Women with International Federation of Gynecology and Obstetrics (FIGO)1 clinical stage IB and IIA cervical cancer have equivalent cure rates when treated primarily with radical surgery or radiation therapy.2 The choice of initial therapy may be influenced by concomitant morbidity, desire for ovarian preservation, or potential for late side effects. Among those initially treated with radical surgery, postoperative radiotherapy is usually recommended when one or more high-risk surgical-pathologic factors exist.2,3 Women who receive both treatments have high morbidity and incur increased costs without any proved survival benefit.2–5
Endocervical adenocarcinomas and adenosquamous carcinomas represent approximately 15% of all cervical cancers.6 These tumors can exhibit unique biologic behavior and response to therapy.2,7,8 Landoni et al2 reported that radical surgery gave superior survival rates compared with primary radiation in women with early cervical adenocarcinoma. Eighty-six percent of women with tumor diameters of more than 4 cm received postoperative radiotherapy, more than doubling their risk of major complications.2 Eifel et al9 reported a fourfold increase in the pelvic recurrence rate after radical surgery alone as compared with primary radiotherapy for cervical adenocarcinoma measuring more than 3 cm in diameter.
Women with early (stage IB and IIA) cervical adenocarcinoma are candidates for radical surgery. Stage IB includes two subgroups based on pretreatment tumor diameter: IB1 or up to 4 cm in diameter, and IB2, or more than 4 cm. Stage IIA cervical carcinoma is defined as tumor extending to the upper two thirds of the vagina without parametrial involvement.1 Increasing tumor diameter is associated with other poor prognostic factors and a high pelvic recurrence rate, often necessitating postoperative radiation. The purpose of this study was to identify selection criteria for radical surgery in early cervical adenocarcinoma based on pretreatment clinical stage and correlation with high-risk surgical-pathologic factors.
Materials and Methods
After obtaining institutional review board approval, we performed a computerized tumor registry search to identify all women treated primarily for cervical adenocarcinoma at Brigham and Women's Hospital and Massachusetts General Hospital from 1982 to 1996. All women were clinically staged before treatment. Records of 175 women with early cervical adenocarcinomas (FIGO stage IB1, IB2, and IIA) were found among 1135 with cervical carcinoma diagnosed during the study interval. We have previously reported 40 of these subjects.3,10
Hematoxylin and eosin-stained sections were reviewed by gynecologic pathologists at Brigham and Women's Hospital (KRL) and Massachusetts General Hospital (CEF). Complete histopathologic review was done in 140 cases (80%). In 35 cases (20%), slides were not available and pathology reports alone were reviewed. Each adenocarcinoma was classified by cell type using standard criteria.11 Patients with minimal-deviation adenocarcinoma, adenoid cystic carcinoma, and adenoid basal carcinoma were excluded. Depth of invasion was measured from the surface of the tumor to the deepest point using a calibrated ×40 magnification field. The percentage of cervical-wall invasion was determined by comparing depth of the invasive tumor with thickness of the cervical wall. Tumor length was defined as the maximal lateral extent of tumor as measured on any one slide, or the gross tumor length of the specimen if this exceeded the capacity of a single slide. Parametrial tumor extension was determined by clinical or pathologic findings.
Indications for postoperative radiotherapy were based on surgical-pathologic features such as lymph node metastases, positive surgical margins, deep cervical invasion, and histologic cell type. The indications were not uniform among clinicians. External-beam radiation generally consisted of 40–50 Gy delivered through standard ports with megavoltage equipment in a four-field box technique over 4.5–5.5 weeks at 150–200 cGy per fraction. An external-beam parametrial boost or para-aortic extension was done in some cases, depending on the extent of disease. Standard brachytherapy was used to boost the radiation dose to the cervix and adjacent tissue.
Medical records were reviewed retrospectively for clinical data. Current follow-up and disease status were determined in all cases from chart review, tumor registry data, and correspondence with health care providers. Persistent disease was defined as carcinoma at a pelvic site known to be previously involved within 6 months of staging. Recurrent disease was defined as a new extrapelvic area of tumor or pelvic disease more than 6 months after staging in a location previously free of tumor. Persistent or recurrent disease was documented by surgical exploration, biopsy, or progression on imaging studies. The time to recurrence or death was calculated from the date of original staging. Major complications were defined as morbid events after treatment that required surgical intervention. The end of the follow-up period was June 1998.
Overall survival and disease-free survival estimates were calculated using the Kaplan-Meier product-limit method.12 Comparisons between survival curves were made using the Cox proportional hazards regression model and log-rank statistics.13,14 The two analyses were virtually identical, and only the Cox results are reported. Multivariate analysis of prognostic factors for disease-free survival was performed using the Cox proportional hazards regression model, controlling for clinical stage. Fisher exact test was used to compare the frequency of prognostic factors with clinical stage. Two-sided P values are reported. Thirteen women who died of causes unrelated to cervical cancer were censored at the time of death.
The median age of the patients was 42 years (range 22–89). Median follow-up was 77 months (range 24–188). Ninety percent of the women were white, 7% Hispanic, and 3% black; 23% were nulliparous. Fifty-two percent presented with abnormal vaginal bleeding, 37% with an abnormal Papanicolaou smear, 7% for a routine physical examination without symptoms, 3% with abnormal vaginal discharge, and 1% with pain.
The overall 5-year survival rate was 87% (95% confidence interval [CI] 81%, 93%) for stage IB1, and 61% (95% CI 46%, 77%) for stage IB2-IIA (P < .001). The 10-year survival rate was 84% (95% CI 77%, 91%) for stage IB1 and 48% (95% CI 29%, 66%) for stage IB2-IIA (P < .001). Clinical stage (Figure 1) and several other prognostic factors were predictive of disease recurrence (Tables 1 and 2). There was no difference in disease-free survival between institutions or based on time of entry. One hundred three women (59%) had endocervical cell type, 49 (28%) had adenosquamous cell type, and 23 (13%) had other cell types (clear cell, n = 10; endometrioid, n = 7; intestinal, n = 5; mesonephric, n = 1).
One hundred fourteen (86%) of 132 stage IB1 subjects were treated initially with class II (n = 5) or III (n = 109) radical hysterectomy and pelvic lymphadenectomy15; eight (6%) others had radical surgery aborted based on the intraoperative findings. Six (5%) treated with radiation alone were compromised medically (n = 3) or older than 75 years (n = 3). Four (3%) who had extrafascial hysterectomy for suspected endometrial carcinoma received postoperative radiation.
Nineteen (44%) of 43 stage IB2-IIA subjects were treated initially with class II (n = 5) or III (n = 14) radical hysterectomy, and one (2%) had radical surgery aborted. Twenty patients (47%) received primary radiotherapy; nine received no further therapy and 11 underwent extrafascial hysterectomy. There was no difference in disease-free survival between the primary radical surgery group (n = 19) and the primary radiotherapy group (n = 20) for stage IB2-IIA disease. Two women (5%) who had extrafascial hysterectomy for suspected endometrial carcinoma and one (2%) who had a staging laparotomy received postoperative radiation.
Lymph node metastases, lymph-vascular space invasion, adenosquamous cell type, deep cervical invasion, and positive surgical margins were more than twice as frequent in stage IB2-IIA subjects who had radical surgery than in stage IB1 subjects (Table 3). Based upon the presence of high-risk surgical-pathologic factors in 133 women who had radical surgery, postoperative radiotherapy was recommended for 18 (16%) of 114 stage IB1 patients and 18 (95%) of 19 stage IB2-IIA patients (P < .001). Of the stage IB1 patients, nine of 27 (33%) with adenosquamous cell type and nine of 21 (43%) with lymph-vascular space invasion received postoperative radiation.
Five stage IB1 patients developed major complications (vesicovaginal fistula, n = 3; intraoperative splenic laceration; ureteral transection), all after radical surgery alone. Three of 19 (16%) of the stage IB2-IIA subjects treated with radical surgery and postoperative radiotherapy developed major complications (vesicovaginal fistula, bowel stricture, ureteral transection), compared with one of 20 (5%) who received primary radiotherapy (rectovaginal fistula). There were no significant differences in the frequency of major complications by primary treatment and clinical stage.
Four patients had persistent disease and died within 9 months of clinical staging. Forty had recurrence (median 12 months after staging; range 6–108 months): 32 died of disease, seven were without evidence of disease 2–96 months after treatment of recurrence, and one died 67 months after treatment of recurrence with no evidence of disease.
We agree that most women with FIGO clinical stage IB1 cervical adenocarcinoma have an excellent chance of cure with radical surgery alone.16 Women who underwent radical surgery in our study infrequently had lymph node metastases, lymph-vascular space invasion, adenosquamous cell type, grade 3 histology, deep cervical invasion, or positive surgical margins. Less than 20% needed postoperative radiotherapy based on one or more high-risk surgical-pathologic factors. Major complications were rare.
Adenosquamous cell type and lymph-vascular space invasion are high-risk surgical-pathologic factors that are potentially detectable before initiation of therapy. A prospective study analyzing the importance of cell type in early cervical cancer concluded that adenosquamous cell type was predictive of shorter survival compared with either pure adenocarcinoma or squamous carcinoma.17 Lymph-vascular space invasion is another well-documented risk factor in early cervical adenocarcinoma.16 Although our findings strongly support their prognostic significance, less than half of the stage IB1, subjects who had radical surgery with adenosquamous cell type (33%) or lymph-vascular space invasion (43%) received postoperative radiation therapy. Primary treatment should be individualized when pretreatment biopsy reveals either of these high-risk surgical-pathologic factors.
In a study of histologic cell types, Gallion et al18 reported that extrafascial hysterectomy after radiation therapy reduced tumor recurrence in patients with stage IB barrel-shaped cervical cancer without increasing treatment-related complications. Eifel et al19 found no improvement in local disease control or survival among any subgroup of women with cervical adenocarcinoma similarly treated. Because only 11 of the stage IB2-IIA subjects in our study were treated with primary radiation and adjuvant hysterectomy, we cannot draw meaningful conclusions about the effectiveness of this treatment for reducing the risk of recurrence.
Patients with stage IB2-IIA disease in our study were treated primarily with either radical surgery (46%) or radiotherapy (47%), reflecting differences in approach, but we found no difference in disease-free survival based on primary treatment. Virtually all those with stage IB2-IIA disease who underwent radical surgery had one or more high-risk surgical-pathologic factors identified afterward, and 95% of these received radiotherapy. We observed a trend toward increased major complications among women who had radical surgery and postoperative radiation (16%) compared with primary radiation (5%). Because two treatments are no more effective than one4,5 and there is strong evidence that combined-modality therapy increases morbidity,2,3 one must question the choice of radical surgery for primary treatment of FIGO clinical stage IB2-IIA cervical adenocarcinoma.
Firm recommendations cannot be made for the primary treatment of early cervical adenocarcinoma in the absence of a randomized clinical trial. Continued investigation should improve the preoperative selection process to identify those women most likely to benefit from radical surgery. We conclude that radical surgery for FIGO clinical stage IB1 cervical adenocarcinoma and primary radiotherapy for stage IB2-IIA disease would largely avoid combined-modality therapy, thereby reducing treatment-related toxicity and cost.
1. Creasman WT. FIGO news. Modifications in the staging for stage I vulvar and stage I cervical cancer. Int J Gynaecol Obstet 1995;50:215–6.
2. Landoni F, Maneo A, Colombo A, Placa F, Milani R, Perego P, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997;350:535–40.
3. Schorge JO, Molpus KL, Koelliker D, Nikrui N, Goodman A, Fuller AF Jr. Stage Ib and IIa cervical cancer with negative lymph nodes: The role of adjuvant radiotherapy after radical hysterectomy. Gynecol Oncol 1997;66:31–5.
4. Kinney WK, Alvarez RD, Reid GC, Schray MF, Soong S, Morley GW, et al. Value of adjuvant whole-pelvis irradiation after Wertheim hysterectomy for early-stage squamous carcinoma of the cervix with pelvic nodal metastasis: A matched-control study. Gynecol Oncol 1989;34:258–62.
5. Morrow CP. Panel report: Is pelvic radiation beneficial in the postoperative management of stage IB squamous cell carcinoma of the cervix with pelvic node metastases treated by radical hysterectomy and pelvic lymphadenectomy? Gynecol Oncol 1980;10:105–10.
6. Shingleton HM, Bell MC, Fremgen A, Chmiel JS, Russell AH, Jones WB, et al. Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix? Cancer 1995;76:1948–55.
7. Berek JS, Hacker NF, Fu YS, Sokale JR, Leuchter RC, Lagasse LD. Adenocarcinoma of the uterine cervix: Histologic variables associated with lymph node metastasis and survival. Obstet Gynecol 1985;65:46–51.
8. Drescher CW, Hopkins MP, Roberts JA. Comparison of the pattern of metastatic spread of squamous cell cancer and adenocarcinoma of the uterine cervix. Gynecol Oncol 1989;33:340–3.
9. Eifel PJ, Burke TW, Delclos L, Wharton JT, Oswald MJ. Early stage I adenocarcinoma of the uterine cervix: Treatment results in patients with tumors <4 cm in diameter. Gynecol Oncol 1991;41:199–205.
10. Schorge JO, Molpus KL, Fuller AF Jr. Stage Ib and IIa cervical cancer with lymph node metastases. J Gynecol Tech 1997;3:27–32.
11. Wright TC, Ferenczy A, Kurman RJ. Carcinoma and other tumors of the cervix. In: Kurman RJ, ed. Blaustein's pathology of the female genital tract. 4th ed. New York: Springer-Verlag, 1994:279–326.
12. Kaplan EL, Meier R. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.
13. Cox DR. Regression models and life tables. J R Stat Soc 1972;34:187–220.
14. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemo Rep 1966;50:163–70.
15. DiSaia PJ, Creasman WT, eds. Clinical gynecologic oncology. 5th ed. St. Louis: Mosby-Year Book, Inc, 1997.
16. Matthews CM, Burke TW, Tornos C, Eifel PJ, Atkinson EN, Stringer CA, et al. Stage I cervical adenocarcinoma: Prognostic evaluation of surgically treated patients. Gynecol Oncol 1993;49:19–23.
17. Look KY, Brunetto VL, Clarke-Pearson DL, Averette HE, Major FJ, Alvarez RD, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 1996;63:304–11.
18. Gallion HH, van Nagell JR, Donaldson ES, Hanson MB, Powell DE, Maruyama Y, et al. Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer. Cancer 1985;56:262–5.
19. Eifel PJ, Morris M, Oswald MJ, Wharton JT, Delclos L. Adenocarcinoma of the uterine cervix: Prognosis and patterns of failure in 367 cases. Cancer 1990;65:2507–14.