Vaginal brachytherapy alone is sufficient adjuvant treatment of surgical stage I endometrial cancer,
Solhjem MC, Petersen IA, Haddock MG.     IJROBP 2005;62:1379-1384

To determine the efficacy and complications of adjuvant vaginal high-dose-rate brachytherapy alone for patients with Stage I endometrial cancer in whom complete surgical staging had been performed.  Between April 1998 and March 2004, 100 patients with Stage I endometrial cancer underwent surgical staging (total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic paraaortic nodal sampling) and postoperative vaginal high-dose-rate brachytherapy at our institution.

The total dose was 2100 cGy in three fractions. Results With a median follow-up of 23 months (range 262), no pelvic or vaginal recurrences developed. All patients underwent pelvic dissection, and 42% underwent paraaortic nodal dissection. The International Federation of Gynecology and Obstetrics stage and grade was Stage IA, grade III in 5; Stage IB, grade I, II, or III in 6, 27, or 20, respectively; and Stage IC, grade I, II, or III in 13, 17, or 10, respectively. The Common Toxicity Criteria (version 2.0) complications were mild (Grade 12) and consisted primarily of vaginal mucosal changes, temporary urinary irritation, and temporary diarrhea. Conclusion Adjuvant vaginal high-dose-rate brachytherapy alone may be a safe and effective alternative to pelvic external beam radiotherapy for surgical Stage I endometrial cancer.

Endometrial carcinoma is the most common gynecologic malignancy and fourth most common cancer in women, affecting an estimated 40,320 women in 2004 . Approximately 75% of patients have uterus-confined (International Federation of Gynecology and Obstetrics [FIGO] Stage I) disease at diagnosis . The current standard treatment for Stage I disease is surgical removal of the uterus, fallopian tubes, and ovaries (total abdominal hysterectomy, bilateral salpingo-oophorectomy [TAH/BSO]) with or without adjuvant radiotherapy (RT).

Adjuvant RT is recommended based on the perceived risk of disease recurrence in the pelvic lymph nodes and/or vagina. Surgical-pathologic studies have shown that the risk of pelvic nodal disease increases mainly with increasing depth of myometrial invasion and greater pathologic grade. In Creasman, the pelvic nodal risk ranged from 0% for low-grade tumors not invading the myometrium to 34% for high-grade tumors invading the outer one-third of the myometrium.

In two large randomized trials, adjuvant pelvic external beam RT (EBRT) alone significantly decreased the pelvic and vaginal recurrence rate compared with no further treatment. Recently published data from the Gynecologic Oncology Group (GOG)-99 study  and Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study  revealed that most pelvic recurrences after surgery and pelvic EBRT are located in the vagina. GOG-99 found that pelvic EBRT reduced the risk of any recurrence by 58%. The authors suggested that the substitution of whole pelvis EBRT with vaginal vault brachytherapy might result in a similar reduction in recurrence.

Whole pelvis EBRT can have significant acute and long-term side effects, such as diarrhea, small bowel obstruction, and bowel damage, and it may increase the risk of post-lymphadenectomy lower extremity lymphedema. High-dose-rate (HDR) brachytherapy, in contrast, has very few side effects. Another advantage of brachytherapy is that it is given in only a few treatments, whereas EBRT requires 2528 treatments during a 56-week period.

At our institution, patients with Stage I endometrial cancer typically undergo complete pelvic and paraaortic lymph node dissection. Assuming that patients with negative nodes after surgery may be at a very low risk of extravaginal pelvic recurrence, vaginal HDR brachytherapy without pelvic EBRT has been used since 1997 in surgical Stage I patients when adjuvant RT has been recommended. This study reports the data on this series of patients.

The HDR brachytherapy procedure was well-tolerated by the patients. Treatment-related side effects are listed. No Common Toxicity Criteria (version 2.0) Grade 34 toxicity occurred. The side effects were mild (Common Toxicity Criteria Grade 12) and consisted of transient vaginal mucositis (17%), vaginal cuff telangiectasia (14%), vaginal atrophy, stricture, or adhesions (16%), dyspareunia (5%), temporary urinary irritation (9%), and temporary diarrhea (9%). Four patients had mild intermittent urinary incontinence after treatment, possibly related to surgery, brachytherapy, or other unidentified factors.

The results of our study have confirmed previous findings and added to the body of literature showing the high efficacy and low morbidity of adjuvant HDR brachytherapy alone for intermediate-risk Stage I endometrial cancer. To date, no published prospective randomized trials have compared pelvic EBRT and HDR vaginal brachytherapy as adjuvant therapy for early-stage endometrial cancer. However, an ongoing randomized trial (PORTEC 2) in Europe is comparing pelvic EBRT and HDR vaginal brachytherapy. Results from this study will not be available for many years.

The recent Dutch PORTEC trial included an analysis of survival after vaginal relapse of endometrial cancer and showed that, after vaginal recurrence, the 5-year survival rate was only 65% when relapsed patients were treated curatively with RT and/or surgery . GOG-99  found that 5 (38%) of 13 patients with vaginal recurrence after surgery (in the no-radiation arm) died as a result of their endometrial cancer. Other studies have found worse 5-year survivals after salvage therapy for isolated vaginal recurrences, ranging from 20% to 69% . On the basis of these results, it seems preferable to treat selected patients initially with adjuvant HDR brachytherapy, given its minimal morbidity and high efficacy, rather than observe and attempt salvage therapy when vaginal recurrence occurs. In our series and others, the vaginal recurrence rate after HDR brachytherapy was 01%. Salvage RT (pelvic EBRT with or without brachytherapy) is associated with significantly more morbidity than adjuvant HDR brachytherapy, given the need for greater radiation doses and larger treatment volumes. Adjuvant pelvic EBRT, as demonstrated in GOG-99, can result in significantly greater Grade 3 to 4 morbidity compared with no treatment (7.9% vs. 1.0%).

The most common side effects of vaginal RT were vaginal changes seen on follow-up pelvic examinations (i.e., mucosal telangiectasia, atrophy, stricture, or adhesions). Most of these changes were not bothersome to the patient. Vaginal mucositis occurred in 17 patients. Dyspareunia was occasionally bothersome and may have improved with regular use of a vaginal dilator. About 20% of patients had temporary vaginal discharge and/or mild bleeding after brachytherapy.

The long-term side effects were not available for our series because of the short follow-up. However, it is unlikely that the toxicity of HDR brachytherapy will approach that of pelvic EBRT in terms of bowel obstruction or damage. The radiation dose distribution is more localized with HDR brachytherapy, conforming to the shape of the vagina. Thus, the dose to the small bowel is negligible. Also, the rectal dose is kept below a threshold to avoid long-term rectal complications. The PORTEC trial found a 2% incidence of Grade 34 gastrointestinal toxicity after pelvic EBRT.

The published English data on early-stage endometrial cancer and adjuvant HDR brachytherapy has been summarized. Multiple, single-institution studies have found the pelvic and vaginal recurrence rate after HDR brachytherapy to be 04% and 02.3%, respectively. In all, of 2042 patients, only 16 vaginal recurrences have been reported (0.78%) with adjuvant HDR brachytherapy alone. In addition, only 12 pelvic recurrences (1.1%) occurred in 1128 patients, excluding series with unspecified numbers of pelvic recurrences.

The results of our study have confirmed previous findings and added to the body of literature showing the high efficacy and low morbidity of adjuvant HDR brachytherapy alone for intermediate-risk Stage I endometrial cancer. To date, no published prospective randomized trials have compared pelvic EBRT and HDR vaginal brachytherapy as adjuvant therapy for early-stage endometrial cancer. However, an ongoing randomized trial (PORTEC 2) in Europe is comparing pelvic EBRT and HDR vaginal brachytherapy. Results from this study will not be available for many years.

A recent survey of radiation oncologists revealed that only 5% treat the entire vagina  with HDR brachytherapy in the adjuvant setting and 95% treat either the upper third or half of the vagina. It has been our practice to treat most of the vagina to within 12 cm of the urethral meatus. This has been based on retrospective studies showing that approximately one-third of vaginal recurrences occur in the suburethral region below the cuff. In addition, in the recent PORTEC trial, 2937% of vaginal recurrences occurred in the distal vagina. Given the minimal vaginal morbidity seen in our patients treated with HDR brachytherapy alone, it may be advantageous to treat most of the vagina to prevent potential recurrences in the distal vagina, as well as the cuff.

Our results may not be directly applicable to the patient with minimal or absent lymph node sampling. Our patients, in contrast, have undergone extensive nodal dissections frequently with ≥30 nodes removed from the pelvis. On the basis of the absence of pelvic nodal relapse in this series, it can be assumed that these patients were at a very low risk of developing an extravaginal pelvic recurrence. However, patients with minimal or absent staging may be at greater risk of pelvic nodal relapse. Selected patients in retrospective series have been treated with vaginal brachytherapy alone. Six of the studies included patients with no surgical staging and only 6 of 775 patients developed a vaginal recurrence after HDR vaginal brachytherapy alone. However, patients who have not undergone complete surgical staging and have significant risk of lymph node involvement should be considered for treatment with EBRT because of the randomized GOG study.

To date, no published randomized comparison of pelvic EBRT vs. HDR vaginal brachytherapy or HDR vaginal brachytherapy vs. observation as adjuvant therapy for Stage I endometrial cancer has been done. However, the ongoing PORTEC 2 trial results will hopefully be available within the next decade. Future research should prospectively evaluate HDR vaginal brachytherapy and quality-of-life concerns.