Vaginal intraepithelial neoplasia (VAIN), a rare premalignant condition, is difficult to eradicate. We assess the effectiveness of high-dose rate intracavitary brachytherapy (HDR-ICR) in patients with VAIN or carcinoma
We reviewed 34 patients treated for posthysterectomy VAIN or CIS of the vagina by brachytherapy as the sole treatment. All patients underwent a coloposcopic-directed punch biopsy or had abnormal cytology, at least 3 consecutive times. All patients were treated with a vaginal cylinder applicator. The total radiation dose was mainly 40 Gy in 8 fractions during the periods of 4 weeks at a prescription point of the median 0.2 cm (range, 0 to 0.5 cm) depth from the surface of the vaginal mucosa.
Acute toxicity was minimal. Seven patients had grade 1/2 acute urinary and rectal complications. There were 15 cases of late toxicity, predominantly vaginal mucosal reaction in 12 patients. Of these patients, two patients suffered from grade 3 vaginal stricture and dyspareunia continuously. After a median follow-up time of 48 months (range, 4 to 122 months), there were 2 recurrences and 2 persistent diseases, in which a second-line therapy was needed. The success rate was 88.2%. The average prescription point in failure patients was 1.1 mm from the surface of the vagina compared to an average of 2.6 mm in non-recurrent patients (p=0.097).
HDR-ICR is an effective treatment method in VAIN patients. In spite of high cure rates, we should consider issues regarding vaginal toxicity and radiation techniques to reduce the occurrence of failure and toxicity.
Vaginal intraepithelial neoplasia (VAIN) or carcinoma
The most important risk factor to consider for VAIN is a history of cervical neoplasia, which is also caused by an human papillomavirus infection [
Although the best treatment option for VAIN is uncertain, there are various choices, including partial or total colpectomy, laser ablation, cavitational ultrasonic surgical application, vaginectomy, topical application of 5-fluorouracil, and brachytherapy [
Here, we report a single institution study of the application of high-dose-rate intracavitary brachytherapy (HDR-ICR) for the treatment of VAIN.
We retrospectively reviewed the medical charts to evaluate the clinical usefulness of HDR-ICR for the treatment of VAIN. Between December 1998 and January 2011, 34 patients were treated for post-hysterectomy VAIN at Seoul St. Mary's Hospital. All patients had previous history of total hysterectomy, developed VAIN or CIS of the vagina, and were treated with brachytherapy as the sole treatment.
The diagnosis was based on repeated vaginal smears or on vaginal biopsies performed during a colposcopic procedure. All included patients who had not undergone a colposcopic-directed punch biopsy had no definite visible lesion that could be biopsied and had abnormal cytology results at least 3 consecutive times.
All patients were treated with HDR-ICR delivered by a remotely controlled afterloading system (micro Selectron) with a train of iridium-192 source. In all patients, a cylinder applicator was used to irradiate most parts of the whole vagina. The exact length of the vagina included in the treatment field was decided by the site and the number of lesions. The median prescription point was 0.2 cm (range, 0 to 0.5 cm) in depth to the surface of the vaginal mucosa. The radiation dose was mainly 40 Gy in 8 fractions during the periods of 4 weeks. Five cases were treated with other dose schedules (
The radiation plan was accepted when the dose to the rectum and bladder was below 80% of the prescription dose. The bladder point was marked at the center of the radio-opaque contrast filled Foley catheter balloon on the frontal radiograph and at the posterior surface of the balloon on the lateral radiograph following the Internaltional Committee on Radiation Units and Measurements (ICRU) report No. 38. The rectal reference was defined at the closest point from the applicator on the anterior wall of the rectum, defined by a barium contrast radiograph (
All patients underwent radiation therapy on an outpatient basis, by the benefit of good performance status. Subsequent follow-up included clinical, cytological, and colposcopic assessments at intervals of 3 to 6 months. Toxicity grade was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0.
The clinical and treatment features are summarized in
Three patients had a history of previous external radiation therapy for cervical cancer treatment. They received an external radiation therapy as an adjuvant purpose, and one of these patients received concurrent chemotherapy. The radiation dose was 50.4 Gy in 28 fractions for two patients and 49.3 Gy in 29 fractions for one patient. The time interval between external radiation and brachytherapy was 17.5, 75.2, and 139.5 months in each of the three patients.
All patients tolerated well, and treatment interruption was not necessary for any patient. Complications are summarized in
There were 15 cases of late toxicity, predominantly vaginal mucosa reaction in 12 patients. Of these patients, 10 patients received hormone replacement and the symptom subsided. Two patients continuously complained of grade 3 vaginal stricture and dyspareunia, and needed consistent special gynecologic care. Rectal complication occurred in 2 patients, 6-9 months after treatment that were both grade 2 rectal bleeding. The symptom was mild, did not require any further treatment and subsided within 3 months. One patient had grade 3 cystitis and was hospitalized three times.
After a median follow-up time of 48 months (range, 4 to 122 months), all patients were alive at the last follow up. However, there were 2 recurrences and 2 persistent diseases. The success rate was 88.2%. Both recurred patients relapsed in low grade VAIN, 2 years and 7 months after the brachytherapy respectively. Two persistent disease patients had continuous abnormal cytology. One patient was successfully treated with second-line brachytherapy. The other patient did not receive any further treatment at the last follow-up. There were no patients who developed invasive vaginal carcinoma. During the follow-up, there were 6 cases of repeated abnormal cytology, which was confirmed as benign inflammation from a biopsy. All these patients showed some symptoms of vaginal complication.
There was no definite risk factor of recurrence. The prescription point in failure patients was on average 1.1 mm from the surface of the vagina compared to an average of 2.6 mm in non-recurrent patients, but this was not statistically significant (p=0.097).
The patient who suffered from grade 3 cystitis had a history of radiation (50.4 Gy of external radiation and 30 Gy of brachytherapy) 12 years ago in the course of treatment for cervical cancer. However, we failed to define a dose-toxicity relationship in these patients with vaginal or rectal complications.
There are many controversies regarding the management of VAIN due to the rarity of the disease. There exists a debate of whether it is appropriate to treat VAIN patients aggressively. The main risk of VAIN is the possibility of progression to invasive vaginal carcinoma. Aho et al. [
The second issue is which treatment option is the best. There yet exists a randomized control study comparing the different treatment methods. Surgical excision, laser ablation, ultrasonic surgical aspiration, vaginectomy, radiation therapy and topical 5-fluorouracil (5-FU) are the options that are widely used at present [
In spite of the high cure rate, the toxicity of brachytherapy should always be considered. It is difficult to draw a conclusion from only several studies due to various radiation doses, different toxicity reporting systems, and limitation in the retrospective nature of the studies. However, it seems that a clear acute toxicity is minimal and almost always self-limiting. In all studies, the treatment was well tolerated and no limiting toxicities were encountered. The major late toxicity is vaginal toxicity, such as stenosis and ulcer. Graham et al. [
Analyzing their simulation films, they received the whole pelvis irradiation with the lower border at the bottom line of the obturator foramen level. This suggests that those previous external radiations had not included the entire vagina because of the patient's young age. In patients whose lower border was the tuberosity of the ischium, treatment options, other than brachytherapy, were selected. Another point to consider with regard to them is that we prescribed the tumor dose at the vaginal surface (0 mm depth from vaginal cylinder) rather than 2 to 5 mm in depth to the surface of the vaginal mucosa at the time of brachytherapy planning. In spite of careful patient selection and the efforts to reduce the toxicities in these patients, we should keep in mind that there can be a potential risk of complication in patients who had previous external pelvic irradiation.
Considering the toxicities of brachytherapy, this treatment option for low grade (grade 1 or 2) VAIN can be an aggressive and inconvenient approach. Although topical 5-FU, laser ablation or even observation can be a treatment option for low grade VAIN [
Lastly, we should consider a radiation technique. It seems that both low-dose-rate (LDR) and HDR brachytherapy show a similar high successful rates in VAIN (
The second issue to consider in radiation technique is which intracavitary brachytherapy (ICR) device should be used. There are a number of ICR devices designed for treating the vagina. Although ovoid has an advantage to concentrate the dose on the upper vagina, there is a risk of underdosing the dysplastic changes that can be involved with the entire vagina. In contrast, cylinder has an advantage of treating the entire vagina uniformly. However, treating the entire vagina is correlated with high rates of late toxicity, especially the urethral necrosis [
Third, there can be an argument of prescription point and dose. MacLeod et al. [
The outcome of this study shows that HDR-ICR is an effective treatment method in VAIN patients. In spite of high cure rates, we should consider issues regarding vaginal toxicity and radiation techniques to reduce the occurrence of failure and toxicity. More basically, because no national or international guidelines exist for the management of VAIN, the choice of treatment modality should be decided carefully.
Conflict of interest relevant to this article was not reported.
Antero-posterior and lateral simulation films of cylinder insertion. The rectal point and bladder point is marked on the films.
Patient and treatment characteristics
Characteristic | No. (%) |
---|---|
Median age (range, yr) | 53 (33-71) |
Reason of hysterectomy | |
CIN or CIS | 13 (38.2) |
Cervical cancer | 9 (26.5) |
Benign disease | 12 (35.3) |
Duration between hysterectomy |
|
Cervical neoplasia patients | 12.1 |
Benign disease patients | 137.1 |
Previous radiation therapy on pelvis (+) | 3 (8.8) |
Biopsy result | |
No biopsy (only positive cytology) | 9 (26.5) |
VAIN grade 1 | 6 (17.6) |
VAIN grade 2 | 6 (17.6) |
VAIN grade 3 | 11 (32.4) |
Carcinoma |
2 (5.9) |
Radiation prescription point (from surface) | |
0 cm | 7 (20.6) |
0.2 cm | 13 (38.2) |
0.3 cm | 7 (20.6) |
0.5 cm | 7 (20.6) |
Radiation dose | |
500 cGy×6 fractions | 2 (5.9) |
500 cGy×8 fractions | 27 (79.4) |
500 cGy×10 fractions | 2 (5.9) |
700 cGy×4 fractions | 3 (8.8) |
CIN, cervical intraepthelial neoplasia; CIS, carcinoma
Complication of treatment
Urinary | Rectal | Vaginal | |
---|---|---|---|
Frequency/dysuria | Frequent defecation | Vaginal discharge | |
Acute toxicity | |||
Grade 1-2 | 5 | 2 | 1 |
Grade 3 or more | - | - | |
Cystitis | Bleeding | Inflammation/stricture | |
Late toxicity | |||
Grade 1-2 | - | 2 | 10 |
Grade 3 or more | 1 | - | 2 |
The grade of toxicity was recorded according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0.
Brachytherapy studies for vaginal intraepithelial neoplasa (VAIN)
Author | Methods | No. of |
Included |
Follow-up |
Dose/Fraction |
Success |
Late complication (n) | ||
---|---|---|---|---|---|---|---|---|---|
Vaginal | Rectal | Bladder | |||||||
Woodman et al. (1988) [6] |
LDR | 11 | VAIN 3 | 25 | 27-51 Gy (1) | 100 | G2 (6) |
N/A | N/A |
Blanchard et al. (2011) [11] |
LDR | 28 | VAIN 3 | 41 | 60 Gy (0.5) | 93 | G1 (7) | G1, 2 (4) | 0 |
Graham et al. (2007) [10] |
MDR | 22 | VAIN 3 | 77 | 48 Gy/ |
86.4 | G3 (4) |
G1, 2 (3) | G2 (2) |
MacLeod et al. (1997) [9] |
HDR | 14 | VAIN 3 | 46 | 34-45 Gy/ |
85.7 | G1, 2 (12) |
0 | 0 |
Ogino et al. (1998) [8] | HDR | 14 |
CIN 3 |
90.5 | 20-30 Gy/ |
100 | G3 (2) | G1, 2 (5) | N/A |
Teruya et al. (2002) [7] |
HDR | 13 | CIS | 127 | 30-36 Gy (1) |
100 | G1,2 (11) |
G2 (2) | G2 (1) |
Present study |
HDR | 34 | All VAIN | 48 | 30-50 Gy (0-1) | 88.2 | G1,2 (10) |
G1, 2 (2) | G3 (1) |
LDR, low-dose-rate; N/A, not available; MDR, middle-dose rate; HDR, high-dose rate; CIN, cervical intraepthelial neoplasia; CIS, carcinoma