Brachyterapy: The radiation oncologist opinion

Abstract

The role of the radiation oncologist in the management of patients affected by prostate cancer is increasingly considered thanks to important technological innovations that have marked the radiotherapeutic approach in its three main fields: external beam radiotherapy (EB-RT), brachytherapy (interventional radiotherapy, I-RT), and metabolic radiotherapy (M-RT) through the use of new radiopharmaceuticals. Regarding the modern brachytherapy, the introduction of intensity-modulated techniques (IM-IRT), thanks to the implementation of HDR remote-after loading machines, and image-guided techniques (IG-IRT), has led to advantages in optimizing dose distribution after implantation with the possibility of modulating the dose according to the intraprostatic dominant lesions, limiting the dose to the surrounding tissues with improvement in local control and a significant reduction in side effects. I-RT today represents a safe, scientifically established, effective and well-tolerated treatment for patients affected by prostate cancer. Like most special techniques, in order to obtain the best results, it must be performed in centers with a high volume of activity and consolidated experience with an interdisciplinary approach.

The role of the radiation oncologist in the management of patients affected by prostate cancer is increasingly considered thanks to important technological innovations that have marked the radiotherapeutic approach in its three main fields: external beam radiotherapy (EB-RT), brachytherapy (interventional radiotherapy, I-RT), and metabolic radiotherapy (M-RT) through the use of new radiopharmaceuticals. Regarding the modern brachytherapy, the introduction of intensity-modulated techniques (IM-IRT), thanks to the implementation of HDR remote-after loading machines, and image-guided techniques (IG-IRT), has led to advantages in optimizing dose distribution after implantation with the possibility of modulating the dose according to the intraprostatic dominant lesions, limiting the dose to the surrounding tissues with improvement in local control and a significant reduction in side effects. This evolution is so important that some international groups have suggested a new name: “interventional radiotherapy” (IRT) in order to differentiate this technique from the old brachytherapy. Interventional Radiotherapy has often been considered an alternative min-invasive technique to surgery or external beam radiotherapy for patients with low risk tumors and in selected intermediate/favorable risk cases. The same technique can be considered in intermediate/high risk patients by integrating with external beams as a boost or in recurrences, as reported by various national and international guidelines.^1–4 IRT can be delivered by interstitial implantation of permanent Low-Dose Rate (LDR) seeds ⁵ or by interstitial temporary High-Dose Rate (HDR) implantation ⁶ ; Available clinical data from retrospective studies on these two different approaches show that they can both be considered effective in terms of disease control but the HDR technique let the advantage of “after implant dose painting” thanks to new intensity modulating approach. ⁷

The numerous studies that have evaluated the use of IRT-LDR treatment as monotherapy have reported at 10-year follow-up, biochemical control rates >85%, distant metastasis rates <10%, cancer-specific mortality rates <5% in low-risk patients, including men aged <60 years.^8–11 A retrospective multicenter Italian study on IRT-LDR, reporting the results of 2237 patients, showed cancer-specific survival, overall survival and biochemical failure-free survival at 5 years were 99%, 94%, and 94% at a median follow-up of 65 months, and 89%, 92%, and 88%, at 7 years, respectively. ¹² However, LDR technique presents some critical issues to be evaluated in the therapeutic choice, particularly the problems related to patients’ after implant radioactivity, the impossibility of modify the dose distribution after implantation and the radioactive souces costs. Instead, IRT-HDR involves the temporary insertion of needles carrying the radioactive source at high dose rate within the target volume and can be performed using different imaging modalities for planning such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and multiparametric transrectal ultrasound (mTrUS). ¹³ . The possibility of relying on an mTRUS allows clinicians to achieve very high doses in the areas at greatest risk of prostate recurrence, thus achieving excellent tumor control, at the same time sparing the surrounding OARs as much as possible and therefore with very low late toxicity. ¹⁴ In addition to this, it should be pointed out that it has recently been shown that a high-dose fraction of HDR IRT induces transcriptional changes in the tumor genome that increase sensitivity to subsequent exposure to further radiation, whether the further treatment is interventional radiotherapy or external beam radiation therapy. Another advantage to be emphasized is certainly related to the fact that the implant in the case of HDR IRT is absolutely temporary and no radioactivity remains at the end of the procedure moreover, from the dosimetric point of view, the dose distribution can be optimizing following the implantation based on the final needles arrangement ¹⁵ ; Indeed, after implantation, the source’s staging point and time can be defined, so that the dose can be modulated according to the target and the organs at risk with millimeter precision. Furthermore, the presence of significant intraprostatic calcifications has been associated in LDR IRT with a clinically significant effect on disease control; this issue is absolutely marginal in HDR, which uses higher energies and therefore is not significantly affected by the presence of calcifications. ¹⁶ While it is true that the toxicity profile tends to be superimposable from a temporal point of view, it should be emphasized that in the case of HDR IRT symptoms tend to peak earlier and resolve more rapidly, typically within a few days/weeks, rather than weeks/months as with LDR IRT. ¹⁷ Regarding the use of HDR IRT as monotherapy, a recent systematic literature review with associated meta-analysis included data from more than 3500 patients and showed that in low-risk prostate cancer patients treated with HDR IRT as monotherapy, biochemical disease recurrence-free survival is 97.5%. ¹⁸ Regarding the use of HDR IRT as a boost, data with mature follow-ups exceeding 10 years are now available in the literature. A recent randomized phase 3 trial included 216 patients with localized prostate cancer. Of these, 106 were randomized to ERT alone and 106 to ERT+IRT HDR. With a follow-up of more than 12 years, the authors demonstrated a significant impact of the addition of HDR IRT in terms of recurrence-free survival.

A recent analysis about multiparametric imaging guided HDR interventional radiotherapy boost showed no biochemical or radiological recurrences with median follow-up time of 60 months, without late toxicities and no significant changes of either IPSS (International Prostate Symptoms Score) or IIEF 5 (International Index of Erectile Function Questionnaire) were reported. ¹⁹

In conclusion, IRT today represents a safe, scientifically established, effective, and well-tolerated treatment for patients affected by prostate cancer. Like most special techniques, in order to obtain the best results, it must be performed in centers with a high volume of activity and consolidated experience with an interdisciplinary approach.