Cancer Centers of Northern Arizona Healthcare

As genitourinary radiation oncologists, we live in exciting times. The options and alternatives for managing prostate cancer with radiation have significantly expanded beyond a historical choice between external beam and brachytherapy. The therapeutic regimens we have at our disposal allow for many more technical options and diverse schedules with differing radiobiologic underpinnings.

More-accelerated fractionation schedules may represent a significant advance for our patients. The data thus far is promising. Much of these data for hypofractionation (17-28 fractions) and for stereotactic body radiation therapy (SBRT) are highlighted by Shah et al in this review article.

Left unanswered are many questions of personalization. We regularly use a variety of measures (stage, grade, prostate-specific antigen, urinary function, anatomy, etc) to help our patients select the best treatment. Which patient is best served by conventional fractionation, hypofractionation, or SBRT? Today, this remains an important unanswered question. But for now, we do know that these various treatment schedules have moved from the pure research setting into routine clinical practice worldwide, and this timely review provides the background for future work.

With improvements in technology allowing for highly conformal radiotherapy to be delivered in conjunction with three-dimensional online image guidance, renewed interest in hypofractionated radiotherapy for prostate cancer has emerged. Multiple randomized trials comparing standard fractionation and hypofractionation when treating the prostate +/- seminal vesicles have been performed with comparable clinical outcomes and toxicity, making it a standard of care of option in appropriately selected patients despite limited long-term (> 10 year) outcomes. Limited data are available supporting hypofractionation in post-prostatectomy and whole-pelvis settings. Stereotactic body radiation therapy (SBRT), as a form of extreme hypofractionation, has been evaluated in multiple prospective trials allowing for the completion of treatment in 5 fractions. Despite limited data comparing SBRT to standard or hypofractionated radiotherapy with regards to long-term clinical outcomes and toxicity profiles, the data are promising and appropriately selected patients can be offered such an approach off-protocol.

Prostate cancer represents the most common non-cutaneous cancer among men in the United States, with an annual incidence of 220,000 cases/year.

 Multiple treatment options exist for men based on patient and disease factors, with radiation therapy representing a treatment option for men with low- and intermediate-risk disease and a preferred treatment option in conjunction with androgen deprivation for high-risk disease.

 One major concern regarding external beam radiation therapy is the duration of treatment, with external beam radiation therapy often exceeding 7 weeks. This represents not only a major time commitment, but also increases the cost of therapy for the patient due to time lost and travel costs.

 Therefore, a growing focus on shorter course regimens such as hypofractionated (> 2.0 Gy/fraction) and stereotactic body radiotherapy (SBRT)—5 fractions or less, has emerged.

While a switch from standard doses per fraction (1.8-2.0 Gy/fraction) to higher doses may seem to be a significant treatment paradigm change, this represents a continuation of research and treatment techniques that have been developed over the past several decades. Previously, radiobiologic studies have documented a low alpha/beta ratio (1.5) for prostate cancer, suggesting a benefit in the therapeutic ratio with increased biochemical control probability in comparison with toxicity to surrounding normal organs with larger doses per fraction (moderate hypofractionation).

 This strategy was initially employed with high dose rate (HDR) brachytherapy as the technique allowed for the highly conformal dose distributions necessary to limit doses to at-risk organs.

Multiple studies with long-term follow-up examining high dose rate (HDR) brachytherapy as monotherapy or boost have documented excellent clinical outcomes and low rates of toxicity with large doses per fraction.

 Over the past deDavid cade, advances in linear accelerator technology, treatment planning (intensity modulated radiation therapy [IMRT], volumetric modulated arc therapy), and image guidance (cone beam computed tomography with soft tissue/fiducial alignment) have allowed for delivery of highly conformal external beam radiation therapy plans delivering hypofractionated stereotactic treatments with data supporting these approaches in other treatment sites such as lung and spine tumors.

 A question that remains when evaluating such advances is the decision as to when the data are sufficient to make a new treatment/technique a standard of care. With respect to prostate cancer studies in radiation oncology, many consider it impractical and unnecessary to wait 15-20 years to document survival as treatment continues to advance in the interim. Standards of care can often be defined with 5-year toxicity outcomes and 5-10 year biochemical control, allowing for more rapid integration of new techniques into clinical treatment paradigms. The purpose of this review is to evaluate the literature supporting hypofractionated and stereotactic radiation therapy for prostate cancer, and to provide clinical recommendations based on the available data.

Multiple randomized prospective studies have evaluated hypofractionated radiotherapy (greater than 2.0 Gy per fraction) for prostate cancer. Older trials were performed but are limited by their lack of modern treatment techniques and image guidance, and in some cases substandard doses, and therefore outcomes are difficult to interpret.

 More recently, the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHIP) protocol randomized trial included 3163 men and used 3 fractionation schedules: 74 Gy/37 fractions, 60 Gy/20 fractions, and 57 Gy/19 fractions; with 24-month follow up, gastrointestinal (GI) and genitourinary (GU) toxicity rates with the hypofractionated regimens were not statistically increased, although long-term oncologic outcomes have not been published.

 Recently, a randomized study from the Netherlands randomized 820 patients to 78 Gy/29 fractions or 64.6 Gy/19 fractions. Preliminary results demonstrated no difference in acute GU toxicity; however, non-inferiority was not confirmed with higher rates of acute grade 2—nor was greater GI toxicity with hypofractionation.

 A randomized trial from Italy enrolled 168 men with high-risk prostate cancer, comparing 80 Gy/40 fractions (2 Gy/fraction) with 62 Gy/ 20 fractions (3.1 Gy/ fraction), with all patients receiving androgen deprivation therapy (ADT) for 9 months. With a median follow- up of 70 months, hypofractionation reduced 5-year biochemical failures with no difference in local or distant failures. However, among patients with a pre-treatment prostate-specific antigen (PSA) < 20, hypofractionation improved biochemical failure, as well as local and distant failure rates.

 Similarly, a randomized study from Lithuania enrolled patients with localized prostate cancer (91 initial report/124 update) to receive either 74 Gy/37 fractions (2 Gy/fraction) or 57 Gy/17 fractions (3 Gy X 13 fractions, 4.5 Gy X 4 fractions). No acute grade 3 or 4 toxicities were noted with a reduction in Grade 2 GU toxicity (19.1% vs 47.7%, 

 A second study from the institution compared 76 Gy/38 fractions (2 Gy/fraction) with 63 Gy/20 fractions 4 times weekly (3.15 Gy/fraction) with simultaneous integrated boost to the pelvis using standard fractionation in 124 patients.

Toxicity data demonstrated no difference in acute maximum GI or GU toxicity and no difference in quality of life (QOL) by technique.

 A randomized study from Fox Chase Cancer Center enrolled 303 patients (favorable to high-risk) comparing 76 Gy/ 38 fractions (2 Gy/fraction) and 70.2 Gy/ 26 fractions (2.7 Gy/fraction). With a median follow-up of 68 months, no differences in biochemical failure or clinical failure were noted (21.4% vs 23.3%). No difference in late toxicity was noted, except for patients with impaired urinary function pre-treatment, in which hypofractionation was associated with worse urinary function after treatment.

Multiple non-randomized studies have also evaluated hypofractionated radiotherapy 

 One of the largest studies came from the Cleveland Clinic; 770 consecutive patients were treated with 70 Gy/28 fractions (2.5 Gy/fraction) between 1998 and 2005. At a median follow-up of 45 months, the 5-year biochemical control was 83% with rates of 95%, 85%, and 68% for low-, intermediate-, and high-risk patients. Toxicity rates were low, with a 9% rate of acute grade 2 rectal toxicity and 18%/1% acute grade 2/3 urinary toxicity rates. Late grade 2/3 rectal toxicity rates were 3.1%/1.3%, and late grade 2/3 urinary toxicity rates were 5.1%/0.1%.

 A prospective phase II study from Princess Margaret Hospital enrolled 92 patients delivering 60 Gy/20 fractions (3.0 Gy/fraction). With a median follow-up of 38 months, no late grade 3 or greater toxicity was noted, with one acute grade 3-4 toxicity noted. Biochemical control was 97% based on the Phoenix definition.

Limited data are available regarding hypofractionated radiotherapy in the setting of adjuvant treatment following prostatectomy. One concern with hypofractionation in this setting is the potential for increased toxicity due to larger volumes of normal structures (bladder, bowel) receiving high doses. A phase I/II trial from Milan enrolled 50 patients prescribing 58 Gy/ 20 fractions (2.9 Gy/fraction) to the prostate fossa. With a median follow-up of 25 months, acute grade 2-3 GU and grade 2 GI toxicity were low, at 12% and 4% respectively, and comparable to a series of 153 patients receiving conventional fractionation.

 An update of 1176 patients (929 conventional fractionation, 247 hypofractionated with various schemes) found that, with a median follow-up of 98 months, hypofractionated treatment was associated with an increase in late grade 3 or greater GU toxicity (18.1% vs 6.9%) with dose per fraction predictive of toxicity.

 The PRIAMOS-1 trial evaluated hypofractionated radiotherapy to the prostate bed with a dose of 54 Gy in 18 fractions (3 Gy/fraction); 40 patients were enrolled and with short follow-up, no grade 3 or greater toxicities were noted. Eighteen percent of patients developed grade 2 GI toxicity with an increase in grade 1 urge incontinence from prior to treatment (23.1% at 10 weeks following radiation therapy [RT] vs 2.6% prior to RT)

. A series of 108 consecutive patients treated with salvage radiation to the prostate bed evaluated a dose of 65 Gy/ 26 fractions (2.5 Gy/ fraction); with a median follow-up of 32 months, biochemical control was 67% with one acute grade 3 GU event and no acute grade 3 GI or late grade 3 events noted.

Table 1: Modern Series Evaluating Hypofractionated Radiation Therapy

CHHIP indicates Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer protocol; SV, seminal vesicle; GI, gastrointestinal; GU, genitourinary; NCI, National Cancer Institute; PSA, prostate-specific antigen.

Massaccesi et al presented outcomes of 49 patients treated following prostatectomy with standard fractionation to the pelvis (45 Gy/ 25 fractions) and a concomitant boost to the prostate bed (62.5 Gy/25 fractions). No acute grade 3 or greater toxicity was noted with 10% and 30% of patients having grade 2 acute GU or GI toxicity, respectively.

 A retrospective analysis from the University of Wisconsin evaluated 50 patients treated with 65-70 Gy (2.5 Gy/fraction) following biochemical failure after prostatectomy. With short follow-up of 19 months, no grade 3 or greater acute or late toxicities were observed with a 73% 2 year biochemical control rate.

Similarly, limited data are available regarding hypofractionation when treating the whole pelvis. Many studies have evaluated hypofractionation to the prostate and seminal vesicles with standard fractionation to the pelvis (1.8-2.0 Gy/fraction) using a simultaneous integrated boost strategy with low rates of toxicity.

 However, one QOL study did find reductions in bowel and sexual function with such an approach that improved but persisted at 18-24 months.

 The previously mentioned randomized trial from Vilnius University did include pelvic radiation in both arms, with a hypofractionated regimen of 44 Gy/20 fractions (2.2 Gy/fraction). No differences in acute GI or GU toxicity were noted with this approach.21 A study from Greece enrolled 48 patients and delivered 47.6 Gy to the prostate bed and 37.8 Gy to the pelvis in 14 fractions (3.4 Gy/fraction, 2.7 Gy/fraction, respectively) with a 15th fraction to the prostate bed only. Treatment was delivered with three-dimensional conformal radiotherapy, and patients received amifostine prior to each fraction. Twenty-three percent of patients required 1-2 week delays due to toxicity with a 19% rate of grade 2 proctitis. At 41 months, biochemical control was 85%.

Based on the randomized as well as prospective data available, hypofractionation (2.5-3.2 Gy/fraction) should be considered a standard-of-care approach for appropriately selected men with low-/intermediate-risk prostate cancer. However, there are insufficient data to recommend hypofractionation in the adjuvant/salvage setting or in cases where pelvic radiotherapy is to be delivered, due to a lack of level I evidence and the potential for higher rates of toxicity with limited long-term outcomes.

SBRT delivers treatment in 5 fractions or less. As noted previously, this treatment technique represents a continuation of the rationale for HDR brachytherapy by using advances in external beam technology and image guidance to provide highly conformal radiation that can be confirmed with three-dimensional image guidance. Multiple techniques exists to deliver SBRT, including linear accelerators with online image guidance and specialized machines used predominantly for SBRT approaches.

Table 2: Studies evaluating SBRT in Prostate Cancer

SBRT indicates stereotactic body radiation therapy; GI, gastrointestinal; GU, genitourinary; UCLA, University of California, Los Angeles; QOL, quality of life.

One of the initial series on prostate SBRT comes from Boike et al, who reported a prospective phase I dose escalation study (45, 47.5, or 50 Gy in 5 fractions) of 45 patients (Gleason 2-6, PSA < 20/ Gleason 7, PSA < 15 , < T2b). With a median follow-up of 30, 18, and 12 months respectively, no biochemical failures were noted. Rates of grade 2+ and grade 3+ GI/GU toxicity were 18%/31% and 12%/4%, respectively

. An update of this trial incorporating 91 patients found 6.6% of patients at the highest dose level having high-grade rectal toxicity, with 5 out of 6 requiring colostomy. Importantly, late rectal toxicity was found to be correlated with the rectal V50 (> 3 cm3) and a V39 Gy > 35% circumference of the rectum, providing clinicians with dosimetric guidelines. Biochemical control was 99% with 42-month follow-up.

 Similar results were seen in a Phase I-II study from Milan, which demonstrated no grade 3 acute GI or GU toxicities with 10%/40% grade 2 rectal/GU toxicity and a Phase I/ II study from the University of Toronto, which demonstrated 98% biochemical control at 5 years with low rates of toxicity.

 A recently published Phase II trial enrolled 102 patients with low-risk prostate cancer; patients were treated with 40 Gy delivered in 5 and 8 Gy fractions every other day with real-time electromagnetic tracking. At 6 years, one patient demonstrated biochemical failure with toxicity profiles demonstrating 3% painless rectal bleeding and 20%/3%/5% rates of Grade 1-2 urinary frequency, dysuria, and retention with limited QOL changes.

A prospective Phase II protocol from Stanford University evaluated 41 patients with low-risk prostate cancer treated with 36.25 Gy in 5 fractions using Cyberknife. With a median follow-up of 33 months, no biochemical failures were noted, with 29% of patients having a PSA bounce. Two patients developed grade 3 chronic GU toxicity while no grade 3 GI toxicities were noted.

An update of this study with median follow-up of 5 years demonstrated a 7% biochemical failure rate with no grade 3+ GI and 1 grade 3 GU toxicity, and with 60% of patients age < 70 able to maintain consistent erections.

 King et al published a pooled analysis of 1100 patients treated in prospective trials at 8 institutions from 2003- 2011 using the Cyberknife technique with 58% low-risk, 30% intermediate-risk, and 11% high-risk. With 3 year follow-up, the 5-year biochemical control was 93% (95% low, 84% intermediate, 81% high) with a PSA bounce noted in 16% of cases.

 Results from prostate SBRT series are presented in 

 While attempts have been made to move beyond limited field (prostate +/- seminal vesicle [SV]) treatment, a recent prospective study that evaluated SBRT with ADT in high-risk patients with 40 Gy delivered in 5 fractions to the prostate, and concomitantly 25 Gy to the pelvis; 16 patients were enrolled with 26% of patients having grade 3+ GI or GU toxicity at 6 months with the phase II terminated.

Limited data are available directly comparing SBRT with standard radiation therapy techniques (IMRT, brachytherapy) and surgical techniques. Recently, a review of the Medicare database compared SBRT with IMRT. At 6 months, SBRT was associated with an increase in GU toxicity (15.6% vs 12.6%), which persisted at 2 years (43.9% vs 36.3%).

 In regards to quality of life, recent studies have documented that with SBRT, QOL declines in GI and GU domains are transient, with return to baseline within 6 months of treatment. A comparison to prostatectomy patients found improvement in urinary QOL with SBRT, as well as bowel QOL decline with SBRT. Late urinary and sexual QOL was significantly lower for surgical patients.

 Also, a QOL comparison of SBRT and EBRT with an HDR boost found that SBRT reduced the decline in GU, GI, and sexual QOL with long-term follow up.

 A recent multi-institutional analysis compared IMRT, brachytherapy, and SBRT, and with 803 patients evaluated, found similar outcomes with respect to urinary and bowel QOL.

 With regards to cost-effectiveness between techniques, Sher et al evaluated SBRT and IMRT and found that SBRT (both robotic and non-robotic) was more cost-effective (>$100,000/QALY) than IMRT in almost all scenarios, even when including the potential for increased toxicity with SBRT, which has been confirmed by several studies.

At this time, SBRT represents a logical progression of hypofractionation and a promising strategy, with excellent clinical outcomes to date, and represents a standard of care for clinicians in high-volume centers. Data on optimal techniques for treatment planning, delivery, and image guidance need to be ascertained in light of the technical complexity associated with the technique.

Multiple randomized and prospective studies are underway to further clarify which patients are ideal candidates for hypofractionated radiation or SBRT and the longterm toxicities associated with such strategies. RTOG 0415 randomized men with prostate cancer (T1-2c, Gleason 2-6, PSA < 10, no lymph node or distant metastases) to 73.8 Gy/41 fractions (1.8 Gy/fraction) versus 70 Gy/28 fractions (2.5 Gy/fractions) with the primary outcome of disease-free survival. The preliminary results of this trial were recently presented, and demonstrated that the hypofractionation arm was non-inferior to conventional fractionation, with disease-free survival rates of 75.6% versus 81.8% at 7 years.

 Studies are also evaluating hypofractionation using proton therapy.

With 220,000 new cases of prostate cancer diagnosed each year, the cost of prostate cancer treatment represents a significant public health issue. Innovations in treatment techniques have the opportunity to not only reduce treatment duration and improvement patient QOL but also can lead to sustainable cost reductions without impairing outcomes or increasing toxicity profiles.1 With respect to hypofractionated radiation therapy, randomized data supports the utilization of the technique as standard of care for treatment of the prostate +/- seminal vesicles with doses less than or equal to 3.2 Gy/fraction. Limited data is available on dosimetric guidelines when utilizing hypofractionated radiotherapy, although guidelines utilized in the randomized studies can serve as a baseline set of criteria. At this time, limited data exist supporting hypofractionated radiotherapy in the post-prostatectomy setting or in the treatment of pelvic lymph nodes. In light of the potential for increased toxicity with these scenarios, further study is required on clinical trial before routine clinical use. SBRT expands upon hypofractionated radiotherapy to offer treatment in 5 fractions and is supported in part by data from HDR brachytherapy, which has long-term outcomes with comparable dose schedules. While mature SBRT outcomes/toxicity data will be valuable, current data support the increasing utilization of the technique. Hypofractionated and SBRT techniques are being refined to help further increase the therapeutic ratio (for example, rectal spacers) and to improve toxicity profiles, increasing the number of patients eligible to receive treatment with such approaches.

Cleveland Clinic, Taussig Cancer Institute, Department of Radiation Oncology (CS, KS, AJ, RT), Cleveland, OH. Cleveland Clinic, Taussig Cancer Institute, Department of Radiation Oncology (AV), Strongsville, OH. 21st Century Oncology (CM), Lehigh Acres, FL. 21st Century Oncology, Michigan Healthcare Professionals (AM, FV), Farmington Hills, MI. 21st Century Oncology (EF), Pembroke Pines, FL Cancer Treatment Centers of America®, Radiation Oncology, Research (SF), Tulsa, OK.. Address correspondence to: Chirag Shah, MD, Department of Radiation Oncology, Cleveland Clinic, Taussig Cancer Institute, 9500 Euclid Ave., Cleveland, Ohio 44195, Phone: 216-445-8180. Fax: 216- 445-1068. E-mail: shahc4@ccf.org

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Articles

Despite limited data comparing stereotactic body radiation therapy to standard or hypofractionated radiotherapy with regards to long-term clinical outcomes and toxicity profiles, the data are promising and appropriately selected patients can be offered such an approach off-protocol.

Eduardo Fernandez, MD

Articles

Hypofractionated and Stereotactic Body Radiotherapy in Prostate Cancer