- Email: [email protected]
Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group
Gynecologic Oncology 100 (2006) 349 – 354 www.elsevier.com/locate/ygyno
Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group Gregory Sutton a,*, Janice H. Axelrod b, Brian N. Bundy c, Tapan Roy d,1, Howard Homesley e,2, Roger B. Lee f,g, Paola A. Gehrig h, Richard Zaino i a
St. Vincent Hospitals and Health Services, Division of Gynecologic Oncology, 8301 Harcourt Road, Suite 202, Indianapolis, IN 46260, USA b Gynecologic Oncology, Western Pennsylvania Hospital, Pittsburgh, PA 15224, USA c Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA d Cancer Institute of Cape Girardeau (St. Louis University Health Science Center), Cape Girardeau, MO 63703, USA e Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA f University of Washington School of Medicine, Tacoma General Hospital, Tacoma, WA 98405, USA g Southwest Washington Gynecologic Oncology, Tacoma General Hospital, Tacoma, WA 98405, USA h Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7570, USA i Department of Pathology, Milton S. Hershey Medical Center of Pennsylvania State University, Hershey, PA 17033, USA Received 23 April 2005 Available online 5 October 2005
Abstract Objectives. To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy. Methods. After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day). Results. Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2). Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1). Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3). Conclusions. Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients. D 2005 Elsevier Inc. All rights reserved. Keywords: Whole abdominal irradiation; Papillary serous; Clear cell; Endometrium; Adjuvant
Introduction * Corresponding author. Fax: +1 317 415 338 6749. E-mail address: [email protected] (G. Sutton). 1 Affiliate of University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. 2 Currently: Gynecologic Oncology Network, Nashville, TN 37203, USA. 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.08.037
Endometrial cancer is the most common malignancy arising in the female reproductive tract and has the lowest death-to-case ratio of all gynecologic cancers. Nonetheless, an estimated 7310 women will die of advanced, recurrent, or metastatic endometrial cancer in 2005 in the United
350
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349 – 354
States [1]. Extirpative surgery followed in selected cases by pelvic radiation therapy is capable of controlling stages I and II disease in the majority of cases. Adjuvant therapy in stage III and localized stage IV disease has not been welldefined, however, and the most appropriate treatment for patients with aggressive papillary serous (PS) and clear cell (CC) cancers awaits delineation. Based upon early experience in treating ovarian cancer at the MD Anderson Cancer Center, Greer and Hamburger [2] suggested that whole abdominal radiotherapy (WAR) utilizing a moving strip technique could be beneficial in treating patients with endometrial cancer in whom tumors had spread to the abdominal cavity. They reported corrected and absolute 5-year survival rates of 80% and 63%, respectively, among 27 women with intraperitoneally disseminated endometrial cancer. None had residual disease greater than 2 cm in diameter, and all received whole abdominal moving-strip radiotherapy with a pelvic boost. Of the patients who developed recurrent disease, three had within-field failures alone and one experienced simultaneous abdominal and distant relapse. Toxicity was limited to early severe enteritis, two cases of ‘‘late’’ partial bowel obstruction, and a vaginal ulcer. Subsequent reports [3] of substantial small bowel toxicity among patients with ovarian cancer treated with the moving strip technique led to the abandonment of this procedure in favor of the whole abdominal ‘‘open field’’ procedure presently used. Hendrickson et al. [4] first demonstrated that PS cancers of the endometrium were associated with an extraordinary risk of relapse characterized by upper abdominal failures that were fatal in the vast majority of patients. They were the first investigators to suggest the use of adjuvant upper abdominal radiotherapy in this disease entity. The Gynecologic Oncology Group (GOG) initiated a study in 1986 to determine progression-free survival (PFS) and overall survival (OS) among patients with advanced endometrial cancer of all histologic types treated with whole abdominal irradiation (WAI) and pelvic (and, in the case of para-aortic metastases, para-aortic) boosts (GOG Protocol 94) [5]. Also included in that study were patients with stages I and II PS and CC cancer of the endometrium. This report summarizes PFS, OS, and sites of recurrence among patients with clinical stages I and II PS and CC carcinomas of the endometrium who received WAI. Methods and materials In this study, eligible patients were to have pathologically confirmed primary endometrial cancer with clinical stage I/II disease without vaginal involvement, parenchymal liver metastases, lung metastases, or spread to extraperitoneal sites, excluding retroperitoneal lymph nodes. It was required that PS or CC histology involves greater than 50% of tumor volume. Patients were ineligible if they had received pelvic or abdominal radiation or chemotherapy or were found to have inadequate hematologic (WBC <3000/Al, platelets <100,000 Al, or granulocytes <1500 cells/mm3), renal (creatinine >2.0 mg%), or hepatic function (bilirubin or AST >2 normal). Also ineligible were patients with GOG performance status of 4, and those with a previous or concomitant malignancy except non-melanoma skin cancer. Participating institutions obtained approval of the study from their Institutional Review Board prior to enrolling any patient on the study.
Patients provided written informed consent in accordance with institutional, state, and federal regulations, prior to the initiation of study therapy.
Pathology review Peritoneal washings were obtained from the pelvis and cytologically evaluated for malignant cells. The uterus was evaluated for size, location of tumor, depth of myometrial invasion, histologic type, and grade of tumor. Lymph nodes and adnexa were also evaluated for the presence and location of metastases. For each patient entered on study, all slides were reviewed centrally by the GOG Pathology Committee to document histological parameters and confirm eligibility.
Surgery Patients were required to undergo total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, and selective para-aortic and pelvic lymph node sampling. Omentectomy was not required; however, careful inspection of the omentum as well as removal of sections of the omentum with gross metastases was necessary. Patients who had received previous therapy with hormonal agents were permitted, as were those with recurrent endometrial cancer, if all other protocol requirements were met.
Radiation therapy Radiation was to be initiated within 8 weeks of surgery. Treatment was delivered by megavoltage equipment ranging from that of cobalt-60 to maximum 25 MeV photons. Minimal source-skin distance was 80 cm, and dose rates between 30 and 200 cGy per minute at midplane were required. Patients were treated with parallel opposed fields (open field technique) to the whole abdomen and pelvis. The abdomen was to be treated first to a dose of 3000 cGy in 20 fractions of 150 cGy each. A decrease in the daily fraction to 125 cGy was permitted if gastrointestinal symptoms or leukopenia precluded the use of the higher dose. After WAI, the pelvis was to be boosted to a midplane dose of 1980 cGy at 180 cGy per fraction for eleven treatments. The combined WAI and total pelvic irradiation required 6 to 7 weeks. The whole abdominal field extended from 1 cm above the top of the diaphragm to the bottom of the obturator foramina. The lateral border extended 1.0 to 1.5 cm beyond the lateral peritoneal margin. Full thickness PA kidney blocks were used throughout therapy. The left heart above the diaphragm and portions of the lower lateral pelvic fields and femoral heads were blocked. The pelvic field extended from the L5 – S1 interspace superiorly to the bottom of the obturator foramina inferiorly. The lateral margins were 1.5 cm lateral to the medial rim of the ilium. In patients with para-aortic metastases, the boost field was bounded by the L5 – S1 interspace inferiorly and the superior margin of the abdominal field superiorly, and the lateral extent was 8 cm wide. Interruptions in treatment exceeding 2 weeks disqualified patients from continuing protocol therapy. Radiation therapy quality control was supervised by the Radiologic Physics Center under the sponsorship of the American Association of Physicists in Medicine. An accuracy of T3% in source output and T5% in prescribed dose delivery was required.
Statistical considerations Evaluation parameters included PFS, OS, and frequency and severity of adverse effects. Progression-free survival was defined as the date from study entry to the date of reappearing or increasing disease or the date of last contact. Overall survival was defined as the observed length of life from study entry to death or to date of last contact. Life tables and medians were computed using the method of Kaplan and Meier. Differences in PFS or OS by patient characteristics were evaluated using the log-rank test. The Pearson Chi-square test was used to identify correlations between the two major categories of cell type and patient/disease characteristics. The Wilcoxon Rank Sum test was used for age at diagnosis and cell type categories.
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349 – 354
Results
Table 2 Adverse events (n = 33a)
Population
Toxicity
Two hundred seventy-four patients were enrolled in the original study between December 1986 and February 1994. Of these, 58 were ineligible for the following reasons: inadequate surgery (20), wrong cell type (22), disease more advanced than was permitted by protocol criteria (3), failed the criteria for advanced stage (4), second primary malignancy (8), and primary that was not endometrial (1). One patient who received no radiation therapy and another patient who had recurrent disease were inevaluable. Among 214 evaluable patients in GOG Protocol 94, 180 with stage III/IV disease have been reported separately [5]; 34 had stage I/II PS (n = 21) or CC (n = 13) cancer; this group is the subject of this report (Table 1). In the patients with stages I and II disease, the median age of those with PS cancer was 68 (range: 51 –83) years compared with a median age of 63 (range: 46 – 86) years for patients with CC cancers. The relative frequency of GOG performance status of 0 was 43% and 62% and for patients with PS and CC cancers, respectively. Two of 21 (10%) patients with PS cancers and four of 13 (31%) of those with clear cell cancers were nonwhite.
Hematologic Gastrointestinal Genitourinary Cardiovascular Pulmonary Hepatic Fever Cutaneous Lymphatics Other a
351
Grade 1
2
3
4
9 11 3 0 5 1 3 6 2 2
6 13 2 1 1 0 1 0 1 3
2 3 1 0 0 0 0 1 0 0
1 3 0 0 0 0 0 0 0 0
1 PS patient refused protocol therapy after registration.
radiotherapy only, and two received doses other than prescribed (one patient had 3319 cGy to the abdomen/1620 cGy to the pelvis, and another patient had 1200 cGy to the abdomen/ 3570 cGy to the pelvic region). Among the 30 patients who received the prescribed RT doses, 2 completed treatment in 35 days or less, 3 finished in 36 – 42 days, and 22 (73%) completed RT in 43 –49 days. For three patients, treatment duration was 50 days. Toxicity
Treatment Because no patient had para-aortic metastases, none received a boost to this area. One patient refused all radiotherapy and was not treated. One patient received pelvic Table 1 Patient characteristics (n = 34) Characteristic
No.
(%)
Cell type Clear cell Papillary serous
13 21
38.2 61.8
Age <50 51 – 60 61 – 70 71 – 80 >80
3 4 16 9 2
8.8 11.8 47.1 26.5 5.9
GOG performance status 0 1 2 3
17 16 1 0
50.0 47.1 2.9 0.0
Race White Black Other
28 5 1
82.4 14.7 2.9
Grade a 1 2 3
0 8 25
0.0 24.2 75.8
a
Adverse events are displayed in Table 2. Nausea and diarrhea were the most common acute gastrointestinal (GI) toxicities. The three patients experiencing grade 3 GI toxicity had bowel obstructions; all were successfully resolved by surgery. One of the three received only pelvic radiation. The other two received radiation therapy dose and timing per protocol, although one received a vaginal cuff boost (protocol violation). Three patients experienced grade 4 toxicity; one had nausea, vomiting, and diarrhea resulting in termination of her radiation therapy and hospitalization. After temporary relief with steroid therapy, she was released, only to be readmitted 3 weeks later; she expired (ruled treatment-related) the following day. Another patient had numerous food intolerances and, 6 months post-radiotherapy, had surgical resection to correct a bowel obstruction; 1 month later, she experienced a grade 3 bladder fistula. This patient was NED at 63 months. The third patient required a Cantor tube to resolve bowel obstruction and suffered with chronic anorexia due to severe radiation proctitis and colitis; this patient died of her disease at 32 months on study. The latter two patients completed their radiation therapy per protocol. Patterns of failure
Histologic grade unknown for one patient.
Of 21 patients with PS carcinoma, one refused radiotherapy after registration and died of disease at 35.2 months. A second patient received a vaginal boost, constituting a major protocol violation. She was alive without disease at 10 years and 5 months after therapy. Of the remaining patients, 7 died of disease from 9.6 to 32.0 months. Other deaths included one attributable to toxicity, one intercurrent death, one patient with a pelvic
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Table 3 Sites of relapse
and 9 months after treatment. PFS for the CC group was 53.9% at 5 years (the last failure occurred at 40.6 months).
Sites
No.
(%)
NED Recurred Vagina Pelvis Abdomen Abdomen + pelvis Retroperitoneal nodes Lung Unknown
22
64.7
Discussion
2 2 2 1 0 4 1
5.9 5.9 5.9 2.9 0.0 11.8 2.9
In 1982, Hendrickson et al. [4] first described uterine papillary serous carcinoma and demonstrated associated longterm survival far inferior to that of a control group of patients with poorly differentiated endometrial cancers of similar stage. Clear cell carcinoma of the endometrium is also felt to be a rare but aggressive variant by many authors [6,7] and for these reasons patients with stages I and II papillary serous and clear cell carcinomas of the endometrium were included in the present study of adjuvant whole abdominal radiotherapy.
recurrence at 49 months who died of complications of secondline systemic chemotherapy, and two deaths of unknown cause. Sites of recurrence for all patients are illustrated in Table 3. Among treated patients, sites of recurrence included lung alone (2), lung and vagina (1), abdomen and pelvis (1), vagina alone (1), and abdomen alone (2). Time to recurrence ranged from 2.8 to 28.9 months. Of 13 patients with CC carcinoma, one received pelvic radiotherapy only and died with intercurrent disease 7.8 months following therapy. An additional five patients died, three died of disease, one of intercurrent disease, and one of unknown cause. Sites of recurrence for disease-related deaths were lung (1), vagina (1), and unknown (1). Time to recurrence ranged from 6.1 to 21.7 months. Progression-free and overall survival Figs. 1 and 2 illustrate PFS and OS, respectively, for PS/CC patients. Eight of 21 (38%) patients with stage I/II PS cancer were alive without disease 59.6 months to 12.8 years after study entry. PFS for the PS group was 38.1% at 5 years (the last failure occurred at 49.1 months). Of 13 patients with CC carcinoma, 7 (54%) were alive without disease 59.9 to 8 years
Clear cell carcinoma Abeler et al. [8] identified 181 patients with clear cell carcinoma of the endometrium in the tumor registry of the Norwegian Radium Hospital between 1970 and 1982, representing just 3.1% of all endometrial cancers seen during that interval. Of these, 155 (86%) patients had disease clinically limited to the uterus and cervix. The mean age of subjects in this study was 66.2 years, compared with 62.1 years for patients with adenocarcinoma of the endometrioid type. The majority of patients in this study received surgery plus radiotherapy (80.1%), and 64.8% of those received pelvic or pelvic plus aortic fields; none were treated with WAR. Sixtynine (44.5%) of 155 patients experienced relapses, and actuarial crude survival for stage I and stage II cases was about 50%. Twenty-four of 75 patients of all stages had relapse in the pelvis only; 21 of 51 with extrapelvic failure had an upper abdominal component. These authors concluded that their ‘‘. . .findings argue against the use of adjuvant pelvic radiotherapy in patients with endometrial clear cell carcinoma.’’ They suggested that cisplatin-based chemotherapy might be the most efficient type of therapy.
Fig. 1. Progression-free survival by cell type.
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349 – 354
353
Fig. 2. Survival time by cell type.
In a later study, Malpica et al. [9] reported 21 patients with stage I/II clear cell carcinomas of the endometrium with an average age of 66 years. All but three of these patients were treated with abdominal hysterectomy and bilateral salpingooophorectomy with or without lymph node sampling. Twelve (57.1%) patients received preoperative and two (9.5%) postoperative radiotherapy; three patients with stage II disease were treated with radiotherapy without surgery because they were poor surgical candidates. A single patient received adjuvant combination chemotherapy and was alive at more than 5 years follow-up. Two patients with stage I disease developed abdominal failures at 3 and 10 months, and a third had a pelvic relapse at 7.5 years. Overall, one of eight patients with stage I disease and three of seven with resected stage II disease (26.7%) developed recurrences with a pelvic component despite radiotherapy; two additional patients with stage I cancer developed abdominal failures. These authors concluded that clear cell carcinomas of the endometrium were dissimilar to papillary serous cancers and behaved more like grade III endometrioid tumors. Although there was no specific recommendation for adjuvant therapy, they did suggest that long follow-up was important because of observed late failures. Taken together, these reports and the current study of patients with surgical stage I/II disease would suggest that patients with early stage clear cell carcinomas of the endometrium may have a better outlook than their counterparts with papillary serous cancer. Papillary serous cancers Nearly all early reports demonstrated poor survival in patients with stages I and II papillary serous carcinomas of the uterus, a finding confirmed by the present study which was initiated in 1986. Typical were the findings of Ward et al. [10] who, in 1990, published a 3-year survival rate of 47% in patients with localized disease. In a later report, these authors [11] showed that aggressive surgical staging, including upper abdominal biopsies and omentectomy, increased the propor-
tion of patients with true stage IV disease from 2% to 73%. They suggested, much as was the case in stage I ovarian cancer, that poor outcomes in early studies reflected understaging. In fact, occult omental involvement has been reported in 22– 25% [12,13] of patients with papillary serous cancers. Subsequent authors have demonstrated excellent survival in appropriately staged stages I and II papillary serous cancers of the uterus with either adjuvant pelvic radiotherapy [14] or even surgery alone [15]. In the present study, it should be recalled that ‘‘. . .careful inspection of the omentum was required, as well as removal of sections of the omentum with gross metastases.’’ Total or infracolic omentectomy was not required in the study. It is conceivable that some microscopic omental metastases could have been missed during staging, although microscopic metastases would potentially have been sensitive to whole abdominal radiotherapy. Although three failures in the present group of patients with papillary serous cancers occurred in the lung or had a pulmonary component, five arose within the treatment fields. However, in a study of radiation with or without chemotherapy in 29 patients with early stage papillary serous cancers of the uterus in which omentectomy was required and completed, 66% still had abdominal, vaginal, or pelvic failures, and 5-year survival was 52% [16]. In summary, both for papillary serous and clear cell histologies, there is a need in stages I and II cases to evaluate other adjuvant approaches, namely chemotherapy, chemoradiotherapy or sequential chemotherapy, and radiation therapy. Acknowledgments This study was supported by National Cancer Institute grants to member institutions of the Gynecologic Oncology Group (GOG). The following GOG institutions participated in this study: University of Alabama at Birmingham (CA 12484), Oregon Health Sciences University, Duke University Medical Center (CA 12534), Abington Memorial Hospital, University of
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Rochester Medical Center (CA 12482), Walter Reed Army Medical Center (CA 23501), Wayne State University (CA 12477), University of Southern California at Los Angeles (CA 37535), University of Mississippi Medical Center (CA 13633), Colorado Gynecologic Oncology Group, P.C. (CA 15975), University of California at Los Angeles (CA 13630), University of Miami School of Medicine (CA 37234), Milton S. Hershey Medical Center (CA 16386), Georgetown University Hospital (CA 16938), University of Cincinnati, University of North Carolina School of Medicine (CA 23073), University of Iowa Hospitals and Clinics (CA 19502), University of Texas Southwestern Medical Center at Dallas (CA 28160), Indiana University Medical Center (CA 21720), Wake Forest University School of Medicine (CA 21946), Albany Medical College (CA 27469), University of California Medical Center at Irvine (CA 23765), Tufts-New England Medical Center (CA 37569), RushPresbyterian-St. Luke’s Medical Center (CA 12485), Stanford University Medical Center (CA 35640), State University of New York Downstate Medical Center (CA 34477), Eastern Virginia Medical School (CA 40296), The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, State University of New York at Stony Brook, Eastern Pennsylvania Gynecology/Oncology Center, P.C., Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Women’s Cancer Center, and University of Oklahoma.
[3] [4]
[5]
[6] [7]
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[14]
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References [1] Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005;55:10 – 30. [2] Greer BE, Hamburger AD. Treatment of intraperitoneal metastatic
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adenocarcinoma of the endometrium by whole-abdominal moving strip technique and pelvic boost irradiation. Gynecol Oncol 1983;16:365 – 73. Dembo AJ. Abdominal radiotherapy in ovarian cancer. Cancer 1985; 55:2285 – 90. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6(2):93 – 108. Sutton G, Axelrod JH, Bundy BN, Roy T, Homesley HD, Malfetano JH, et al. Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2005;97(3):755 – 63. Kurman RJ, Scully RE. Clear cell carcinoma of the endometrium: an analysis of 21 cases. Cancer 1976;37:872 – 82. Christopherson WM, Alberhasky RC, Connelly PJ. Carcinoma of the endometrium I. A clinicopathologic study of clear-cell and secretory carcinoma. Cancer 1982;49:1511 – 23. Abelar VM, Vergote IB, Kjorstad KE, Trope CG. Clear cell carcinoma of the endometrium. Cancer 1996;78:1740 – 7. Malpica A, Tornos C, Burke TW, Silva EG. Low stage clear-cell carcinoma of the endometrium. Am J Surg Pathol 1995;19:769 – 74. Ward BG, Wright RC, Free K. Papillary carcinomas of the endometrium. Gynecol Oncol 1990;39:347 – 51. Tay EH, Ward BG. The treatment of uterine papillary serous carcinoma (UPSC): are we doing the right thing? Int J Gynecol Cancer 1999;9:463 – 9. Goff BA, Kato DT, Schmidt RA, Ek M, Ferry JA. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 1994;54:264 – 8. Geisler JP, Geisler HE, Melton ME, Wiemann MC. What staging surgery should be performed on patients with uterine papillary serous carcinoma? Gynecol Oncol 1999;74:465 – 7. Bristow RE, Asrari F, Trimble EL, Mantz FJ. Extended surgical staging for uterine papillary serous carcinoma: survival outcome of locoregional (stage I – III) disease. Gynecol Oncol 2001;81:279 – 86. Craighead PS, Sait K, Stuart GC, Arthur K, Nation J, Duggan M, et al. Management of aggressive histologic variants of endometrial cancer at the Tom Baker Cancer Center between 1984 and 1994. Gynecol Oncol 2000;77:248 – 53. Sood BM, Jones J, Gupta S, et al. Patterns of failure after multimodality treatment of uterine papillary serous carcinoma. Int J Radiat Oncol Biol Phys 2003;57:208 – 16.
Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group Gregory Sutton a,*, Janice H. Axelrod b, Brian N. Bundy c, Tapan Roy d,1, Howard Homesley e,2, Roger B. Lee f,g, Paola A. Gehrig h, Richard Zaino i a
St. Vincent Hospitals and Health Services, Division of Gynecologic Oncology, 8301 Harcourt Road, Suite 202, Indianapolis, IN 46260, USA b Gynecologic Oncology, Western Pennsylvania Hospital, Pittsburgh, PA 15224, USA c Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA d Cancer Institute of Cape Girardeau (St. Louis University Health Science Center), Cape Girardeau, MO 63703, USA e Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA f University of Washington School of Medicine, Tacoma General Hospital, Tacoma, WA 98405, USA g Southwest Washington Gynecologic Oncology, Tacoma General Hospital, Tacoma, WA 98405, USA h Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7570, USA i Department of Pathology, Milton S. Hershey Medical Center of Pennsylvania State University, Hershey, PA 17033, USA Received 23 April 2005 Available online 5 October 2005
Abstract Objectives. To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy. Methods. After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day). Results. Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2). Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1). Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3). Conclusions. Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients. D 2005 Elsevier Inc. All rights reserved. Keywords: Whole abdominal irradiation; Papillary serous; Clear cell; Endometrium; Adjuvant
Introduction * Corresponding author. Fax: +1 317 415 338 6749. E-mail address: [email protected] (G. Sutton). 1 Affiliate of University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. 2 Currently: Gynecologic Oncology Network, Nashville, TN 37203, USA. 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.08.037
Endometrial cancer is the most common malignancy arising in the female reproductive tract and has the lowest death-to-case ratio of all gynecologic cancers. Nonetheless, an estimated 7310 women will die of advanced, recurrent, or metastatic endometrial cancer in 2005 in the United
350
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349 – 354
States [1]. Extirpative surgery followed in selected cases by pelvic radiation therapy is capable of controlling stages I and II disease in the majority of cases. Adjuvant therapy in stage III and localized stage IV disease has not been welldefined, however, and the most appropriate treatment for patients with aggressive papillary serous (PS) and clear cell (CC) cancers awaits delineation. Based upon early experience in treating ovarian cancer at the MD Anderson Cancer Center, Greer and Hamburger [2] suggested that whole abdominal radiotherapy (WAR) utilizing a moving strip technique could be beneficial in treating patients with endometrial cancer in whom tumors had spread to the abdominal cavity. They reported corrected and absolute 5-year survival rates of 80% and 63%, respectively, among 27 women with intraperitoneally disseminated endometrial cancer. None had residual disease greater than 2 cm in diameter, and all received whole abdominal moving-strip radiotherapy with a pelvic boost. Of the patients who developed recurrent disease, three had within-field failures alone and one experienced simultaneous abdominal and distant relapse. Toxicity was limited to early severe enteritis, two cases of ‘‘late’’ partial bowel obstruction, and a vaginal ulcer. Subsequent reports [3] of substantial small bowel toxicity among patients with ovarian cancer treated with the moving strip technique led to the abandonment of this procedure in favor of the whole abdominal ‘‘open field’’ procedure presently used. Hendrickson et al. [4] first demonstrated that PS cancers of the endometrium were associated with an extraordinary risk of relapse characterized by upper abdominal failures that were fatal in the vast majority of patients. They were the first investigators to suggest the use of adjuvant upper abdominal radiotherapy in this disease entity. The Gynecologic Oncology Group (GOG) initiated a study in 1986 to determine progression-free survival (PFS) and overall survival (OS) among patients with advanced endometrial cancer of all histologic types treated with whole abdominal irradiation (WAI) and pelvic (and, in the case of para-aortic metastases, para-aortic) boosts (GOG Protocol 94) [5]. Also included in that study were patients with stages I and II PS and CC cancer of the endometrium. This report summarizes PFS, OS, and sites of recurrence among patients with clinical stages I and II PS and CC carcinomas of the endometrium who received WAI. Methods and materials In this study, eligible patients were to have pathologically confirmed primary endometrial cancer with clinical stage I/II disease without vaginal involvement, parenchymal liver metastases, lung metastases, or spread to extraperitoneal sites, excluding retroperitoneal lymph nodes. It was required that PS or CC histology involves greater than 50% of tumor volume. Patients were ineligible if they had received pelvic or abdominal radiation or chemotherapy or were found to have inadequate hematologic (WBC <3000/Al, platelets <100,000 Al, or granulocytes <1500 cells/mm3), renal (creatinine >2.0 mg%), or hepatic function (bilirubin or AST >2 normal). Also ineligible were patients with GOG performance status of 4, and those with a previous or concomitant malignancy except non-melanoma skin cancer. Participating institutions obtained approval of the study from their Institutional Review Board prior to enrolling any patient on the study.
Patients provided written informed consent in accordance with institutional, state, and federal regulations, prior to the initiation of study therapy.
Pathology review Peritoneal washings were obtained from the pelvis and cytologically evaluated for malignant cells. The uterus was evaluated for size, location of tumor, depth of myometrial invasion, histologic type, and grade of tumor. Lymph nodes and adnexa were also evaluated for the presence and location of metastases. For each patient entered on study, all slides were reviewed centrally by the GOG Pathology Committee to document histological parameters and confirm eligibility.
Surgery Patients were required to undergo total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, and selective para-aortic and pelvic lymph node sampling. Omentectomy was not required; however, careful inspection of the omentum as well as removal of sections of the omentum with gross metastases was necessary. Patients who had received previous therapy with hormonal agents were permitted, as were those with recurrent endometrial cancer, if all other protocol requirements were met.
Radiation therapy Radiation was to be initiated within 8 weeks of surgery. Treatment was delivered by megavoltage equipment ranging from that of cobalt-60 to maximum 25 MeV photons. Minimal source-skin distance was 80 cm, and dose rates between 30 and 200 cGy per minute at midplane were required. Patients were treated with parallel opposed fields (open field technique) to the whole abdomen and pelvis. The abdomen was to be treated first to a dose of 3000 cGy in 20 fractions of 150 cGy each. A decrease in the daily fraction to 125 cGy was permitted if gastrointestinal symptoms or leukopenia precluded the use of the higher dose. After WAI, the pelvis was to be boosted to a midplane dose of 1980 cGy at 180 cGy per fraction for eleven treatments. The combined WAI and total pelvic irradiation required 6 to 7 weeks. The whole abdominal field extended from 1 cm above the top of the diaphragm to the bottom of the obturator foramina. The lateral border extended 1.0 to 1.5 cm beyond the lateral peritoneal margin. Full thickness PA kidney blocks were used throughout therapy. The left heart above the diaphragm and portions of the lower lateral pelvic fields and femoral heads were blocked. The pelvic field extended from the L5 – S1 interspace superiorly to the bottom of the obturator foramina inferiorly. The lateral margins were 1.5 cm lateral to the medial rim of the ilium. In patients with para-aortic metastases, the boost field was bounded by the L5 – S1 interspace inferiorly and the superior margin of the abdominal field superiorly, and the lateral extent was 8 cm wide. Interruptions in treatment exceeding 2 weeks disqualified patients from continuing protocol therapy. Radiation therapy quality control was supervised by the Radiologic Physics Center under the sponsorship of the American Association of Physicists in Medicine. An accuracy of T3% in source output and T5% in prescribed dose delivery was required.
Statistical considerations Evaluation parameters included PFS, OS, and frequency and severity of adverse effects. Progression-free survival was defined as the date from study entry to the date of reappearing or increasing disease or the date of last contact. Overall survival was defined as the observed length of life from study entry to death or to date of last contact. Life tables and medians were computed using the method of Kaplan and Meier. Differences in PFS or OS by patient characteristics were evaluated using the log-rank test. The Pearson Chi-square test was used to identify correlations between the two major categories of cell type and patient/disease characteristics. The Wilcoxon Rank Sum test was used for age at diagnosis and cell type categories.
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Results
Table 2 Adverse events (n = 33a)
Population
Toxicity
Two hundred seventy-four patients were enrolled in the original study between December 1986 and February 1994. Of these, 58 were ineligible for the following reasons: inadequate surgery (20), wrong cell type (22), disease more advanced than was permitted by protocol criteria (3), failed the criteria for advanced stage (4), second primary malignancy (8), and primary that was not endometrial (1). One patient who received no radiation therapy and another patient who had recurrent disease were inevaluable. Among 214 evaluable patients in GOG Protocol 94, 180 with stage III/IV disease have been reported separately [5]; 34 had stage I/II PS (n = 21) or CC (n = 13) cancer; this group is the subject of this report (Table 1). In the patients with stages I and II disease, the median age of those with PS cancer was 68 (range: 51 –83) years compared with a median age of 63 (range: 46 – 86) years for patients with CC cancers. The relative frequency of GOG performance status of 0 was 43% and 62% and for patients with PS and CC cancers, respectively. Two of 21 (10%) patients with PS cancers and four of 13 (31%) of those with clear cell cancers were nonwhite.
Hematologic Gastrointestinal Genitourinary Cardiovascular Pulmonary Hepatic Fever Cutaneous Lymphatics Other a
351
Grade 1
2
3
4
9 11 3 0 5 1 3 6 2 2
6 13 2 1 1 0 1 0 1 3
2 3 1 0 0 0 0 1 0 0
1 3 0 0 0 0 0 0 0 0
1 PS patient refused protocol therapy after registration.
radiotherapy only, and two received doses other than prescribed (one patient had 3319 cGy to the abdomen/1620 cGy to the pelvis, and another patient had 1200 cGy to the abdomen/ 3570 cGy to the pelvic region). Among the 30 patients who received the prescribed RT doses, 2 completed treatment in 35 days or less, 3 finished in 36 – 42 days, and 22 (73%) completed RT in 43 –49 days. For three patients, treatment duration was 50 days. Toxicity
Treatment Because no patient had para-aortic metastases, none received a boost to this area. One patient refused all radiotherapy and was not treated. One patient received pelvic Table 1 Patient characteristics (n = 34) Characteristic
No.
(%)
Cell type Clear cell Papillary serous
13 21
38.2 61.8
Age <50 51 – 60 61 – 70 71 – 80 >80
3 4 16 9 2
8.8 11.8 47.1 26.5 5.9
GOG performance status 0 1 2 3
17 16 1 0
50.0 47.1 2.9 0.0
Race White Black Other
28 5 1
82.4 14.7 2.9
Grade a 1 2 3
0 8 25
0.0 24.2 75.8
a
Adverse events are displayed in Table 2. Nausea and diarrhea were the most common acute gastrointestinal (GI) toxicities. The three patients experiencing grade 3 GI toxicity had bowel obstructions; all were successfully resolved by surgery. One of the three received only pelvic radiation. The other two received radiation therapy dose and timing per protocol, although one received a vaginal cuff boost (protocol violation). Three patients experienced grade 4 toxicity; one had nausea, vomiting, and diarrhea resulting in termination of her radiation therapy and hospitalization. After temporary relief with steroid therapy, she was released, only to be readmitted 3 weeks later; she expired (ruled treatment-related) the following day. Another patient had numerous food intolerances and, 6 months post-radiotherapy, had surgical resection to correct a bowel obstruction; 1 month later, she experienced a grade 3 bladder fistula. This patient was NED at 63 months. The third patient required a Cantor tube to resolve bowel obstruction and suffered with chronic anorexia due to severe radiation proctitis and colitis; this patient died of her disease at 32 months on study. The latter two patients completed their radiation therapy per protocol. Patterns of failure
Histologic grade unknown for one patient.
Of 21 patients with PS carcinoma, one refused radiotherapy after registration and died of disease at 35.2 months. A second patient received a vaginal boost, constituting a major protocol violation. She was alive without disease at 10 years and 5 months after therapy. Of the remaining patients, 7 died of disease from 9.6 to 32.0 months. Other deaths included one attributable to toxicity, one intercurrent death, one patient with a pelvic
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Table 3 Sites of relapse
and 9 months after treatment. PFS for the CC group was 53.9% at 5 years (the last failure occurred at 40.6 months).
Sites
No.
(%)
NED Recurred Vagina Pelvis Abdomen Abdomen + pelvis Retroperitoneal nodes Lung Unknown
22
64.7
Discussion
2 2 2 1 0 4 1
5.9 5.9 5.9 2.9 0.0 11.8 2.9
In 1982, Hendrickson et al. [4] first described uterine papillary serous carcinoma and demonstrated associated longterm survival far inferior to that of a control group of patients with poorly differentiated endometrial cancers of similar stage. Clear cell carcinoma of the endometrium is also felt to be a rare but aggressive variant by many authors [6,7] and for these reasons patients with stages I and II papillary serous and clear cell carcinomas of the endometrium were included in the present study of adjuvant whole abdominal radiotherapy.
recurrence at 49 months who died of complications of secondline systemic chemotherapy, and two deaths of unknown cause. Sites of recurrence for all patients are illustrated in Table 3. Among treated patients, sites of recurrence included lung alone (2), lung and vagina (1), abdomen and pelvis (1), vagina alone (1), and abdomen alone (2). Time to recurrence ranged from 2.8 to 28.9 months. Of 13 patients with CC carcinoma, one received pelvic radiotherapy only and died with intercurrent disease 7.8 months following therapy. An additional five patients died, three died of disease, one of intercurrent disease, and one of unknown cause. Sites of recurrence for disease-related deaths were lung (1), vagina (1), and unknown (1). Time to recurrence ranged from 6.1 to 21.7 months. Progression-free and overall survival Figs. 1 and 2 illustrate PFS and OS, respectively, for PS/CC patients. Eight of 21 (38%) patients with stage I/II PS cancer were alive without disease 59.6 months to 12.8 years after study entry. PFS for the PS group was 38.1% at 5 years (the last failure occurred at 49.1 months). Of 13 patients with CC carcinoma, 7 (54%) were alive without disease 59.9 to 8 years
Clear cell carcinoma Abeler et al. [8] identified 181 patients with clear cell carcinoma of the endometrium in the tumor registry of the Norwegian Radium Hospital between 1970 and 1982, representing just 3.1% of all endometrial cancers seen during that interval. Of these, 155 (86%) patients had disease clinically limited to the uterus and cervix. The mean age of subjects in this study was 66.2 years, compared with 62.1 years for patients with adenocarcinoma of the endometrioid type. The majority of patients in this study received surgery plus radiotherapy (80.1%), and 64.8% of those received pelvic or pelvic plus aortic fields; none were treated with WAR. Sixtynine (44.5%) of 155 patients experienced relapses, and actuarial crude survival for stage I and stage II cases was about 50%. Twenty-four of 75 patients of all stages had relapse in the pelvis only; 21 of 51 with extrapelvic failure had an upper abdominal component. These authors concluded that their ‘‘. . .findings argue against the use of adjuvant pelvic radiotherapy in patients with endometrial clear cell carcinoma.’’ They suggested that cisplatin-based chemotherapy might be the most efficient type of therapy.
Fig. 1. Progression-free survival by cell type.
G. Sutton et al. / Gynecologic Oncology 100 (2006) 349 – 354
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Fig. 2. Survival time by cell type.
In a later study, Malpica et al. [9] reported 21 patients with stage I/II clear cell carcinomas of the endometrium with an average age of 66 years. All but three of these patients were treated with abdominal hysterectomy and bilateral salpingooophorectomy with or without lymph node sampling. Twelve (57.1%) patients received preoperative and two (9.5%) postoperative radiotherapy; three patients with stage II disease were treated with radiotherapy without surgery because they were poor surgical candidates. A single patient received adjuvant combination chemotherapy and was alive at more than 5 years follow-up. Two patients with stage I disease developed abdominal failures at 3 and 10 months, and a third had a pelvic relapse at 7.5 years. Overall, one of eight patients with stage I disease and three of seven with resected stage II disease (26.7%) developed recurrences with a pelvic component despite radiotherapy; two additional patients with stage I cancer developed abdominal failures. These authors concluded that clear cell carcinomas of the endometrium were dissimilar to papillary serous cancers and behaved more like grade III endometrioid tumors. Although there was no specific recommendation for adjuvant therapy, they did suggest that long follow-up was important because of observed late failures. Taken together, these reports and the current study of patients with surgical stage I/II disease would suggest that patients with early stage clear cell carcinomas of the endometrium may have a better outlook than their counterparts with papillary serous cancer. Papillary serous cancers Nearly all early reports demonstrated poor survival in patients with stages I and II papillary serous carcinomas of the uterus, a finding confirmed by the present study which was initiated in 1986. Typical were the findings of Ward et al. [10] who, in 1990, published a 3-year survival rate of 47% in patients with localized disease. In a later report, these authors [11] showed that aggressive surgical staging, including upper abdominal biopsies and omentectomy, increased the propor-
tion of patients with true stage IV disease from 2% to 73%. They suggested, much as was the case in stage I ovarian cancer, that poor outcomes in early studies reflected understaging. In fact, occult omental involvement has been reported in 22– 25% [12,13] of patients with papillary serous cancers. Subsequent authors have demonstrated excellent survival in appropriately staged stages I and II papillary serous cancers of the uterus with either adjuvant pelvic radiotherapy [14] or even surgery alone [15]. In the present study, it should be recalled that ‘‘. . .careful inspection of the omentum was required, as well as removal of sections of the omentum with gross metastases.’’ Total or infracolic omentectomy was not required in the study. It is conceivable that some microscopic omental metastases could have been missed during staging, although microscopic metastases would potentially have been sensitive to whole abdominal radiotherapy. Although three failures in the present group of patients with papillary serous cancers occurred in the lung or had a pulmonary component, five arose within the treatment fields. However, in a study of radiation with or without chemotherapy in 29 patients with early stage papillary serous cancers of the uterus in which omentectomy was required and completed, 66% still had abdominal, vaginal, or pelvic failures, and 5-year survival was 52% [16]. In summary, both for papillary serous and clear cell histologies, there is a need in stages I and II cases to evaluate other adjuvant approaches, namely chemotherapy, chemoradiotherapy or sequential chemotherapy, and radiation therapy. Acknowledgments This study was supported by National Cancer Institute grants to member institutions of the Gynecologic Oncology Group (GOG). The following GOG institutions participated in this study: University of Alabama at Birmingham (CA 12484), Oregon Health Sciences University, Duke University Medical Center (CA 12534), Abington Memorial Hospital, University of
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Rochester Medical Center (CA 12482), Walter Reed Army Medical Center (CA 23501), Wayne State University (CA 12477), University of Southern California at Los Angeles (CA 37535), University of Mississippi Medical Center (CA 13633), Colorado Gynecologic Oncology Group, P.C. (CA 15975), University of California at Los Angeles (CA 13630), University of Miami School of Medicine (CA 37234), Milton S. Hershey Medical Center (CA 16386), Georgetown University Hospital (CA 16938), University of Cincinnati, University of North Carolina School of Medicine (CA 23073), University of Iowa Hospitals and Clinics (CA 19502), University of Texas Southwestern Medical Center at Dallas (CA 28160), Indiana University Medical Center (CA 21720), Wake Forest University School of Medicine (CA 21946), Albany Medical College (CA 27469), University of California Medical Center at Irvine (CA 23765), Tufts-New England Medical Center (CA 37569), RushPresbyterian-St. Luke’s Medical Center (CA 12485), Stanford University Medical Center (CA 35640), State University of New York Downstate Medical Center (CA 34477), Eastern Virginia Medical School (CA 40296), The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, State University of New York at Stony Brook, Eastern Pennsylvania Gynecology/Oncology Center, P.C., Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Women’s Cancer Center, and University of Oklahoma.
[3] [4]
[5]
[6] [7]
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