Brachytherapy and Chemoradiation for Cervical Cancer

Brachytherapy places a radiation source inside or directly next to the tumour, through a temporary implant or applicator, so a very high dose reaches the tumour while the dose to surrounding organs falls off quickly. Brachytherapy for cervical cancer follows external beam radiotherapy, and together with concurrent chemotherapy it is the standard curative treatment for locally advanced disease.

Dr. Garima Singh, Principal Consultant - Radiation Oncology, BLK-Max Super Speciality Hospital, New Delhi, India, used gynaecological cancers to show how radiotherapy is delivered and how it is combined with surgery and chemotherapy. Her answers to Prof. Dr. Philip Njemanze on when to integrate chemotherapy with radiation, and on whether imaging or cell type weighs more in the decision, set out a stage-by-stage framework that referring doctors can apply. The broader technology story is in the complete guide to advances in radiation oncology.

Two components: external beam radiotherapy and brachytherapy

Radiotherapy for cervical cancer has two parts, given in sequence.

1. External beam radiotherapy (EBRT): in the case Dr. Singh presented, phase 1 was 45 to 50 Gy delivered in 25 sessions to the pelvis.
2. Intracavitary brachytherapy: the boost to the tumour itself.

The reason for the second phase is the balance at the heart of all radiotherapy. The bladder in front of the cervix and the rectum behind it limit how much dose an external beam can safely give. To improve tumour control while reducing bladder and rectal toxicity, the dose to the tumour has to be optimised, and intracavitary brachytherapy is what makes that possible. Placing the source inside the uterus and vagina puts the highest dose exactly where the tumour is.

How intracavitary brachytherapy for cervical cancer works

Dr. Singh's centre uses a high-dose-rate afterloading brachytherapy unit. The standard applicator for cervical cancer is the Fletcher-Suit applicator, which has two parts:

• The intrauterine tandem, a tube placed inside the uterus through the cervix.
• The ovoids, which sit in the vaginal fornices on either side of the cervix.

Once the applicator is in position, the radiation source is passed through it by the machine, delivering a high dose to the cervix and the tissue around it.

For other situations, other applicators are used. After surgery for endometrial cancer, her centre uses a vaginal applicator to treat the vaginal vault.

Afterloading versus preloaded sources

Prof. Njemanze asked about the role of radioactive beads or seeds implanted in the tumour. Dr. Singh answered with the history of the technique. When brachytherapy was first developed for cervical cancer, the sources were preloaded: the radioactive source itself had to be implanted inside the tumour.

The technology has since moved to afterloading. The empty Fletcher-Suit applicator is placed first, and the machine then transfers the source into the tandem and ovoids. Her centre performs afterloading brachytherapy. Remote afterloading also means staff are not exposed to the source while the applicator is positioned.

Interstitial brachytherapy with MUPIT: when needles are needed

When the tumour cannot be adequately covered from inside the uterus and vagina, needles are placed directly through the tissue. Dr. Singh's centre uses MUPIT, the Martinez Universal Perineal Interstitial Template, a perineal template that guides interstitial needles into the tumour. She listed the situations where it is needed in cervical cancer:

• Disease in the lower third of the vagina.
• Involvement of the lateral parametrium, the tissue at the side of the cervix.
• Distorted anatomy, where the cervical os cannot be negotiated and an intracavitary applicator cannot be placed properly.

Bulky residual disease after external beam radiotherapy is another recognised indication for interstitial brachytherapy.

Cervical cancer staging: clinical examination plus MRI

Every treatment decision in cervical cancer starts from the stage, and Dr. Singh was precise about how the stage is set. Prof. Njemanze asked whether imaging or histopathological cell type weighs more in the decision. Her answer was that staging is clinico-radiological.

The first step is clinical examination. If the tumour is confined to the cervix, with no involvement of the vaginal fornices or the parametrium and a size below 4 cm, the patient can be operated on. The second step is MRI, to confirm there is no parametrial invasion and that the vagina is free. If MRI confirms it, the patient goes to surgery.

The reason for this stepwise approach is toxicity. If a bulky tumour, such as stage IB3, is operated on upfront, there is a high chance of finding high-risk features after surgery. A bulky tumour is hard to remove with a negative margin, and a positive margin means the patient then needs chemoradiation as well. The patient ends up with the toxicity of both surgery and radiation. Correct staging before treatment sends that patient straight to chemoradiation instead.

Cervical cancer treatment by stage

Dr. Singh's framework follows international guidelines, and cases at her centre are discussed at a tumour board.

Within this framework, Dr. Singh noted that patients with a large tumour or a heavy nodal burden may start with neoadjuvant chemotherapy, chemotherapy given before radiation, for six weeks, followed by concurrent chemoradiation. The deciding factors throughout are the stage, whether the tumour is operable, and which high-risk features appear on the post-operative histopathology report.

For patients who go to surgery, the procedure is usually a radical hysterectomy; the cost of radical hysterectomy page gives indicative pricing, and the cost of chemotherapy page covers the chemotherapy component of treatment.

Radiation after surgery: the Peters and Sedlis criteria

Whether a patient needs radiation after surgery for early cervical cancer depends on what the pathologist finds. Dr. Singh explained the two sets of criteria that decide it.

Peters criteria (high risk): a positive surgical margin or positive lymph nodes. Involvement of the parametrium also counts as high risk. These patients need concurrent chemoradiation.

Sedlis criteria (intermediate risk): the features Dr. Singh listed are deep stromal invasion (into the outer third of the cervical stroma), tumour size over 4 cm, and lymphovascular space invasion (LVSI, tumour cells inside small blood or lymphatic vessels). Where the margins and nodes are negative but these features are present, the patient needs radiation alone. In the formal Sedlis criteria, these features count in defined combinations rather than singly, for example LVSI with deep stromal invasion, or a tumour of 4 cm or more with middle or deep stromal invasion.

No risk features: if the tumour is under 4 cm, there is no deep stromal invasion, no LVSI, and the margins and nodes are negative, no adjuvant treatment is needed. The patient goes to follow-up.

The same logic applies at every site

Dr. Singh used cervical cancer as the worked example, but the method is general. Endometrial, lung, breast and every other cancer have their own guidelines, from bodies such as the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), and the timing of radiotherapy follows the same three questions: what is the stage, can the tumour be removed with clear margins, and what did the pathology show.

For referring doctors, two practical points follow from her framework. First, a woman with suspected cervical cancer should have a careful clinical examination and a pelvic MRI before anyone decides on surgery, because a bulky tumour operated on upfront may end up needing chemoradiation as well. Second, the post-operative histopathology report is a treatment document: the margins, nodes, depth of invasion, size and LVSI on that report decide whether radiation follows.

The prevention and early detection side of cervical cancer, including screening and the HPV vaccine, is covered in cervical cancer screening and the HPV vaccine, part of the gynaecological cancers series. How stereotactic and proton techniques extend precision to other sites is set out in stereotactic radiosurgery, SBRT and proton therapy, and Dr. Singh's full answers to Prof. Njemanze are in the Live Discussion.