Previously published hypofractionation radiotherapy studies, with different fraction and total doses, different toxicity scores, and different lengths of follow-ups have reported comparable outcomes and endurable toxicities, making it an attractive alternative to standard fractionation prostate radiotherapy. These studies have changed the clinical practice in many American and European medical centers. We have presented the long-term outcomes of a relatively large single-institution cohort of predominantly high-risk, locally advanced, and N1 Chinese prostate cancer patients treated with moderately hypofractionated radiotherapy and ADT. Our results showed satisfactory survival, good disease control, and well-tolerated treatment-related toxicity. The characteristics of the current study are as follows: 1) Chinese prostate cancer patients with predominantly high-risk, locally advanced, and N1 diseases; 2) similar treatment strategy; 3) mature follow-up.
Given the excellent therapeutic outcomes, both in terms of disease control and incidence rates of toxicity, the adoption of alternative modern, dose-escalated fractionation regimens necessitates careful clinical validation prior to widespread implementation. This is particularly important for those with high-grade disease as it has been hypothesized that the α/β ratio for such disease may be higher than that for low-grade prostate cancer [17]. However, multiple fractionated schedules have been clinically implemented, with fraction doses ranging between approximately 2.4–10 Gy [18]. The applicability of the linear quadratic model to accurately calculate the biological equivalent dose in the setting of fraction sizes over 5 Gy remains uncertain [19, 20], which result in difficulty in direct comparison with more moderately hypofractionated regimens. Nevertheless, our results provide valuable information for other moderate hypofractionation regimens employing fraction doses of approximately 2.4-4 Gy, especially for patients with more advanced disease.
There are several phase III randomized trials comparing standard versus moderate hypofractionated radiation therapy using escalated doses. Some researchers recommended hypofractionated radiotherapy as a new standard of care for localized prostate cancer, while others could not confirm that hypofractionation was non-inferior for cumulative late toxicity compared with standard fractionation [9–11, 21, 22]. Lee et al. [10] randomized 1092 patients with low-risk prostate cancer to hypofractionated radiotherapy (70 Gy in 28 fractions) versus conventional radiotherapy (73.8 Gy in 41 fractions). After a median follow-up of 5.8 years, the estimated 5-year disease-free survival was 86.3% in the hypofractionated radiotherapy group and 85.3% in the conventional radiotherapy group. Late grade 2 and 3 GI and GU adverse events were increased (HR, 1.31 to 1.59) in hypofractionated radiotherapy patients. Although an increase in late GI and GU toxicity were observed in the hypofractionated radiotherapy cohort, they concluded that in men with low-risk prostate cancer, the efficacy of their hypofractionated schedule was not inferior to conventional radiotherapy.
The HYPRO trial enrolled 804 intermediate- or high-risk patients, and randomly assigned them to receive either standard fractionation with 39 fractions of 2 Gy (5 fractions per week) or hypofractionation with 19 fractions of 3.4 Gy (3 fractions per week) [21, 22]. 67% of the patients received concomitant ADT for a median duration of 32 months. After a median follow-up of 5 years, 5-year relapse-free survival was 80.5% for patients assigned hypofractionation and 77.1% for those allocated conventional fractionation. The incidence of grade ≥ 2 late GU toxicity at 3 years was 39% in the standard arm and 41.3% in the hypofractionation arm. In addition, cumulative grade ≥ 3 late GU toxicity was significantly higher in the hypofractionation group (19.0% vs 12.9%). As for the 3 year rate of late GI toxicity, this dataset was 17.7% for the standard group compared with 21.9% for the hypofractionation group. There was no significant difference between cumulative grade ≥ 3 late GI toxicity in the two groups (2.6% vs 3.3%). The researchers explained that no planning objectives or constraints for the bladder, hormonal therapy, median age of 71 years, high percentage of patients with baseline GU symptoms, and the use of patients’ self-assessment questionnaires, all contributed to the high incidence of late GU toxicity. The authors did not recommend their hypofractionated radiotherapy regimen as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.
Our finding is more consistent with those reported from the same fraction dose of 2.7 Gy prostate radiotherapy combined with ADT. Pollack et al. [23] conducted a randomized trial to compare the efficacy of moderate hypofractionation radiotherapy (70.2 Gy in 26 fractions) with conventional radiotherapy (76 Gy in 38 fractions) in 303 favorable- to high-risk patients. With a median follow-up of 68.4 months, 5-year biochemical and/or clinical disease failure rate was 23.3% for hypofractionated IMRT and 21.4% for conventional fractionation IMRT (P = 0.745). The overall incidences of grade ≥ 2 late GU and GI reactions for hypofractionated IMRT were 44.9% and 18.1%, respectively. There were no statistically significant differences in late toxicity between the two arms. Recently, Abu-Gheida et al. [5] reported 10-year outcomes for 854 patients across all risk groups treated with daily image-guided IMRT delivered 70 Gy in 28 fractions at 2.5 Gy per fraction. 5- and 10-year biochemical relapse free survival for 244 high risk patients were 63% and 42%, 5- and 10-year clinical failure free survival were 87% and 72%, and 5- and 10-year prostate cancer-specific mortality were 9% and 15%. 5-year cumulative incidence rate for grade ≥ 3 late GU and GI toxicity for their whole patients were 1.3% and 1.2%.
In our study, 77.7% of the patients enrolled were high-risk or more advanced. Nevertheless, this fractionation schedule (67.5 Gy in 25 fractions) still achieved promising results, with the 5- and 10-year FFS of 80.0% and 63.5%, and the 5- and 10-year PCSS rates of 95.7% and 88.2%. Also, there were no clinical in-field recurrence cases in our group, and the clinical failure presented as distant metastasis, indicating that this dose segmentation scheme was reasonable for the control of local prostate lesions, although our total dose was lower than that reported by Pollack et al [23]. In this study, none of our low- and intermediate-risk patients died of prostate cancer. However, 23.8% of N1 patients died of distant metastasis of prostate cancer. Therefore, for N1 patients, local treatment is not enough, but an effective approach of systemic treatment is indispensable.
Compared with the above reports, severe late GU and GI toxicity events in our study were also low, and eased over time in line with the results from other studies [5, 23, 24]. However, a slightly increased rate of late GI toxicity was observed in our study. A potential explanation might that we applied image guidance selectively, not daily throughout treatment. This was due to a heavy workload, tight medical resources, and high treatment costs. Furthermore, older age and the use of ADT might account for this higher trend [21, 25]. In addition, we selectively radiated the pelvic lymph nodes to 45–50 Gy for 55.3% patients and local concomitant boosts were administered for 33 N1 patients who had residual metastatic pelvic lymph nodes after neoadjuvant ADT. Based on our promising efficacy and acceptable toxicity, this dose-escalated moderately hypofractionation schedule appears to be beneficial to Chinese prostate cancer patients, and our data are likely generalizable to other countries where PSA screening is not routinely carried out and whose prostate cancer populations typically present with more advanced disease.
There are several limitations to our study. This is a single-institution, single-arm, retrospective study involving a Chinese population, ranging from low risk to N1 disease. As a result, target volume and ADT duration varied greatly. Secondly, N1 disease was detected using imaging (CT and/or MRI) and was not histologically confirmed. Furthermore, toxicity outcomes were physician reported rather than patient reported. In addition, modern daily image-guided delivery techniques were selectively used in our patients. Finally, the median follow-up time was relatively short, and the sample size was relatively small for prostate cancer.