Outcomes of high-dose intensity-modulated radiotherapy alone with 1 cm planning target volume posterior margin for localized prostate cancer

The most common options for definitive treatment of early-stage prostate cancer are radical prostatectomy, brachytherapy, and external beam radiotherapy. In selected patients, androgen deprivation therapy or active surveillance may be used.

Radiotherapy (RT) with doses above 74 Gy is an important, well-established treatment for prostate cancer control. A meta-analysis of randomized clinical trials comparing high-dose versus low-dose RT for patients with clinically localized prostate cancer showed a significant reduction in biochemical failure over 5 years for the group of patients treated with high doses [1].

However, the delivery of high doses of radiation to the prostate is associated with higher rates of treatment-related gastrointestinal (GI) and genitourinary (GU) complications. Kuban et al. [2] showed that GI complication rates greater than grade 2 after 10 years of follow-up were twice as high (26% versus 13%) in patients treated to 78 Gy with three-dimensional conformal radiotherapy (3D-RT) than in those treated to 70 Gy with conventional RT.

In recent years, significant advances in conformal treatment delivery in the form of intensity-modulated radiotherapy (IMRT) have allowed excellent target coverage with high doses of radiation and concurrent dose reduction to adjacent normal tissues, thereby offering potentially more effective treatment. In a cohort of prostate cancer patients treated to 81 Gy with IMRT and a median follow-up of 99 months, the rate of grade ≥ 2 GI complications after 10 years was 3% [3].

It is worth emphasizing that the highly conformal nature of IMRT requires meticulous implementation and execution with rigorous quality control, in order to be effective.

The aim of this study was to report the results of disease control and toxicity in patients with clinically localized prostate cancer treated with definitive IMRT alone with 1 cm posterior planning target volume (PTV) margin and doses above 74 Gy.

Of the 140 patients included in the study, most were white (89%). Mean age was 68.6 years (Standard Deviation = 7.9 years) and median follow-up time was 58.3 months (range: 12.3 to 138.9 months). Table 1 summarizes patients’ characteristics, including tumor stage, pre-treatment PSA value, Gleason score, risk group, and prescription dose.

This study reports the results of disease control and toxicity in patients with clinically localized prostate cancer treated with definitive IMRT alone with 1 cm posterior PTV margin and doses above 74 Gy.

Excellent disease control rates were observed, with 5-year biochemical failure-free survival of 91.7%, 82.5% 85.9% for low-, intermediate-, and high-risk patients, respectively.

A unique feature of our series is that none of the patients received any kind of HT and/or pelvic lymph node irradiation, even those classified as high or intermediate risk. All high-risk patients in this study were offered 2–3 years of HT, and all intermediate-risk patients were offered 6 months of HT. These patients did not receive HT either due to potential side effects, or comorbidities, or patient preference.

The role of HT concomitant with RT is well established for high-risk prostate cancer patients [6‐9] however, most published studies used low doses (< 74 Gy) with pelvic lymph node irradiation, and focused on patients with locally advanced disease. In that specific group, HT is almost mandatory, given that it is associated with higher rates of overall survival.

In intermediate- and high-risk patients with localized, small-volume disease, i.e., those with a Gleason score of ≥ 7 and/or PSA ≥ 10 ng/ml and ≤ T2c, the benefits of HT are not very clear. In our series, 99 patients presented intermediate- or high-risk prostate cancer with localized, small-volume disease. Of these, 15 (15%) had biochemical failure, 3 (3%) presented metastases, and 1 (1%) died of prostate cancer in a median follow-up period of 58 months. Stage T2 patients presented a risk of biochemical failure almost three times higher than the stage T1 patients. In a study reported by D’Amico et al., intermediate- and high-risk stage ≤ T2b prostate cancer patients were randomized into groups that received either RT together with 6 months of HT or RT only (both treatments with a dose of 70 Gy). The group that received combined treatment presented a 21% rate of biochemical failure and no death from prostate cancer in a median follow-up period of 54 months [10]. Our results suggest that the additional benefit of HT could be replaced by RT doses above 74 Gy, as the role of radiation dose escalation is well documented to increase biochemical control and reduce clinical failure [1, 11]. Because HT is associated with some significant side effects [12], replacing it with high-dose RT, as demonstrated in our series, could represent a less toxic treatment strategy for these patients. Yet, no randomized studies have tested this hypothesis. Once completed, the Radiation Therapy Oncology Group (RTOG) 0815 protocol may help to answer this question.

Despite the benefits offered by dose escalation, higher toxicity rates are expected. Series that used doses above 74 Gy and 3D-RT showed rates of late grade ≥ 2 GI and GU complications of 16–35% and 15–37%, respectively [13‐17]. Series in which IMRT was used with doses above 74 Gy, rates of late grade ≥ 2 GI and GU complications were 1.5–24% and 5–29%, respectively [3, 18, 19]. A comparison of complication rates associated with 3D-RT and IMRT strongly suggests that rates are lower for IMRT [20, 21].

In our study, rates of late grade 2 GI and GU complications were 12.6% and 18.6%, respectively, and comparable values for grade 3 were 3.1% and 1.6%. Tools for measuring the degree of toxicity are not standardized, and the assessment methods remain subjective. Though, there is striking variation in complication rates between the different published series. For example, in the Alicikus et al. study, 170 patients with prostate cancer received 81 Gy using IMRT and late grade 2 GI toxicity occurred in 4 patients (2%). Among these patients, 2 developed grade 2 rectal bleeding [3]. In our study, 16 patients developed grade 2 GI toxicity but only 3 developed grade 2 rectal bleeding.

Another finding of our study was a significant correlation between acute and late toxicities, as between acute GI and GU toxicities. Similarly, in a study by Zelefsky et al., the authors detected that the occurrence of acute grade ≥ 2 GI and GU toxicity was significant predictor of late grade ≥ 2 GI and GU toxicity [21]. These findings may help to identify those patients who should be followed closely for late side effects.

In the current study, a symmetric PTV margin of 1 cm around the CTV (including the posterior margin) was used. There is no consensus on the ideal safety margin to use, which is typically determined by technical considerations at each treatment facility. However, usually the posterior margin is reduced in order to achieve a better rectal sparing, despite the risk of missing the target. Table 4 shows an overview of late toxicities in some IMRT dose-escalation reports and the posterior margin used. Even with larger margin, our results were comparable with those with smaller margins.

A major concern regarding the use of IMRT in treating prostate cancer is the risk of missing the target due to the internal movement of organs. Some published studies have suggested that the inter and intrafractions changes in rectal volume could compromise effective treatment [22‐24]. This risk is directly related to the PTV margins definition which is related to the precision of each technique.

Image-guided radiotherapy (IGRT) is the best method to safely reduce the margins, leading to a reduction of complication rates without compromising disease control. Zelefsky et al. recently reported the toxicity rates and biochemical control outcomes in patients treated with high dose IMRT using IGRT for clinically localized prostate cancer. One hundred eighty-six patients were treated at a dose of 86.4 Gy with daily correction of the target position based on kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated with IMRT to the same prescription dose but without implanted fiducial markers in place (non-IGRT). The 3-year likelihood of grade 2 and higher urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p = 0.02) [25].

In our study, no image-guidance was used, and the excellent rates of local control, even with no HT, are probably due to the high doses and PTV margins used. And, as already pointed, unlike to what would be expected, toxicity rates were low, and comparable to the already published ones.

In 2006 we started IGRT at our department with cone beam CT for some patients receiving IMRT for prostate cancer. In the first moment we decided to keep the same margins of 1 cm in all directions. After 2009 we formally initiated to delivery radiation for these patients with smaller margins (0.5 to 0.7 cm) and daily cone beam CT. We expect that the use of IGRT will be related with less morbidity, given its higher precision.

The major limitations of the current study, including the biases inherent to a retrospective review, are the physician-based assignment of toxicities scores which warrant consideration in interpretation of the results, the low number of patients studied and the short follow-up. A longer follow-up time is needed to determine the duration of tumor control and to assess the incidence of additional late complications.

Some patients with clinically localized prostate cancer may benefit from RT as a single treatment modality. The IMRT technique used in this cohort, delivering doses of 74 Gy or higher with 1 cm posterior PTV margin was safe, well-tolerated, and effective.