Long-Term Outcomes of Dose-Escalated Pelvic Lymph Node Intensity-Modulated Radiation Therapy (IMRT) With a Simultaneous Hypofractionated Boost to the Prostate for Very High-Risk Adenocarcinoma of the Prostate: A Prospective Phase II Clinical Trial

Abstract

Purpose:

There remains limited data as to the feasibility, safety, and efficacy of higher doses of elective radiation therapy to the pelvic lymph nodes in men with high-risk prostate cancer. We conducted a phase II study to evaluate moderate dose escalation to the pelvic lymph nodes using a simultaneous integrated boost to the prostate.

Methods and Materials:

Patients were eligible with biopsy-proven adenocarcinoma of the prostate, a calculated lymph node risk of at least 25%, Karnofsky performance scale ≥70, and no evidence of M1 disease. Acute and late toxicity were prospectively collected at each follow-up using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). The pelvic lymph nodes were treated to a dose of 56 Gy over 28 fractions with a simultaneous integrated boost to the prostate to a total dose of 70 Gy over 28 fractions using intensity-modulated radiation therapy.

Results:

Thirty patients were prospectively enrolled from October 2010 to August 2014. Median patient age was 70 years (57-83), pretreatment prostate-specific antigen was 11.5 ng/mL (3.23-111.5), T stage was T2c (T1c-T3b), and Gleason score was 9 (6-9). CTCAE v4.0 rate of any grade 1 or 2 genitourinary and gastrointestinal toxicity were 55% and 44%, respectively, and there was 1 reported acute grade 3 genitourinary and gastrointestinal toxicity, both unrelated to protocol therapy. With a median follow-up of 6.4 years, the biochemical failure free survival rate was 80.2%, and mean biochemical progression free survival was 8.3 years (95% confidence interval [CI], 7.2-9.4). The prostate cancer specific survival was 95.2%, and mean prostate cancer specific survival was 8.7 years (95% CI, 8.0-9.4). Five-year distant metastases free survival was 96%. Medians were not reached.

Conclusions:

In this single arm, small, prospective feasibility study, nodal radiation therapy dose escalation was safe, feasible, and seemingly well tolerated. Rates of progression free survival are highly encouraging in this population of predominately National Comprehensive Cancer Network very high-risk patients.

Introduction

Prostate cancer is an extremely common malignancy that affects approximately 1 in 9 men and hundreds of thousands of patients annually.¹ Within the spectrum of localized prostate cancer there are a wide array of risk categories, from clinically insignificant to highly aggressive. National Comprehensive Cancer Network (NCCN) very high-risk, clinically localized prostate cancer represents one of the most aggressive categories of prostate cancer and is a challenging clinical circumstance. This includes patients with at least 1 of the following: T3b-T4 disease, primary Gleason pattern 5, and >4 cores with grade group 4 or 5.² A frequently used treatment strategy for this category of malignancy is long-term androgen deprivation therapy and dose-escalated external beam radiation therapy (RT) with consideration of brachytherapy.³ Most data guiding the management of this rare category of prostate cancer are retrospective in nature.

Dose-escalated RT to the primary prostate tumor has shown multiple clinical benefits, including improvements in biochemical control along with lower rates of salvage therapy.^4–9 However, treatment of the pelvic lymph nodes remains controversial. Multiple prospective trials have examined treatment of the pelvic lymph nodes with low, prophylactic RT doses ranging from 45 to 50.4 Gy.^10–12 Such doses of RT represent the current standard of care; however, these have failed to routinely demonstrate robust or consistent improvements in clinical outcomes. Adequately powered studies have been completed (NCT01368588) examining the role for lower dose (4500 cGy) prophylaxis to the pelvic nodes, compared with prostate alone, and follow-up of these clinical data are ongoing and expected. The role for pelvic nodal treatment in men with high-risk prostate cancer remains uncertain and controversial.

An under-explored category of therapeutic intensification includes RT dose escalation of the pelvic lymph nodes. With novel RT techniques, including intensity-modulated RT and image-guided RT, higher doses of RT to the pelvic lymph nodes are both safe and highly feasible.¹³ Although such techniques have been shown in phase I studies to be safe, long-term clinical outcomes using dose-escalated radiation to the pelvic nodes remain limited.¹³ We conducted a single arm, prospective, phase II trial to examine the effect of higher doses of RT to the pelvic lymph nodes (NCT02177292). We present long-term clinical outcomes associated with this treatment strategy.

Methods and Materials

Inclusion criteria

Our inclusion criteria were men aged at least 18 years old, Karnofsky performance status ≥70, and a histologically confirmed adenocarcinoma of the prostate staged T1-T4N0M0 with a calculated risk of pelvic lymph node involvement of >25% via Roach formula.¹⁴ Patients had to be without evidence of nodal or metastatic disease on bone scan or cross-sectional imaging within 3 months of registration. Patients with a history of prior collagen vascular disease, ulcerative colitis, or Chron’s disease were excluded. Patients were followed daily during RT, every 3 months for the first 2 years, every 6 months from years 3 to 5, and annually thereafter. Acute and late toxicities were prospectively collected at each follow-up using Common Terminology Criteria for Adverse Events version 4.0. Acute toxicity was defined as occurring within 90 days of treatment.

Hormonal therapy

All patients underwent treatment with luteinizing hormone-releasing hormone agonists +/− antiandrogens. The protocol required that patients had at least ≥2 months neoadjuvant hormonal therapy, concurrent with radiation, and 2-years of adjuvant (luteinizing hormone-releasing hormone agonist only) after the completion of RT.

Radiation therapy

RT was given 5 days per week (Monday through Friday) for a total of 28 fractions with a total treatment time of approximately 5.5 weeks. Megavoltage photon beams were used with effective photon energies of 6 Megavoltage (MV) or greater. Treatment planning computed tomography (CT) scans were required to define both target volumes and critical local normal structures. Magnetic resonance imaging scans were encouraged. Two different clinical target volumes (CTVs) were defined for this treatment protocol. The first was the primary CTV (CTV-P), which included the entire prostate and proximal 1- to 1.5-cm seminal vesicle, as seen on the simulation CT and magnetic resonance imaging (if available). If the patient had clinically stage T3b or higher disease, the entire seminal vesicle was included. The second CTV was the lymph node CTV (CTV-L), which has been previously described.¹⁴ Briefly, the CTV-L included the low common iliac vessels, the left and right internal, external iliac vessels, bilateral obturator nodes, and presacral nodes, carving out bowel, bladder, and bone. The planning target volume (PTV) added to each of these CTVs consisted of 5 mm in all directions with the exception of 3 mm posteriorly on the PTV-P. Both the CTV-P and the PTV-P were prescribed 70 Gy over 28 fractions such that 95% of this PTV was covered with the prescription dose. The CTV-L was prescribed 56 Gy over 28 fractions, and the PTV-L was required to receive at least at minimum of 50.4 Gy, also over 28 fractions. Normal tissues contoured and constrained included the bladder, rectum, pubic bone, penile bulb, femoral heads (to the level of the bottom of the ischial tuberosities), small bowel (if present in whole pelvis field), large bowel, and skin surface. Daily image guidance was used consisting of either MV CT (tomotherapy), CT on rails, or Kilovoltage (KV) cone beam. Bladder and rectal filling, as well as prostate position, were examined on each daily CT used for image guidance. Dose specifications and normal organ constraints are included in Table 1.

Table 1.

Dose specifications and constraints

Structure	IG-IMRT with simultaneous integrated boost
	Dose per fraction x number of fractions	Dose constraints
CTV-L	2.0 × 28	95% @ 56 Gy
PTV-P	2.5 × 28	95% @ 70 Gy
PTV-L	1.8 × 28	95% @ 50.4 Gy
Structure	Dose constraints	Comments
Rectum	<45% @ 45 Gy
	<25% @ 55 Gy
	≤15% @ 65 Gy
Bladder	<45% @ 45 Gy
	<25% @ 55 Gy
	≤15% @ 65 Gy
Femoral heads	<1% @ 50 Gy
Penile bulb	Document dose	Tracking purposes only
Pubic bone	≤30% @ 60
Small bowel	Max 300 ccs receiving >46.5
Large bowel	0% @ 55.0 <105% of prescription

Abbreviations: CTV-L = clinical target volume lymph nodes; IG, image guided; IMRT = intensity-modulated radiation therapy; PTV-L = planning target volume lymph nodes; PTV-P = planning target volume prostate.

Statistical considerations and study endpoints

As the study was designed to assess feasibility, no formal statistical power calculation was performed. With regard to study endpoints, time to prostate-specific antigen (PSA) failure was defined according to the Radiation Therapy Oncology Group (RTOG) Phoenix definition¹⁵: Biochemical failure is defined as a rise of >2.0 ng/mL above the nadir. The date of failure is defined as the date the PSA rose >2.0 ng/mL above the nadir. The time to distant failure is measured from the date of study entry to the date of documented extra pelvic nodal failure or distant disease relapse. Patients with evidence of biochemical failure, but a negative prostate biopsy, were considered as distant failure only. Full study protocol is included in Supplementary Materials. The results of this study were designed to be compared with the 2008 publication of RTOG 92-02, in terms of biochemically and distant metastases free survival (DMFS).¹⁶

Results

Thirty men were prospectively enrolled in this initial feasibility cohort; 1 patient was unable to bladder fill for RT; 1 withdrew consent; and 1 was ineligible due to <25% risk of lymph node involvement. Thus, a total of 27 were found to be eligible for protocol enrollment. The median patient age was 70 years (57-83), median pretreatment PSA was 11.5 ng/mL (3.23-111.5), median T stage was T2c (T1c-T3b), median Gleason score was 9 (6-9), and 59% of patients had grade group 5 consisting of either 4 + 5 = 9 or 5 + 4 = 9 disease. The majority of patients (70%, n = 21) were NCCN very high-risk, and the rest were NCCN high-risk. A total of 4 of the patients were African American, 1 was of Hispanic ethnicity, and the remainder were Caucasian. Additional patient characteristics can be seen in Table 2.

Table 2.

Patient characteristics

Variable (n = 30)
Age (years)
Median (range)	70 (57-83)
Sex, % (n)
Male	100% (30)
Race, n
Caucasian	25
African American	4
Other	1
Ethnicity, n
Non-Hispanic	29
Hispanic	1
Risk category (NCCN) % (n)
High-risk	30% (9)
Very high-risk	70% (21)
Pretreatment PSA
Median (range)	11.5 (3.23-111.5)
Gleason score
Median (range) % (n)	9 (6-9)
Gleason score 6	3% (1)
Gleason score 7	14% (4)
Gleason score 8	28% (8)
Gleason score 9	59% (17)
T-stage
Median (range) % (n)	T2c (T1c-T3b)
T1c	27% (8)
T2a	3% (1)
T2b	3% (1)
T2c	13% (5)
T3a	30% (10)
T3b	13% (5)
T4	0

Abbreviations: NCCN = National Comprehensive Cancer Network; PSA = prostate specific antigen.

Failure events and overall survival

With a median follow-up of 76.8 months (6.4 years), 5-year biochemical failure free survival rates were 80.2%, median biochemical progression free survival was not met, and mean biochemical progression free survival was 8.3 years (95% confidence interval [CI], 7.2-9.4). Five-year overall survival was 88.4%, median overall survival was not met, and mean overall survival was 7.9 years (95% CI, 7-8.84). Several patients died of causes deemed unrelated to protocol therapy or prostate cancer. Five-year prostate cancer-specific survival was 95.2%, median prostate cancer specific survival was not met, and mean prostate cancer specific survival was 8.7 years (95% CI, 8.0-9.4). (Fig 1a–c). Five-year DMFS was 96%, median DMFS was not met. No patients developed distant metastases after 40 months.

Figure 1.

(a) Biochemical progression-free survival. (b) Overall survival. (c) Distant metastases-free survival.

Toxicity

Common Terminology Criteria for Adverse Events rates of any acute grade 1 to 2 genitourinary (GU) and gastrointestinal (GI) toxicity were 55% and 44%, respectively. There was 1 reported acute grade 3 GU and 1 reported acute grade 3 GI toxicity, and both were determined to be unrelated to protocol therapy. No acute grade 4 or higher toxicities were reported. At a median follow-up of over 5 years, rates of late grade 1 to 2 GU and GI toxicity were 17.2% and 27.5%, respectively, and there were no reported late grade 3 or higher toxicities. Figure 2 graphically represents these results.

Figure 2.

Acute and late Common Terminology Criteria For Adverse Events (CTCAE) version 4.0 toxicity events.

Discussion

The management of clinically localized NCCN very high-risk prostate cancer represents a challenge in need of prospective research to define optimal management. Historically, patients with NCCN very high-risk prostate cancer represent a rare cohort and have relatively poor clinical outcomes.² Prospective data understanding novel RT treatment strategies, specifically in this cohort of patients, remain limited, and mostly consist of early phase trials with limited follow-up or large retrospective series.^3,13,17 Herein, we present the results of a prospective trial describing the outcomes of 27 patients treated with an RT dose intensification strategy to the pelvic nodes. With a median follow-up of over 5 years, the results of this study demonstrate biochemical control rates of over 80%, without any attributable grade 3 or higher toxicity.

There has been extensive prospective examination over the past several decades into RT dose intensification to the primary tumor in men with prostate cancer.^4,5,7,8,18 Methods of dose escalation have included both brachytherapy and external beam dose escalation strategies, including heavy ions. There have been several large, prospective, multi-institutional phase III clinical trials that have examined dose escalation to the prostate, which included thousands of patients.^4–8 A relatively consistent benefit to dose escalation has been shown across these series. This led to the hypothesis that in patients with a high risk of micro metastatic disease in the pelvis, dose escalation to pelvic nodes may also confer a benefit.

There have been a few prospective trials that have examined RT dose intensification strategies for the treatment of pelvic lymph nodes. The first of these was conducted by Adkison et al,¹³ which examined a very similar strategy to that examined in the current study. In this phase I trial by Adkison et al, a similar cohort of NCCN very high-risk patients were treated with a hypofractionated course of RT to the pelvic nodes to a total dose of 56 Gy, with a concomitant treatment of the prostate to 70 Gy, all given over 28 fractions. With a median follow-up of approximately 2 years, there was a relatively low rate of grade 2 or higher toxicity.¹³ Similarly, the rates of late GI and GU toxicity were both low. Conclusions were that this strategy should be explored further in cohorts of patients with high-risk prostate cancer. Despite this compelling preliminary data, long-term clinical outcome data examining this strategy have not been previously published to our knowledge. A second important trial to have examined higher doses to the pelvic lymph nodes was the Prostate and pelvis Versus Prostate Alone Treatment for Locally Advanced Prostate Cancer (PIVOTAL) trial.¹⁹ In this randomized study a total of 124 patients were randomized between prostate-only radiation (74 Gy in 37 fractions) and prostate with pelvic lymph node intensity-modulated RT (74 Gy in 37 fractions, with 60 Gy over 37 fractions to the nodes). With a primary endpoint of acute GI toxicity, patients were randomized to either prostate-only or prostate with pelvic nodal treatment. No difference in acute GI toxicity was seen between the 2 arms. This study had a median follow-up of 37.6 months (shorter than our median follow-up of 76 months) and had similar rates of late grade 2 GI toxicity. Specifically, these rates were 24% in the PIVOTAL trial and 28% in the current study. An important difference to consider is that our study used a moderate hypofractionation approach, specifically a total of 28 fractions, while the PIVOTAL trial treated the pelvic nodes over 37 total fractions. Despite this, the similarity in late grade 2 toxicity events across the 2 studies is reassuring.¹⁹

Several other series have examined the management of patients with NCCN very high-risk prostate cancer, with standard RT dose to the pelvic nodes. Nearly all of these are retrospective. Kishan et al¹⁷ has conducted 2 retrospective analyses presenting the outcomes of patients with NCCN very high-risk disease.³ These retrospective studies concluded that extreme dose escalation using brachytherapy was the preferred management approach for patients with Gleason 9 to 10 prostate cancer.³ Limitations to the role of brachytherapy boosting along with retrospective series to evaluate this have been previously published.²⁰ Moreover, the specifics regarding the radiotherapeutic treatment of the pelvic nodes remain poorly discussed in this series.

The outcomes that are seen in the Kishan et al series illustrate the relatively poor control rates associated with either standard dose external beam RT and androgen deprivation therapy or surgical resection for patients with high-risk prostate cancer. For the small percentage of patients who achieved a follow-up of 10 years, the DMFS rate falls below 60%. The results of our small prospective series are favorable in comparison, with biochemical failure free survival at a median follow-up of 5 years of over 80% and DMFS rates considerably higher. This favorable comparison was maintained when examining the results of RTOG 92-02.¹⁶ It remains unclear if modest dose escalation of the pelvic nodes contributed to these favorable results; however, given the exceedingly low toxicity rate associated with the methods presented in our series, it is certainly compelling to consider. Additional evaluation in larger cohorts of patients is warranted. It should also be noted that longer term follow up will be required of these patients.

There are limitations to the current series that merit careful consideration. First is that the series is small and was not formally powered statistically for a primary endpoint. Second is that advanced molecular imaging was not performed. Such imaging would have been highly likely to reveal occult distant metastatic disease, otherwise not detectable on CT and bone scan, but unfortunately access to such imaging is limited in our state for new diagnoses of prostate cancer. We have presented long-term follow-up of a prospectively collected and examined feasibility cohort. Larger and expanded clinical trials are needed to understand if RT dose intensification of the pelvic nodes is warranted or improves outcomes.

In conclusion, we have presented long-term clinical outcomes of a prospective phase II study examining RT dose intensification to the pelvic lymph nodes. Long-term cancer control rates and toxicity rates were both excellent. Given these very encouraging results, larger and expanded prospective trials evaluating the outcomes of dose escalation to the pelvic nodes in patients with NCCN very high-risk prostate cancer are warranted.