Interstitial Brachytherapy for Vaginal Recurrences of Endometrial Carcinoma

Objective. The aim of this study was to evaluate the efﬁcacy of interstitial brachytherapy in the management of vaginal recurrences of endometrial carcinoma. (60%) also received external beam radiotherapy (mean dose, 48 Gy) as part of their treatment for vaginal recurrence. Twenty-eight patients (93%) experienced a complete clinical response. Ten patients re-lapsed in the vagina ( n 5 5) or at distant sites ( n 5 5). Eleven patients are dead of disease. From the time of vaginal recurrence, the median overall survival was 60 months and the cause of death adjusted 5-year survival rate was 65%. Major morbidity included radiation proctitis ( n 5 2), ﬁstula ( n 5 2), and radiation stricture ( n 5 1). Conclusion. Interstitial irradiation resulted in favorable local control as well as a 5-year survival rate and morbidity comparable to that reported previously for conventional brachytherapy.


INTRODUCTION
Although the majority of women with endometrial cancers are diagnosed at an early stage and are thus highly curable, there nonetheless remains a subset of patients who will fail primary therapy and present with recurrent disease. Historically, the vagina has been a common site of recurrence in endometrial carcinoma, with some older series reporting 8 -15% vaginal recurrence rates after total abdominal hysterectomy and bilateral salpingo-oophorectomy [1,2]. Although the selective use of perioperative adjuvant radiation based on a thorough surgical-pathologic evaluation may reduce vaginal recurrence, the problem is not eliminated, as evidenced by an overall 2% rate of isolated vaginal recurrence which persisted in the 1991 Gynecologic Oncology Group evaluation of 895 patients who were prospectively surgically staged [3].
Early investigators suggested both prophylactic treatment for patients at high risk for recurrent disease and various treatment strategies for those who do relapse. In 1929, Joe Vincent Meigs observed a very poor survivorship among patients with vaginal recurrences, despite regression of the vaginal lesion following therapy [4]. In 1958, Felix Noah Rutledge advised prophylactic irradiation of the vagina with a Bloedorn applicator following hysterectomy [5]. Theoretically, this would obliterate potential metastatic channels and sterilize existing microscopic vaginal disease (if present), lowering the risk of vaginal recurrence. In 1961 Alexander Brunschwig described a radical surgical approach to vault recurrences (e.g., pelvic exenteration); however, morbidity was high and only 28% of patients were alive at 5 years [6].
Given that the morbidity of surgical salvage may be substantial [6,7] and that chemotherapy in this setting is rarely curative [8,9], most therapeutic approaches for patients with isolated vaginal recurrences employ one of various radiotherapeutic techniques. Historically, this has consisted of external beam radiotherapy, usually followed by intracavitary brachytherapy in the form of vaginal cylinders or ovoids. Unfortu-nately, correct placement of these brachytherapy devices, and hence dosimetry, is frequently compromised by tumor volume and the postsurgical absence of the uterus. Using these standard techniques, multiple series in the literature report 5-year salvage rates in patients with vaginal recurrence of 20 -60% [4, 10 -23]. For those patients who relapse after treatment of their vaginal recurrence, the development of distant metastatic disease remains a stubbornly common feature that awaits the development of effective systemic adjuvant treatment. However, the need for improved brachytherapy techniques is also suggested by the fact that as many as 20 to 40% of patients treated for vaginal recurrence do not achieve local control of their tumor [1].
In recognition of the limitations of conventional brachytherapy, the Department of Radiation Oncology and the Gynecologic Oncology Division at the University of California, Irvine, began employing interstitial irradiation in the treatment of patients with vaginal recurrence of endometrial cancer in 1979. Interstitial brachytherapy may allow for a more precise application of radiation directly to the tumor, resulting in a homogeneous radiation field with potential sparing of the bladder and rectum. This may result in improved dosimetry compared with intracavitary techniques, particularly for deeply infiltrating tumors and bulky recurrences with complex geometries. Interstitial irradiation techniques were reintroduced by Syed and co-workers in the early 1980s for the management of gynecologic cancer [24,25], but have only rarely been reported in the treatment of vaginal recurrences [26,27].
The work about to be described is a summary to date of our experience in managing vaginal recurrences of endometrial carcinoma with interstitial irradiation.

MATERIALS AND METHODS
In order to identify patients treated with interstitial brachytherapy for vaginal recurrences of endometrial cancer, we reviewed the tumor registry abstracts and radiation oncology log books of the University of California, Irvine-Medical Center and Long Beach Memorial Medical Center. During the study period between 1979 and 1991, 488 patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic lymph node sampling for primary endometrial cancer. Twenty-two of these patients (4.5%) experienced a vaginal recurrence in the absence of pelvic sidewall or distant metastatic disease. 2 In addition, 8 patients underwent primary surgical management for endometrial cancer elsewhere and were referred in for treatment of their vaginal recurrence. Thus a total of 30 patients received interstitial brachytherapy for treatment of vaginal recurrences and comprise the clinical material of this retrospective study.
The primary tumor profiles are recorded in Table 1. The median age at the time of primary diagnosis was 66 years, with a range of 45 to 81 years. FIGO surgical stage was retroactively assigned and 40% of the study population had evidence of extrauterine spread at the time of primary diagnosis. This may in fact be an underestimate, since particularly in the early years or in patients who had their hysterectomy in an outside hospital, surgical staging may not have been as rigorous as currently advocated. The majority of the lesions were adenocarcinomas (n ϭ 21), but uterine papillary serous (n ϭ 6), adenosquamous (n ϭ 2), and clear cell (n ϭ 1) carcinomas were also observed. The grade distribution included grade I (n ϭ 8), grade II (n ϭ 12), and grade III (n ϭ 10). Thirteen patients (43%) had previously received postoperative prophylactic external beam radiation therapy, secondary to high-risk factors.
In addition to biopsy-confirmation of vaginal recurrence, all patients underwent detailed pelvic examination, cystoscopy, proctosigmoidoscopy or barium enema, computed axial tomography of the pelvis and abdomen, and chest radiography.
External beam radiotherapy was first administered via a linear accelerator to 17 previously unirradiated patients and to 1 patient who had received radiotherapy 10 years earlier but showed minimal evidence of radiation change. Using anterior and posterior parallel opposed pelvic portals, radiation was generally delivered over a 28-day period at a dose of 1.8 Gy per day, 5 days per week, for a mean dose of 48 Gy. Note. TAH-BSO, total abdominal hysterectomy and bilateral salpingooophorectomy.
All 30 patients with vaginal recurrence were treated with interstitial brachytherapy. Using a Syed-Neblett dedicated vaginal template (Figs. 1A and 1B), implants were placed transperineally, most employing epidural analgesia. Multiple 17-gauge stainless steel guide needles were inserted through the template, into the tumor-bearing regions of the vaginal vault. The implants were individualized with respect to the number of guide needles and depth of insertion.
X-ray localization films with inactive dummy sources were next obtained, followed by computerized dose distribution plotting and volume analysis using the ROC Program Module (Fig. 1C). The placement of radio-opaque contrast material in the rectum and Foley catheter balloon permitted calculation of the radiation dose that would be received by the rectum and bladder. Radioactive iridium-192 seeds, spaced 1 cm apart in plastic ribbons, were afterloaded into the guide needles and left in place for a mean interval of 42 h. The prescription dose of minimum radiation was delivered to the perimetry of the radiated field. Regions encompassed by the isodose curves received a higher dose of radiation.
Ten patients received interstitial brachytherapy in conjunction with laparotomy, which permitted the size and extent of recurrent disease to be more precisely determined. There were no cases of extensive disease discovered at the time of lapa- rotomy which would have necessitated aborting the "open" implant procedure in patients treated by this technique for vaginal recurrence. Bowel and bladder adhesions to the tumor were separated surgically and the guide needles were placed through the perineal template into the entire lesion under direct vision and palpation. An omental pedicle graft was always interposed between the tumor and the bladder and rectum, thereby preventing small bowel loops from adhering to the implant site and providing a new blood supply to the area to be irradiated. In addition, marker seeds were used to facilitate dosimetry planning and optimal needle placement of a second implant procedure when required (see below). This open implant approach was adopted in the later years of the study period [28,29].
In order to deliver an optimal total dose of interstitial radiation, a second implant procedure was planned for patients with lesions larger than 2 cm in diameter (n ϭ 16). In addition, six women with vaginal recurrences less than 2 cm in diameter also received a second interstitial implant secondary to the presence of significant macroscopic residual disease following the first procedure. This second application was performed 3 weeks after the first implant using the "closed" transperineal approach described above.
The mean maximal tumor dose delivered by each brachytherapy application was 25.5 Gy. The mean maximal total tumor dose was 85.8 Gy for 18 patients who received teletherapy plus interstitial brachytherapy for vaginal recurrence. The mean maximal total tumor dose was 98.5 Gy for 12 previously irradiated patients (mean dose, 47.7 Gy) who received interstitial irradiation only (mean dose, 50.8 Gy) for treatment of vaginal recurrence. The mean radiation dosages per implant received by the bladder and the rectum was 12.5 and 12.1 Gy, respectively. The mean total radiation dosages to the bladder were 60.5 Gy (teletherapy plus one implant) and 69.8 Gy (teletherapy plus two implants); the mean total radiation dosages to the rectum were 60.1 Gy (teletherapy plus one implant) and 69.2 Gy (teletherapy plus two implants).
Statistical methods employed for survival analysis included Kaplan-Meier Lifetable analysis and nonparametric univariate linear rank statistics using the Statistical Analysis Systems. A P value Ͻ0.05 was considered statistically significant. The survival rate was adjusted for cause of death from endometrial cancer and calculated at 5 years. Table 2 summarizes the characteristics of the vaginal recurrences. Vaginal relapses were diagnosed at a mean interval of 28.7 months following primary diagnosis, but an extraordinary range from 3 months to 10 years (i.e., 119 months) to recurrence was observed. The histologic grade distribution was not radically different from that of the primary uterine tumors.

Vaginal Recurrences
Although there was a trend toward an inverse relationship between time to recurrence and histologic grade, with mean intervals to relapse of 45 months for Grade I (range, 9 -119 months), 25 months for Grade II (range, 5-84 months) and 19 months for Grade III (range, 3-43 months), respectively, this was not statistically significant (P ϭ 0.149). The cell types of the recurrent lesions were identical to those of the primary uterine malignancy.
Sixteen patients (53%) were symptomatic, presenting with vaginal bleeding or pain, while 14 patients (47%) were asymptomatic. Sixteen patients (53%) had lesions greater than 2 cm in diameter, and in 9 patients (30%), the lesions were larger than 3 cm in diameter. The majority of the lesions were confined to the vaginal apex, although 12 patients (40%) had extension of disease from the apex to more distal sites along the vaginal cylinder. There were no patients with isolated distal or suburethral vaginal recurrence.
Twenty-two patients (73%) had disease limited to the vaginal mucosa or submucosa only, while 8 patients (27%) had clinical evidence of parametrial involvement. No patient had evidence of pelvic sidewall disease or distant metastases.

Local Control
Twenty-eight patients (93%) experienced complete clinical resolution of the vaginal vault recurrence, i.e., a complete clinical response. Twenty-three of these patients maintained local control for a minimum of 5 years, while 5 patients suffered a second relapse within the vagina, at a median interval of 16 months (range, 7-48 months) following interstitial brachytherapy. Two patients experienced only a partial response to radiation therapy. Thus the 5-year local control rate for the study population was 77%.

Distant Metastases
Five patients who achieved and maintained a complete response in the vagina and pelvis failed at distant sites, relapsing at a median interval of 11 months (range, 2-54 months) following interstitial brachytherapy.

Survival
All patients have been followed for a minimum of 5 years or until death. A total of 11 patients are dead of disease, including the 2 patients who experienced only partial responses to interstitial brachytherapy, 4 of the 5 patients who developed a second vaginal recurrence, and all 5 patients who failed at distant sites. The 1 survivor of a second vaginal relapse was salvaged by an abdominal radical upper vaginectomy followed by treatment with a progestational agent (Megace) and remains disease free 96 months later.
The cause of death adjusted 5-year disease-free survival rate is 65% for the study population, with a median overall survival of 60 months following treatment with interstitial irradiation. This includes 10 of 16 patients (62%) with vaginal vault recurrences greater than 2 cm in diameter and 7 of 13 patients (54%) who had received prior radiotherapy. Two of 6 women with recurrent papillary serous endometrial carcinoma have been salvaged. Eight patients are dead of intercurrent disease, with mortality occurring beyond 5 years in each case.
Nonparametric univariate analyses were performed because of the small sample size. There was not a significant difference in median survival after vault recurrence as a function of previous radiotherapy, tumor grade (I vs II/III), interval to recurrence (Յ12 months vs Ͼ12 months), size of the recurrence (Յ3 cm vs Ͼ3 cm), or the use of the open implant technique. Kaplan-Meier Lifetable analysis was performed to evaluate differences in survival adjusting for cause of death from endometrial cancer and did not demonstrate a survival advantage based on the variables analyzed by univariate analysis.

Sequelae of Therapy
All interstitial implants were well tolerated. The most common acute morbidities observed were urinary tract infection and transient fever. None of the patients who received interstitial brachytherapy in conjunction with a laparotomy experienced any significant acute morbidity (e.g., prolonged ileus, blood transfusion).
Significant long-term morbidity occurred in five patients (17%). Two patients who had received a total dose of 83.0 and 80.4 Gy to the rectum developed severe radiation proctitis. Both received a permanent descending end colostomy. An additional two previously irradiated patients who had received 49 and 39 Gy for vaginal recurrence by interstitial irradiation suffered a colovaginal fistula and a rectovaginal fistula, respectively. Neither patient was a candidate for colonic diversion as they experienced a second vaginal recurrence during the period of fistula diagnosis and subsequently expired from progressive disease; it is uncertain as to whether the fistulas resulted from radiotoxicity, tumor progression, or both. Finally, one patient who had received an open interstitial implant was subsequently explored for a large bowel obstruction; a radiation stricture of the sigmoid colon was discovered and treated without colonic diversion.

DISCUSSION
Although the prognosis for patients with endometrial cancer is generally good, there nonetheless exists a subset of patients who are at risk for treatment failure, recurrence, and death. In 1991, Lurain and co-workers from Northwestern Prentice Women's Hospital in Chicago studied 264 consecutive patients with clinical stage I endometrial carcinoma and identified several prognostic factors which may influence the risk of recurrence; these included advancing patient age, histopathology, tumor grade, lymph node status, nonnodal extrauterine disease spread, peritoneal cytology, and tumor size Ͼ2 cm [30]. However, the precise selection of patients for prophylactic postoperative radiation is frustrated by the fact that 30 to 50% of the vaginal recurrences in this and other studies originate in patients who should be considered "low risk" by virtue of superficial myometrial invasion, low histologic grade, and/or no extrauterine disease at the time of primary hysterectomy.
An extensive literature has previously reported the salvage of patients with vaginal recurrence of endometrial cancer using external beam radiotherapy and conventional intracavitary brachytherapy and is listed in Table 3 [4, 10 -23]. Survival rates at 5 or more years have ranged from 20 to 60%, with an average of approximately 37%. Morgan and colleagues have reported the only series with a 5-year survival in excess of 50%; one possible explanation may lie in the fact that nearly two-thirds of their patients had vaginal recurrences of less than 2 cm in diameter [22].
In contrast, only two institutions have previously reported the use of interstitial irradiation, either alone or in combination with external beam radiotherapy, in the management of isolated vaginal relapses of endometrial carcinoma. Nag and co-workers from the Arthur G. James Cancer Hospital in Ohio and Charra and colleagues from the Centre Hospitalier Lyon-Sud in France have reported 5-year survival rates of 68 and 56%, respectively [26,27]. The present series updates this interstitial experience with a 5-year survival rate of 65% ( Table  4). Comparisons of survival rates between Tables 3 and 4 must be made cautiously, as patient selection bias may have profoundly influenced the results in many of the series, including our own. In addition, it would appear that survival rates have increased with time (see Table 3), possibly reflecting a more detailed clinical and surgical evaluation both at initial diagnosis of endometrial carcinoma and at the time of vaginal recurrence.
The treatment-related complication rate of 17% which appears in the present analysis is comparable with complication rates previously reported for vaginal recurrences treated with external beam radiotherapy and conventional intracavitary brachytherapy. Series published from 1987 to 1993 which have contained 18 to 51 patients have documented severe complications in 10 -16% of patients following treatment [18,21,22]. Although Pai and co-workers rescued fewer than 50% of patients utilizing modern high-dose-rate intracavitary brachytherapy, they observed a 25% acute complication rate and only one severe late complication attributable to radiotherapy in their series of 20 patients with vaginal recurrence [23]. As in the present series, there is a predominance of rectal and colonic toxicities distributed throughout these literatures.
The small number of patients in our study and many other published works often confounds the determination of important clinicopathologic features which influence survival following vaginal recurrence. However, some investigators have made noteworthy observations. In 1992, Podczaski and coworkers from Hershey Medical Center reported that the site of recurrence, time interval of surgery to recurrence, and use of postoperative pelvic radiotherapy were statistically related to patient prognosis [32]. In 1988, Curran and colleagues from the Fox Chase Cancer Center in Philadelphia applied a primary vaginal carcinoma staging system to vaginal recurrences of endometrial carcinoma and observed that a higher rate of pelvic control was observed for apical than for suburethral recurrences [19]. In many of the vaginal recurrence series previously cited, survival analyses often combined patients with both upper and distal vaginal relapses. Indeed, adjusting Ingersoll's data to consider only the 25 patients with apical vaginal recurrences, the 5-year survival rate increases from 48 to 64% [15]. Perhaps apical vaginal disease truly represents a different tumor biology than distal/suburethral vaginal recurrence.
It must be acknowledged that the patient population in our study is composed of a very select group. Specifically, all 30 patients underwent a thorough clinical and radiographic evaluation, which included a laparotomy in 10 patients. Thus, our group consisted of cases where disease was known with some certainty to be confined to the vagina or adjacent parametria. Patients with unrecognized extravaginal disease (e.g., pelvic sidewall disease, intra-abdominal metastases) may have contributed significantly to the relatively poor salvage rates reported in prior studies in the literature. Moreover, perhaps some failures of local radiotherapy for apparent isolated vaginal recurrences may relate to theories of vaginal recurrence which emphasize retrograde lymphatic and venous metastasis. In such cases, vaginal recurrence may represent just an external manifestation of a more ominous pelvic recurrence, because lymphatic spread and venous dissemination will probably not be restricted to the vagina.
Our data show that interstitial brachytherapy alone, or in combination with external beam radiation therapy, can effect long-term local control and cure in many patients who suffer vaginal recurrence of endometrial cancer. Whether such a treatment modality is superior to that of conventional intracavitary techniques is difficult to ascertain given the paucity of interstitial series in the literature and the highly selected nature of the present study's patient population. However, despite the fact that nearly half of the patients in our series were retreatments (i.e., 13 patients had previously received radiation therapy as part of adjunctive primary treatment), the cause of death adjusted survival rate of 65% reported here in this study of interstitial therapy was achieved with acceptable morbidity and compares favorably with that of prior published series. This should prompt further study of this treatment modality.