 covers radiation oncology issues focused on genitourinary cancer and head and neck cancers. The lead article, “Changes in Prostate Cancer Presentation for Radiation Oncology Care” by Su and colleagues addresses the 2008 decision by the US Preventive Services Task Force (USPSTF) to recommend against prostate-specific antigen (PSA) screening for men over the age of 75, and the agency’s follow-up in 2012, which recommended against PSA screening for all men. How these guidelines have affected patient presentation to radiation oncology remains unclear. The researchers note that the 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. However, they recommend that future research assess the longer-term impact of these guidelines nationally.

The second genitourinary cancer manuscript focuses on the debate about organ preservation versus extirpative cystectomy. “Are Surgery and Chemotherapy Sufficient to Treat Locally Advanced Bladder Cancer?” says there is a paucity of clinical research directed toward the locoregional tumor eradication rate following surgery. The authors note that both awareness about pelvic failure following contemporary cystectomy has been raised and clinical trials to pursue the amelioration of this problem have commenced.

Head and neck cancers make this month’s issue with studies involving glottis cancer and parotid gland cancer. The authors of “Therapeutic Ratio of Hypofractionation in Early Glottic Cancer: A Topic Worth Revisiting?” state that optimal fractionation for this cancer is unclear. The study addresses the researchers’ experience at the Sylvester Comprehensive Cancer Center at the University of Miami using the therapeutic ratio of 2.25 Gy versus 2 Gy in this cancer. They found that treatment of early glottic cancer with 2.25 Gy/fraction may result in greater acute toxicity than 2 Gy/fraction without improved efficacy.

A study to determine the frequency and clinical characteristics of parotid gland metastasis and the criteria for elective inclusion of parotidean nodes in the radiotherapy clinical target volume marks the second head-and-neck cancer manuscript. “Parotid Node Metastases in Locally Advanced Nasopharyngeal and Oropharyngeal Cancer: Implications for Radiotherapy Target Volume Delineation” concluded that the ipsilateral parotidean nodes may be at risk for metastatic involvement when bulky ipsilateral level II metastases and multilevel nodal disease are co-existent, possibly due to retrograde lymphatic drainage. Inclusion of the ipsilateral parotid gland in the clinical target volume should be considered in such cases. This month’s Strategic Alliance Partnership articles highlight activities at the University of Arizona’s Center for Applied NanoBioscience and Medicine and the Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center at Yale University.

The Center for Applied NanoBioscience and Medicine has developed expertise in creating new platform technologies that integrate genomic and proteomic biomarker signatures into assay platforms for molecular-based biodosimetry. These platforms can assess toxicity and tissue radio-sensitivity in order to gain knowledge about the biological mechanisms that could guide precise therapies. Researchers from COPPER collaborate across a wide spectrum of translational cancer research projects, employing expertise in clinical epidemiology, comparative effectiveness, and health services research. In addition to performing original research, COPPER provides training and mentorship to the next generation of cancer policy and outcomes researchers.

Articles

Far-reaching PSA Guidelines Affect Radiation Oncologists

For those who think that men can’t die of prostate cancer, they can spend the day with me in clinic and meet some of the bravest men on the planet who are in the fight of their lives and are unfortunately afflicted with advanced metastatic prostate cancer.

Prostate cancer is the most commonly diagnosed cancer, affecting an estimated 220,800 men. In 2015, an estimated 27,540 will die of this disease. Thus, identifying those who have aggressive, potentially fast-growing disease is of paramount importance.

In 2008, there was indeed such an action. The United States Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA) screening for men over age 75. In 2012, however, USPSTF extended the recommendation against PSA-based screening to all men.

Interestingly, there were no urologists or radiation oncologists on the USPSTF panel. The recommendations were based on the following beliefs: a) the screening process can result in pain, suffering, and a small risk for other complications; b) the screening process can result in a psychological consequence of receiving a false-positive test; and c) the screening process can result in men with prostate cancer receiving overtreatment because of the potential difficulty distinguishing prostate cancers that are life-threatening from those that are indolent. Yet, numerous expert organizations, including the American Urological Association and National Comprehensive Cancer Network, support prostate cancer screening with appropriate education.

For every action there’s an equal and opposite reaction. Fewer PSA draws imply fewer patients being diagnosed with prostate cancer, implying fewer referrals to urologists, implying fewer appropriate referrals to radiation oncologists.

, “Changes in Prostate Cancer Presentation for Radiation Oncology Care in Southwest Florida, 2007-2013,” the authors demonstrate a significant decrease in the volume of prostate patients seen across all radiation oncology and urology clinics in Lee County in Florida. The estimated number of low-risk patients decreased as did the number of intermediate- risk patients.

Although it is difficult to know exactly the reason behind the decrease, what profits wisdom when there’s nothing to be done? The fact is, there is a decrease in the volume of patients with prostate cancer who are seen early in the course of their disease. This occurs in an era in which treatments for prostate cancer have gotten better and better with improved radiation therapy techniques, surgical acumen, and novel agents such as Provenge, Xofigo, Zytiga, and Xtandi, which are defining the metastatic castrate resistant landscape in which a decade ago there was little.

Additionally, diagnostic improvements via available genomic testing and advanced imaging are highlighting more personalized care. Many believe we have been using primitive tools for the screening, diagnosis, and risk grouping of all patients. The introduction of advanced genetic testing for appropriate patients first identified by simple blood tests can potentially identify the patients at real risk of dying from their disease, so that ultimately the screening can be more targeted.

I encourage all who read this to think about what this means for current decision making in our own practices.

For those who think that men can’t die of prostate cancer,
they can spend the day with me in clinic and meet some
of the bravest men on the planet who are in the fight of
their lives and are unfortunately afflicted with advanced
metastatic prostate cancer.

Prostate Cancer: Every Action Has a Reaction

The ability to obtain high-quality radiobiological information about the interactions between tumor and healthy tissue, when using ionizing radiations, would contribute to the development of more effective and personalized radiotherapy treatments. It would also benefit both medical research and clinical radio-oncology communities involved in technology development of molecular assays, such as genomic-based biodosimetry or predictive proteomic assay for lateeffects toxicity. Today, biomedical imaging is also allowing noninvasive molecular phenotyping and providing molecular- specific predictive and response biomarkers to clinical therapies. The spectrum of approaches is broad, and our team at the University of Arizona’s Center for Applied NanoBioscience and Medicine (the Center) has since developed expertise in creating new platform technologies integrating genomic and proteomic biomarker signatures into assay platforms for molecular-based biodosimetry, or for assessing toxicity and tissue radio-sensitivity in view of gaining knowledge in the biological mechanisms that could guide precise therapies.

Our aim is to operate a Center of Excellence dedicated to translational research and to the convergence of multidisciplinary technological skills of national or international significance in the fields of nano-biotechnology and radiobiological sciences. Since 2005, the Center has innovated multiple molecular profiling platforms for biodosimetry through its projects portfolio sponsored by federal agencies (eg, Department of Health and Human Services/Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases); more recently, by international consortia (eg, RadioGenomic Consortium), that contributed to the emerging field of radiomics (ie, genomics, metabolomics, and imaging textural analysis) providing molecular biomarkers of tissue specific responses to radiations. The Center has also entered a memorandum of understanding agreement with the National Centre of Oncological Hadrontherapy in Italy allowing it access to facilities infrastructure for conducting comparative studies of photon, proton and carbon ion treatments. These resources provide an operational framework structured in 3 major research themes: (1) integrated microsystems for automating biospecimen workflow processing and molecular assay chemistries, (2) in vitro radiobiology models, and (3) preclinical trials on patients.

		Radiomics Assays Platforms for Personalizing Radiotherapies

Over the last several years, the Center has developed microfluidic platforms and instrumentation for integrating the entire workflow processing of biological fluid samples onto lab-on-chip devices. The Lab-on-a-Chip technology has arisen out of the desire to incorporate multiple lab processes within a single platform. This is done for a variety of reasons: to optimize speed, reliability, reagent usage, cost reduction, contamination, and automation, among many others. In particular, rapid DNA analysis from buccal swabs, saliva, and a small volume of blood collected from a fingerstick have been implemented for multiplex genomic profiling of short tandem repeats bio-signatures used in tissue or human identification.

Similarly, white blood cell separation from the whole blood is important for genomic or proteomic analysis of the cells for clinical diagnostics; and for medical countermeasures in a disaster response. In the case of a radiological event, such as a dirty bomb attack or a clinical radiotherapy accident, individuals may be exposed to different doses of radiation that shall trigger different medical treatments.

Current tests take several days to complete, far too long for patients who must be treated within hours of exposure with medications to bolster their blood and immune systems. A novel approach using gene expression-based biodosimetry can convert genomic testing into a rapid portable system that can assess a small volume of blood samples in less than 1 hour.

 The automation of the sample processing comprises the separation of white blood cells from a blood sample by using a low-cost deterministic hydrodynamic microfluidic plastic chip.

 Direct signal amplification assay chemistries (eg, quantitative nuclease protection assay, chemical ligation-dependent probe amplification) are then used to obtain a dose-response genetic profile derived from a set of less than 30 genes.5 Such an approach to measure the dose of radiation absorbed by the body could be applied in clinical situations such as for monitoring the dose of radiation received by patients undergoing radiotherapy treatments. Several preclinical studies have been initiated on patients undergoing radiotherapy treatment for validating these platforms and methodologies with in-vivo samples, (eg, from patients undergoing bone marrow transplantation or heterogeneous bone fracture radio-treatments).

Other potential biomarkers of response to radiations comprise proteins,

 small metabolite molecules, and microRNAs (miRNAs), which are small non-coding RNAs expressed in different tissue and cell types that function as major players of posttranscriptional gene regulation. MiRNAs represent a great opportunity to enhance the efficacy of radiotherapy treatments—they can be used to profile the radioresistance of tumors before radiotherapy, and monitor their response throughout the treatment; thus they help to select intensification strategies and to define the final response to therapy along with risks of recurrence or metastatization.

 It is now recognized miRNAs can be dysregulated in radioresistant cancer cells to promote cancer radioresistance. The Center is designing microfluidic devices for investigating circulating biomarkers identifying plasma miRNAs fingerprinting in patients treated by radiotherapy for correlating with radioresistance status (eg, in breast, cervical, or prostate tumors).

Novel radiation strategies (eg, particle beam or hadrons radiotherapy) are the subject of a growing interest in broad clinical use in the most common categories of cancers. However, there are still needs for developing platform technologies for assessing the biological response(s) and/or any potential adverse effects; more importantly, to optimize the conditions for predicting toxicity risk through novel imaging and biomarker approaches exploiting pretreatment biomolecular assay in the patient blood samples and tumor biopsy specimen. These biologically targeted dosimetry and radiotherapies will enable personalized care and guide precise treatment while providing new research tools for gaining fundamental knowledge in radiobiology with many applications in clinical oncology.

: Frederic Zenhausern, PhD, MBA, Director and Professor, Center for Applied NanoBioscience and Medicine, University of Arizona, 145 S. 79th Street, AZ 85226, Chandler, USA; Phone: (602) 827-2051 ; Fax: (602)-827-9115 ; E-mail: fzenhaus@email.arizona.edu.

			Estes MD, Yang Jianing, Duane B, et al. Optimization of multiplexed PCR on an integrated microfluidic forensic platform for rapid DNA analysis. 

			Brengues M, Paap B, Bittner M, et al. Low density gene expression array for acute radiation dose assessment. 

			Badie C, Kabacik S, Bernard N, et al. Comparison of established and emerging biodosimetry assays. 

			Brengues M, Gu J, Chen X, East P, et al. Automation of sample processing for gene expression radiobiological assays. 

			Lucas J, Dressman HK, Suchindran S, et al. A translatable predictor of human radiation exposure. 

. 2014;(9): e107897. doi:10.1371/journal. pone.0107897.

			Lacombe J, Azria D, Mange A, et al. Proteomic approaches to identify biomarkers predictive of radiotherapy outcomes. 

			Ghandi SA, Weber W, Melo D, Doyle-Eisele M,et al. Effect of 90Sr internal emitter on gene expression in mouse blood. 

. 2015 16:586:doi 10.1186. s12864-015-1774-z.

The ability to obtain high-quality radiobiological information about the interactions between tumor and healthy tissue, when using ionizing radiations, would contribute to the development of more effective
and personalized radiotherapy treatments.

Platform Technology Development for Biologically Targeted Dosimetry and Radiotherapy

In the decades’ long debate around the feasibility, efficacy and desirability of attempting organ preservation versus extirpative cystectomy, there has been a relative paucity of attention directed towards the exact locoregional tumor eradication rate following surgery. Rather, this argument about surgery versus organ preservation has distracted the uro-oncology community from critically examining and addressing this important matter. Pelvic tumor recurrence following contemporary cystectomy has traditionally been considered a relatively infrequent event. Cagiannos and Morash

 compiled 8 institutional series published between 1977 and 2006 reporting local recurrence rates ranging from 3.9% to 29%. These series may have underestimated the true risk of pelvic relapse for patients with locally advanced disease for a variety of reasons including: excluding failures when observed co-synchronously with distant metastases or when there was no biopsy confirmation, using simple numerator/denominator crude risk calculations rather than cumulative incidence rates that account for loss of follow-up and competing risks, or aggregating risk assessments across low and high-risk cohorts.

More recent assessments of pelvic failure risks have suggested the rates are higher than previously assumed. Herr et al,

 reporting the surgical parameters in the neoadjuvant chemotherapy SWOG 8710 trial, demonstrated that despite requiring biopsy confirmation, the crude risk of developing local recurrence following cystectomy in pT3/4 disease was 32%. The 2011 update of the MRC neoadjuvant chemotherapy— cystectomy trial (International Collaboration of Trialists) reported a 48% and 49% rate of pelvic recurrence with and without neoadjuvant chemotherapy, respectively. In a 2011 Canadian survey of contemporary cystectomy, comparably high 48% to 50% cumulative incidence rates of pelvic failure were found.

 As neither neoadjuvant nor adjuvant chemotherapy reduce pelvic failure, locoregional control currently is pursued by optimizing nodal dissection. The well-characterized University of Southern California (USC) experience together with the Memorial Sloan Kettering Cancer Center (MSKCC) and SWOG 8710 reports emphasize the importance of thorough node dissections defined as a minimum of 10-12 nodes. In a 2012 reanalysis of the USC experience following adequate dissection and counting all pelvic failures except those that occur subsequent to the diagnosis of distant metastases, there is a 24% pelvic recurrence rate (Daneshmand, MD, oral communication). In 2014, Christodouleas

 reported the University of Pennsylvania and SWOG 8710 pelvic recurrence experience and identified low, intermediate, and high risk groups according to stage, extent of node dissection, and margin status. These risk groups experienced 8%, 20%, and 41% pelvic recurrence rates at 5 years, respectively.

In aggregate, to date, these clinical data emphasize the neglected problem of significant pelvic failure in pT3/4 patients following cystectomy. In the entire arena of locally advanced solid tumor management—except for bladder cancer&mdash;clinical experience and formal experimentation have established multimodality treatment involving varying combinations of surgery, radiotherapy, and systemic treatments to be pivotal in securing optimal cure rates and symptom control. The exhaustive list includes melanomatous and non-melanomatous skin cancer, sarcomas, CNS tumors, head and neck cancers, thyroid cancers, breast, lung, esophagus, gastric, pancreatic, rectal, anorectal, endometrial, cervix, vulvovaginal, and prostate cancers. It is possible that the nexus of under enumeration of pelvic relapse, contention that pelvic recurrence is trumped out of clinical relevance by distant metastases, and concern about the toxicity of integrating cystectomy with adjuvant radiotherapy has created a reluctance to study this approach in the uro-oncologic community, save for in Egypt.

		Figure 1. Axial CT of a patient with prior radical cystectomy.

		The image shows a proposed clinical target volume (red), planning target volume (blue) and 80% plus dose distribution for adjuvant radiation of bladder cancer.

Urologists are rightly addressing the importance of pelvic tumor control by emphasizing that, whilst in 2015 the standard cystectomy has to involve a meticulous node dissection, there may be further surgical pelvic tumor control gains to be had by a still more cephalad-extended nodal dissection. This is being formally examined in an ongoing SWOG phase 3 trial. This pelvic failure can be observed in isolation or co-synchronously with distant metastases. As such, it constitutes an absolute ceiling on the curability of bladder cancer by surgery and chemotherapy, and also can be a source of significant patient morbidity. One randomized and several retrospective series of postoperative radiotherapy in squamous and transitional bladder cancer suggest superior pelvic control and survival. In 1992, Zaghloul et al,

 published the results of a phase III trial of postoperative radiotherapy in mainly squamous cell bladder cancer showing reduced pelvic failure. In 1999, Cozzarini from Milan

presented their retrospective review of postcystectomy radiotherapy. They compared partial/ total cystectomy alone versus with postoperative radiotherapy of 45-66Gy (median 50.4Gy). Adjuvant RT to doses 50.4 Gy or higher was associated with improved survival and improved pelvic control. There was an attendant 7% risk of bowel obstruction reported, emphasizing the importance of further careful study.

While the NRG has this year opened the randomized phase 2 trial discussed below, colleagues in England, France, and India are well advanced in designing their own prospective trials examining postoperative radiotherapy. In NRG GU001, the hypothesis to be tested is that postoperative intensity-modulated radiation therapy (IMRT) will reduce any pelvic tumor recurrence (occurring either in isolation or together with distant metastases) with acceptable toxicity in patients with pT3/ T4 urothelial bladder cancer following cystectomy. This trial is important, as it will be the first prospective randomized trial in Europe and North America to address the significant problem of pelvic failure. The IMRT regimen utilized will mirror the radiotherapy delivered postoperatively in uterine cancers in RTOG trials. This contemporary radiotherapy minimizes both gastrointestinal and pelvic marrow toxicity. The latter is particularly relevant in patients who may have received neoadjuvant or adjuvant chemotherapy and in those patients who might need chemotherapy for the palliation of metastatic disease. Using IMRT we can expect to achieve this improved pelvic control with certainly no more, and likely less toxicity than reported from the Egyptian and European experiences.

The Cairo group has published in April 2013 the results of their pre- versus post-op randomized phase III radiotherapy trial demonstrating very low rates of gastrointestinal and surgical serious toxicity with 50Gy/25 fractions with non-IMRT radiotherapy. To avoid the potential for radiation to damage a reconstructed urinary reservoir, patients with “neobladders” will be ineligible in the NRG study. Stringent collection of all serious bowel toxicity encountered will be buttressed by well-defined stopping rules to ensure that we identify any clinically significant increase in bowel toxicity that requires surgical correction. To reconcile the concept of studying radiotherapy in only those patients who have had the ideal operation (minimum of ten removed nodes and negative margins) when the ideal is commonly not achieved, we will study all radical cystectomy pT3/T4 patients and stratify according to intermediate and high-risk failure grouping. In a similar vein, we will utilize a pragmatic approach to the issue of adjuvant and neoadjuvant chemotherapy. Clinical guidelines call for the use of neoadjuvant chemotherapy but only 8% of patients get neoadjuvant chemotherapy in North America. In addition, in many centers, there is a strong conviction that patients should be considered for post-operation adjuvant chemotherapy while in others, many patients may not receive any peri-operative chemotherapy. The heterogeneity in the use of peri-operative chemotherapy challenges any adjuvant radiation therapy trial design. Specifically, randomization before chemotherapy will likely result in a proportion of patients not getting the assigned adjuvant radiotherapy because of chemotherapy toxicity, overall treatment fatigue, and early manifestation of some of the 30% of pelvic recurrences that occur within 6 months of cystectomy.

Thus, we will register trial eligible patients 4-6 weeks post cystectomy and randomize regarding adjuvant radiotherapy at that time for patients not getting chemotherapy, but delay that randomization until after chemotherapy in patients so treated. However, the pelvic relapse data will be collected in all registered patients. This approach that deals with issues of the surgical quality and chemotherapy grounding the study in the reality of contemporary North American management of locally advanced bladder cancer allows us to ask in a generalizable way whether adjuvant radiotherapy can usefully help the pelvic recurrence problem. In summary, the challenge of pelvic failure following contemporary cystectomy has been engaged and the clinical trials to pursue the amelioration of this problem have commenced.

Department of Radiation Oncology, Ottawa Hospital (LE), Ottawa, ON, Canada; Department of Radiation Oncology, Hospital of the University of Pennsylvania (JC), Philadelphia, PA; Department of Radiation Oncology, Massachusetts General Hospital (JE), Boston, MA. Corresponding author: Libni Eapen, MD; The Ottawa Hospital; Regional Cancer Centre; 501 Smyth Road; Box 902; Ottawa; Ontario; K1H 8L6. E-mail: LEapen@toh.on.ca.

			Cagiannos I, Morash C. Surveillance strategies after definitive therapy of invasive bladder cancer. 

			Herr HW, Faulkner JR, Grossman HB, et al. Surgical factors influence bladder cancer outcomes: a cooperative group report.

			Eapen L, Breau R, Belanger E et al. Substantial Pelvic recurrence rates after contemporary radical cystectomy for pT3/4 N0-3 transitional bladder cancer: a multi-instututional Canadian study.

			Christodouleas JP, Baumann BC, He J, et al. Optimizing bladder cancer locoregional failure risk stratification after radical cystectomy using SWOG 8710. 

			Zaghloul MS, Awwad HK, Akoush HH, et al. Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control. 

			Cozzarini C, Pellegrini D, Fallini M, et al. Reappraisal of the role of adjuvant radiotherapy in muscle-invasive transitional cell carcinoma of the bladder [Abstract]. 

			Baumann BC, Noa K, Wileyto EP, et al. Adjuvant radiation therapy for bladder cancer: a dosimetric comparison of techniques. 

The challenge of pelvic failure following contemporary cystectomy has been engaged and the clinical trials to pursue the amelioration of this problem have commenced.

Are Surgery and Chemotherapy Sufficient to Treat Locally Advanced Bladder Cancer?

		Williams and Eisbruch have addressed an uncommon clinical scenario in the setting of bulky jugulodigastric adenopathy. Their observation of parotid lymph node failures prompted a review of their experience and of the literature. They have thoroughly considered a number of factors including anatomic and physiologic considerations initially described by Million and Rouvier. The absolute number of parotid failures is small in any series, calling into question our ability to accurately estimate clinical risk. However, by invoking classic anatomic literature combined with lymphatic physiology the authors have constructed a strong argument for covering parotid lymph node stations as a potential site of failure in bulky neck disease.

		The presence of adenopathy causing retrograde flow into otherwise low risk sites has long been a fundamental tenet of the rationale for nodal station risk and associated need for treatment. Nonetheless, the decision to cover parotid lymph node stations should not be taken lightly since it may significantly increase the risk of severe xerostomia and associated changes in quality of life.

		It is fitting that these observations and suggested policies come from perhaps the most senior and well respected pioneer of three-dimensional and intensity modulated radiotherapy (IMRT). Eisbruch and colleagues thus extend and continue to refine our knowledge base, further advancing the art and science of radiotherapy.

	To determine the frequency and clinical characteristics of parotid gland metastasis (PGM) from nasopharyngeal cancer (NPC) and oropharyngeal cancer (OPC) and define criteria for elective inclusion of parotidean nodes in the radiotherapy clinical target volume (CTV).

	All cases of NPC and stage III/IV OPC referred for radiotherapy at our institution between 2003 and 2011 were reviewed. Incidence and risk factors for PGM at presentation and at time of failure were analyzed. A literature review of PGM incidence in head and neck squamous cell carcinoma was performed.

	Of 52 NPC and 231 OPC patients, two (3.8%) NPC patients and 4 (1.9%) patients presented with PGM. All PGMs were located ipsilateral to the primary tumors in patients with bulky, ipsilateral level II and multilevel ipsilateral lymph node involvement of aggregate size greater than 6 cm in diameter. Similar rates and characteristics were found in the literature after an extensive search.

	The ipsilateral parotidean nodes may be at risk of metastatic involvement when bulky ipsilateral level II metastases and multilevel nodal disease are co-existent, possibly due to retrograde lymphatic drainage. Inclusion of the ipsilateral parotid gland in the CTV should be considered in such cases.

The most common oral complication and cause for reductions of quality of life (QOL) after head and neck radiation is salivary gland dysfunction and xerostomia.

 Parotid gland-sparing intensity-modulated radiation therapy (IMRT) techniques have become standard of care in an attempt to prevent salivary flow dysfunction and xerostomia. IMRT has facilitated parotid-sparing by virtue of enabling steep dose gradients between normal tissue and clinical target volumes (CTV) in close apposition. Indeed, the use of IMRT has increased dramatically in the United States.

 Furthermore, in comparisons between IMRT and conventional radiation for head and neck cancer (HNC), no significant increases in the rate of locoregional relapse have been found with the use of IMRT.

Given the steep dose gradients typical of IMRT, awareness of the risk of involvement to various adjacent sites is critical for appropriate target delineation and avoidance of marginal failures. While the presence of clinically- evident disease in a parotid gland (PG) precludes its exclusion from the radiation target volume, there has been some controversy as to whether the ipsilateral PG should be spared when it is not clinically involved.

 Although the PG should likely be included in the CTV when it is at high risk for subclinical disease, no clear clinical factors to date have been identified to indicate when the PG is at high risk. Others have previously reported recurrences in the region of a spared PG after IMRT.

 In a publication by Chao et al, a patient with squamous cell carcinoma (SCC) of the piriform sinus developed a surgical bed recurrence near the spared PG.5 Cannon et al also reported 3 additional cases of tumor recurrence in the region of the spared PG.

 Two of these recurrences were in peri-parotid lymph nodes (LNs), and the third in the skin near the tail of the spared PG. An additional 3 cases of peri-parotid metastases have been reported by Chen et al,

 with all 3 recurrences occurring in or near the spared contralateral PG. However, the overall frequency of these recurrences has not been well-reported.

In the present study, we sought to identify cases of pathologically-proven PG metastases in patients with previously-untreated nasopharyngeal and oropharyngeal cancer (NPC and OPC, respectively), perform a review of the relevant literature on PG metastases in head and neck squamous cell carcinoma (HNSCC), and determine common clinical characteristics of patients with PGM to generate indications for inclusion of the PG in the CTV.

This retrospective study was approved by the University of Michigan Internal Review Board (IRB). Existing databases of all cases of NPC and stage III/IV OPC presenting for consultation at the Department of Radiation Oncology from 2003-2011 were queried to identify patients with clinical and/or radiological evidence of PG metastases. Cases of SCC metastatic to the parotid when the primary site was unknown were excluded. The presence of metastases within the parotid gland, rather than within level II, was confirmed in all cases by an attending neuroradiologist. Clinical characteristics of patients with confirmed PGM were retrospectively reviewed. A PubMed literature review was performed to determine the incidence of parotid metastasis (PM) from mucosal HNC, and potentially identify clinical factors predisposing patients to metastatic dissemination to the PG.

Between 2003 and 2011, 52 patients with NPC and 231 patients with OPC were identified. Of these, 2 of 52 (3.8%) patients with NPC and 4 of 231 (1.7%) with OPC presented with PMs. All PGM were ipsilateral to the primary tumor, and all patients had extensive multilevel ipsilateral nodal involvement with bulky level II adenopathy. Of all nasopharynx and oropharynx cases that presented to us from 2003 to 2011, 33 patients had N3 disease.

			MRI contrast-enhanced T1-weighted axial images of a T2N1M0 nasopharyngeal carcinoma. A) Arrows demonstrate involvement of lateral retropharyngeal nodes and arrowhead an involved left junctional node. B) Arrows demonstrate involved cervical nodes in levels II and V of the left neck. C) Arrows indicate involved level II and V left neck nodes. Arrowhead indicates an enlarged, suspicious LN associated with the inferior PG. D) Diffuse left neck lymphadenopathy (arrows) in level II and V, as well as periparotid LNs (arrowheads) inferior to the PG.

			MRI contrast-enhanced T2-weighted axial images of a T4N1M0 nasopharyngeal carcinoma. A) Arrow delineates infiltrative right nasopharyngeal mass, while arrowhead delineates right parotid LN mass. B) Arrows depict bulky ipsilateral lymphadenopathy in level II.

			CT contrast-enhanced axial images of 2 cases (A/B, C/D) of tonsillar cancer with PG involvement. A) Arrow demonstrates involvement of the left tonsil primary tumor. Arrowhead indicates an enlarged, suspicious LN associated with the left PG. B) Arrows demonstrating primary tumor and significant involvement of left level II LNs, with arrowhead demonstrating the involved parotid LN. (C) Arrows showing involvement of the left tonsillar primary tumor and associated level II lymphadenopathy. Arrowhead shows the involved LN in the left PG. (D) Arrows showing diffuse, bulky involvement of levels IB and II more inferiorly.

			CT contrast-enhanced axial images of a T2N2cM0 base of tongue squamous cell cancer. A-C) Arrows demonstrates involvement of the left base of tongue and bilateral cervical lymphadenopathy in level II. Arrowheads indicate an enlarged, suspicious LN associated with the left inferior PG. D) Arrows demonstrates involvement of level IA and contralateral level III.

			PET-CT axial images of a T1N2cM0 glossotonsillar sulcus SCC. A) Arrows demonstrate right level II involvement. Arrowhead depicting inferior parotid lesion. B-C) Arrows demonstrate diffuse right level II involvement. D) Arrows demonstrate right level III, V, and left level III involvement.

	Three of the 6 patients with PGM underwent definitive chemoradiation using IMRT at our institution. Of these 3, no LRR has been observed thus far, at a median follow-up of 14 months (range 9-21). In addition, no patient who presented to us with oral cavity, larynx, or hypopharynx primary carcinomas presented with PG involvement. The clinical details of the 6 patients presenting with PGM are discussed below.	

	A 52-year old man with stage III T2N2M0 nasopharyngeal carcinoma presented with lateral retropharyngeal lymphadenopathy, junctional lymphadenopathy 

, as well as extensive LN involvement ipsilaterally in levels IIIV, including upper level II

. In addition, he was found to have an enlarged LN in the PG tail 

, and additional suspicious peri-parotid LNs more inferiorly 

. Fine needle aspiration was performed on the enlarged parotidean node and returned positive for nasopharyngeal carcinoma. This patient elected to pursue chemoradiation outside of our institution and was subsequently lost to follow-up.	

	A 21-year old female with stage IVA T4N1M0 nasopharynx carcinoma presented to our institution with a large right, infiltrative nasopharynx primary tumor. CT and MR imaging revealed multiple, bulky upper ipsilateral level II nodes, as well as a biopsy-confirmed large right intraparotid lymph node 

. She was treated with definitive concurrent chemoradiation with IMRT at our institution, with all gross disease receiving 70 Gy in 35 fractions, followed by 2 cycles of adjuvant cisplatin and 5-fluorouracil. Six months after radiation, she developed osseous metastases and was treated with palliative radiation, though remained without evidence of local-regional recurrence (LRR) at 21 months after chemoradiation.	

	A 54-year old male with a stage IVA T3N2cM0 left tonsillar SCC presented with associated large, necrotic ipsilateral LNs in level II

. In addition, a large necrotic LN mass was noted in the inferior tail of the parotid 

. Fine needle aspiration was performed on this enlarged node and returned positive. The presence of the PM occurred in the absence of nasopharyngeal extension of the primary mass. He received definitive concurrent chemoradiation, and the PG and necrotic LN mass were included in the treatment volumes, with the gross disease receiving 70 Gy in 35 fractions. He remained without evidence of recurrence at 9 months after chemoradiation.	

	A 56-year old male, heavy smoker, with stage IVB T3N3M0 HPV-negative invasive SCC of the left tonsil presented with diffuse lymphadenopathy, particularly with advanced, bulky level IB and II ipsilateral disease 

. The PET-CT revealed a left parotidean LN which was FDG-avid, and biopsied positive. The patient elected to pursue definitive concurrent chemoradiation outside our institution.	

	A 49-year old male with stage IVA T2N2cM0 HPV-positive poorly differentiated SCC of the base of tongue initially presented with multi-level lymphadenopathy with diffuse involvement of level I and levels II-III bilaterally 

, as well as a large necrotic LN mass in the left PG

. An ipsilateral level I-IV selective neck dissection was performed, and the enlarged LN was found at the inferior portion of the lateral PG. All LN levels and the inferior parotid mass were positive for SCC. He received postoperative concurrent chemoradiation, with all gross tumor receiving 70 Gy in 35 fractions. He developed lung metastases 9 months after treatment completion, but has no evidence of LRR 14 months after treatment.	

	A 57-year old male with stage IVA T1N2cM0 HPV-positive SCC of the glossotonsillar sulcus presented with massive ipsilateral lymphadenopathy (levels II, III, and V), right carotid artery encasement, and left cervical lymphadenopathy (levels II and III) 

. In addition, an FDG-avid lesion in the inferior portion of the right PG was noted 

. Fine-needle aspriation (FNA) of the parotid lesion returned positive. He was referred for definitive concurrent chemoradiation outside our institution.	

The results of a literature search for patients with mucosal HNC who developed PG metastases, either at initial presentation or at recurrence are shown in 

. Many series do not report the overall incidence of PG metastases in mucosal HNSCC. Of those that do, the incidence of PMs appears to be 4% or less, consistent with the findings in the present series.

Based on anatomic/radiologic studies, lymphatic drainage from the PG generally follows an orderly fashion, from intraparotid and peri-parotid LNs, to ipsilateral level II and III LNs. While both PM at initial presentation and recurrences in the parotid bed after therapy are rare, it is clear that the extensive network of intraparotid lymphatics puts the parotid region at risk for dissemination of tumor cells from a wide variety of HNC sites.

As locoregional control improves with more modern therapy, identifying factors which predispose mucosal HNC patients to developing PMs bears significant importance for radiation. In patients receiving IMRT, Cannon and Lee documented 3 cases of patients with peri-or intra-parotid recurrences who had no evidence of parotid involvement on pre-treatment imaging. In their report and associated editorials, it has been postulated that altered lymphatic anatomy in the cervical lymphatics after surgery or definitive chemoradiation could contribute to these LRRs, in addition to natural routes of lymphatic dissemination that exist.

In nasopharyngeal cancer, level II and retropharyngeal LNs represent the primary route of lymphatic drainage. Fletcher and Million documented that the incidence of peri-parotid/parotid/pre-auricular LN involvement at presentation for nasopharyngeal cancer is about 1-2%

. Furthermore, radiologic studies combining MRI and FDG-PET have demonstrated an incidence of 3.4% of parotid bed nodal metastases in patients with nasopharyngeal carcinoma. 

 These rates of parotid LN involvement in nasopharyngeal carcinoma are consistent with our institutional experience. Parotid LN involvement can potentially be attributed to known pathways of spread through lymphatic channels directly draining the Eustachian tube in the region of the nasopharyngeal tumor, which were originally depicted by Rouviere

. However, as the Eustachian tube is frequently involved in advanced nasopharyngeal cancer, if this route was responsible for PM, it is likely that we would have observed these metastases with higher frequency than we have in our (and other) series.

In the literature, involvement of the PG from oral cavity and oropharynx primaries appears to be very infrequent. In a large surgical series of 1500 patients, Olsen et al reported an overall incidence ~1% with oral cavity/oropharynx primary SCCs with pathologically-proven PG involvement. While 42% of these cases were associated with disease at presentation, 58% resulted from recurrences after the primary disease was treated. The majority of these metastases occurred in the inferior portion (tail) of the PG.

		Table 1. Publications describing parotidean metastases in patients with mucosal HNSCC.

		RT=radiation; NPX=nasopharynx; OP=oropharynx; HP=hypopharynx; OC=oral cavity; SGL=supraglottic larynx; MS=maxillary sinus; NS=Not specified; NA=Not applicable. *= 6 cases were SCC, 4 were other histologies. † =The 3 parotid cases were always associated with disease in the ipsilateral retropharyngeal nodes or level II nodes. Based on the above studies, the total number of parotid metastasis cases for each primary site are as follows: nasopharynx= 6, oral cavity= 24, oropharynx= 15, larynx= 6, maxillary sinus= 3, hypopharynx= 2.

Another surgical series reported on 239 patients with oral cavity SCC who underwent elective parotid tail resection (below the marginal mandibular branch of the facial nerve).

 Parotid node involvement occurred in 2.5% of the cases. Furthermore, they observed an increased risk of parotid node involvement with an increased number of involved cervical nodes. There were 14.3% of patients with 3 or more LNs had PMs, compared to less than 2% with only 1-2 positive cervical LNs. In this report, we document 4 of 231 (1.7%) cases of oropharyngeal cancer with biopsy-proven involvement of the PG at initial presentation, consistent with that reported in the literature. To our knowledge, there is no evidence citing direct drainage from oropharyngeal tumors to the PG. In addition, our cases argue against the notion that all PMs result from direct spread from the mucosa to parotidean LNs.

Diffuse and bulky involvement of the ipsilateral upper jugular chain (especially upper level II) was common among all 6 of our observed cases of biopsy-proven PG metastases. In fact, all 6 cases had advanced ipsilateral nodal disease with an aggregate lymph node mass having a total largest dimension > 6 cm. We believe that this commonality is the driving force for PG involvement, and is likely due to retrograde flow from heavily obstructed, tumor-laden level II-III ipsilateral lymphatics. This was also observed by Ng et al in their MRI and fluorodeoxyglucose FDG-PET imaging-based survey of nasopharyngeal carcinoma: all 3 patients who presented with PG metastases had significant disease either in the ipsilateral retropharyngeal or level II LNs.

 Furthermore, all 5 patients in the report by Olsen et al who presented initially with pathologic evidence of PM, had stage IVA-IVB with N2b-N3 nodal disease.

 In the report by Harada et al, PG involvement with oral cavity cancers also appeared to directly correlate with the number of involved cervical nodes.

Given the difficulty of salvaging a patient successfully with a LRR after primary radiation, and that PM results in poor prognosis, we believe all efforts should be made to address all known clinical and potential subclinical disease at the time of the initial curative treatment. Thus, in the setting of bulky or diffuse lymphadenopathy such as significant upper level II involvement in nasopharynx primaries or N2b-N3 disease in non-nasopharyngeal primaries, consideration should be paid to include the ipsilateral parotid in the CTV, even in the absence of radiologic involvement. In such cases, we would recommend that the PG be included in the low-risk CTV, which typically receives 54-56 Gy over 32-35 fractions using IMRT. An alternative strategy may be to compromise and avoid defining the ipsilateral parotid either as an organ-at-risk or as a target, thus providing moderate “incidental” dose to the organ.

Since the rarity of these cases precludes a systematic evaluation regarding the clinical factors (eg, number and size of LNs, presence of extracapsular spread, etc), decisions to include the PG in the CTV need to be made on a case-by-case basis for the present. The concern for ablating the ipsilateral PG function should be tempered by the desire to prevent recurrence, as well as the growing awareness that many other factors aside from parotid dose may affect QOL and xerostomia, including submandibular gland dose and oral cavity/minor salivary gland mean dose.

 Finally, with massive involvement of the cervical nodes, substantial sparing of the PG ipsilaterally is often not achievable due to the need to cover the level II lymphatics to the base of skull.

		Distribution of metastases to LNs in 99 patients with nasopharyngeal epithelial tumors. Two patients presented with ipsilateral pre-auricular/parotid involvement, with one patient also having contralateral pre-auricular/parotid involvement (arrows) (adapted from Mendenhall16). Coronal diagram demonstrating lymphatic flow from the nasopharynx through the Eustachian tube lymphatic channels to the internal jugular, pre-auricular, and superior and inferior parotid nodal chains. [EAC= external auditory canal; RP= retropharyngeal] (adapted from Rouviere17).

In summary, we believe that the prudent measure is to strongly consider including the PG in patients with massive level II lymphadenopathy. Our standard of care has recently been changed to reflect the findings reported here.

Terence Williams, MD, PhD, Department of Radiation Oncology, The Ohio State University, 300 W. 10th Avenue, Columbus, OH 43210. Tel: (614) 293-5557; Fax: (614) 293-4044; E-mail: terence.williams@osumc.edu The authors declare no actual or potential conflicts of interest.

The authors thank Steven Kronenberg for expert illustrations. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI (TMW, JMV, MS, AE); Department of Otolaryngology — Head and Neck Surgery, University of Michigan, Ann Arbor, MI (MES, DBC).

			Cooper JS, Fu K, Marks J, et al. Late effects of radiation therapy in the head and neck region. 

			Bjordal K, Kaasa S, Mastekaasa A. Quality of life in patients treated for head and neck cancer: a follow-up study 7 to 11 years after radiotherapy. 

			Sher DJ, Neville BA, Chen AB, et al. Predictors of IMRT and conformal radiotherapy use in head and neck squamous cell carcinoma: a SEER-Medicare analysis. 

			Cannon DM, Lee NY. Recurrence in region of spared parotid gland after definitive intensity-modulated radiotherapy for head and neck cancer. 

			Chao KS, Majhail N, Huang CJ, et al. Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques. 

			Lee NY, de Arruda FF, Puri DR, et al. A comparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy for locally advanced oropharyngeal carcinoma. 

			Dandekar V, Morgan T, Turian J, et al. Patterns-of-failure after helical tomotherapy- based chemoradiotherapy for head and neck cancer: implications for CTV margin, elective nodal dose and bilateral parotid sparing. 

			Chen AM, Farwell DG, Luu Q, et al. Marginal misses after postoperative intensity- modulated radiotherapy for head and neck cancer. 

			Harari PM. Beware the swing and a miss: baseball precautions for conformal radiotherapy. 

The ipsilateral parotidean nodes may be at risk of metastatic involvement when bulky ipsilateral level II metastases and multilevel nodal disease are co-existent, possibly due to retrograde lymphatic drainage.

Parotid Node Metastases in Locally Advanced Nasopharyngeal and Oropharyngeal Cancer: Implications for Radiotherapy Target Volume Delineation

		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 (

-value for age group-year interaction <.001).

We observed similar trends for the 3818 patients presenting to urology clinics in the region (

). The annual number of patients decreased 45% over our study period, from 778 to 428 (

 <.001). The number of patients age ≥75 years decreased 49% from 376 to 191, while the number of patients age <75 years decreased 41%, from 402 to 237. For both age groups, increasing year was associated with decreasing patient volume (

 <.001). There was no significant difference in the magnitude of decrease in patient volume between age groups (

 value for age groupyear interaction = .13).

		Figure 2: Number of Patients Presenting With Incident Prostate Cancer to Urology Clinics, 2007-2013

The distribution of cancer characteristics at radiation oncology clinics changed over time 

. The proportion of patients presenting with NCCN low-risk disease decreased significantly from 46.1% to 29.3% (

 <.01). There was a trend toward increased proportions of intermediate-risk (35.3% to 41.9%), high-risk (17.4% to 25.8%), and metastatic (1.2% to 3.1%) disease, although none of these reached significance (

 = .08, .06, and .39, respectively). We found a significant difference in the overall NCCN risk distribution across years (

 <.001). We also found a significant reduction in low-risk disease when we categorized risk by T-stage (

The estimated annual number of patients presenting within each NCCN risk category also changed over time 

. The annual number of low-risk patients decreased significantly, from 858 (95% CI, 779-939) to 354 (307-405) patients per year. The number of intermediate- risk patients decreased to a lesser though still significant degree, from 657 (95% CI, 583-736) to 506 (454-560). There was no significant change in the number of high-risk or metastatic patients.

We estimated a decreasing number of lower-risk patients and a stable number of higher-risk patients for both men ≥ 75 years and <75 years 

. For men ≥75 years, the annual number of low-risk patients decreased significantly from 275 (234-317) to 84 (64-108), while the number of intermediate-risk patients decreased significantly from 250 (210-292) to 165 (139-192). We found no significant changes in the number of high-risk and metastatic patients. For men <75 years, the number of low-risk patients also decreased significantly from 610 (539-679) to 293 (248- 342). However, we found no significant changes in the number of intermediate-risk, high-risk, or metastatic patients.

We found a significant reduction in the number of patients presenting with prostate cancer to radiation oncology practices. Over our study period, we observed a significant decrease in the number of men with low-risk disease, a modest decrease in intermediate-risk disease, and no significant changes in high-risk or metastatic disease. Our findings are consistent with our hypothesis that the 2008 USPSTF guidelines decreased the detection rate of prostate cancer, primarily through the reduction of low-risk disease, and that this has translated into reduced patient volume at radiation oncology practices.

Prior studies have assessed the impact of the 2008 guidelines, with most finding only marginal decreases in PSA screening.

However, a study of national tumor registry data found that the number of patients age ≥75 years presenting with early-stage prostate cancer decreased 25.4% from 2007 to 2009.16 Our findings build upon this prior work by highlighting the impact of the guidelines on specialty care up through 2013. Because prostate cancer is currently the second most common indication for radiation therapy, the reduction in patient volume observed in our study suggests that future demand for radiation oncology services may be less than previously estimated.19 We considered whether practice trends other than decreased disease detection could have accounted for this reduction in patient volume. Specifically, we did not find evidence of increasing use of competing treatment modalities (eg, use of robotic surgery), as we also observed a parallel decrease in patient volume at urology clinics. Although the use of radiotherapy for prostate cancer may be decreasing in favor of watchful waiting or active surveillance,

this would be unlikely to affect patient volume, as patients managed with these strategies would still receive an initial referral to specialty care.

		Figure 3: Estimated Number and Risk Distribution of Patients Presenting to Radiation Oncology Clinics in 2007 and 2013 a.) All patients, b.) Patient’s age ≥75 Years, c.) Patient’s age <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.

October 2015 | Contemporary Radiation Oncology

Far-reaching PSA Guidelines Affect Radiation Oncologists

Prostate Cancer: Every Action Has a Reaction

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Are Surgery and Chemotherapy Sufficient to Treat Locally Advanced Bladder Cancer?

Parotid Node Metastases in Locally Advanced Nasopharyngeal and Oropharyngeal Cancer: Implications for Radiotherapy Target Volume Delineation

Changes in Prostate Cancer Presentation for Radiation Oncology Care

Therapeutic Ratio of Hypofractionation in Early Glottic Cancer: A Topic Worth Revisiting?