Possibilities of using radiotherapy in the treatment of vaginal recurrence in patients with uterine cancers

Marta Biedka1,2, Tamara Kuźba-Kryszak2, Krzysztof Koper3 Received: 29.11.2016 Accepted: 14.12.2016 Published: 30.12.2016 © Curr Gynecol Oncol 2016, 14 (4), p. 222–230 DOI: 10.15557/CGO.2016.0027 Możliwości zastosowania radioterapii w leczeniu nawrotu w pochwie u chorych z nowotworami narządu rodnego Possibilities of using radiotherapy in the treatment of vaginal recurrence in patients with uterine cancers


INTRODUCTION
A major problem in cancer treatment is disease recurrence, i.e. a situation in which the standard procedures turned out to be ineffective and the previously used therapy significantly limits its next use.Disease recurrence in the vaginal stump after cancer treatment is a relatively common phenomenon among patients with uterine cancers -its prevalence ranges between 2.4 and 15% (Tab. 1) (1) .Treatment which prevents recurrence in the vaginal stump region includes brachytherapy and/or radiotherapy as well as systemic treatment in high-risk patients (2)(3)(4)(5)(6)(7) .The vaginal stump is surrounded by at-risk organs which are very sensitive to radiotherapy such as the rectum, intestines and urinary bladder (1,5,8) , which limits therapeutic options, including the possibility of using another course of radiotherapy.Therefore, brachytherapy often remains the method of choice (9)(10)(11) .The aim of this paper is to present clinical situations in which patients with recurrence and/or metastasis in the vagina may derive significant benefit from radiation therapy and/or brachytherapy.

ROLE OF RADIOTHERAPY IN THE TREATMENT OF VAGINAL RECURRENCE
In uterine cancers the disease sometimes recurs in the vaginal stump.There are various forms of therapy; however, due to the extent of and technical difficulties involved in surgery as well as possible complications the

Nawrót w pochwie Vaginal recurrence
Leczenie chirurgiczne z dodatnim marginesem od strony pochwy Surgical treatment with a positive margin from the side of the vagina

Przetrwałe zmiany po radioterapii lub radiochemioterapii Persistent lesions following radiotherapy or radiochemotherapy
Tab. 1. Sytuacje kliniczne, w których obserwuje się nawrót choroby w pochwie Tab. 1. Clinical situations in which vaginal recurrence is observed radiation-related reactions that are acceptable for the patient while protecting critical organs.The introduction of new therapeutic devices allowed for the use of different treatment techniques, including intensity-modulated radiation therapy, image-guided radiotherapy, RapidArc, tomotherapy, intraoperative radiotherapy and stereotactic body radiotherapy, which contributed to a significant increase in the role of repeat radiotherapy.One needs to remember about the possibilities of systemic treatment, although it is usually palliative in nature.Brachytherapy may be considered for the treatment of recurrent disease if the lesions are located in the region of the vagina or vaginal stump or if infiltration is found in the parametria; in other situations treatment combined with external beam radiotherapy should always be considered.The choice of brachytherapy method depends on the location of the lesion and the extent of infiltration.If the infiltration is up to 5 mm deep, intracavitary brachytherapy is performed.If the infiltration is deeper, the use of interstitial brachytherapy is indicated.
recommended method for small tumors is brachytherapy and/or teleradiotherapy (12) .For larger tumors the recommended management of the disease is palliative treatment (11) .

External beam radiotherapy
These days extension of indications for radiotherapy, including repeat radiotherapy, has been observed.This is due to the dynamic development of techniques for planning and conducting treatment.These allow for the irradiation of the target volume which causes radiation-related reactions that are acceptable for the patient while protecting critical organs (11) .Radical treatment is sometimes impossible in patients with locally advanced abdominal and/or pelvic cancers.External beam radiotherapy (with or without chemotherapy) is often palliative in nature, which is due to the fact that it is impossible to administer a total dose of over 50 Gy safely for critical organs.For positive margins after surgery the total dose should be approximately 60 Gy and it should exceed 60 Gy in residual tumors.Therefore, for adjuvant treatment the safe doses range between 45 and 50 Gy with, however, inferior local control (13) .Fujiwara et al. (14) assessed a group of 20 single or multiple relapses in women with ovarian cancer in whom metastasis was excluded.The average number of recurrences per patient was 2 (1-5) and 44 relapse lesions were found in total in 20 individuals.The patients received radiotherapy with a total dose of 40-68 Gy at a fractionated dose of 1.6-2.0Gy.For 42 recurrences tumor regression was observed as soon as the treatment was completed and in 39 cases patients responded within 2-3 months after radiotherapy.The rate of regression was higher in patients with lesions under 5 cm and in those cases in which recurrence was found in the lymph nodes rather than other regions of the pelvis.According to the authors, in the majority of patients the disease progressed outside of the irradiated area.Every form of repeat radiotherapy is associated with a high risk of radiation-related complications, primarily involving the intestines, rectum and urinary bladder (perforations, fistulas, bleeding from dilated rectal blood vessels, vaginal obliteration, ureter fibrosis).Last century repeat radiotherapy in uterine cancer recurrences was associated with a statistically significant increase in mortality and a complication rate of 5.3-35% (15)(16)(17) .However, Sharma et al. (17) did not demonstrate any statistically significant relationship between the volume of the tumor and serious complications despite relatively large sizes of tumors -over 10 cm 3 (except for one case).New techniques for radiotherapy planning such as intensitymodulated radiation therapy (IMRT), RapidArc and tomotherapy allow for the maximum protection of critical organs while ensuring precision and short treatment time when used with techniques which visualize the position of the Nowe techniki planowania radioterapii, takie jak IMRT (intensity-modulated radiation therapy), czyli modulacja intensywności wiązki, RapidArc i tomoterapia, pozwalają na maksymalną ochronę narządów krytycznych, a jednocześnie zapewniają precyzję i krótki czas leczenia, jeśli stosuje się techniki obrazujące codziennie położenie guza -IGRT (image-guided radiation therapy), czyli radioterapię sterowaną obrazem.Wszystko to sprawia, że powtórna radioterapia staje się możliwa.

Brachytherapy
Brachytherapy may be considered for the treatment of vaginal recurrence if the lesions are located in the vagina or vaginal stump region or if infiltration is found in the parametria.

Ryc. 1. Rozkład dawki z brachyterapii w obszarze tarczowym i okolicznych tkankach
For the whole cycle of treatment between 1 and 4 single doses are administered in 5-7-day intervals (25) .Such dosing is adopted since the residual tumor is characterized by the lack of vasculature, ischemia and hypoxia, thus being resistant to standard doses of radiotherapy.For this reason, from the radiobiological point of view, in order to obtain a therapeutic effect, higher fractionated doses should be applied, which is possible with brachytherapy (26) .A problem associated with irradiation of limited areas is the fact that good control is involved only in the irradiated area.At the same time such treatment of the disease is associated with a high rate of regression and/or symptom relief and even in the case of metastasis it translates into a long time of disease stabilization.Therefore, brachytherapy is considered to be an effective form of treatment (27) .In a study by Okazawa et al. (22) in 15 patients (12 with cervical cancer and 3 with endometrial cancer) with confirmed disease recurrence permanent brachytherapy using Au-198 was introduced in the previously treated area.All patients had previously been treated with radiation and 9 of them underwent teletherapy.The mean tumor size was 1 cm and the most common locations included vaginal stump, vaginal walls and the vulva.Only 1 patient had teletherapy preceding brachytherapy.The follow-up time was 18.8 months.In 13 patients complete remission was achieved; however, in 10 of them the disease recurred again and time to recurrence ranged between 2.5 and 49.7 months.A rectovaginal fistula occurred in 1 patient 14 months after the treatment; grade 3 proctitis and grade 2 cystitis were noted in 1 patient 22 months after the implantation of brachytherapy.In no other woman were late grade 3 complications observed.

Intraoperative radiotherapy (IORT)
Intraoperative radiotherapy (IORT) is a new method for the treatment of cancer.It provides the possibility of administering a single high dose of radiation while protecting critical organs.It is always used in combination with surgery or other forms of radiotherapy (33) .Intraoperative radiotherapy has a few advantages in comparison with teletherapy.During the procedure the tumor bed is available with margins where cancer cells may have been left in the incision line.The risk of a "geographical error" is reduced and the dose applied to the skin and subcutaneous tissue is smaller.A single high dose is used in IORT, which has a larger radiobiological effect than conventional radiotherapy (33) .In a study by Tran et al. (34) 38 patients with 44 sites of disease recurrence were assessed.The mean follow-up time was 50 months.The primary locations of cancer included the uterine cervix -47%, endometrium -31%, vulva -14%, vagina -6%, fallopian tubes -3%; 72% of patients had previously been treated with radiotherapy.In 85% of women maximum cytoreduction was performed and in 18% of cases pelvic exenteration was conducted.The tumor diameter was 5 cm (0.5-12 cm) and the total dose administered during intraoperative radiotherapy was 11.52 Gy (6-17.5 Gy).Adjuvant radiotherapy was prescribed to 53% of patients and chemotherapy to 24% of patients.Five-year local control rate was 44%, distant metastasis-free survival rate was 51% and disease-free survival rate was 47%.The authors emphasize the fact that uterine cancer recurrences are associated with a poor prognosis; however, intraoperative radiotherapy can improve the prognosis, but in carefully selected groups of patients (33) .

ROLE OF SYSTEMIC THERAPY IN THE TREATMENT OF VAGINAL RECURRENCE
In patients with recurrence systemic treatment is also used, although it is usually palliative in nature.In the case of cervical cancer recurrence response to chemotherapy using cisplatin (the most active drug) is low: 17-38% (35) .In their study Mabuchi et al. administered paclitaxel with carboplatin and achieved longer progression free survival compared
to the cisplatin regimen; however, the median progressionfree survival was 7 months (36) .

ROLE OF SURGERY IN THE TREATMENT OF VAGINAL RECURRENCE
For recurrent tumors larger than 4 cm radical treatment involves pelvic exenteration surgery (1) .However, indications for exenteration are significantly limited; in addition, it is associated with a high risk of complications and a significantly compromised quality of life.Therefore, in the majority of patients the treatment of choice remains radiation therapy (19) .Kasamatsu et al. (37) estimated the 5-year-survival rate following exenteration to be 36% and the mortality associated with the procedure was 6% in their study.

PROSPECTS
The techniques of implanting and conducting brachytherapy are constantly being developed.In order to limit the risk of complications in critical organs, before a brachytherapy procedure percutaneous gel injections are used (e.g. using hyaluronic gel) in order to increase the distance between critical organs and the target for a high dose of radiation.This idea was adapted from the treatment of prostate cancer using brachytherapy (38) .The effectiveness and safety of this technique have been widely discussed; however, the ease of this procedure and the possibility of significantly reducing the dose directed at critical organs, especially in patients undergoing repeat radiotherapy, makes it a very interesting option (1) .As a result of the development of radiation therapy techniques first papers on the use of stereotactic body radiotherapy (SBRT) in patients with recurrent uterine tumors have been published (39)(40)(41) .In a large study Guckenberger et al. (39) treated 19 patients with recurrent disease using SBRT and teletherapy with or without brachytherapy.The mean size of the recurrent tumor was 4.5 cm (1.5-6.5 cm) and the rate of 3-year local control was 81% (median follow-up time: 22 months).The authors conclude that SBRT may be an appropriate method even for patients with a large recurrent tumor; however, further research is necessary.

CONCLUSION
In the recent years the role of radiation therapy for the treatment of vaginal recurrences has increased; combining various techniques may result in good local control with side effects that are acceptable for patients even after repeat radiotherapy.In recurrent and/or metastatic vaginal tumors brachytherapy alone and brachytherapy combined with teletherapy may be useful and effective methods of treatment.