SHARP hypofractionated stereotactic radiotherapy is well tolerated in prostate cancer

A prospective single-center clinical study was performed in low- and intermediate-risk localized prostate cancer patients (according to the National Comprehensive Cancer Network, NCCN). All patients underwent thoracic X-ray, abdominal ultrasonography, pelvic magnetic resonance (MR), and bone scintigraphy.

Patients were considered eligible for inclusion in this study if they had previously untreated, histologically confirmed adenocarcinoma of the prostate. The analysis included 68 men (age 55–83 years, mean 72.5 years, median 73 years) treated between August 2011 and September 2013 at the Department of Radiation Oncology of the Independent Public Health Care Facility of the Ministry of the Interior with Warmia and Mazury Oncology Centre in Olsztyn, Poland. The clinical stage of prostate cancer was T1c-T2cN0M0, the combined Gleason score was 3–8 (mean and median 6), PSA level was 4–20 ng/mL (mean 10.9 ng/mL, median 10 ng/mL). Neoadjuvant androgen deprivation therapy beginning a maximum of 6 months before radiotherapy was given to 52 patients (76.5 %). Hormonal therapy was stopped after 6 months in 31 patients (45.5 %). For 21 patients (31 %), androgen blockade was planned for 2 to 3 years; this was stopped during follow-up in all patients except two. Of the patients who did not receive androgen deprivation therapy, 16  (23.5 %) had a median pretreatment PSA level of 7.53 ng/mL (mean 8.55 ng/mL; Tab. 1).

Preparation for radiotherapy, according to the protocol prepared for this study, did not cause a problem for the patients. The daily setup took approximately 50 minutes; radiotherapy was delivered in about 6 minutes per fraction.

All patients completed the treatment. The average and median follow-up was 24 months. The follow-up was stopped after 9 months for one patient and after 12 months for another because of other illnesses; all other patients had a follow-up visit at least 18 months after the end of treatment. No patients died during the observation period. One patient developed sigmoid colon cancer 24 months after the end of radiotherapy.

The PSA response was favorable. The median 3‑month posttreatment PSA levels were 0.08 ng/mL for all patients and 2.8 ng/mL for those who did not receive androgen deprivation therapy. Twelve months after the end of radiotherapy, the median PSA levels were 0.06 ng/mL for all patients, 1.6 ng/mL for those who did not receive androgen deprivation therapy, and 0.04 ng/mL for patients who underwent 6 months of hormone therapy. Twenty-four months after the end of radiotherapy, the median PSA levels were 0.1 ng/mL for all patients, 0.4 ng/mL for those who did not receive androgen deprivation therapy, and 0.1 ng/mL for patients who underwent 6 months of hormone therapy. The median nadir PSA levels were 0.03 ng/mL (mean 0.22 ng/mL) for all patients and 0.6 ng/mL (mean 0.7 ng/mL) for patients without hormone treatment. At the median 24-month follow-up, there were no patients with PSA failure (nadir plus 2 ng/mL). After 6 months of androgen deprivation, the PSA level of two patients increased by over 1 ng/mL from the nadir during the observation period. More than two thirds of the patients (75 %) showed stable or decreased levels of PSA.

Patients’ tolerance of the treatment was good. There were no acute grade IV toxicities. Most of the patients (67.6 %) developed mild and moderate (grade I or II) acute genitourinary and/or gastrointestinal toxicities: 24 patients (35.3 %) developed grade II acute bladder toxicity and 7 patients (10.3 %) grade II acute rectum toxicity. Only one patient (1.5 %) had grade III genitourinary toxicities; no patients demonstrated grade III acute gastrointestinal toxicities. No grade III or higher late genitourinary or gastrointestinal or toxicities were reported. More than one third of all patients (38 %) did not develop any late radiation-related complications. More than 3 months after radiotherapy, 8 patients (11.8 %) had moderate (grade II) urinary symptoms. No urinary incontinence was observed. Only 3 patients (4.4 %) presented moderate (grade II) gastrointestinal symptoms more than 3 months after the treatment had ended (Tab. 2, Fig. 1).

Evaluations of QoL were done thrice: at 9 months after radiotherapy, T1 for all patients except 2 (because of difficulty in coming for evaluation due to other diseases); at 21 months after the end of radiotherapy (63 patients), T2; and at 30 months after the end of radiotherapy (23 patients), T3. The global health status (GHS)/QoL improved during the observational period (mean, M; median, Me; standard deviation, SD): MQoL1 = 10.09 (N = 66; MeQoL1 = 10.00; SD = 1.44), MQoL2 = 10.51 (N = 63; MeQoL2 = 10.00; SD = 1.70), and MQoL3 = 11.30 (N = 23; MeQoL3 = 12.00; SD = 1.18), 9, 21 and 30 months after radiotherapy, respectively. The biggest functional issues for prostate cancer patients were physical and emotional functioning. In turn, the dominant symptom was fatigue, which decreased during the observation period (Fig. 2). We observed significant or close to significant effects at three measurement points for specific functional subscales of QoL and general symptoms connected with cancer and oncologic treatment: physical functioning (F[2.44] = 3.731; p < 0.05; eta2 = 0.145), emotional functioning (F[2.44] = 3.074; p = 0.056; eta2 = 0.123), cognitive functioning (F[2.44] = 5.714 with Greenhouse-Geisser correction, GGc; p < 0.01; eta2 = 0.206), social functioning (F[2.44] = 2.997 with GGc; p = 0.068; eta2 = 0.120), and general functional QoL (F[2.44] = 5.747 with GGc; p < 0.01; eta2 = 0.207; Tab. 3). Among 25 prostate cancer-specific medical issues, five variances were reported to be significant: “urinating frequently at night” (F[2.42] = 5.370 with GGc; p < 0.05; eta2 = 0.204), “hurrying to get to the toilet” (F[2.42] = 4.177; p < 0.05; eta2 = 0.166), “not getting enough sleep because of the need to get up frequently at night to urinate” (F[2.42] = 3.249 with GGc; p < 0.05; eta2 = 0.134), “difficulty in going out of the house because of the need to be near a toilet” (F[2.42] = 5.332 with GGc; p < 0.05; eta2 = 0.202), and “hot flushes” (F[2.42] = 5.332 with GGc; p < 0.05; eta2 = 0.202).

Hypofractionated SBRT is a novel technique for the treatment of early-stage prostate cancer. Preliminary data have shown that this approach leads to successful tumor control without increasing complications [25‐27].

Acute urinary and rectal toxicities during and after SBRT are not higher than those for 3D-CRT and IMRT. Collins et al. [12] reported the good outcome of 232 patients with both early and advanced disease who were treated with 36 Gy in 6 fractions. Soete et al. [28] reported no grade III or IV acute toxicity among 36 prostate cancer patients treated with 56 Gy in 16 fractions. King et al. [26], on behalf of the Multi-institutional Consortium of Prospective Trials, presented an analysis of 864 patients from phase II clinical trials of SBRT (median dose of 36.25 Gy in 4–5 fractions) for localized prostate cancer (median follow-up of 3 years; 194 patients remained evaluable at 5 years). Some problems with the bladder and rectum were observed within the first 3 months after SBRT, but the conditions returned to baseline status or better within 6 months.

In the current study, 42 % of patients showed no treatment-related reaction during the radiotherapy schedules. There were no grade III or IV toxicities in the rectum, and only one patient (1.5 %) developed grade III toxicity in the bladder. Similarly, in the SHARP study [19], only one acute grade III genitourinary toxicity during treatment was reported (2.5 %). In the present study, 31 % of the patients had no bladder reaction, compared with up to 49 % in the SHARP trial. Furthermore, in the SHARP trial, 61 % of the patients had no acute (during and 1 month after the end of treatment) gastrointestinal toxicity, whereas this value was 63.5 % in our study. The late toxicity result in our study was similar to that in the SHARP trial: no grade III or higher late gastrointestinal or genitourinary toxicities were reported. No late genitourinary toxicity was developed by 55 % of the patients in the SHARP trial and 47 % in our study. Late gastrointestinal toxicity was even rarer, with 62.5 % of the patients in the SHARP trial and 78 % in our study not developing such toxicity. There were no grade III rectal reactions either in the SHARP trial or in our study. The King et al. series [29], with a median follow-up of 2.7 years, reported no grade III or higher rectal toxicity and no grade IV urinary toxicity; only 3.5 % of the patients developed grade III urinary toxicity (36.25 Gy in 5 fractions).

Yarbro and Ferrans [30] demonstrated that radiotherapy has little impact on deterioration of QoL. Our research confirms that QoL of prostate cancer patients undergoing SBRT is at a satisfactory level. We observed that the GHS/QoL of the patients was good 9 months after the end of treatment and significantly improved during the following months. Functional aspects, such as physical, emotional, cognitive, social, and general functioning, also improved.

The American Society for Therapeutic Radiation and Oncology (ASTRO) definition of biochemical PSA failure as a surrogate endpoint for recurrence is three consecutive increases in the PSA level after the posttreatment PSA nadir dated at the midpoint between the nadir and the first increase [31]. The RTOG Phoenix definition consists of a PSA level that increases to more than 2.0 ng/mL from the nadir. As a potential surrogate endpoint in clinical trials, the Phoenix definition of PSA failure is a strong correlate of mortality and a predictor of metastatic disease; it is superior to the ASTRO definition [32]. The 2‑year survival rate without PSA failure ranges from 90 to 100 % [33]. Thus far, only one observation of patients treated with SBRT has been performed, with a median follow-up of 5 years [34]: the biochemical progression-free survival rate was 93 % in a cohort of 41 consecutive patients (35 or 36.25 Gy in 5 fractions); the median PSA nadir was 0.3 ng/mL. Madsen et al. [35], who applied the same fractionation schedule, found that the majority of nadirs were less than 1.0 ng/mL. In our study, the median PSA nadir for patients without hormone treatment was 0.6 ng/mL. At a median 24-month follow-up, there were no patients with PSA failure. For 2 patients, the PSA level increased by over 1 ng/mL from the nadir; for 15 patients, the increase was 0.2–1.0 ng/mL from the nadir (25 % of all patients). King et al. [36] observed an increase in PSA level of > 0.2 ng/mL in 16 % of patients at a median 36-month follow-up.

There is more information about the CyberKnife (Accuray, Sunnyvale, CA, USA) than linear accelerator (LINAC) use for SBRT of prostate cancer patients. Our study used a LINAC, and all our results (acute and late toxicities, QoL, and PSA increase and failure) are similar to those obtained with the CyberKnife series.

One of the potential benefits of SBRT is a short treatment period and probably lower costs compared with other advanced techniques. Sher at al. [37] showed that SBRT is a more cost-effective (in terms of radiotherapy, treatment of acute and late toxicities, and quality-adjusted life year) external beam modality than IMRT.

Our data are preliminary, as the number of treated patients is relatively small and follow-up should be longer. In the intermediate risk-group patients treated with hormonal therapy, the potential curative effect of radiotherapy cannot be assessed reliably during hormonal treatment; therefore the efficacy of SBRT in our patients could not be estimated precisely and further follow-up is necessary. Follow-up is planned for 10 years and will be presented in the future. One of the potential shortcomings was lack of the pre-study QoL assessment; however we believe that QoL measured thrice after treatment is informative.

Hypofractionated stereotactic radiotherapy for low- and intermediate-risk prostate cancer patients is a safe and convenient treatment in terms of its duration, PSA response, toxicity and patients’ QoL assessment in the short term. However, a longer follow-up is needed.