Targeted, adaptive radiotherapy against cervical cancer

Image-guided brachytherapy can deliver very high doses of radiation, which prevent the tumour from growing in over 90 percent of cervical cancer patients, with fewer side-effects than standard radiotherapy,  researchers said at the 2nd Forum of the European Society for Radiotherapy and Oncology (ESTRO).

One of the problems with radiotherapy for cervical cancer is that the vagina receives a high dose of radiotherapy, which can cause symptoms such as vaginal dryness, vaginal narrowing and shortening, with a loss of flexibility (stenosis), mucositis, or bleeding. One of the most serious but rare complications of this procedure is vaginal fistula. The bowel and bladder can also be affected by radiotherapy for cervical cancer.

Image-guided brachytherapy involves delivering radiotherapy to the tumour by placing a radioactive source in an applicator, positioned internally in the tumour region. Imaging, either by repeated computer tomography (CT) scans or preferably magnetic resonance imaging (MRI), is used at the time of brachytherapy in order to delineate both the tumour and organs at risk in relation to the applicator. This enables radiation oncologists to measure and evaluate the tumour response to the treatment, and adjust the dose accordingly, while sparing surrounding organs.

However, until now, there have been few studies investigating the relationship between the dose of radiotherapy and the effects it has on the vagina during brachytherapy for cervical cancer, according to Ms Kathrin Kirchheiner, PhD student in the Department of Radiotherapy at the Medical University Vienna, Austria, reporting on the international, multi-centre prospective clinical trial EMBRACE (European and international study on MRI-guided brachytherapy in locally advanced cervical cancer) at the ESTRO meeting.

“The EMBRACE study has followed 523 patients in 19 centres for an average of 14 months to establish a benchmark for clinical outcomes with regard to control of the tumour’s growth, patient survival, adverse effects of treatment and quality of life,” said Ms Kirchheiner.

Patients with cervical cancer that had started to spread from the original site to nearby tissues and lymph nodes (locally advanced cancer) underwent external beam radiotherapy, chemotherapy and MRI-guided brachytherapy. The vagina and the effects of the treatment on it (morbidity) were assessed at the start of treatment, every three months afterwards for the first year, once every six months in the second and third year, and annually thereafter. MRI was used to assess the amount of dose being delivered to the upper part of the vaginal wall.

“Our results show that severe vaginal side-effects are rare,” said Ms Kirchheiner. “The majority of patients are likely to experience mild to moderate (grade I or II) vaginal morbidity in the first two years after the end of treatment. The most frequently reported symptom is vaginal shortening and narrowing in the upper vagina. We performed a dose response analysis to measure the relationship between the amount of dose delivered to the upper vaginal wall and the probability of vaginal morbidity and found that with increasing dose to this region, the probability for moderate vaginal morbidity increases significantly.”

This is the first time that the occurrence of mild and moderate side-effects on the vagina have been systematically recorded and related to the amount of radiation dose in this way. “This is important for patients because studies on their quality of life have shown that mild and moderate vaginal symptoms and associated sexual dysfunction can cause long-term distress in cervical cancer survivors, but until now a clear dose response relationship had not been established.

“Brachytherapy is an essential part of the curative treatment of locally advanced cervical cancer, because of the high dose that can be delivered to the tumour while sparing organs at risk of damage from the treatment. With the possibility of dose adaptation and optimisation in image guided adaptive brachytherapy, a highly individualised and tailored treatment has become possible, comparable to the targeted, personalised therapies in medical oncology,” concluded Ms Kirchheiner.

 

Dose-response relationship

Another presentation at the meeting described a second study, which looked at data on 592 cervical cancer patients undergoing external beam radiotherapy, chemotherapy and image-guided adaptive brachytherapy (IGABT) based on MRI or CT scans.

The study, carried out by associate professor Kari Tanderup of the Department of Oncology at Aarhus University Hospital in Denmark, showed clearly that the higher the dose of brachytherapy, the better the tumour’s response, allowing the achievement of local control in over 90 percent of cases of patients undergoing adaptive brachytherapy.

The study also shows that brachytherapy gives the opportunity for administration of higher doses where the tumour demands it, something which is not possible with external beam radiotherapy as it will increase the dose to critical organs significantly.

A dose-response relationship is evidenced by this study. This has not been clearly defined in the past, as brachytherapy had been previously based on planning rather than 3D imaging with the invaluable help of CT and MRI scans. Prof Tanderup said: “Retro-EMBRACE makes it possible for institutions to change their dose prescription in order to optimise the balance between local control and adverse side-effects; and it demonstrates that the adaptive target concept which has been developed for MRI-guided brachytherapy is robust in a multi-centre setting.”

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