Developments in radiotherapy have made it possible to increase the radiation dose to prostate cancer cells only, without a simultaneous increase in toxicity. IMRT at a dose > 70 Gy in conventional fractions is the standard of care for prostate cancer [1]. Similarly, BT is an established treatment option for delivering a high dose only to the target lesion using a shallow dose fall-off while maintaining a low irradiation dose to the surrounding healthy tissues. In addition, a low α/β ratio (1.5) has enhanced the use of high single doses in EBRT and SBRT, and it has been introduced in clinical practice [1]. Moreover, hydrogels have led to a reduction in toxicity for both gastrointestinal and sexual functions in men with localized prostate cancer [24].
In this study, we assessed data from 1,374 men who had undergone modern radiotherapy and found that those in the HRLG group had better outcomes than those in the HRHG group. The indolent nature of HRLG cancer lesions was confirmed in terms of their outcomes, in that no clinical failures nor prostate cancer-related deaths occurred in patients in the HRLG group. The outcomes for patients in the HRLG group were equivalent to those of an intermediate-risk group [22], even in the presence of high-risk factors, such as T3–4 or iPSA ˃20 ng/mL. Accordingly, we speculate the potential for downstaging the patients with HRLG prostate cancer to a lower-risk group. At least, no further intensive treatment (whole pelvic radiotherapy, boost radiotherapy using BT, new drug etc.) would be required for HRLG. Our findings may be beneficial for counseling individual patients with HRLG lesions with respect to their treatment choices and prognoses.
More than 50 years ago, Donald Gleason introduced a grading system for prostate cancer, and the Gleason scoring system has remained an essential tool to predict disease outcomes and to facilitate clinical decision-making [25]. Several studies have confirmed the importance of this grading system concerning its predictive value in relation to prostate cancer mortality (Gleason score ˃8–10), as well as showing the indolent nature of prostate cancer lesions with a Gleason score ≤ 6 [1–10]. While a Gleason score ≤ 6 includes neoplasia from a histological perspective, it is typically indicative of an indolent non-neoplastic precursor lesion. Reclassifying this type of lesion as non-cancerous re-mains controversial; however, such reclassification could help to minimize overtreatment, and reduce treatment-related side-effects, patient anxiety, and the financial bur-den to healthcare systems. Kweldam et al. reported no disease-specific death or metastasis in patients with a Gleason score ≤ 6 following radical prostatectomy [11]. Eggener et al. observed that only 3 of 9,557 patients with localized prostate cancer and a Gleason score ≤ 6 had died during a 15-year follow-up period [12]. Finally, several patients with Gleason scores ≤ 6 reportedly did not require immediate intervention and were often eligible for AS [1, 2].
Underestimation of high-grade cancer cases after prostate needle biopsy remains an important issue. As prostate cancer is a heterogeneous disease, it is estimated that 30–50% of patients with low-risk prostate cancer and 13% with very low-risk prostate cancer exhibit occult high-grade disease on surgical pathology after radical prostatectomy [26]. Epstein et al. reported that 36% of cases (1,841/5,071) were upgraded from a needle biopsy derived Gleason score of 6 to a higher grade following surgical pathological ex-amination [26, 27]. Leeman et al. demonstrated the role of advanced age in upgrading and upstaging in patients with prostate cancer and with a Gleason score of 6 after radical prostatectomy. Of 3,571 patients analyzed, 115 (3.22%), 245 (6.86%), and 254 (7.11%) were upgraded, upstaged, or had positive surgical margins, respectively, with advanced age at diagnosis being associated with an increased risk of upgrading the disease to a Gleason score ≥ 7 after prostatectomy T3/T4 and positive surgical margins (adjusted odds ratios, 1.05, 1.02, and 1.02, respectively). Similarly, advanced age was associated with an in-creasing number of men with disease upgraded to a Gleason score ≥ 7 or upstaged to pT3/4- or pT2-positive surgical margins among those with 33% positive biopsy scores (but not < 33%), following staging using multiparametric magnetic resonance imaging (MRI). Therefore, multiparametric MRI should be considered in healthy older men with a Gleason score ≤ 6 and ≥ 33% positive biopsy cores.
Furthermore, underestimation can be a more significant factor in radiotherapy than in surgery as pathological specimens are not obtained during radiotherapy, especially with radiotherapy usually applied in more advanced disease than surgery. Therefore, several investigations have been undertaken to improve biopsy quality. Pepe et al. re-ported good accuracy for quantitative histological examinations in predicting non-localized prostate cancer using other biopsy parameters [28]. Ngnen et al. reviewed biopsy-based genomic classifier (GC: gene expression biomarker) in high-risk prostate cancer from prospective randomized trials and reported an independent association between the GC score with DMSF, PCSM, and OS [29]. Long term follow-up of randomized trials has shown that > 70% of men with high-risk prostate cancer after definitive radiation therapy and long-term ADT will never develop metastatic disease [29]. Thus, Ngnen et al. concluded that high-risk prostate cancer is a heterogeneous disease state, and using the GC score can improve risk stratification to facilitate personalized shared decision making [29]. Our data might also be useful to improve risk stratification in relation to high-risk prostate cancer using this simple method.
The probability of grade-up transformations, which involves progression in a Gleason score ≤ 6 to high-grade disease, should also be considered [30]. Molecular data suggest that genomic instability, which causes tumor progression, precedes the detection of histologically visible changes, and the potential risk of metastasis or mortality from prostate cancer with a Gleason score of 6 should be considered [30]. In a cohort of extensive AS studies, up to 33% of patients with Gleason scores of 6 required therapeutic intervention, primarily owing to upgrading [2, 31]. Tosoian et al. examined a prospective AS cohort of 1,818 patients at a single institution using multiparametric MRI and ultra-sound fusion-targeted biopsy and found that the risk of cancer death or metastasis was < 1% over a long-term follow-up period [31]. Moreover, recent advanced technologies, such as prostate-specific membrane antigen positron emission tomography imaging, can alter AS conditions.
Conversely, low-risk patients with a Gleason score ≤ 6 may be good candidates for AS. Based on a Japanese national survey, approximately 90% of urologists proposed AS for low-risk disease [32], and the number of AS cases has increased over the past decades in Japan. However, not all physicians (urologists) recommend AS, even for low-risk patients. In addition, some patients request treatment even if they have a Gleason score ≤ 6 because they fear disease progression, especially younger patients. Kato et al. conducted a national questionnaire survey of Japanese urologists (involving 922 urologists at Japanese Urological Association Teaching Base Hospitals) regarding AS for patients with low- and intermediate-risk prostate cancer [32] and reported that 90.5%, 90%, 39.5%, 48.7%, 15%, and 22% urologists proposed AS for patients in low-risk/no comorbidity, low-risk/with comorbidity, intermediate-risk 3 + 4/no comorbidity, intermediate-risk 3 + 4/with comorbidity, intermediate-risk 4 + 3/no comorbidity, and intermediate-risk 4 + 3/with comorbidity groups, respectively. Therefore, approximately 40% of these urologists proposed AS for intermediate-risk cases.
This study had some limitations. First, it was a retrospective and multi-institutional study with substantial heterogeneity. Additionally, different biopsy methods were used, ranging from random to 12-core biopsy, as well as recent multiparametric MRI-fused biopsy methods at several institutions. Moreover, data are limited concerning the core number of positive cases in public databases. Additionally, there is a lack of consensus concerning grading among pathologists owing to the absence of a central pathological review system, which has resulted in different follow-up protocols and treatment modalities. Therefore, to obtain more accurate results, studies with a relatively longer follow-up period with a larger patient cohort are required. Despite these limitations, to our knowledge, this is the first and largest comprehensive study to analyze the usefulness of Gleason scores ≤ 6 compared with Gleason scores ≥ 7 in terms of modern radiotherapy outcomes in patient with high-risk prostate cancer.