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High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina

High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina Purpose: The purpose of this study was to evaluate the efficacy of HDR brachytherapy for primary or recurrent vaginal cancer. Methods: Between the years 2000 to 2006, 18 patients with primary or recurrent vaginal cancer were treated with brachytherapy (HDRB). Six patients had primary vaginal cancer (stage II to IVA) while 12 were treated for isolated vaginal recurrence (primary cervix = 4, vulva = 1 and endometrium = 7). Five patients had previous pelvic radiation therapy. All except one patient received external beam radiation therapy to a median dose of 45 Gy (range 31.2–55.8 Gy). The HDRB was intracavitary using a vaginal cylinder in 5 patients and interstitial using a modified Syed- Nesblett template in 13 patients. The dose of interstitial brachytherapy was 18.75 Gy in 5 fractions delivered twice daily. The median follow-up was 18 months (range 6–66 months). Results: Complete response (CR) was achieved in all but one patient (94%). Of these 17 patients achieving a CR, 1 had local recurrence and 3 had systemic recurrence at a median time of 6 months (range 6–22 months). The 2-year actuarial local control and cause-specific survival for the entire group were 88% and 82.5%, respectively. In subset analysis, the crude local control was 100% for primary vaginal cancer, 100% for the group with recurrence without any prior radiation and 67% for group with recurrence and prior radiation therapy. Two patients had late grade 3 or higher morbidity (rectovaginal fistula in one patient and chronic vaginal ulcer resulting in bleeding in one patient). Both these patients had prior radiation therapy. Conclusion: Our small series suggests that HDRB is efficacious for primary or recurrent vaginal cancer. Patients treated with primary disease and those with recurrent disease without prior irradiation have the greatest benefit from HDRB in this setting. The salvage rate for patients with prior radiation therapy is lower with a higher risk of significant complications. Additional patients and follow-up are ongoing to determine the long-term efficacy of this approach. Page 1 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 The HDRB was intracavitary brachytherapy for superfi- Background Primary or recurrent vaginal carcinoma is an uncommon cially invasive tumors (less than 5 mm of invasion), while tumor [1]. The initial tumor volume, tumor extent within interstitial brachytherapy was used for more deeply inva- the vagina, histologic type and grade, lymphatic involve- sive tumors greater than 5 mm. Five patients had intracav- ment and previous treatment are all important determi- itary brachytherapy utilizing Delclos Vaginal Applicators nant for overall outcome. Although surgical resection of system. Two of these patients had shielded vaginal appli- the tumor is occasionally possible, radiation therapy is cators to protect the uninvolved vaginal mucosa. Orthog- currently the standard treatment for this disease [2-6]. The onal X-ray films were obtained for planning and radiation therapy regimen includes external beam radia- verification of applicator placement. The median dose for tion therapy (EBRT), brachytherapy, or a combination intracavitary brachytherapy was 20 Gy (12 – 20 Gy) in thereof. 3–5 fractions prescribed at 0.5 cm from the surface of the applicator. One of these patients had intracavitary brach- Brachytherapy has been shown to be an important com- ytherapy only because of previous radiation therapy with ponent of treatment in these patients. Treatment selection EBRT plus HDR brachytherapy. Interstitial brachytherapy can be adapted to account for stage and location of the using a modified Syed-Nesblett template was performed tumor. It can be done with either intracavitary or intersti- in 13 patients. We have previously described this tech- tial approach. The majority of published studies with nique [13]. In brief, the procedure was performed under interstitial brachytherapy have reported data using low- general anesthesia intra-operatively and epidural analge- dose-rate brachytherapy (LDRB) [2-9]. There have been sia was used to control post-operative pain during the only few series using high-dose-rate brachytherapy course of treatment. Laparoscopic guidance was used for (HDRB) for vaginal tumors [10-12]. tumors involving the vaginal apex to avoid injury to the bladder or adjacent small bowel. CT simulation for inter- The purpose of this study was to evaluate the efficacy and stitial brachytherapy planning was performed and the toxicities of HDRB for primary or recurrent vaginal cancer. dose was prescribed to clinical target volume defined based on clinical and imaging findings at the time of Methods implantation(Figure 1). Pretreatment clinical findings Between January 2000 and December 2006, 18 patients and imaging were also taken for reference for defining the with primary or recurrent vaginal cancer were treated with target volume. The median number of needles used were HDRB. The median age was 69 yrs (range 43–88 yrs). Six 14 (range 7–18). The dose of interstitial brachytherapy patients had primary vaginal cancer (stage II – 4 patients, was 18.75 Gy in 5 fractions delivered twice daily. stage III – 1 patient and stage IV A – 1 patient). Twelve patients were treated for isolated vaginal recurrence (pri- The biologically equivalent dose (BED) in terms of equiv- mary cervix = 4, vulva = 1 and endometrium = 7). The alent doses given at 2 Gy per day (EQ2) was calculated stage and grade (G) of endometrial cancer were IB G1-1 using the LQ equation [14]. The α/β ratio was taken to be patient, IB G2-2 patients, IC G3-2 patient, IIA G 3 – 1 10 Gy for tumor effects and 3 Gy for late effects. The patient and IIB G2 – 1 patient. The median time to recur- median EQ2 for the tumor was 66.48 Gy (31.25 – 75.4 rence for all patients was 12 months (range 3 months – 18 Gy) for the entire group. The median EQ2 for the late years). Six of these patients had prior pelvic radiation ther- effects on vaginal mucosa was 75.71 Gy (55.99 – 105.99 apy. The type of previous radiation was EBRT alone 1 Gy). The cumulative EQ2 for late effects on vaginal patient, EBRT plus brachytherapy 3 patients and brachy- mucosa for four patients who had prior overlapping field therapy alone 2 patients. The median time since previous radiation was 120.7 Gy, 130.31 Gy, 142.98 Gy and radiation to recurrence was 4 years (6 months – 18 years). 154.54 Gy, respectively The recurrence was marginal (within 2 cm of previous field) in 2 patients and within the previous field in 4 The median follow-up was 18 months (range 6–66 patients. The sites of disease were proximal vagina 9 months) for the entire group. Complete response (CR) patients, distal vagina 6 patients and diffuse disease in 3 was achieved in all but one patient (94%). This one patients. patient with previous radiation therapy had recurrent pap- illary serous endometrial cancer and had partial regres- All except one patient received a combination EBRT and sion of the tumor. Of the 17 patients achieving a CR, 1 HDRB. The median dose of EBRT was 45 Gy (range had local recurrence and 3 had systemic recurrence at a 31.2–55.8 Gy) at 1.8 to 2 Gy per fraction. The technique median time of 6 months (range 6–22 months). The one of EBRT was 3D conformal in 9 patients and IMRT in 8 local recurrence was in the patient treated with previous patients. Five out of six patents with vaginal cancer also adjuvant radiation therapy for endometrioid adenocarci- had concurrent weekly cisplatinum at 40 mg/m2 along noma. Two patients have died of disease at 12 and 18 with EBRT. months, respectively. Both patients had recurrent Page 2 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 Pre- Figure 1 RT MRI image (T1 with contrast) showing large vaginal cancer with extension to pelvic side wall and peri-urethral region Pre-RT MRI image (T1 with contrast) showing large vaginal cancer with extension to pelvic side wall and peri- urethral region. Interstitial implantation showing coverage of clinical tumor volume (red) with isodose lines (100%-red, 90%- blue, 75%-yellow, and 50% – green). Page 3 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 endometrial cancer with papillary serous and carcinosar- patients in either study were treated with intracavitary coma histology, respectively. Persistence of local disease brachytherapy with only 2 patients having interstitial was noted in one of these patients. The 2-year actuarial implantation. In contrast, in our study 13/18 patients had local control, cause-specific and overall survival for the interstitial brachytherapy. The technique of intracavitary entire group was 88%, 82.5% and 78%, respectively. In is recommended for non-bulky recurrences (thickness < 5 subset analysis, the crude local control was 6/6 (100%) mm after the completion of EBRT) while interstitial for primary vaginal cancer, 6/6 (100%) for the group with brachytherapy is preferred approach for bulky recurrences recurrence without any prior radiation and 4/6 (67%) for [16]. group with recurrence and any prior radiation therapy. Interstitial brachytherapy has been traditionally per- No grade 3 or worse early toxicity was observed. Two formed using LDRB techniques in this setting. Our tech- patients had late grade 3 or 4 morbidity. One patient had nique involved one Syed-Neblett template implantation rectovaginal fistula 2 years after radiation therapy and procedure delivering 5 fractions twice a day for a total other patient had chronic vaginal ulcer with significant HDRB dose of 18.75 Gy over 48 – 56 hours. Because of narrowing and shortening of vagina (length of residual lack of published data, the American Brachytherapy Soci- vagina was about 2 cm). Both these patients had proximal ety (ABS) did not make any recommendation on HDRB vaginal disease and had prior radiation therapy and their interstitial brachytherapy dose and fractionation schedule EQ 2 for total doses were 142.98 Gy and 154 Gy, respec- for vaginal recurrences and preferred LDRB as the tech- tively. The cumulative doses were highest in these two nique for interstitial brachytherapy [16]. Our treatment patients. No other significant grade 3 or higher morbidity regimen was well tolerated with excellent local control was noted. and low toxicities in patients with no prior radiation. Discussion Similarly, there are only few published studies on HDRB Radiotherapy is the main therapeutic modality in the for primary vaginal cancer. Kusher, et al. first reported on management of primary or recurrent vaginal cancer. 19 patients treated with the combination of intracavitary Brachytherapy remains integral part of definitive radia- and interstitial brachytherapy [10]. The median HDRB tion therapy for these patients [2-9]. The preponderance dose was 23 Gy (LDR equivalent of 29.8 Gy) after median of the published literature on brachytherapy in this setting EBRT dose of 40 Gy. The 2-year progression-free survival demonstrates a wide variation on techniques and dose was 39.3% while the 2-year overall survival was 66.1%. utilized for LDRB. Although HDRB is widely available and Three patients developed serious and/or late complica- used for a variety of gynecologic malignancies, the pub- tions including urethral stenosis, painful vaginal necrosis lished data on this technique for vaginal cancer treatment and small bowel obstruction of which two had interstitial are limited. The HDR planning software offers the ability brachytherapy. The largest series of HDRB for vaginal can- to optimize the dwell time and position of the radioiso- cer is from Vienna reporting on a total of 86 patients of tope source (Ir-192) in order to create conformal radia- primary vaginal carcinoma treated with HDRB [12]. Early tion treatment to a specified target. This improvement in stages of disease (stages 0–II) were treated with intravagi- dose uniformity and ratios between tumor and normal nal HDR brachytherapy alone (n = 26/86), whereas tissue is important advantage of HDR brachytherapy. patients with locally advanced disease (stages II-IV) These advantages of HDRB over LDRB have to be weighed received HDR brachytherapy combined with external against the need to use a larger number of HDR fractions beam therapy (n = 55/86). The prescribed dose per frac- and the inconvenience of multiple implantations. tion varied from 5 Gy to 8 Gy, with a mean dose of 7 Gy. In this large series only 8 patients had interstitial brachy- In a review of the literature regarding salvage treatment therapy. The 5-year recurrence-free survival were 100%, options for vaginal recurrence, only two studies have 77%, 50%, 23%, and 0% for stage 0, I, II, III and IV respec- examined the efficacy of HDRB for treatment of vaginal tively. Chronic grade 1–4 side effects were observed in ≤ recurrences [11,15]. The study by Petignat, et al. on 22 2% (bladder, rectum) and 1%–6% (vagina). Our series patients with recurrent endometrial cancer reported local only had 6 patients of primary vaginal cancer and all had tumor control rate and the 5-year disease-specific survival interstitial brachytherapy with 2-year local control of rate of 100% and 96%, respectively [11]. Similarly, in the 100%. The toxicity profile was favorable with no grade 3 series by Pai, et al. on 20 patients, 10-year local control or higher toxicities. rate and disease-free survival rates were 74% and 46%, respectively [15]. Our study with shorter follow-up shows In LDRB literature for vaginal cancer, an inverse relation- comparable local control and cause-specific survival. The ship between the total dose and rates of local recurrences major difference between the published series and our have been reported by several authors [17,18]. Chyle, et al. data is the technique of HDRB. The majority of the noted an increasing risk of local recurrences in patients Page 4 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 a retrospective analysis of 51 patients. Int J Radiat Oncol Biol Phys who received <55 Gy when compared with those receiving 1989, 17(1):29-34. >55 Gy (53% vs. 17%) [12]. Similarly Fine, et al. reported 5. Campagnutta E, Giorda G, De Piero G, Sopracordevole F, Visentin local failures in 25%, 33% and 62% of patients for the MC, Martella L, Scarabelli C: Surgical treatment of recurrent endometrial carcinoma. Cancer 2004, 100(1):89-96. administered dose of >75 Gy, 60–75 Gy and <60 Gy 6. Barakat RR, Goldman NA, Patel DA, Venkatraman ES, Curtin JP: Pel- respectively [18]. Our median EQ2 of 66.48 Gy is compa- vic exenteration for recurrent endometrial cancer. Gynecol Oncol 1999, 75(1):99-102. rable with these doses recommended in LDRB literature. 7. Jhingran A, Burke TW, Eifel PJ: Definitive radiotherapy for Besides, our calculation of biological equivalence is based patients with isolated vaginal recurrence of endometrial car- on the assumption of complete repair of sub-lethal radia- cinoma after hysterectomy. Int J Radiat Oncol Biol Phys 2003, 56(5):1366-1372. tion damage between the two fractions [14]. With a twice- 8. Nag S, Yacoub S, Copeland LJ, Fowler JM: Interstitial brachyther- daily (BID) fractionation schedule and time interval of 6 apy for salvage treatment of vaginal recurrences in previ- hours between fractionation, the sublethal damage may ously unirradiated endometrial cancer patients. Int J Radiat Oncol Biol Phys 2002, 54(4):1153-1159. not be complete thereby causing more injury to both 9. Tewari K, Cappuccini F, Brewster WR, DiSaia PJ, Berman ML, Man- tumor and normal tissues than predicted by BED models. etta A, Puthawala A, Nisar Syed AM, Kohler MF: Interstitial brach- ytherapy for vaginal recurrences of endometrial carcinoma. Gynecol Oncol 1999, 74(3):416-422. Notwithstanding, our small series with preliminary 10. Kushner DM, Fleming PA, Kennedy AW, Wilkinson DA, Lee E, Saffle results shows that HDRB is efficacious for primary or PA: High dose rate (192)Ir afterloading brachytherapy for cancer of the vagina. Br J Radiol 2003, 76(910):719-725. recurrent vaginal cancer. The fractionation schedule used 11. Petignat P, Jolicoeur M, Alobaid A, Drouin P, Gauthier P, Provencher was well tolerated with a low incidence of acute or later D, Donath D, Van Nguyen T: Salvage treatment with high-dose- rate brachytherapy for isolated vaginal endometrial cancer toxicities. Additional patients and follow-up are ongoing recurrence. Gynecol Oncol 2000, 101(3):445-449. to determine the long-term efficacy of this approach. The 12. Mock U, Kucera H, Fellner C, Knocke TH, Pötter R: High-dose-rate limitation of our retrospective study is small size with lim- (HDR) brachytherapy with or without external beam radio- therapy in the treatment of primary vaginal carcinoma: ited follow up and heterogeneous patient population long-term results and side effects. Int J Radiat Oncol Biol Phys evaluated (inclusion of both primary and recurrent dis- 2003, 56(4):950-957. ease). The incidence of primary or recurrent vaginal cancer 13. Beriwal S, Bhatnagar A, Heron DE, Selvaraj R, Mogus R, Kim H, Gerszten K, Kelley J, Edwards RP: High-dose-rate interstitial is low so that it is difficult for a single institution to have brachytherapy for gynecologic malignancies. Brachytherapy a large series. That was the rationale to combine heteroge- 2006, 5(4):218-222. 14. Nag S, Gupta N: A simple method of obtaining equivalent neous disease together to see the efficacy and toxicities of doses for use in HDR brachytherapy. Int J Radiat Oncol Biol Phys this approach. As HDR equipment is widely available, 2000, 46(2):507-513. there are more institution doing HDR interstitial brachy- 15. Pai HH, Souhami L, Clark BG, Roman T: Isolated vaginal recur- rences in endometrial carcinoma: treatment results using therapy. We may need to consider multi-institutional high-dose-rate intracavitary brachytherapy and external pooled analysis similar to the LDR experience [19] to see beam radiotherapy. Gynecol Oncol 1997, 66(2):300-307. the impact of this technique for local control and toxici- 16. Nag S, Erickson B, Parikh S, Gupta N, Varia M, Glasgow G: The American Brachytherapy Society recommendations for ties and to define optimal fractionation schedules. high-dose-rate brachytherapy for carcinoma of the endometrium. Int J Radiat Oncol Biol Phys 2000, 48(3):779-790. 17. Fine BA, Piver MS, McAuley M, Driscoll : The curative potential of Authors' contributions radiation therapy in the treatment of primary vaginal carci- SB – Took part in design and implementation of study, noma. Am J Clin Oncol 1996, 19(1):39-44. drafted manuscript, performed statistical analysis. DEH – 18. Chyle V, Zagars GK, Wheeler JA, Wharton JT, Delclos L: Definite radiotherapy for carcinoma of the vagina: Outcome and Lead in drafting manuscript. RM – Helped in data collec- prognostic factors. Int J Radiat Oncol Biol Phys 1996, 35(5):891-905. tion. RPE – Participated in study design and patient selec- 19. Huh WK, Straughn JM, Mariani A, Podratz KC, Havrilesky LJ, Alvarez- tion. JLK – Participated in study design and patient Secord A, Gold MA, McMeekin DS, Modesitt S, Cooper AL, Powell MA, Mutch DG, Nag S, Alvarez RD, Cohn DE: Salvage of isolated selection. PS – Conceived the study, participated with vaginal recurrences in women with surgical stage I endome- design and coordinated/helped with patient selection. All trial cancer: a multiinstitutional experience. Int J Gynecol Can- cer 2007, 17(4):886-889. authors read and approved the final manuscript. Acknowledgements Source(s) of funding: Departmental. References 1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics. CA Cancer J Clin 2003, 53:5-26. 2. Greven K, Olds W: Isolated vaginal recurrences of endome- trial adenocarcinoma and their management. Cancer 1987, 60:419-421. 3. Poulsen MG, Roberts SJ: The salvage of recurrent endometrial carcinoma in the vagina and pelvis. Int J Radiat Oncol Biol Phys 1988, 15(4):809-813. 4. Kuten A, Grigsby PW, Perez CA, Fineberg B, Garcia DM, Simpson JR: Results of radiotherapy in recurrent endometrial carcinoma: Page 5 of 5 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina

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Publisher
Springer Journals
Copyright
Copyright © 2008 by Beriwal et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
eISSN
1748-717X
DOI
10.1186/1748-717X-3-7
pmid
18271958
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Abstract

Purpose: The purpose of this study was to evaluate the efficacy of HDR brachytherapy for primary or recurrent vaginal cancer. Methods: Between the years 2000 to 2006, 18 patients with primary or recurrent vaginal cancer were treated with brachytherapy (HDRB). Six patients had primary vaginal cancer (stage II to IVA) while 12 were treated for isolated vaginal recurrence (primary cervix = 4, vulva = 1 and endometrium = 7). Five patients had previous pelvic radiation therapy. All except one patient received external beam radiation therapy to a median dose of 45 Gy (range 31.2–55.8 Gy). The HDRB was intracavitary using a vaginal cylinder in 5 patients and interstitial using a modified Syed- Nesblett template in 13 patients. The dose of interstitial brachytherapy was 18.75 Gy in 5 fractions delivered twice daily. The median follow-up was 18 months (range 6–66 months). Results: Complete response (CR) was achieved in all but one patient (94%). Of these 17 patients achieving a CR, 1 had local recurrence and 3 had systemic recurrence at a median time of 6 months (range 6–22 months). The 2-year actuarial local control and cause-specific survival for the entire group were 88% and 82.5%, respectively. In subset analysis, the crude local control was 100% for primary vaginal cancer, 100% for the group with recurrence without any prior radiation and 67% for group with recurrence and prior radiation therapy. Two patients had late grade 3 or higher morbidity (rectovaginal fistula in one patient and chronic vaginal ulcer resulting in bleeding in one patient). Both these patients had prior radiation therapy. Conclusion: Our small series suggests that HDRB is efficacious for primary or recurrent vaginal cancer. Patients treated with primary disease and those with recurrent disease without prior irradiation have the greatest benefit from HDRB in this setting. The salvage rate for patients with prior radiation therapy is lower with a higher risk of significant complications. Additional patients and follow-up are ongoing to determine the long-term efficacy of this approach. Page 1 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 The HDRB was intracavitary brachytherapy for superfi- Background Primary or recurrent vaginal carcinoma is an uncommon cially invasive tumors (less than 5 mm of invasion), while tumor [1]. The initial tumor volume, tumor extent within interstitial brachytherapy was used for more deeply inva- the vagina, histologic type and grade, lymphatic involve- sive tumors greater than 5 mm. Five patients had intracav- ment and previous treatment are all important determi- itary brachytherapy utilizing Delclos Vaginal Applicators nant for overall outcome. Although surgical resection of system. Two of these patients had shielded vaginal appli- the tumor is occasionally possible, radiation therapy is cators to protect the uninvolved vaginal mucosa. Orthog- currently the standard treatment for this disease [2-6]. The onal X-ray films were obtained for planning and radiation therapy regimen includes external beam radia- verification of applicator placement. The median dose for tion therapy (EBRT), brachytherapy, or a combination intracavitary brachytherapy was 20 Gy (12 – 20 Gy) in thereof. 3–5 fractions prescribed at 0.5 cm from the surface of the applicator. One of these patients had intracavitary brach- Brachytherapy has been shown to be an important com- ytherapy only because of previous radiation therapy with ponent of treatment in these patients. Treatment selection EBRT plus HDR brachytherapy. Interstitial brachytherapy can be adapted to account for stage and location of the using a modified Syed-Nesblett template was performed tumor. It can be done with either intracavitary or intersti- in 13 patients. We have previously described this tech- tial approach. The majority of published studies with nique [13]. In brief, the procedure was performed under interstitial brachytherapy have reported data using low- general anesthesia intra-operatively and epidural analge- dose-rate brachytherapy (LDRB) [2-9]. There have been sia was used to control post-operative pain during the only few series using high-dose-rate brachytherapy course of treatment. Laparoscopic guidance was used for (HDRB) for vaginal tumors [10-12]. tumors involving the vaginal apex to avoid injury to the bladder or adjacent small bowel. CT simulation for inter- The purpose of this study was to evaluate the efficacy and stitial brachytherapy planning was performed and the toxicities of HDRB for primary or recurrent vaginal cancer. dose was prescribed to clinical target volume defined based on clinical and imaging findings at the time of Methods implantation(Figure 1). Pretreatment clinical findings Between January 2000 and December 2006, 18 patients and imaging were also taken for reference for defining the with primary or recurrent vaginal cancer were treated with target volume. The median number of needles used were HDRB. The median age was 69 yrs (range 43–88 yrs). Six 14 (range 7–18). The dose of interstitial brachytherapy patients had primary vaginal cancer (stage II – 4 patients, was 18.75 Gy in 5 fractions delivered twice daily. stage III – 1 patient and stage IV A – 1 patient). Twelve patients were treated for isolated vaginal recurrence (pri- The biologically equivalent dose (BED) in terms of equiv- mary cervix = 4, vulva = 1 and endometrium = 7). The alent doses given at 2 Gy per day (EQ2) was calculated stage and grade (G) of endometrial cancer were IB G1-1 using the LQ equation [14]. The α/β ratio was taken to be patient, IB G2-2 patients, IC G3-2 patient, IIA G 3 – 1 10 Gy for tumor effects and 3 Gy for late effects. The patient and IIB G2 – 1 patient. The median time to recur- median EQ2 for the tumor was 66.48 Gy (31.25 – 75.4 rence for all patients was 12 months (range 3 months – 18 Gy) for the entire group. The median EQ2 for the late years). Six of these patients had prior pelvic radiation ther- effects on vaginal mucosa was 75.71 Gy (55.99 – 105.99 apy. The type of previous radiation was EBRT alone 1 Gy). The cumulative EQ2 for late effects on vaginal patient, EBRT plus brachytherapy 3 patients and brachy- mucosa for four patients who had prior overlapping field therapy alone 2 patients. The median time since previous radiation was 120.7 Gy, 130.31 Gy, 142.98 Gy and radiation to recurrence was 4 years (6 months – 18 years). 154.54 Gy, respectively The recurrence was marginal (within 2 cm of previous field) in 2 patients and within the previous field in 4 The median follow-up was 18 months (range 6–66 patients. The sites of disease were proximal vagina 9 months) for the entire group. Complete response (CR) patients, distal vagina 6 patients and diffuse disease in 3 was achieved in all but one patient (94%). This one patients. patient with previous radiation therapy had recurrent pap- illary serous endometrial cancer and had partial regres- All except one patient received a combination EBRT and sion of the tumor. Of the 17 patients achieving a CR, 1 HDRB. The median dose of EBRT was 45 Gy (range had local recurrence and 3 had systemic recurrence at a 31.2–55.8 Gy) at 1.8 to 2 Gy per fraction. The technique median time of 6 months (range 6–22 months). The one of EBRT was 3D conformal in 9 patients and IMRT in 8 local recurrence was in the patient treated with previous patients. Five out of six patents with vaginal cancer also adjuvant radiation therapy for endometrioid adenocarci- had concurrent weekly cisplatinum at 40 mg/m2 along noma. Two patients have died of disease at 12 and 18 with EBRT. months, respectively. Both patients had recurrent Page 2 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 Pre- Figure 1 RT MRI image (T1 with contrast) showing large vaginal cancer with extension to pelvic side wall and peri-urethral region Pre-RT MRI image (T1 with contrast) showing large vaginal cancer with extension to pelvic side wall and peri- urethral region. Interstitial implantation showing coverage of clinical tumor volume (red) with isodose lines (100%-red, 90%- blue, 75%-yellow, and 50% – green). Page 3 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 endometrial cancer with papillary serous and carcinosar- patients in either study were treated with intracavitary coma histology, respectively. Persistence of local disease brachytherapy with only 2 patients having interstitial was noted in one of these patients. The 2-year actuarial implantation. In contrast, in our study 13/18 patients had local control, cause-specific and overall survival for the interstitial brachytherapy. The technique of intracavitary entire group was 88%, 82.5% and 78%, respectively. In is recommended for non-bulky recurrences (thickness < 5 subset analysis, the crude local control was 6/6 (100%) mm after the completion of EBRT) while interstitial for primary vaginal cancer, 6/6 (100%) for the group with brachytherapy is preferred approach for bulky recurrences recurrence without any prior radiation and 4/6 (67%) for [16]. group with recurrence and any prior radiation therapy. Interstitial brachytherapy has been traditionally per- No grade 3 or worse early toxicity was observed. Two formed using LDRB techniques in this setting. Our tech- patients had late grade 3 or 4 morbidity. One patient had nique involved one Syed-Neblett template implantation rectovaginal fistula 2 years after radiation therapy and procedure delivering 5 fractions twice a day for a total other patient had chronic vaginal ulcer with significant HDRB dose of 18.75 Gy over 48 – 56 hours. Because of narrowing and shortening of vagina (length of residual lack of published data, the American Brachytherapy Soci- vagina was about 2 cm). Both these patients had proximal ety (ABS) did not make any recommendation on HDRB vaginal disease and had prior radiation therapy and their interstitial brachytherapy dose and fractionation schedule EQ 2 for total doses were 142.98 Gy and 154 Gy, respec- for vaginal recurrences and preferred LDRB as the tech- tively. The cumulative doses were highest in these two nique for interstitial brachytherapy [16]. Our treatment patients. No other significant grade 3 or higher morbidity regimen was well tolerated with excellent local control was noted. and low toxicities in patients with no prior radiation. Discussion Similarly, there are only few published studies on HDRB Radiotherapy is the main therapeutic modality in the for primary vaginal cancer. Kusher, et al. first reported on management of primary or recurrent vaginal cancer. 19 patients treated with the combination of intracavitary Brachytherapy remains integral part of definitive radia- and interstitial brachytherapy [10]. The median HDRB tion therapy for these patients [2-9]. The preponderance dose was 23 Gy (LDR equivalent of 29.8 Gy) after median of the published literature on brachytherapy in this setting EBRT dose of 40 Gy. The 2-year progression-free survival demonstrates a wide variation on techniques and dose was 39.3% while the 2-year overall survival was 66.1%. utilized for LDRB. Although HDRB is widely available and Three patients developed serious and/or late complica- used for a variety of gynecologic malignancies, the pub- tions including urethral stenosis, painful vaginal necrosis lished data on this technique for vaginal cancer treatment and small bowel obstruction of which two had interstitial are limited. The HDR planning software offers the ability brachytherapy. The largest series of HDRB for vaginal can- to optimize the dwell time and position of the radioiso- cer is from Vienna reporting on a total of 86 patients of tope source (Ir-192) in order to create conformal radia- primary vaginal carcinoma treated with HDRB [12]. Early tion treatment to a specified target. This improvement in stages of disease (stages 0–II) were treated with intravagi- dose uniformity and ratios between tumor and normal nal HDR brachytherapy alone (n = 26/86), whereas tissue is important advantage of HDR brachytherapy. patients with locally advanced disease (stages II-IV) These advantages of HDRB over LDRB have to be weighed received HDR brachytherapy combined with external against the need to use a larger number of HDR fractions beam therapy (n = 55/86). The prescribed dose per frac- and the inconvenience of multiple implantations. tion varied from 5 Gy to 8 Gy, with a mean dose of 7 Gy. In this large series only 8 patients had interstitial brachy- In a review of the literature regarding salvage treatment therapy. The 5-year recurrence-free survival were 100%, options for vaginal recurrence, only two studies have 77%, 50%, 23%, and 0% for stage 0, I, II, III and IV respec- examined the efficacy of HDRB for treatment of vaginal tively. Chronic grade 1–4 side effects were observed in ≤ recurrences [11,15]. The study by Petignat, et al. on 22 2% (bladder, rectum) and 1%–6% (vagina). Our series patients with recurrent endometrial cancer reported local only had 6 patients of primary vaginal cancer and all had tumor control rate and the 5-year disease-specific survival interstitial brachytherapy with 2-year local control of rate of 100% and 96%, respectively [11]. Similarly, in the 100%. The toxicity profile was favorable with no grade 3 series by Pai, et al. on 20 patients, 10-year local control or higher toxicities. rate and disease-free survival rates were 74% and 46%, respectively [15]. Our study with shorter follow-up shows In LDRB literature for vaginal cancer, an inverse relation- comparable local control and cause-specific survival. The ship between the total dose and rates of local recurrences major difference between the published series and our have been reported by several authors [17,18]. Chyle, et al. data is the technique of HDRB. The majority of the noted an increasing risk of local recurrences in patients Page 4 of 5 (page number not for citation purposes) Radiation Oncology 2008, 3:7 http://www.ro-journal.com/content/3/1/7 a retrospective analysis of 51 patients. Int J Radiat Oncol Biol Phys who received <55 Gy when compared with those receiving 1989, 17(1):29-34. >55 Gy (53% vs. 17%) [12]. Similarly Fine, et al. reported 5. Campagnutta E, Giorda G, De Piero G, Sopracordevole F, Visentin local failures in 25%, 33% and 62% of patients for the MC, Martella L, Scarabelli C: Surgical treatment of recurrent endometrial carcinoma. Cancer 2004, 100(1):89-96. administered dose of >75 Gy, 60–75 Gy and <60 Gy 6. Barakat RR, Goldman NA, Patel DA, Venkatraman ES, Curtin JP: Pel- respectively [18]. Our median EQ2 of 66.48 Gy is compa- vic exenteration for recurrent endometrial cancer. Gynecol Oncol 1999, 75(1):99-102. rable with these doses recommended in LDRB literature. 7. Jhingran A, Burke TW, Eifel PJ: Definitive radiotherapy for Besides, our calculation of biological equivalence is based patients with isolated vaginal recurrence of endometrial car- on the assumption of complete repair of sub-lethal radia- cinoma after hysterectomy. Int J Radiat Oncol Biol Phys 2003, 56(5):1366-1372. tion damage between the two fractions [14]. With a twice- 8. Nag S, Yacoub S, Copeland LJ, Fowler JM: Interstitial brachyther- daily (BID) fractionation schedule and time interval of 6 apy for salvage treatment of vaginal recurrences in previ- hours between fractionation, the sublethal damage may ously unirradiated endometrial cancer patients. Int J Radiat Oncol Biol Phys 2002, 54(4):1153-1159. not be complete thereby causing more injury to both 9. Tewari K, Cappuccini F, Brewster WR, DiSaia PJ, Berman ML, Man- tumor and normal tissues than predicted by BED models. etta A, Puthawala A, Nisar Syed AM, Kohler MF: Interstitial brach- ytherapy for vaginal recurrences of endometrial carcinoma. Gynecol Oncol 1999, 74(3):416-422. Notwithstanding, our small series with preliminary 10. Kushner DM, Fleming PA, Kennedy AW, Wilkinson DA, Lee E, Saffle results shows that HDRB is efficacious for primary or PA: High dose rate (192)Ir afterloading brachytherapy for cancer of the vagina. Br J Radiol 2003, 76(910):719-725. recurrent vaginal cancer. The fractionation schedule used 11. Petignat P, Jolicoeur M, Alobaid A, Drouin P, Gauthier P, Provencher was well tolerated with a low incidence of acute or later D, Donath D, Van Nguyen T: Salvage treatment with high-dose- rate brachytherapy for isolated vaginal endometrial cancer toxicities. Additional patients and follow-up are ongoing recurrence. Gynecol Oncol 2000, 101(3):445-449. to determine the long-term efficacy of this approach. The 12. Mock U, Kucera H, Fellner C, Knocke TH, Pötter R: High-dose-rate limitation of our retrospective study is small size with lim- (HDR) brachytherapy with or without external beam radio- therapy in the treatment of primary vaginal carcinoma: ited follow up and heterogeneous patient population long-term results and side effects. Int J Radiat Oncol Biol Phys evaluated (inclusion of both primary and recurrent dis- 2003, 56(4):950-957. ease). The incidence of primary or recurrent vaginal cancer 13. Beriwal S, Bhatnagar A, Heron DE, Selvaraj R, Mogus R, Kim H, Gerszten K, Kelley J, Edwards RP: High-dose-rate interstitial is low so that it is difficult for a single institution to have brachytherapy for gynecologic malignancies. Brachytherapy a large series. That was the rationale to combine heteroge- 2006, 5(4):218-222. 14. Nag S, Gupta N: A simple method of obtaining equivalent neous disease together to see the efficacy and toxicities of doses for use in HDR brachytherapy. Int J Radiat Oncol Biol Phys this approach. As HDR equipment is widely available, 2000, 46(2):507-513. there are more institution doing HDR interstitial brachy- 15. Pai HH, Souhami L, Clark BG, Roman T: Isolated vaginal recur- rences in endometrial carcinoma: treatment results using therapy. We may need to consider multi-institutional high-dose-rate intracavitary brachytherapy and external pooled analysis similar to the LDR experience [19] to see beam radiotherapy. Gynecol Oncol 1997, 66(2):300-307. the impact of this technique for local control and toxici- 16. Nag S, Erickson B, Parikh S, Gupta N, Varia M, Glasgow G: The American Brachytherapy Society recommendations for ties and to define optimal fractionation schedules. high-dose-rate brachytherapy for carcinoma of the endometrium. Int J Radiat Oncol Biol Phys 2000, 48(3):779-790. 17. Fine BA, Piver MS, McAuley M, Driscoll : The curative potential of Authors' contributions radiation therapy in the treatment of primary vaginal carci- SB – Took part in design and implementation of study, noma. Am J Clin Oncol 1996, 19(1):39-44. drafted manuscript, performed statistical analysis. DEH – 18. Chyle V, Zagars GK, Wheeler JA, Wharton JT, Delclos L: Definite radiotherapy for carcinoma of the vagina: Outcome and Lead in drafting manuscript. RM – Helped in data collec- prognostic factors. Int J Radiat Oncol Biol Phys 1996, 35(5):891-905. tion. RPE – Participated in study design and patient selec- 19. Huh WK, Straughn JM, Mariani A, Podratz KC, Havrilesky LJ, Alvarez- tion. JLK – Participated in study design and patient Secord A, Gold MA, McMeekin DS, Modesitt S, Cooper AL, Powell MA, Mutch DG, Nag S, Alvarez RD, Cohn DE: Salvage of isolated selection. PS – Conceived the study, participated with vaginal recurrences in women with surgical stage I endome- design and coordinated/helped with patient selection. All trial cancer: a multiinstitutional experience. Int J Gynecol Can- cer 2007, 17(4):886-889. authors read and approved the final manuscript. Acknowledgements Source(s) of funding: Departmental. References 1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics. CA Cancer J Clin 2003, 53:5-26. 2. Greven K, Olds W: Isolated vaginal recurrences of endome- trial adenocarcinoma and their management. Cancer 1987, 60:419-421. 3. Poulsen MG, Roberts SJ: The salvage of recurrent endometrial carcinoma in the vagina and pelvis. Int J Radiat Oncol Biol Phys 1988, 15(4):809-813. 4. Kuten A, Grigsby PW, Perez CA, Fineberg B, Garcia DM, Simpson JR: Results of radiotherapy in recurrent endometrial carcinoma: Page 5 of 5 (page number not for citation purposes)

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Published: Feb 13, 2008

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