SEER Data, Corpus Uteri Cancer: Treatment Trends versus Survival for FIGO Stage II, 1988–1994

Gynecologic Oncology 74, 350 –355 (1999) Article ID gyno.1999.5501, available online at http://www.idealibrary.com on

SEER Data, Corpus Uteri Cancer: Treatment Trends versus Survival for FIGO Stage II, 1988 –1994 Terri L. Cornelison, M.D.,* ,† Edward L. Trimble, M.D., M.P.H.,† ,‡ and Carol L. Kosary, M.A.§ *Division of Cancer Prevention ‡Division of Cancer Treatment and Diagnosis and §Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland 20892; and †Division of Gynecologic Oncology Department of Gynecology and Obstetrics, The Johns Hopkins Hospital and Medical Institutes, Baltimore, Maryland 21287 Received February 1, 1999

by radiation. The good surgical risk patient with disease confined to the endometrial cavity was treated with intrauterine radium followed by removal of the uterus, fallopian tubes, ovaries, and vaginal apex. Studies showed that 50% of postradiated hysterectomy specimens contained pathologic evidence of persistent carcinoma, and local recurrent disease was common. A developing belief that recurrences found in the vaginal canal after surgery were due to retrograde lymphatic dissemination rather than implantation at the time of surgery, coupled by a resurgence of radical dissection of pelvic lymphatics for cervical cancer in the 1950s, prompted adaptation of the Wertheim-type hysterectomy and pelvic node dissection for treatment of corpus uteri cancer [5, 10 –12]. But routine use of the radical hysterectomy was not feasible [5]. It had limited applicability in the elderly corpus cancer population and was accompanied by high postoperative complication incidence. The combination of radiation therapy followed by conservative hysterectomy found greater usefulness and was deemed the treatment of choice. Radical surgery was used in patients unable to undergo optimal radiotherapy. However, preoperative pelvic radiotherapy can change the histologic appearance and apparent extent of disease found at operation, and clinical assessment of cervical involvement can be inaccurate, predisposing some patients to inadequate surgical therapy or unnecessary radiotherapy [4, 7, 13–15]. As attention became directed to tailoring therapy to areas of documented anatomic involvement, radical hysterectomy gained favor as an alternative to preoperative radiation to (1) permit initial operation on patients with suspected cervical involvement, (2) allow accurate staging of disease, and (3) offer wide excision of the primary tumor and regional nodes [1, 4, 5, 14]. By 1998, 64.6% (31/48) of gynecologic oncology centers surveyed in North America used radical type II or III hysterectomy for cervical involvement or to avoid radiotherapy in corpus cancer [2, 16]. We evaluated the Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 1994 to determine

Objective. 1998 Surveillance, Epidemiology, and End Results (SEER) data estimate an 83.1% 5-year survival rate for corpus uteri adenocarcinoma FIGO stage II. The SEER data were evaluated to determine whether primary treatment differences using simple hysterectomy or radical hysterectomy, with or without radiation, altered disease survival. Materials and Methods. SEER incidence data for FIGO II uterine corpus cancer of adenocarcinoma histology from 1988 to 1994 were stratified by hysterectomy type (simple versus radical) and whether radiation was given. Survival rates were calculated using a relative survival method and are expressed as percentages. Statistical analysis was done using a Z test. Results. The 5-year cumulative survival rate for patients with stage II uterine corpus adenocarcinoma who received surgery alone as primary therapy was 84.36% with simple hysterectomy and 92.96% with radical hysterectomy (P < 0.05). Survival for patients who received combination radiation and surgery as primary therapy was 82.77% with simple hysterectomy and 88.02% with radical hysterectomy (P < 0.05). Pelvic and para-aortic nodes were negative. There was no significant survival difference for radiation versus no radiation in either surgical group. Conclusion. Radical hysterectomy is associated with better survival when compared to simple hysterectomy for FIGO II corpus uteri adenocarcinoma. Key Words: SEER; corpus uteri cancer; adenocarcinoma; FIGO II; radical hysterectomy; survival.

INTRODUCTION The management of corpus uteri cancer with cervical involvement remains a controversy [1]. Although there is general agreement about the usefulness of staging and primary surgery in corpus cancer, there exist significant differences in therapeutic approach to International Federation of Gynecology and Obstetrics (FIGO) stage II disease [2, 3]. Treatment options range from extrafascial hysterectomy to radical hysterectomy, with or without radiation [1, 4 –9]. Historically, corpus cancer was treated in two ways [10]. The elderly, poor surgical risk patient was treated definitively

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whether primary treatment differences using simple hysterectomy or radical hysterectomy, with or without radiation, altered disease survival in patients with FIGO stage II corpus uteri cancer.

TABLE 1 FIGO II Corpus Uteri Cancer, 5-Year Survival Simple hysterectomy

N

5-Year cumulative survival

N

5-Year cumulative survival

190 365

84.36% 82.77%

108 269

92.96% 88.02%

MATERIALS AND METHODS Case Selection Cases of cancer of the corpus uteri diagnosed between 1988 and 1994 and registered in the SEER program of the National Cancer Institute were selected. SEER is a population-based program with a data base containing information on 1,089,344 females diagnosed with cancer from nine registries including Connecticut, Iowa, New Mexico, Utah, Hawaii, and metropolitan areas of Detroit, San Francisco–Oakland, Seattle–Puget Sound, and Atlanta [17]. The SEER program catchement represents an estimated 10% of the U.S. population. Cases are predominantly ascertained from hospital records. Changes in the delivery of medical care in recent years, however, have led to an increased reliance on outpatient identification. Further, only those cases which were microscopically confirmed adenocarcinoma in the surgical specimen, and were primary or first occurrence, were included in the analysis. Cases of uterine sarcoma were excluded. Also excluded were individuals diagnosed at autopsy, individuals for whom the only diagnosis was a death certificate, and individuals with inadequate follow-up information. FIGO Staging Extensive disease information relating to size of primary tumor, extension of disease, and lymph node status was collected from medical, surgical, and pathologic records for each case, in accordance with SEER 1988 extent of disease codes and coding guidelines [18]. The size of the primary tumor was specified as microscopic, #2 mm up to 9901 mm in 1-mm increments, or size unknown. Extent of disease was specified as in situ; confined to endometrium; extension to myometrium inner half, myometrium outer half, serosa, cervix uteri (including endocervix invaded), broad ligament, round ligament, uterosacral ligament, pelvic wall, ovary, fallopian tube, rectal wall, bladder wall, vagina, rectal mucosa, or bladder mucosa; extension beyond true pelvis; distant metastasis; or extent unknown. Lymph node status was specified as no lymph node involvement; positive regional lymph nodes: parametrial, paracervical, common iliac, internal iliac, external iliac, obturator, sacral, or aortic; positive distant lymph nodes: superficial inguinal or deep inguinal; or lymph node status unknown. FIGO staging for corpus uteri cancer according to the 1988 guidelines [3] was assigned by computer algorithm using this information [19]. The SEER 1988 extent of disease codes and coding guidelines, uniformly used for data abstraction from 1988 forward, do not subcategorize cervical involvement of

No radiation Radiation

Radical hysterectomy

Note. SEER incidence data for FIGO II uterine corpus cancer, 1988 –1994, stratified by hysterectomy type and whether radiation was given.

corpus uteri cancer into endocervical glandular involvement or cervical stromal invasion, therefore FIGO stage II cases cannot be further staged to IIA or IIB. Treatment Information First-course treatment information was abstracted from the medical records, surgical records, and primary treatment plan for each case [20]. Statistical Analysis Survival was calculated as relative survival rate [21]. Relative survival merely comprises a ratio between the survival observed for a given cohort of cases and the survival which would have been expected for this cohort given its lifetable expectations. Relative survival serves to account for those causes of death in the cohort other than the diagnosed cancer and will also compensate for any possible differences in the age distribution between several compared cohorts. Differences between groups were determined through the use of a Z test. Corrections were made to account for the multiple comparisons performed. RESULTS Simple versus Radical Hysterectomy The data were first analyzed to determine whether the type of hysterectomy performed, simple versus radical, altered disease survival. The 5-year cumulative survival rate for patients with stage II uterine corpus adenocarcinoma who received surgery alone as their primary therapy was 84.36% with simple hysterectomy and 92.96% with radical hysterectomy (P , 0.05) (Table 1). Survival for patients who received combination radiation and surgery as their primary therapy was 82.77% when simple hysterectomy was performed and 88.02% when a radical hysterectomy was performed (P , 0.05). All patients had either pelvic and/or para-aortic nodal dissection or lymphadenectomies and all nodes were negative, or pelvic and/or para-aortic nodal palpation or radiographic assessment with no

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survival difference for radiation versus no radiation in either surgical group. Tumor Histology and Grade

FIG. 1. Percentage of 5-year relative survival of patients from time of treatment according to type of hysterectomy received and whether radiation was given in cases diagnosed from 1988 to 1994.

enlarged nodes. The radical hysterectomies were type II or type III or modified type III. Five-year relative survival curves for these patients are shown in Fig. 1. No Radiation versus Radiation The data were also analyzed to determine whether use of radiation altered disease survival. There was no significant

Tumor histology data were collected for each patient and the distribution is shown in Table 2 for patients treated with simple hysterectomy with no radiation, simple hysterectomy with radiation, radical hysterectomy with no radiation, and radical hysterectomy with radiation as their primary therapy. Endometrioid adenocarcinoma was diagnosed in 16.7% of patients treated with radical hysterectomy and no radiation, compared to 7.4% of patients treated with simple hysterectomy and no radiation (P , 0.01), and was diagnosed in 17.8% of patients treated with combination radical hysterectomy and radiation, compared to 9.3% of patients treated with combination simple hysterectomy and radiation (P , 0.01). Clear cell and papillary serous cystadenocarcinoma occurred at a slightly greater rate in radical than in simple hysterectomy specimens, but this finding was not statistically significant. There was no difference in tumor histology distribution seen in radiated versus nonradiated patients in either surgical group. Tumor grade is shown in Table 3 for patients treated with simple hysterectomy without radiation, simple hysterectomy with radiation, radical hysterectomy without radiation, and radical hysterectomy with radiation. Of patients with poorly or undifferentiated tumors, 50.2% (129/257) were treated with radical hysterectomy, compared to 40.7% (161/396) of patients with moderately differentiated tumors (P , 0.05) and 31.7% (76/240) of patients with well-differentiated tumors (P , 0.05). Likewise, patients with moderately differentiated disease were treated more frequently by radical hysterectomy than were patients with well-differentiated disease (P , 0.05).

TABLE 2 Tumor Histology Simple hysterectomy No radiation

Radical hysterectomy Radiation

No radiation

Radiation

Adenocarcinoma

N

%

N

%

N

%

N

%

Adeno, no other specification Papillary adeno Clear cell Adeno with squam Mucinous Adenosquamous Endometrioid Papillary serous cystadeno

136 8 5 3 7 11 14 6

71.6 4.2 2.6 1.6 3.7 5.8 7.4 3.1

269 8 7 8 4 23 34 12

73.7 2.2 1.9 2.2 1.1 6.3 9.3 3.3

63 5 4 4 0 6 18 8

58.3 4.6 3.7 3.7 0.0 5.6 16.7 7.4

169 12 7 7 1 14 48 11

62.8 4.5 2.6 2.6 0.4 5.2 17.8 4.1

Total

190

100.0

365

100.0

108

100.0

269

100.0

Note. Tumor histology distribution in each primary treatment group: simple hysterectomy with no radiation, simple hysterectomy with radiation, radical hysterectomy with no radiation, and radical hysterectomy with radiation.

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TREATMENT TRENDS IN FIGO II CORPUS CANCER

TABLE 3 Tumor Grade Simple hysterectomy No radiation

Radical hysterectomy

Radiation

No radiation

Radiation

Grade

N

%

N

%

N

%

N

%

Well differentiated (N 5 240) Moderately differentiated (N 5 396) Poorly differentiated (N 5 225) Undifferentiated (N 5 32) Unknown (N 5 39)

70 83 31 4 2

36.8 43.7 16.3 2.1 1.1

94 152 85 8 26

25.8 41.6 23.3 2.2 7.1

23 55 23 7 0

21.3 50.9 21.3 6.5 0.0

53 106 86 13 11

19.7 39.4 32.0 4.8 4.1

190

100.0

365

100.0

108

100.0

269

100.0

Total

Note. Tumor grade distribution in each primary treatment group: simple hysterectomy with no radiation, simple hysterectomy with radiation, radical hysterectomy with no radiation, and radical hysterectomy with radiation.

Patients with poorly or undifferentiated tumors were significantly more likely (P , 0.05) to receive radiation as part of their treatment (74.7% (192/257)) than were patients with either moderately differentiated (65.2% (258/396)) or welldifferentiated disease (61.3% (147/240)). Patients with moderately differentiated tumors did not receive radiation more frequently than patients with well-differentiated disease. Concurrent Therapies In general, patients did not receive chemotherapy or hormones as part of their primary therapy. Two patients treated with simple hysterectomy alone, seven patients treated with simple hysterectomy and radiation, four patients who received radical hysterectomy alone, and five patients who received radical hysterectomy and radiation received first-line chemotherapy. Three patients treated with simple hysterectomy alone, five patients treated with simple hysterectomy and radiation, three patients who received radical hysterectomy alone, and seven patients who received radical hysterectomy and radiation were treated with hormonal therapy. DISCUSSION The optimal management of patients with FIGO stage II corpus uteri adenocarcinoma remains to be established, with treatment plans composed of extrafascial hysterectomy or radical hysterectomy, with or without radiation [1, 4 –9, 22]. While no prospective randomized trial compares all regimens, retrospective reviews have indicated that each treatment plan may be a reasonable option for specific patient subsets. Homesley et al. showed that in patients with microscopic cervical tumor, radical hysterectomy alone did not improve survival rate compared to simple hysterectomy alone or preoperative radium plus either simple or radical hysterectomy, but they advocated radical surgery with node dissection in

patients with gross cervical spread of tumor [6]. Boothby et al. found no significant difference in survival among patients treated by radiation alone, radical hysterectomy and lymphadenectomy, or combination radiation and surgery, but they recommended radical hysterectomy and lymphadenectomy for stage II, grade 1 or 2 tumor with microscopic cervical involvement and negative nodes [21]. Mannel et al. reported 90% 5-year survival for those patients at low risk for pelvic recurrence, relative to 60% 5-year disease-free survival in all clinical stage II patients, and therefore suggested use of an extrafascial instead of a radical hysterectomy for patients with no cervical stromal invasion, and a type II radical hysterectomy for patients with cervical stromal or gross cervical involvement [4]. Elia et al. recommended an extrafascial hysterectomy for microscopic cervical involvement and radical hysterectomy for gross cervical involvement [1]. Tamura et al. observed improved survival with radical compared to simple hysterectomy, but not to statistical significance [23]. They suggested that patients with minimal involvement of the cervix may be satisfactorily treated with simple hysterectomy, while patients with gross cervical spread should be treated with radical hysterectomy. Leminen et al. found that radical hysterectomy compared to simple hysterectomy did not improve survival and suggested that simple hysterectomy was sufficient operative treatment for stage II disease [24]. Although the above studies recommend treatment plans for specific patients, no report could prove one method superior. Boente et al. evaluated 202 patients with clinical and surgical stage II corpus uteri adenocarcinoma and found a survival advantage for patients treated by radical surgery compared to more conventional treatments [25]. The 5-year actuarial survival rate in patients treated with radical hysterectomy with or without radiation therapy was 86% compared to 77% for patients treated with extrafascial hysterectomy alone, 65% for patients treated with preoperative radiation and extrafascial

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hysterectomy, and 61% for patients treated with postoperative radiation and simple hysterectomy. When only patients with gross cervical disease greater than 3 cm were considered, 5-year survival for the radical hysterectomy group was 74% versus 18% for the group treated with preoperative radiotherapy and extrafascial hysterectomy. Our report agrees with the Boente study. We were able to show that radical hysterectomy improved survival compared to simple hysterectomy. Our analysis of 932 patients with FIGO II corpus uteri adenocarcinoma showed 5-year survival of 92.96% in patients treated with radical hysterectomy and no radiation and 88.02% in patients treated with radical hysterectomy and radiation, compared to 84.36 and 82.77% in patients treated with simple hysterectomy, respectively, without or with radiation. When the survival benefit of radiation is addressed in the literature, little difference is identified between radical surgery alone and combined radiation and surgery, although there tends to be a slight survival advantage to patients treated with combined-modality therapy [7, 8, 21]. Berman et al. compared surgery alone versus radiation and surgery and found no difference in survival [26]. Bruckman et al. and Kinsella et al. both showed 83% 5-year relapse-free survival in patients treated with combined radiation and surgery and recommended this treatment option for patients with stage II disease [7, 8]. Carl et al. did show a survival benefit of radiation. In their study, adjuvant 50-Gy radiation improved 5-year crude survival from a rate of 60 to 80% in patients with stage II disease, independent of depth of myometrial invasion [27]. However, Roberts et al., in a GOG study, reported that adjuvant radiation in women with intermediate-risk endometrial corpus cancer decreased recurrence but had no appreciable effect on survival [28]. We were not able to show significant survival benefit for radiation. One reason for this may be that our patients who received radiation may have had poorer disease status, increased complications from postoperative radiation, or increased comorbidity compared to patients who did not receive radiation. SEER data do not give information about lymphovascular space involvement, lower uterine involvement, depth of myometrial invasion once disease has spread to cervix, gross cervical disease, cervical diameter, depth of cervical invasion to glands or stroma, ploidy analysis, molecular biologic markers, or comorbidities. Each of these may have directed treatment approach toward adjuvant radiation therapy, causing a greater proportion of patients with potentially poor prognostic factors to be in the radiation treatment groups. Adverse prognosticators may have also directed treatment toward radical surgery, causing a decrease in the observed survival in our radical hysterectomy groups. An advantage of the SEER program is that it has information on patients from nine regions of the country and gives data representative of a broad heterogeneous population. This is

also a disadvantage as data from a nonhomogeneous population may be confounded by differences in medical facilities, treatment protocols, health care access, health behavior attitudes, regional customs, socioeconomics, or environmental hazzards. The SEER database has several important limitations. First, it does not offer a randomized prospective evaluation. Second, it does not subcategorize cervical involvement of corpus uteri cancer into endocervical glandular involvement or cervical stromal invasion and therefore cannot further stage FIGO II to IIA or IIB. Since treatment protocols may specify simple hysterectomy for stage IIA, and radical hysterectomy or adjuvant radiation for stage IIB, there may be an uneven distribution of these substages in our treatment groups, worsening survival for the radical hysterectomy and radiation groups. Third, SEER designation of no lymph node involvement may include nonenlarged unresected nodes. Also, SEER data abstractors do not collect peritoneal cytology information. Therefore the SEER program is not able to upstage patients with positive nonenlarged unresected lymph nodes or positive peritoneal cytology. Our data may include patients with stage III disease. Fourth, the SEER database does not indicate per patient the specific lymph node evaluation method used (surgical staging, palpation, or radiographic assessment). A greater percentage of patients with radical hysterectomy may have had lymph node sampling than did patients with simple hysterectomy, and therefore, the poor survival for patients treated with simple hysterectomy could be a reflection of inadequate staging. Fifth, SEER data abstraction from hospital medical records may not consistently collect outpatient chemotherapy information. Also SEER collects no data on recurrent disease. Therefore, treatment groups may not be stratified, and survival rates may not be adjusted for some outpatient or any recurrent disease treatments the patient may have received. Sixth, the SEER data do not distinguish between preoperative and postoperative radiation, so we do not know the chronologic order of radiation relative to surgery for our patients. However, this should not have affected our analysis. Reports have shown that the preoperative versus postoperative timing of radiotherapy is not an independent predictor of outcome in stage II endometrial corpus cancer [29 –31]. The selection of a treatment modality is not a random process [7]. Radical excision or radiation tend to be chosen for extensive cervical involvement, deep myometrial invasion, aggressive histology, or poor tumor grade. In our study, cell type did not seem to significantly affect therapy choice. Papillary serous and clear cell adenocarcinoma were not found in higher percentages among patients treated with radical hysterectomy, although this may have been because of small numbers. Endometrioid histology was found in a greater proportion of patients who had received a radical versus simple hysterectomy. This was an unexpected finding, as endometrioid histology is not associated with more aggressive disease. This ob-

TREATMENT TRENDS IN FIGO II CORPUS CANCER

servation may just represent a chance event in our data. Tumor grade, however, did seem to affect therapy choice in our report. A higher percentage of patients with undifferentiated or poorly differentiated disease were treated with radical hysterectomy than were patients with moderately or well-differentiated tumors, and a higher percentage of patients with undifferentiated or poorly differentiated disease received radiotherapy than patients with other tumor grades. This treatment bias may have decreased the observed survival in patients treated with radical hysterectomy or radiation. SEER does not collect information on depth of myometrial invasion if disease has extended to the cervix or outside the uterus. In conclusion, SEER data from 1988 to 1994 show that radical hysterectomy is associated with better survival when compared to simple hysterectomy for FIGO II corpus uteri adenocarcinoma. It is our recommendation that when cervical involvement is known or highly suspected, radical hysterectomy as a surgical treatment option should be considered. REFERENCES 1. Elia G, Garfinkel DA, Goldberg GL, Davidson S, Runowicz CD: Surgical management of patients with endometrial cancer and cervical involvement. Eur J Gynaecol Oncol 16:169 –173, 1995 2. Maggino T, Romagnolo C, Landoni F, Sartori E, Zola P, Gadducci A: An analysis of approaches to the management of endometrial cancer in North America: a CTF study. Gynecol Oncol 68:274 –279, 1998 3. FIGO News: Int J Gynecol Obstet 28:189 –193, 1989 4. Mannel RS, Berman ML, Walker JL, Manetta A, DiSaia PJ: Management of endometrial cancer with suspected cervical involvement. Obstet Gynecol 75:1016 –1022, 1990 5. Rutledge F: The role of radical hysterectomy in adenocarcinoma of the endometrium: Gynecol Oncol 2:331–347, 1974 6. Homesley HD, Boronow RC, Lewis JL Jr.: Stage II endometrial adenocarcinoma: Memorial Hospital for Cancer, 1949 –1965. Obstet Gynecol 49:604 – 608, 1977 7. Bruckman JE, Goodman RL, Murthy A, Marck A: Combined irradiation and surgery in the treatment of stage II carcinoma of the endometrium. Cancer 42:1146 –1151, 1978 8. Kinsella TJ, Bloomer WD, Lavin PT, Knapp RC: Stage II endometrial carcinoma: 10-year follow-up of combined radiation and surgical treatment. Gynecol Oncol 10:290 –297, 1980 9. Madoc-Jones H: Adenocarcinoma of the endometrium, stage II: problems in definition and management. Int J Radiat Oncol Biol Phys 6:887– 890, 1980 10. Parsons L, Cesare F: Wertheim hysterectomy in the treatment of endometrial carcinoma. Surg Gynecol Obstet 108:582–590, 1959 11. Randall CL: Letter to editor: panhysterectomy for uterine carcinoma. Am J Obstet Gynecol 59:942, 1950 12. Brunschwig A, Murphy A: Rationale for radical panhysterectomy and pelvic node excision in carcinoma of corpus uteri; clinical and pathological data on mode of spread of endometrial carcinoma. Am J Obstet Gynecol 68:1482–1488, 1954 13. Fletcher GH: Clinical dose–response curves of human malignant epithelial tumours. Br J Radiol 46:1–12, 1973

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