Brachiterapia ad alto dosaggio e radioterapia stereotassica nel trattamento di pazienti con cancro alla prostata

Prostate cancer is the most common non cutaneous malignancy diagnosed in the United States. Men with newly diagnosed disease are currently stratified based on their PSA, Gleason score, and DRE into one of three groups: low risk, intermediate risk, or high risk. Low risk is defined as either Gleason score 6 or below, PSA <10, and T1-T2a. Intermediate risk is defined as T2b-T2c or Gleason score 7 or PSA 10-20 ng/ml. High-risk disease is defined as PSA >20 or Gleason >7 or T2c or greater. The current standard non-surgical treatment for men with intermediate risk prostate cancer is radiation therapy.

Recently, there have been multiple phase III trials demonstrating the benefit of radiation dose escalation in the treatment of both low risk, intermediate risk, and high risk prostate cancer. These trials have all used external beam radiation therapy and have set a new standard dose for radiation treatment for men with prostate cancer that has been endorsed by the NCCN.

In addition to increasing the total dose delivered by EBRT, dose escalation can be achieved using brachytherapy. The radiation can be delivered either with low activity radioactive seed sources (termed low dose rate or LDR brachytherapy) or using a temporary implant with a higher activity source (high dose rate or HDR brachytherapy). HDR brachytherapy is a standard of care in the United States and Europe to deliver a radiation boost to the prostate when combined with external beam radiation. Three large studies including over 500 men received a combination of EBRT and HDR. All reported excellent outcome with PSA progression free survival between 70-90% for men with both intermediate and high-risk disease.

Further, the rate of late GI/GU toxicity was quite low as well with late grade 3 GU toxicity ranging from 2.1-6.7%, late grade 4 GU toxicity of 0-1%, late grade 3 GI toxicity of 0-1% and late grade 4 GI toxicity of 0-0.5%.

In addition, a phase III randomized trial compared EBRT alone or EBRT combined with an HDR boost. This trial demonstrated a significant improvement in actuarial biochemical relapse-free survival is seen in favor of the combined brachytherapy schedule. However, this trial was criticized that the EBRT alone arm had a lower biologic radiation dose than the combined arm. A retrospective study from Memorial Sloan Kettering Cancer Center compared patients who received EBRT alone to 86.4 Gy with those who underwent HDR brachytherapy combined with EBRT. Dose escalation by adding HDR brachytherapy provided improved PSA relapse-free survival in the treatment of prostate cancer compared with ultra-high-dose EBRT, independent of risk group on multivariate analysis, with the most significant benefit for intermediate-risk patients. Finally, a systemic review of the literature compared results from EBRT alone, EBRT combined with LDR, and EBRT combined with HDR. This study concluded that combination of external beam radiotherapy and HDR brachytherapy results in a superior biochemical control and overall survival.

Radiation effects in prostate cancer cells have been typically studied using clonogenic cell survival curves, which allow cell death to be modeled using a linear quadratic equation. The dose response of tumors and normal tissues to fractionated radiation therapy can be predicted according to a formula: S= e^(-D-D2), where and are the linear and quadratic components of the model. Based upon this model, an alpha/beta ratio can be calculated which allows various dose and fractionation schemes to be compared. The alpha-beta ratio is generally >10 Gy for early-responding tissue such as skin, mucosa, and most tumors and <5 Gy for late responding tissue such as connective tissues and muscles. Recent evidence reveals that prostate cancer has a low alpha/beta ratio, implying that those cells are more sensitive to doses delivered in larger fraction size. Further, given the lower alpha-beta ratio for prostate cancer than bladder and rectal mucosa (where the most significant late toxicity occurs) creates the potential for therapeutic gain with larger fraction sizes. Based upon this, there is an increasing trend to reduce the total treatment time by administering higher dose/fraction.

There have been a number of phase I trials reporting the use of hypofractionated regimens for the treatment of low and intermediate risk prostate cancer in the (primary) definitive setting. These trials show excellent biochemical control and toxicity profiles. A five institutional cooperative phase I/II trial that explored the tolerance and efficacy of 3 increasingly hypofractionated radiation regimens with equivalent predicted late toxicity was recently reported in abstract form. A total of 307 men were enrolled and biochemical progression free survival was 95% at 5 years. At 2 years, actuarial rectal bleeding was 8% with all cases resolving either spontaneously or after minor intervention.

One caveat with dose escalation to doses between 74-80 Gy is that current radiation therapy treatment is given in daily fractions of sizes of 2 Gy/day and treatments last for approximately 2 months. The prolonged nature of the radiation treatment course has been cited by prostate cancer patients as a primary reason for not choosing RT.

The combination of high dose rate brachytherapy and external beam radiation therapy has been recently published. The protocol used a single HDR treatment of 15 Gy followed by EBRT to a dose of 37.5 Gy in 15 fractions. One hundred and twenty three patients were followed for a median of 45 months. Biochemical disease-free survival was 95% and the two year prostate biopsy was positive in only 4% of men. Further, acute grade 3 or higher GU toxicity was experienced by only 2 patients and 1 patient developed a grade 3 late GU toxicity. The grade 3 toxicity was hemorrhagic cystitis that required cysto-prostatectomy; however the patient was also diagnosed with scleroderma and telangiectasia (CREST) syndrome, which is generally a contraindication to radiation therapy and may have been a contributing factor to his toxicity. There was 4% grade 2 GI toxicity consisting of proctitis. Patient reported toxicity using the EPIC tool was notable for decrease in urinary, bowel and sexual domain scores in the first 2 years following treatment, but median urinary and bowel domain scores were not significantly different from baseline at 3 and 4 years.

The study duration is planned for 28 years, including follow-up.