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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Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. 

. 2011 ;6:3. doi: 10.1186/1748- 717X-6-3.

Wiegner EA, King CR. Sexual function after stereotactic body radiotherapy for prostate cancer: results of a prospective clinical trial. 

. 2010 ;78(2):442-448. doi: 10.1016/j.ijrobp.2009.07.1748.

Lee YH, Son SH, Yoon SC, et al. Stereotactic body radiotherapy for prostate cancer: a preliminary report. 

. 2014 ;10(2):e46-53. doi: 10.1111/j.1743-7563.2012.01589.x.

Kang JK, Cho CK, Choi CW, et al. Image-guided stereotactic body radiation therapy for localized prostate cancer. 

Madsen BL, Hsi RA, Pham HT, et al. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 GY in five fractions for localized disease: first clinical results.

King CR, Brooks JD, Gill H, et al. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer.

. 2012;82(2):877-882. doi: 10.1016/j.ijrobp.2010.11.054.

Oliai C, Lanciano R, Sprandio B, et al. Stereotactic body radiation therapy for the primary treatment of localized prostate cancer. 

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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.

Hypofractionated and Stereotactic Body Radiotherapy in Prostate Cancer

		Mr. Su is a 4th year medical student currently attending Yale University School of Medicine

		Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. Death rates for prostate cancer in the United States have fallen dramatically, largely due to early detection and improved treatment. Nevertheless, the screening of men for prostate cancer is probably the most hotly debated clinical topic in this country. In 2008, the US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen-based screening program for men over age 75, and in 2012, for all men. Other expert physician organizations, including the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN), support prostate cancer screening with balanced and proper patient education preceding the PSA draw.

		Significant flaws of the US randomized screening study, which largely formed the basis for the USPSTF recommendations, have been addressed by many leaders in the field of prostate cancer. The effect of this recommendation on the well-being of US men will take more years to become apparent; however its effect on the healthcare system is already obvious, with fewer patients being diagnosed with prostate cancer, leading to fewer referrals to urologists, medical, and radiation oncologists.

		This manuscript documents a significant decrease in the volume of patients seen across all radiation oncology and urology clinics in Lee County in southwest Florida. The analysis does not prove that this trend is directly related to the USPSTF recommendations. Nevertheless, these findings are important for healthcare budgeting, physician training, and workforce allocation. It will be interesting to compare this trend to those seen at academic institutions across the country. With a longer follow-up, the authors are encouraged to re-evaluate the percentage of patients presenting with locally advanced and metastatic disease. Modeling studies will then be necessary to determine if these clinical outcomes are related to the USPSTF recommendations. One day, we will know whether the experts on the USPSTF panel got it right or wrong. Time will tell.

	Background: In 2008, the US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen-based screening for prostate cancer in men age ≥75, and in 2012, recommended against screening in all men. It is unknown how these guidelines have impacted patient presentation to radiation oncology care.

	We conducted a retrospective study of patients presenting with localized prostate cancer to 21st Century Oncology radiation oncology clinics in southwest Florida, which supply nearly all radiation oncology services for the region. We assessed trends in patient volume and the risk distribution of a random sample of patients (using National Comprehensive Cancer Network risk criteria) to estimate the total patient volume within each risk group.

	Results: From 2007 to 2013, the number of patients presenting with prostate cancer decreased from 1,860 to 1,209 (p <.001). The estimated number of low-risk patients decreased from 858 (779-939) to 354 (307-405), as did the number of intermediate-risk patients, from 657 (583-736) to 506 (454-560). There was no significant change in the number of patients with high-risk (323 [267-389] to 312 [267-361]) or metastatic disease (22 [10-48] to 37 [23-61]). Similar trends held in all age groups, except intermediate-risk disease decreased significantly for men ≥75 years, but not younger men.

	USPSTF guidelines may have decreased the number of patients presenting with prostate cancer for radiation oncology care, particularly those with low-risk disease, without a short-term increase in higher-risk disease. Future research should assess the longer-term impact of these guidelines nationally.

Prostate cancer is the most common cancer among males in the United States, with an estimated 233,000 new cases in 2014.

 Because a large proportion of men with prostate cancer do not experience symptoms during their lifetime, the significant increase in the incidence of prostate cancer since the introduction of prostatespecific antigen (PSA)-based screening has raised concerns of overdiagnosis and overtreatment.

 In 2008, the US Preventive Services Task Force (USPSTF) issued a recommendation against PSA-based screening for prostate cancer in men age ≥ 75,3 which was expanded in 2012 into a recommendation against screening in all men.4 These guidelines have generated substantial controversy, with some professional societies and patient advocacy groups arguing that screening can reduce mortality.

Several studies have evaluated the impact of the 2008 guidelines, and most have found only a small decrease in the use of screening PSA.

 Decreased screening presumably decreases the detection rate of prostate cancer and could result in some men progressing to higher-risk disease before they present with symptoms. However, only one study has evaluated whether the guidelines have changed the number or risk profile of patients presenting with prostate cancer. A study of Surveillance, Epidemiology, and End Results (SEER) found that the number of patients presenting with prostate cancer declined from 2005 through 2009, with a more pronounced reduction in early than late-stage disease, but did not have sufficient follow-up time after the 2008 guideline change to fully assess its clinical impact.

As the time it takes for asymptomatic prostate cancer to progress to clinically detectable disease can vary,

 it is important to understand the longer-term impact of the guidelines on patient presentation. Furthermore, no studies have assessed the impact of the guidelines on specialty care.

Patient presentation for radiation oncology care is of particular interest for several reasons. First, changes in patient volume and risk profile at radiation oncology clinics can be considered markers for changes in the detection of prostate cancer because radiation therapy is one of the most common curative treatments for prostate cancer, especially for the elderly.

 Second, changes in patient volume may affect the projected demand for radiation oncology services since the treatment of prostate cancer accounts for nearly 20% of radiation therapy administered.

Third, the volume of patients presenting with prostate cancer may affect rates of both treatment-related benefits and harms. Treatment with radiation therapy may decrease mortality for some diagnosed patients,

 but could also increase overall healthcare costs and lead to unnecessary adverse events in patients who would not otherwise have had progressive disease.

Trends in patient presentation at radiation oncology clinics highlight the downstream effects of reduced screening and will inform future debates regarding the consequences of the guidelines on actual clinical practice.

		Table: Prostate Cancer Characteristics and Risk Distribution

 P-value is for chi-squared test of difference in the distribution of cancer characteristics across years.

 denotes a significant change (p <.05) in the proportion of patients in a risk group, comparing 2007 versus 2013 using two sample test of proportions

To address these gaps in knowledge, we studied the numbers and risk profiles of patients presenting with prostate cancer to radiation oncology practices from 2007 to 2013. Because more than 5 years have passed since the 2008 guidelines, one might expect a change in patient presentation for men age ≥75, for whom the guidelines apply.

Although the 2012 guidelines apply to men of all ages, it is unclear whether enough time has passed for changes to manifest. We focused our study on a single county in southwest Florida, where every radiation oncology practice is affiliated with 21st Century Oncology, a specific radiation oncology provider. Thus, a review of patients presenting to 21st Century Oncology clinics encompassed the majority of radiation oncology referrals within this region. Although our study focused on radiology oncology, we also assessed patient volume at urology clinics in the region to determine whether changes in radiation oncology patient volume were due to substitution by urologic care.

We conducted a retrospective study of patients presenting to 21st Century Oncology radiation oncology clinics in Lee County, Florida. The largest radiation oncology organization is 21st Century Oncology; it is also one of the largest groups of urologists in the United States.

 All radiation oncology practices in southwest Florida and all urology practices within Lee County are affiliated with 21st Century Oncology. We restricted our analysis to 12 radiation oncology clinics that were part of the 21st Century Oncology system from at least 2005-2013; this ensured that changes in the numbers of patients presenting were not due to the acquisition or loss of centers during the study period. In addition, we included 4 21st Century Oncology urology clinics in the region as a secondary sensitivity analysis to assess whether the USPSTF guidelines affected the use of competing treatment modalities—for instance, whether decreased patient volume at radiation oncology clinics corresponded with increased patient volume at urology clinics. However, cancer characteristic data were accessible only at radiation oncology clinics for our analysis of patient risk profiles.

We identified all patients age ≥18 who presented with newly diagnosed prostate cancer between 2007 and 2013 at one of 12 radiation oncology practices or 4 urology practices (Table). Most patients with newly diagnosed prostate cancer, including those ultimately managed with watchful waiting or active surveillance, are evaluated at least once by a radiation oncologist or urologist. Hence, we included all patients presenting to specialty care, regardless of subsequent treatment or lack thereof, to fully capture trends in prostate cancer detection. For each calendar year, we excluded any patients who had been seen in the practice in the prior year. We also randomly sampled a subgroup of patients presenting to radiation oncology clinics in 2007 (before USPSTF recommendations) and 2013 (after USPSTF recommendations); we conducted a chart review on this subgroup to determine cancer characteristics at presentation.

Patient characteristics include age at diagnosis (≥ 75 years or <75 years) and year of diagnosis. We noted the specific 21st Century Oncology practice and type of practice (radiation oncology or urology) at which the patient first presented; if a patient presented to multiple practices, we only counted the first.

		Figure 1: Number of Patients Presenting With Incident Prostate Cancer to Radiation Oncology Clinics, 2007-2013

For a random subgroup of patients in 2007 and 2013, risk at presentation was categorized by T-stage, PSA, Gleason score (by biopsy), or National Comprehensive Cancer Network (NCCN) risk strata.

 T-stage was categorized into low (T1-T2A), intermediate (T2B-T2C), or high (T3-T4). PSA was categorized into low (<10 ng/ml), intermediate (10-20 ng/ml), or high (>20 ng/ml). Gleason score was categorized into low (<6), intermediate (7), or high (>8). NCCN risk was categorized into low (low-risk PSA and Gleason and T-stage), intermediate (intermediate risk PSA or Gleason or T-stage), high (high-risk PSA or Gleason or T-stage), or metastatic (N1 or M1). We conducted a chart review for patients classified as metastatic to assess whether the use of advanced imaging contributed to the detection of metastatic disease.

To assess trends in patient volume, we calculated the number of patients age ≥75 years and <75 years presenting with prostate cancer to radiation oncology or urology practices in 2007 through 2013, and analyzed yearly trends using Poisson regression. We tested for an interaction between age group and year to assess whether changes in patient volume differed by age group. For the random subgroup of patients in 2007 and 2013 we categorized risk at presentation as outlined above, and calculated 95% confidence intervals (CIs) for the proportion of patients within each risk category, as well as P-values using 2 sample proportions. We compared differences in proportions across risk categories using chi-squared tests for all patients and for patients ≥75 years and <75 years, separately. We multiplied the proportion of patients within each risk category by the total patient volume in 2007 and 2013 to estimate the number of patients presenting within each risk category.

Similarly, we transformed the 95% CIs of the proportions by multiplying them by the total patient volume. We performed statistical analyses using SAS version 9.4 (SAS Institute Inc, Cary, North Carolina), Stata 13 (College Station, Texas) and Microsoft Excel. The Yale Human Investigations Committee and the Western Institutional Review Board deemed this study exempt from review.

We identified 9334 patients who presented to radiation oncology clinics with prostate cancer from 2007 to 2013. Over our study period, the annual number of patients decreased by 35%, from 1860 to 1209 (

 <.001). From 2007 to 2013, the number of patients age ≥ 75 years decreased 41% (from 689 to 408), while the number of patients age <75 years decreased 32% (from 1171 to 801). For both age groups, increasing year was associated with decreasing patient volume (

 <.001). The magnitude of the decrease in patient volume was greater among patients age ≥ 75 than for patients <75 years (

USPSTF guidelines may have decreased the number of patients presenting with prostate
cancer for radiation oncology care, particularly those with low-risk disease, without a
short-term increase in higher-risk disease.

Steven E. Finkelstein, MD

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