curettings or positive cervical biopsies with no gross disease, 5000 cGy of whole pelvic external beam radiation therapy was delivered, Patients with gross cervical disease received 4000-5000 cGy of whole pelvic external beam radiation therapy and intracavitary irradiation with a tandem and ovoids to bring the dose to point A to 7000 cGy. Treatment volumes included the whole pelvis using a four-field technique with an average field dimension of 15 x 14 cm for the anterior and posterior fields and an average field dimension of 15 x 12 cm for the opposed lateral fields. Approximately 4 weeks after completion of radiation
--c
Overall Survival
20 1
1
04. 0
8 12
"1'.
24
'. 36
1.. 40
' 60
MONTHS
FIG. 1. Five-year actuarial survival of all patients treated with preoperative radiation therapy.
therapy, all patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pelvic lymph node sampling was performed only when inspection revealed suspicious nodes because dissection in a previously irradiated pelvis can increase morbidity. However, 16 patients underwent a paraaortic lymph node sampling to include those nodes from the bifurcation of the aorta to the right renal vessel and 15 patients underwent peritoneal washings. The entire abdomen was also explored for any evidence of extrauterine disease. Follow-up was calculated from the date of diagnosis. All patients were followed for at least 2 years, with a median of 36 months. Actuarial survival rates were determined by the method of Kaplan and Meier [16]. Patients who died of intercurrent disease were censored at the time of death. RESULTS
The 5-year actuarial survival for the entire group was 69% (Fig. 1). The 5-year actuarial survival for the 22 patients with favorable histologies was 82% versus 38% for those patients with unfavorable histologies (Fig. 2). Follow-up revealed eventual treatment failure in eight patients, of whom five had a recurrence in the upper abdomen (Table 1). Three of these patients had papillary serous carcinoma, one had papillary carcinoma, and the fifth had clear cell carcinoma. Two patients had recurrences in extraabdominal sites. The only local failure occurred in a patient with an undifferentiated small cell carcinoma. Only one of five patients with gross cervical disease had a recurrence. This patient failed in a supraclavicular node.
176
REISINGER ET AL.
maining tumor is removed by total abdominal hysterectomy. Our series of 25 patients with microscopic cervical involvement alone included 1 pelvic failure in a patient with small cell carcinoma. We know of one other series where only preoperative pelvic external beam therapy was used, that of Gagnon et al. [14], whose 13 patients included 1 with vaginal failure. That report did not include survival results, however. A literature review shows that others have used preoperative pelvic external beam radiation therapy along Favorable Histologies with intracavitary radiation therapy with tandem and Unfavorable Histologies 20 ovoids [5-S, 10-13, 171. The rationale behind intracavitary radiation therapy is to treat the paracervical and paravaginal tissue to reduce the incidence of vaginal rea! currence. In our experience, external beam radiation ther0 12 24 38 48 60 apy alone appeared to prevent vaginal and pelvic reMONTHS currence in the absence of gross cervical disease. FIG. 2. Five-year actuarial survival of favorable histologies versus Furthermore, most series describe using 4000 cGy of pelunfavorable histologies. vic radiation therapy with additional intracavitary radiation therapy to bring the dose to the pelvic lymphatics Sixteen patients underwent paraaortic lymph node sam- to a total of 5000 cGy [5,13]. Indeed, Cox et al. [6] noted pling to include those nodes from the bifurcation of the more lateral failures in those patients with Stage II-III aorta to the right renal vessel and none were found to endometrial cancer who received less than 5000 cGy to have positive paraaortic lymph nodes. Peritoneal wash- the lateral pelvic wall. Our treatment philosophy calls for ings obtained in 15 patients showed that 1 patient with 5000 cGy of pelvic radiation therapy in order to treat the clear cell carcinoma had positive cytology. Two patients pelvic lymphatics. This approach is obviously more ecowith papillary serous carcinoma had disseminated intraab- nomical and easier for the patient. However, it is our dominal malignancy at the time of exploration. Exami- policy in those patients with gross cervical involvement nation of the uterus after radiation therapy revealed 12 to use intracavitary irradiation along with external beam patients with less than one-third myometrial invasion, 6 radiation therapy. This is because these patients are likely patients with greater than one-third myometrial invasion, to have tumor spread into the parametrium [18], necesand 5 patients with residual tumor in the cervix. In 7 sitating a higher dose of radiation therapy to that region. patients, the preoperative radiation therapy had totally No patient with gross cervical involvement in our series eradicated their disease with no evidence of tumor re- failed locally. Our survival results of 69% are consistent with those maining in the uterus. Twelve of the thirty patients underwent preoperative found in the literature. Ahmad et al. [2] recently sumCT. None of these patients had a previously positive CT marized the modern literature for Stage II endometrial or ultrasound, and surgery confirmed these negative findings in all but one patient, who was found to have disTABLE 1 seminated intraabdominal disease at the time of surgery. Initial Site of FailureStage II Endometrial Carcinoma Three additional patients underwent a sonography to deMicroscopic versus tect extrauterine extension. Their negative findings were Site of gross disease confirmed at surgery and all of them are alive and free Patient of the cervix initial failure Histology of disease.
I
DISCUSSION The treatment protocol for clinical Stage II endometrial carcinoma at Thomas Jefferson University Hospital calls for 5000 cGy of preoperative external beam pelvic radiation therapy for patients without gross cervical involvement. External beam pelvic radiation therapy is used to treat the pelvic lymphatics, parametrium, and upper vagina, and to reduce tumor bulk in the uterus. The re-
1 2
Gross Microscopic
Adenocarcinoma Papillary serous
Neck Abdomen at time of surgery
3 4 5
Microscopic Microscopic Microscopic
Papillary serous Papillary Papillary serous
Abdomen Abdomen Abdomen at time of surgery
6 I 8
Microscopic Microscopic Microscopic
Small cell Papillary Clear cell
Pelvis Lung Abdomen
STAGE II ENDOMETRIAL
carcinoma treated with a combination of radiation therapy and surgery. They found an average survival of 74% with a range of 44 to 91.2%. Eight of our patients did have papillary serous clear cell or undifferentiated small cell carcinoma. The 5-year actuarial survival for these 8 patients was 38%. When these 8 patients were excluded, the 5-year actuarial survival for the remaining 22 patients with favorable histologies was 82%. The revised 1988 FIG0 staging system is a surgical staging system. The obvious advantage of surgical staging is a more accurate assessment of the extent of disease. Treatment may then be tailored according to the surgical findings. However, preoperative radiation therapy can be a useful method of sterilizing the parametrium and pelvic lymph nodes, thereby decreasing the need for a more extensive operative procedure such as a radical hysterectomy and pelvic lymph node dissection. Also, many theoretical advantages for preoperative radiation have been proposed such as decreased risk of tumor dissemination at surgery, increased ease of operability due to diminution of the uterus and tumor size, prevention of vaginal recurrences, and treatment of well-oxygenated tissues [4]. Note that of our 30 patients, 12 patients underwent a CT and 3 patients underwent pelvic sonography. Since all patients had a careful workup as described above, this patient selection may account for the finding of no positive periaortic lymph nodes at the time of hysterectomy. Furthermore, only 2 of our patients had disseminated intraabdominal malignancy at the time of exploration. Both had papillary serous histologies; 1 had not had a preoperative CT and the other reportedly had a negative CT. Those patients who were noted to have abnormalities on preoperative CT were treated in a manner consistent with their disease spread and were not included in this study. It is our impression that accurate preoperative staging of patients with endometrial carcinoma is mandatory to select those patients who would benefit from preoperative pelvic radiation therapy. However, we do not recommend preoperative radiation therapy in patients with papillary serous or clear cell carcinoma. It has been noted that patients with papillary serous and clear cell histologies have a lower survival rate [9,10,19,20]. Others have reported a high incidence of pelvic and paraaortic lymph nodes in patients with clinical Stage I or Stage II papillary serous carcinoma [21-231. Furthermore, various authors have noted abdominal failures in patients with clinical Stage I [24-261. Operative staging also reveals more frequent advanced disease than clinicians tend to assume. Christman et al. [19] recorded that 5 of 10 patients required upstaging, with 4 of 7 patients having positive peritoneal washings. Chambers et al. [27] also noted that 50% of patients with clinical Stage I papillary serous car-
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CARCINOMA
cinoma had pelvic or abdominal metastases at the time of surgery. Two of our patients with papillary serous carcinoma were found to have intraabdominal metastasesat the time of surgical exploration. As predicted by previous reports in the literature, four of our seven patients with papillary serous or clear cell histologies eventually had a relapse in the upper abdomen. This suggests that treatment of patients with clear cell or papillary serous histologies needs to be more comprehensive, with serious consideration of either chemotherapy or total abdominal radiation therapy after surgical exploration. In summary, preoperative pelvic radiation therapy with 5000 cGy of external beam irradiation for microscopic cervical involvement appears to provide excellent local control. Intracavitary treatment is reserved for patients with gross cervical disease. If preoperative pelvic radiation therapy is used, then all patients should be evaluated with a CT scan and/or possibly an MRI and ultrasound to select patients with extrauterine extension of disease who would require different treatment. Papillary serous and clear cell histologies should be identified. Tumors with these histologies tend to behave in an aggressive fashion, and limiting treatment to preoperative pelvic radiation therapy for these patients appears inadequate because of the strong likelihood of upper abdominal recurrence. REFERENCES 1. Cancer statistics 1990, Cu Cancer J. Clin. 41, 28 (1991). 2. Ahmad, K., Kim, Y. H., Deppe, G., Malone, J., Herskovic, A.,
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