Postoperative Radiotherapy for Patients with Invasive Cervical Cancer Following Treatment with Simple Hysterectomy

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Dwight Matthews
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1 Jpn J Clin Oncol 2003;33(9) Postoperative Radiotherapy for Patients with Invasive Cervical Cancer Following Treatment with Simple Hysterectomy Shang-Wen Chen 1,2, Ji-An Liang 1,2, Shih-Neng Yang 1,2 and Fang-Jen Lin 1,2,3 1 Department of Radiation Therapy and Oncology, China Medical College Hospital, Taichung, 2 China Medical College, School of Medicine, Taichung and 3 Department of Radiation Therapy and Oncology, Shin Kong Memorial Hospital, Taichung, Taiwan Received June 23, 2003; accepted August 8, 2003 Background: This study aimed to investigate the survival and complications of patients who received adjuvant radiotherapy for invasive cervical cancer following inadvertent simple hysterectomy. Methods: From September 1992 through to December 1998, 54 patients who had received simple hysterectomies for benign lesions, but were incidentally found with invasive carcinoma of the cervix in the surgical specimen, were referred to our department for postoperative irradiation. They were categorized into two groups according to pathological findings. Group A consisted of 25 patients whose specimen showed microinvasion alone, with the depth of stromal invasion <5 mm. Group B consisted of 29 patients whose pathological findings included deep stromal invasion, tumor emboli in cervix, lymphovascular permeation, positive or close resection margin, endometrial or myometrial invasion and vaginal involvement. After external beam irradiation dose of 44 Gy in 22 fractions over 4 5 weeks to the whole pelvis, the radiation field was reduced to true pelvis for a further 10 Gy in five fractions. Brachytherapy was performed using an Ir-192 remote after-loading technique for 1 2 courses. The prescribed dose for each treatment was 7.5 Gy to the vaginal surface. A retrospective analysis was conducted to compare radiation-therapy outcomes for these 54 patients. Results: After months of follow-up (median, 58 months), 47 patients were alive without evidence of disease; five patients in Group B died of the disease (three with distant metastasis, one with local relapse, one with both). Two patients died of other concurrent diseases. The 5- year actuarial survival (AS) and disease-free survival (DFS) rates for all patients were 88 and 90%, respectively. The respective 5-year AS and DFS rates for Group A/B were 95/82% (P = 0.07) and 100/83% (P = 0.03). Ten patients (18.5%) developed RTOG Grade 1 4 rectal complications. Five patients (9.3%) developed RTOG Grade 3 4 bladder complications. Eight patients (14.8%) had RTOG Grade 1 4 non-rectal gastrointestinal complications. Conclusions: For patients with invasive cervical cancer following inadvertent simple hysterectomy, external beam radiotherapy combined with one or two fractions of intravaginal brachytherapy could achieve satisfactory disease control. It is recommended to select a high-risk group for intensive adjuvant treatment. Further optimization of the irradiation strategy is also imperative to decrease the incidence of complications. Key words: cervical carcinoma simple hysterectomy adjuvant radiotherapy INTRODUCTION Carcinoma of the uterine cervix is the leading gynecologic malignancy in Taiwan. The conventional treatment of early cervical carcinoma consists of either radical hysterectomy or primary radiotherapy. These treatment modalities are equally For reprints and all correspondence: Ji-An Liang, Department of Radiation Therapy and Oncology, China Medical College Hospital, No 2, Yuh-Der Road, Taichung, Taiwan vincent @yahoo.com.tw efficient in both local control and survival (1,2). Occasionally, however, due to inadequate preoperative work-up, invasive carcinomas of the cervix have been incidentally found in the surgical specimens after simple hysterectomies had been performed. Extrafascial abdominal hysterectomy is not curative because paracervical and paravaginal soft tissues and vaginal cuff are not removed. Furthermore, it may be technically difficult to perform an adequate radical hysterectomy after a previous simple hysterectomy (3). When a less comprehensive dissection is performed, it is critical that patients receive post Foundation for Promotion of Cancer Research

2 478 Cervical cancer after hysterectomy Table 1. Patient characteristics (total 54 patients) Age at treatment (median) 47 (32 71) Histology type Squamous cell carcinoma 52 Adenocarcinoma 2 Group A (microinvasion 2 5 mm) total: 25 Group B total: 27 Deep stromal invasion (>5 mm) 12 Lymphovascular permeation 7 Tumor emboli in cervix 3 Endocervical invasion 1 Endometrial invasion 7 Vaginal invasion 4 Parametrial invasion 2 Paracervical soft tissue invasion 2 Perineural invasion 1 >0.5 cervical thickness 5 >0.5 cervical circumference 3 Positive resection margin 4 Reason for simple hysterectomy Uterine leiomyoma 41 Adenomyosis 6 Dysfunction uterine bleeding 3 Ovarian cysts 2 Unknown 2 operative radiotherapy immediately after the operation, otherwise the prognosis is much worse (2,4). In this study, we retrospectively analyzed the efficacy and complication rate for postoperative adjuvant radiotherapy following inadvertent simple hysterectomy. PATIENTS AND METHODS PATIENT CHARACTERISTICS From September 1992 through to December 1998, our department had admitted 57 patients who received simple hysterectomy for benign lesions but were incidentally found with carcinoma of the cervix in the surgical specimen, for postoperative irradiation. A total of 54 patients who completed planned radiotherapy and had a minimum follow-up of 36 months were enrolled into the analysis for radiation-therapy outcomes. The mode of surgery was simple/total hysterectomy with or without bilateral salpingo-oophorectomy, and none of these patients received pelvic node dissection. Histopathology of the uterine cervical malignancy consisted mostly of squamous cell carcinoma (52 cases) and two cases of adenocarcinoma. They were categorized into two groups according to the extent of pathological findings. Group A consisted of 25 patients whose specimens showed microinvasion alone, with the depth of stromal invasion <5 mm (range 2 5 mm). Group B consisted of 29 patients whose pathological findings included deep stromal invasion (>5 mm), tumor emboli in cervix, lymphovascular permeation, positive or close resection margin, endometrial or myometrial invasion and vaginal involvement. The patient characteristics, pathological findings of specimens and reason for hysterectomy are summarized in Table 1. All patients had detailed work-ups before the initiation of adjuvant radiotherapy, including pelvic examination, chest X-ray and tumor markers (squamous cell and carcinoembryonic antigens). For the 50 patients who received postoperative CT scans, none had obvious residual disease in the pelvic cavity or para-aortic lymph nodes. RADIOTHERAPY The treatment consisted of external beam radiotherapy (EBRT) followed by high-dose-rate intravaginal brachytherapy (HDRIVB). Initially, the whole pelvis was treated with 10 MV X-rays via anterior and posterior parallel fields (AP/PA), or a box field when the AP diameter was >20 cm. After irradiation dose of 44 Gy in 22 fractions for 4 5 weeks over the whole pelvis, the radiation field was reduced to the true pelvis for a further 10 Gy in five fractions. For patients treated with the two-field technique, the EBRT dose was calculated at midplane, while the dosimetry of the box field was calculated using computer-based software (Nucletron Plato System, Version 2, The Netherlands). After the completion of EBRT, HDRIVB was performed using an Ir-192 remote after-loading technique at 1-week intervals. Forty-nine patients (90.7%) received two insertions, while five patients had only one insertion. The standard prescribed dose for each HDRIVB was 7.5 Gy to the vaginal surface and the whole vagina was included within the treatment length. The overall duration of the treatment ranged from 32 to 69 days (median, 54 days). FOLLOW-UP After completion of radiotherapy, the patients received regular follow-up every 1 2 months during the first year, and every 3 months subsequently. A pelvic examination was performed during each follow-up visit, while tumor markers were checked every 3 6 months, and a radiographic examination (chest X-ray, abdominopelvic CT scan) was conducted annually. Patients who had bloody stools or hematuria underwent sigmoidoscopy or cystoscopy to identify the site of bleeding, and complete blood count was followed every 2 4 weeks for surveillance of the severity of complications. STATISTICAL AND COMPLICATION ANALYSIS Patient survival was measured from the date of the initiation of therapy to the date of the last follow-up examination. The survival rate was determined using the Kaplan Meier method. The statistical significance between the survival curves was

3 Jpn J Clin Oncol 2003;33(9) 479 Table 2. RTOG late radiation morbidity scoring scheme Grade 1 Grade 2 Grade 3 Grade 4 Small intestine mild diarrhea mild diarrhea obstruction necrosis mild cramping colic bleeding requiring surgery perforation bowel movement < 5 times daily bowel movement > 5 times daily Rectum slight rectal discharge excessive rectal mucus bleeding requiring surgery fistula slight rectal bleeding intermittent rectal bleeding Bladder minor telangiectasia moderate frequency severe frequency necrosis (microscopic hematuria) generalized telangiectasia (microscopic hematuria) frequent hematuria contracted bladder severe hemorrhagic cystitis Table 3. Recurrent disease Patient Pathological characteristics Time to recurrence (months) Site of recurrence Case 1 endometrial involvement 26 para-aortic LN, neck LN Case 2 parametrial involvement, deep stromal invasion 15 pelvis (RT field), lung Case 3 tumor emboli in cervix, positive resection margin 44 pelvis (RT field) Case 4 endometrial involvement 23 lung, bone Case 5 paracervical soft tissue, full thickness of cervix 24 bone calculated using the log-rank test. Rectal and bladder complications, and non-rectal gastrointestinal sequelae were scored according to the RTOG grading scale (5). The scoring schemes of RTOG late radiation morbidity are listed in Table 2. RESULTS SURVIVAL After months of follow-up (median, 58 months), 47 patients were alive without evidence of disease, five patients in Group B died of the disease (three with distant metastasis, one with local relapse, one with both). The pathological characteristics and patterns of failure are listed in Table 3. Two patients died of other concurrent diseases (one with diabetes-related complications in Group A, one with cerebral vascular disease in Group B). None of the patients died of complications related to the treatment. The 5-year actuarial survival (AS) and disease-free survival (DFS) rates for all patients were 88 and 90%, respectively. The respective 5-year AS and DFS rates for Group A/B were 95/82% (P = 0.07) and 100/83% (P = 0.03) and are depicted in Figures 1 and 2. Figure 1. Actuarial survival curve according to pathological findings. Group A, straight line; Group B, dotted line. Figure 2. Disease-free survival curve according to pathological findings. Group A, straight line; Group B, dotted line.

4 480 Cervical cancer after hysterectomy Table 4. Radiotherapy-related complications COMPLICATIONS Ten patients (18.5%) developed RTOG Grade 1 4 rectal complications. One of these patients received a colostomy for rectovaginal fistula, which was categorized as a Grade 4 rectal complication. The median time for the development of rectal complications was 12 months (range, 6 20 months) after radiotherapy. Five patients (9.3%) developed RTOG Grade 3 4 bladder complications, including one who received ileal conduit. Eight patients (14.8%) had RTOG Grade 1 4 non-rectal gastrointestinal complications, and one of these patients received laparotomy for severe abdominal pain. Two patients had lower-leg edema. The details of treatment-related complications are summarized in Table 4. DISCUSSION Group A Group B Time to complication (months) (median) Rectal complication 12 Grade Grade Non-rectal GI complication 14 Grade Grade Bladder complication 26 Grade Most gynecologic and radiation oncologists agree that a single modality treatment is preferable to a combination of major therapeutic interventions. However, for patients with invasive carcinoma of the cervix that were incidentally found in the surgical specimen after simple hysterectomy, it is critical that postoperative adjuvant radiotherapy is received immediately (2,4). Although carcinoma of the uterine cervix is a common gynecologic malignancy in Taiwan and Latin America, the women in endemic areas have not been well educated about, nor do they understand the importance of, Papanicolaou smear tests. Occasionally, because of inadequate preoperative workups, simple hysterectomies are performed and invasive carcinomas of the cervix are found incidentally in the surgical specimens. In this study, the AS and DFS rates were comparable with those of other series (3,4,6,7), and the majority of treatmentrelated sequelae were categorized as RTOG Grade 1 2 minor complications. The results confirm that our current irradiation strategy is acceptable for patients with invasive cervical cancer following inadvertent treatment with a simple hysterectomy. Since all the enrolled patients received the same mode of surgical resection and uniform irradiation doses, we were able to assess the treatment outcome in relation to the extent of pathological findings. For patients with advanced pathological findings, the DFS was not satisfactory. Therefore, adjuvant radiotherapy with the combination of external beam irradiation and brachytherapy is recommended. On the other hand, it is reasonable to select a high-risk group for concurrent chemo radiotherapy. As has been suggested in recent studies (8,9), concurrent chemotherapy and radiotherapy may be more effective than radiation alone in terms of distant metastasis and survival rate. However, since the patient number in Group B was relatively small, we cannot conclude which pathological factors produce higher risk. As reported by Perez et al., an increase in the incidence of distant metastasis was noted in patients with endometrial invasion (10). Two of four patients with distant metastasis had endometrial involvement in our study. For patients with microinvasion <5 mm, since none of the patients died of disease and 36% (9/25) of these patients developed rectal or non-rectal gastrointestinal complications, it is reasonable to reduce the treatment-related morbidity by reducing the irradiation dose or changing the treatment strategy. Perkins et al. reported good outcomes for 32 patients who received AP/PA whole pelvis irradiation following simple hysterectomy, and noted that there were no demonstrable advantages in adding transvaginal brachytherapy (6). However, vaginal relapse was reported in 50% (6/12) of their recurrent patients. When compared with our results, showing that none of the recurrent disease was noted in the vaginal stump, it is risky to completely omit intravaginal brachytherapy. Ampil et al. described results in 44 patients who received postoperative irradiation after hysterectomy for stage IB or IIA cervical cancer (15 patients were treated with radical hysterectomy). They suggested that the combination of EBRT with additional vaginal cuff irradiation is recommended for patients treated with simple hysterectomy (3). On the other hand, Andras et al. suggested that early-stage disease could be treated with intracavitary radium alone (4). Because of the variations in patients background and radiation strategies, comparison of treatment results among different institutions is not possible at present. There were three approaches to optimize the radiation strategy in our retrospective study. The first was to reduce the EBRT dose and volume. In our series, the median EBRT dose to the true pelvis was 54 Gy, which was higher than that used in other series (3,4,6,7), therefore it is advisable to reduce the dosage to reduce the probability of gastrointestinal morbidity. On the other hand, as radiation morbidity is strongly associated with irradiation volume (11 13), for patients with microinvasion <5 mm, we suggest using lower pelvic field to minimize gastrointestinal complications. Kridelka et al. (14) reported on 25 patients with negative lymph node who received 50.4 Gy (1.8 Gy per fraction) of adjuvant small field irradiation to pelvis. There was one recurrence (4%) recorded at 16 months. No major radiation morbidity was reported. Moreover, when the depth of the stromal invasion was ensured to be <3 mm, EBRT might be suspended because the probability of pelvic lymph node metastasis was reported to be only 1% (15).

5 Jpn J Clin Oncol 2003;33(9) 481 The second approach was to modify the prescribed dose of HDRIVB. Despite the questionable radiobiological disadvantages, high-dose-rate brachytherapy has been widely used in Asia and Europe, and HDRIVB for additional vaginal stump irradiation might narrow the therapeutic window (16). Since the radiation dose of the anterior rectal wall was estimated to be 5 Gy on each insertion, the cumulative dose to the anterior rectal wall would be ~64 Gy. As the rectum is late-reacting tissue, an / of three was used in the calculations. The calculated cumulative rectal biologically equivalent dose (adding the biological effective doses of EBRT and HDRIVB together) was 107 Gy 3, using the linear-quadratic formula as described in Fowler s review (17). In comparison with the results of our previous study, the cut-off value for the development of rectal complications was either the cumulative rectal dose of 65 Gy or the cumulative biologically equivalent dose of 110 Gy 3, according to statistical analysis (18). Therefore, it is imperative to lower the prescribed dose of HDRIVB to decrease the risk of rectal complications. Finally, close surveillance for selected patients in Group A might be feasible. Smith et al. reported that 272 patients with early invasive adenocarcinoma of the cervix (FIGO IA1 and IA2) had an excellent prognosis and simple hysterectomy might be appropriate (19). Schorge et al. suggested that for patients with microinvasive carcinoma who met criteria for FIGO stage IA1 cervical cancer and had disease limited to the cervix, simple hysterectomy might offer a definitive treatment (20). CONCLUSION For patients with cervical cancer following inadvertent simple hysterectomy, radiotherapy with EBRT combined with one or two fractions of intravaginal brachytherapy could achieve satisfactory disease control. The incorporation of chemotherapy during radiotherapy is recommended for high-risk patients to improve survival rates. For patients with microinvasion <5 mm, optimization of the radiation treatment strategy and patient selection for adjuvant radiotherapy are also imperative to decrease the incidence of complications. References 1. Hatch KD. Cervical Cancer. In: Berek JS, Hacker NF, editors. Practical Gynecologic Oncology, 2nd ed. Baltimore: Williams & Wilkins, 1994; Perez CA. Uterine Cervix: Principles and Practice of Radiation Oncology, 3rd ed. Philadelphia: Lippincott-Raven 1998; Ampil F, Datta R, Datta S. Elective postoperative external radiotherapy after hysterectomy in early stage carcinoma of cervix: Is additional vaginal cuff irradiation necessary? Cancer 1997;60: Andras EJ, Fletcher GH, Rutledge F. Radiotherapy of carcinoma following simple hysterectomy. Am J Obstet Gynecol 1973;115: Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31: Perkins PL, Chu AM, Jose B, Achino E, Tobin DA. Posthysterectomy megavoltage irradiation in the treatment of cervical carcinoma. Gynecol Oncol 1984;17: Papavasilious C, Yiagarakis D, Pappas J, Keramopoulos A. Treatment of cervical carcinoma by total hysterectomy and postoperative external irradiation. Int J Radiat Oncol Biol Phys 1980;6: Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340: Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340: Perez CA, Camel HM, Askin F, Breaux S. Endometrial extension of carcinoma of uterine cervix: a prognostic factor that may modify staging. Cancer 1981;48: Fioricca JV, Roberts WS, Greenberg H, Hoffman MS, LaPolla JP, Cavanagh D. Morbidity and survival patterns in patients after radical hysterectomy and postoperative adjuvant pelvic radiotherapy. Gynecol Oncol 1990;36: Barter JF, Soong SJ, Shingleton HM, Hatch KD, Orr JW. Complications of combined radical hysterectomy and postoperative radiation therapy in women with early stage cervical cancer. Gynecol Oncol 1989;32: Cunningham MJ, Dunton CJ, Corn B, Noumoff J, Morgan MA, King S, et al. Extended field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 1991;43: Kridelka FJ, Berg DO, Neuman M, Edwards LS, Robertson G, Grant PT, et al. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection. Cancer 1999;86: Bohm JW, Kruoo PJ, Lee FYL, Batson HW. Lymph node metastases in microinvasive epidermoid cancer of the cervix. Obstet Gynecol 1976;48: Eifel PJ. High-dose-rate brachytherapy for carcinoma of the cervix. High tech or high risk? Int J Radiat Oncol Biol Phys 1992;24: Fowler JF. Review article The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62: Chen SW, Liang JA, Yang SN, Liu RT, Lin FJ. The prediction of late rectal complications following the treatment of uterine cervical cancer by highdose-rate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47: Smith HO, Quall CR, Romero AA, Webb JC, Dorin MH, Padilla LA, Key CR. Is there a difference in survival for IA1 and IA2 adenocarcinoma of the uterine cervix? 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