Injectable gel spacers in the treatment of gynaecologic malignancy

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Cervical cancer is the fourth most common cancer among women. One of the treatment options for women with this gynaecological malignancy is brachytherapy, a form of internal radiation therapy. The downside of this treatment, however, is that adjacent organs such as the rectum are put at risk of high-dose radiation, leading to complications like rectal bleeding and rectovaginal fistula formation. Dr Tairo Kashihara of the National Cancer Center Hospital in Japan is utilising perirectal hyaluronate gel injections (HGI) in their brachytherapy patients to reduce the radiation reaching the surrounding organs.

In 2018, the World Health Organization (WHO) estimated that cervical cancer occurred in 570,000 women globally, with an estimated 311,000 dying of the disease. Treatment options include surgery to remove the tumour, chemotherapy, immunotherapy, and radiation therapy. Radiation therapy utilises high-energy X-rays that can penetrate and destroy the cancer cells. Typically, external-beam radiation therapy is used: in this method, the radiation is emitted from a machine outside the body. Another form of radiation is an internal therapy called brachytherapy. By this method, oncologists can deliver high doses of radiation to more targeted areas of the cervix. Depending on the type of treatment needed, brachytherapy can be administered at a high-dose-rate from a few minutes up to 20 minutes, once or twice a day for several days or weeks.

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As effective as the treatment is overall, there are certain undesirable side effects of brachytherapy. Dr Tairo Kashihara from the National Cancer Center Hospital in Japan explains that “high-dose-rate brachytherapy is indispensable to irradiate high radiation doses to tumours because it has shown superiority to external beam radiotherapy in radiation dose distribution. However, adverse effects on the rectum, such as rectal ulcer and rectovaginal fistula formation, are major problems in gynaecological brachytherapy.”

High-dose-rate brachytherapy is indispensable to irradiate high radiation doses to tumours.

Space makers

The uterus and vagina are positioned close to organs such as the rectum and bladder. In terms of radiotherapy in gynaecological cancers, the rectum and bladder are considered organs at risk (OAR) as they surround the vagina and uterus and can be affected by the radiation intended for the target area. The total dose of radiation that can be applied to the tumour is limited because of the surrounding OAR. In order to reduce the effects of the brachytherapy radiation reaching OAR, hyaluronate gel injections (HGI), also called gel spacers or rectal spacers, have been a promising technique in prostate cancer. Like the name suggests, the gel creates space between the target area and OAR so that they are protected from the radiation. They also help to deliver a more therapeutic radiation dose to the target.

Rectovaginal fistula is an abnormal connection between the rectum and the vagina.

Dr Kashihara and colleagues conducted a retrospective analysis of 36 patients who had received HGIs before gynaecologic brachytherapy. The initial experience with HGI was reported in a 2019 paper. The authors describe that the injections were administered under local anaesthesia with real-time transrectal ultrasound (TRUS) guidance. Once the needle tip reached between the vagina and rectum, the gel was slowly released (5-20cm3).

Planning is key

Radiotherapy treatment planning is crucial for the execution of successful treatment. Surgery to remove a tumour is done by direct visualisation of the tumour. In radiotherapy, however, the tumour is not visualised directly; instead, it is visualised via computerised imaging (computed tomography, CT). The physician needs to plan the volume of tissue that needs to be targeted by a therapeutic dose of internal radiation (target volume, TV). The TV is made up of subsets; the gross tumour target volume (GTV) is what can be seen, measured or felt of the tumour. The clinical target volume (CTV) includes areas outside of the GTV that are at risk for microscopic spread of the tumour.

SEM image of cervical carcinoma. royaltystockphoto.com/Shutterstock.com

Dosimetry is the measurement and calculation of the amount of radiation absorbed by a tumour, organ or whole body. The research team analysed the dosimetric effect of the HGI. CT scans of before and after the HGI were used to calculate the radiation exposure to the rectum and bladder. The team reports that the HGI was well tolerated in all the patients that received it, and only minor discomfort was experienced. However, two patients that had prior radiation therapy experienced severe toxicities. One patient had Grade 3 rectal bleeding, and another had rectovaginal and vesicovaginal fistulas. Regarding the radiation dose, the authors explain “the maximum dose to the most exposed 0.1 cm3 (D0.1 cm3) and the most exposed 2.0 cm3 (D2.0 cm3) of the organ were used as index values for the rectum dose evaluation”. For the bladder dose and TV coverage, the dose indexes were Bladder D2.0cm3 and D0.1 cm3, and TV indexes were V100 (percentage of the CTV receiving 100% of the prescribed dose) and V90 (the minimum dose covering 90% of the CTV).

HGI enhances treatment tolerability

Results showed that the radiation doses at the Rectum D2.0cm3 and D0.1 cm3 were decreased by HGI, significantly. The average dose difference between pre-HGI and post-HGI for the Rectum D2.0cm3 was
110.5 cGy (centigray – a measurement unit for absorbed radiation dose) and D0.1 cm3 was 111 cGy. Moreover, no significant difference was seen in the dosimetric parameters of bladder and TV coverage. The researchers noticed that 14 out of 15 patients that received the brachytherapy as the first treatment for cervical cancer were able to have more sessions of brachytherapy as compared to the recommended treatment sessions and dose outlined by the Japanese guidelines for cervical cancer treatment.

Fig. 1. Hyaluronate gel injection (HGI) is performed under real-time transrectal ultrasound (TRUS) guidance. (A) Sagittal TRUS image obtained before HGI. (B) Sagittal TRUS image obtained during HGI. An application needle is inserted between the vagina and rectum via a transperineal approach, and hyaluronate gel is being injected into the pararectal space. Sagittal CT images before HGI (C) and after HGI (D) are also shown. The red line marks the hyaluronate gel and the brown line the rectum. Photo Credit: https://academic.oup.com/jrr/article/60/4/501/5481572

Interstitial catheters are hollow narrow tubes inserted into the tumour to hold the radionuclide source. The researchers observed that for patients with more interstitial catheters, this correlated negatively with the dosimetric effect of the HGI. The authors speculated that the high-dose volume overlapping the rectum increases with the increased number of interstitial catheters, as larger tumours require more catheters. The researchers concluded that the amount of hyaluronate gel used in patients with larger tumours was not enough to create space between the rectum and the tumour. Using more hyaluronate gel in the case of larger tumours may help to mitigate this negative correlation.

The effectiveness and safety can be enhanced by injecting the gel between the tumours and the organs at risk.

Another factor that also negatively correlated was the length from the anal verge to the most cranial point at which 100% (Lcranial 100%) and 80% (Lcranial 80%) prescription isodose lines crossed the rectum. Isodose lines are a way to show where the certain dose lies within a tissue, using CT images. This is used for treatment planning to ensure the certain dose of radiation is reaching the GTV. In this way, physicians can ensure the CTV is receiving at least the prescribed dose. The surrounding area then receives less and less dose and therefore saves adjacent organs from the effects of the radiation. The authors put this negative correlation down to the gel catheter needles not being long enough to reach the cranial rectum section and so a dose reduction was not possible. As a result of this, Dr Kashihara and his team have now adopted longer catheter needles which are able to deliver the hyaluronate gel to more cranial level spaces of the perirectal area and thus enhance “the impact of HGI in OAR dosimetry when the PRV is located more cranially within a small pelvis”.

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Further configuration of HGI

The results of this study indicate that HGIs are effective in reducing the dose of radiation to the rectum during gynaecological brachytherapy. In a further study, Dr Kashihara and colleagues have reported the findings of the use of HGI in the rectovaginal septum (a thin structure that separates the vagina and rectum) and found that it reduced rectal bleeding in patients with gynaecological malignancies. In addition, the team have also been conducting configuration analysis to determine the optimal position and shape of the gel spacers to achieve effective radiation dose reduction to OAR during gynaecological brachytherapy.

Looking ahead, Dr Kashihara says that “the effectiveness and safety can be enhanced by injecting the gel between the tumours and the organs at risk”. No doubt the work by Dr Kashihara and his team will pave the way for the development of this technique for many types of malignancies and make these difficult cancer treatments a little more bearable for patients.


What inspired you to conduct this research?

We sometimes experience rectal bleeding and rectovaginal fistula formation after radiotherapy including brachytherapy for gynaecological malignancies. Therefore, we started HGI to reduce these late adverse effects in accordance with K Kishi et al.

 

References

  • Kashihara, T., Murakami, N., Tselis, N., et al. (2019). Hyaluronate gel injection for rectum dose reduction in gynecologic high-dose-rate brachytherapy: initial Japanese experience. J Radiat Res., 60(4), 501-508. Available at: https://doi.org/10.1093/jrr/rrz016
  • Murakami, N., Shima, S., Kashihara, T., Tselis, N., et al. (2019). Hyaluronic gel injection into the vesicovaginal septum for high-dose-rate brachytherapy of uterine cervical cancer: an effective approach for bladder dose reduction. J Contemp Brachytherapy, 11(1), 1-7. Available at: https://doi.org/10.5114/jcb.2019.82612
  • Murakami, N., Nakamura, S., Kashihara, T., et al. (2020). Hyaluronic acid gel injection in rectovaginal septum reduced incidence of rectal bleeding in brachytherapy for gynecological malignancies. Brachytherapy, 19(2), 154-161. Available at: https://doi.org/10.1016/j.brachy.2019.11.004
  • Iijima, K., Murakami, N., Nakamura, S., Nishioka, S., et al. (2020). Configuration analysis of the injection position and shape of the gel spacer in gynecologic brachytherapy. Brachytherapy, S1538-4721(20), 30196-3. Available at: https://doi.org/10.1016/j.brachy.2020.08.021
DOI
10.26904/RF-134-5861

Research Objectives

Dr Kashihara and his team utilise perirectal hyaluronate gel injection (HGI) in gynaecologic brachytherapy.

Collaborators

  • Naoya Murakami
  • Kotaro Iijima
  • Satoshi Nakamura
  • Jun Itami

Bio

Dr Tairo Kashihara has been working at the National Cancer Center Hospital in Tokyo, Japan since 2014.
Dr Tairo Kashihara

Contact

E: tkashiha@ncc.go.jp

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