The University of Texas MD Anderson Cancer Center

Although homogeneous dose prescriptions have been the standard in radiation therapy delivery, advanced technology integration now creates the potential for dose painting (DP). With the article by Crane et al in this issue, differential dose deposition is explored in those pancreatic cancer patients with extensive vascular involvement on the basis that higher biologically effective doses may be needed to facilitate conversion to negative margin resection. The incorporation of intensity-modulated radiation therapy and motion management allow the highly precise delivery of 63 Gy to that portion of the tumor at higher risk for residual disease, should resection become feasible.

Contextually, this data invites consideration of novel dose painting strategies, suggesting that the future may invite innovative heterogeneous dose escalation. Recent data from radiomic studies have reported that intra-tumoral heterogeneity is present with marked molecular differences between cells in the core of the tumor vs the tumor edge.1 Analysis of metastatic liver tumor deposits from colorectal cancer has shown that those tumors with higher intra-individual genetic heterogeneity have worse 3-year survival.2 With the improved imaging techniques now available, the near future may herald the capacity for the prospective imaging delineation of clinically relevant microhabitats to guide molecularly targeted radiation therapy.

This article therefore sets the stage for new dose exploration in the setting of patients with unresectable pancreatic cancer. The authors report their experience with this technique, raising the question of how radiation oncologists can best maximize a DP approach to improve outcomes. Improved correlation of imaging data with intra-tumoral molecular phenotypes has the future potential to significantly accelerate a new dosimetric paradigm.

1. Gillies RJ, Kinahan PE, Hricak H. Radiomics: images are more than pictures, they are data. 

. 2016;278(2):563-577. doi: 10.1148/radiol.2015151169.

2. Sveen A, Loes IM, Alagaratnam S, et al. Intra-individual genetic heterogeneity among liver metastases in metastatic colorectal cancer. ASCO Meeting Abstracts. 2016;34(4_suppl):555.

There is substantial interest in the use of escalated doses of radiation to improve tumor resectability in pancreatic cancer, but true radiographic downstaging does not frequently occur. We reviewed our experience integrating a radiation boost to the tumor-arterial interface in borderline resectable and locally advanced pancreatic cancer with the objective of downstaging.

Twenty-three patients with borderline resectable (n = 14) or locally advanced disease (n = 9) received chemoradiation with an integrated radiation boost to the tumor-arterial interface (median dose: 63 Gy in 28 fractions). We recorded patient outcomes and compared CT scans before and after radiotherapy to evaluate response.

There was no downstaging in 21 of 23 patients. The 2 patients who achieved downstaging of their primary tumor had early distant metastasis (DM) that precluded surgery. Three patients with borderline resectable disease underwent margin-negative resection. Many patients developed DM soon after chemoradiation as median distant metastasis-free survival (DMFS) was 8 months. The median local progression-free survival (LPFS) was 23 months and median overall survival (OS) was 16 months.

An integrated boost with conventional fractionation to the tumor-arterial interface is unlikely to lead to downstaging in borderline resectable and locally advanced pancreatic cancer.

Surgical resection remains the only potentially curative treatment for pancreatic cancer. However, fewer than 20% of patients present with potentially resectable disease.

Consequently, outcomes remain poor with an estimated 5-year relative survival rate of 6%.

 For those patients who proceed to surgical resection, negative margins (R0) have been established as crucial in attaining long-term survival.

 Pancreatic cancer has a tendency to spread along the vasculature of the retroperitoneal border, and the most common site of microscopically positive resection is the superior mesenteric artery (SMA) margin.

 Thus, in the absence of distant metastasis (DM), the primary determinant of resectability in pancreatic cancer is the extent of vascular involvement.

Because the majority of patients present with locally advanced disease, significant attention has been focused on neoadjuvant (preoperative) strategies to decrease the size and extent of the primary tumor, thus increasing the probability of R0 margins in patients with borderline resectable and, to a lesser extent, locally advanced tumors. The definition of borderline resectable includes a very heterogeneous group ranging from minimal venous involvement (T3) to extensive arterial involvement with or without venous involvement (T4).

Rigidly defined, downstaging in pancreatic cancer is characterized as changing the radiographic stage from T4 to T3 with the use of neoadjuvant therapy. The term “downstaging” can also be used to describe a reduction of the amount of arterial involvement (T4) to less than 180 degrees that would allow surgical resection. However, it is often incorrectly associated with T3 tumors with venous involvement that eventually undergo successful resection after neoadjuvant therapy.

Downstaging following conventional doses of neoadjuvant chemoradiation is a rare occurrence in patients with borderline resectable disease.

 However, recent studies have suggested administering higher doses of neoadjuvant radiation can improve downstaging of pancreatic cancer.

 Still, data are inconsistent with regard to this phenomenon and are further confounded by varying definitions and subjective criteria of resectability among various trials and institutions.

 Here, we reviewed our institutional experience of patients with borderline resectable and locally advanced pancreatic cancer with extensive venous or arterial involvement who received neoadjuvant chemoradiation with a strategy of dose escalation to the tumor-arterial interface with the objective of downstaging.

The University of Texas MD Anderson Cancer Center (MDACC) Institutional Review Board approved this study. We retrospectively reviewed all patients who were treated with neoadjuvant chemoradiation with dose escalation to the tumor-arterial interface at MDACC between 2005 and 2010. We identified 23 patients and reviewed their characteristics, treatment regimens, and outcomes.

Based on vessel involvement, patients were classified as potentially resectable, borderline resectable, or locally advanced by MD Anderson Criteria and the definition proposed by the American Hepatopancreatobiliary Association (AHPBA), Society of Surgical Oncology (SSO), and Society for Surgery of the Alimentary Tract (SSAT) and endorsed by the National Comprehensive Cancer Network (NCCN).

 The primary tumor stage (T stage) was determined by American Joint Committee on Cancer (AJCC) 7th edition guidelines.

Characteristics of the 23 patients are shown in Table 1.

Twenty-two patients received gemcitabine-based induction chemotherapy for a median duration of 3 months (range, 1-9 months) and underwent subsequent intensity modulated radiotherapy (IMRT) with concurrent chemotherapy.

Radiologic Review and Classification of Resectability

Image guidance was achieved using daily orthogonal film alignment. Primary tumor and nodal regions were treated to 50.4 Gy in 28 fractions. The median escalated dose to the tumor-arterial interface was 63 Gy (range, 57.5-64.4 Gy) in 28 fractions (range, 25-35 fractions). Assuming an alpha/beta ratio of 10, median BED10 was 77 Gy. An example of the integrated boost technique is shown in Figure 1. Eight patients proceeded to laparoscopy or laparotomy after neoadjuvant therapy to evaluate for resection. Four patients underwent resection.

Bhosale reviewed the pre-therapy and immediate post-chemoradiation staging CT scans for all patients. We recorded tumor size, regional node status by RECIST criteria (>15mm), and tumor involvement of the SMA, celiac axis (CA), common hepatic artery (CHA), superior mesenteric vein (SMV), portal vein (PV), and superior mesenteric vein-portal vein confluence (SMV-PV). Tumor-vessel involvement was documented as no involvement, abutment (<180 degrees of vessel circumference), or encasement (>180 degrees of vessel circumference). Occlusion of the SMV-PV was also recorded. 

To characterize the changes in tumor size and disease stage, Bhosale compared the greatest dimension of the primary tumor and each tumor-vessel interface depicted in pre-treatment and post-chemoradiation images at first restaging. Changes were described using definitions in Supplemental Table 1 and by modified RECIST criteria (version 1.1).

To grade response of the primary tumor alone, we also report RECIST classifications with omission of DM as criteria for progressive disease (PD).

Downstaging was defined as radiographic conversion of a T4 to a T3 stage tumor. Additionally, our definition included conversion of the tumor stage from locally advanced to borderline resectable disease, or borderline resectable to potentially resectable disease by MD Anderson and/or AHPBA/ SSO/SSAT criteria. Tumor-vessel improvement was defined as conversion from encasement to abutment, encasement to no involvement, or abutment to no involvement. Tumor- vessel worsening was defined as conversion from no involvement to abutment, no involvement to encasement, or abutment to encasement. Additionally, for patients who progressed locally, we compared the CT scan demonstrating local progression with treatment planning images to determine the local pattern of failure by isodose line.

Duodenal toxicity was recorded and scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. All of the recoded duodenal toxicity events were confirmed by endoscopic evaluation. The time to toxicity was defined in months after the completion of radiation therapy to endoscopic confirmation.

We recorded failure patterns at any time after treatment and did not censor patients after first evidence of progression. Local progression free survival (LPFS) was defined as the time from beginning of induction chemotherapy to primary tumor PD on imaging or surgical exploration; we censored patients who died without evidence of primary tumor PD. Distant metastasis free survival (DMFS) was defined as the time interval between beginning of induction chemotherapy and development of DM found by either imaging or surgical exploration; we censored patients who died without evidence of DM. Overall survival (OS) was defined as the time from initiation of induction chemotherapy to death.

Inability to Resect Due to Progressive Disease Of the 14 patients who were initially borderline resectable, 8 patients showed radiographic progression which precluded surgery (1 progressed locally and 7 developed DM).

The other 6 patients with borderline resectable disease underwent surgical exploration. Three of these patients were found to have unresectable disease based on DM (n=2) or local tumor anatomy rendering the patient unresectable (n=1). The other 3 patients who underwent surgical exploration had R0 resections; none of these 3 patients had any major unexpected acute or long-term complications after escalated radiation and surgery.

Lack of Radiographic Downstaging After Dose Escalation

Of the 9 patients with initially locally advanced disease, 7 patients remained unresectable. One patient was found to have DM at laparoscopy. Another patient was deemed unresectable, but did not follow up with surgeons at MDACC and underwent resection at an outside institution.

All 23 patients were restaged after chemoradiation (median duration of 1.3 months, range of 0.6-1.5 months). Three of the 23 patients met radiographic criteria to change the stage of their primary tumor, 2 of which were downstaged while the third was upstaged. Both patients whose primary tumors were downstaged developed DM, which precluded surgical resection.

By RECIST criteria, 10 patients (43%) had stable disease (SD), 5 patients (22%) had a partial response (PR), and 8 patients (35%) had PD because of an increase in the greatest dimension of the primary tumor (n = 1) or the development of DM (n = 7). When analyzing only the primary tumor and omitting DM as criteria for PD, 15 patients (65%) had SD, 7 patients (30%) had a PR, and 1 patient (4%) had PD (Figure 2). No patients had a complete response. Of 72 tumor-involved vessels, following treatment, 9 (13%) demonstrated radiographic improvement and 5 (7%) worsened. Detailed response of the tumor- vessel interface is reported in Supplemental Table 2.

Of the 8 patients who progressed locally, 5 patients progressed within the 50.4 Gy isodose line, and 3 patients progressed within the 54 Gy isodose line. 

Eighteen of the 23 patients in this study were included in a recent analysis of duodenal toxicity following chemoradiation at our institution.

 In the current study, 5 of the 23 patients (22%) were noted to have duodenal toxicity occurring at a median of 3.4 months (range, 3-11) after treatment. One patient had grade 1 duodenitis, which was found incidentally. One patient had a grade 2 bleeding duodenal ulcer. Two patients had grade 3 bleeding duodenal ulcers requiring blood transfusion. One patient developed grade 5 toxicity. This patient was found to have a large bleeding duodenal ulcer at 11 months after radiation that was not controlled by argon plasma coagulation. Given the patient’s extensive disease progression, the family opted for comfort care and the patient died. No patients experienced duodenal perforation. 

Median follow-up was at 17 months. All 23 patients died, and median OS was 16 months. Eight patients had local progression. The median LPFS was 23 months. Twenty patients developed DM. The median DMFS was 8 months. Kaplan Meier estimates of OS, LPFS, and DMFS are shown in Figure 3.

In this study we provide a detailed analysis of patients with borderline resectable and locally advanced pancreatic cancer who underwent neoadjuvant chemoradiation with an integrated radiation boost to the tumor-arterial interface with the objective of downstaging. Following dose escalation to a median of 63 Gy in 28 fractions (BED10=77 Gy) to this region, we did not observe clinically significant downstaging. Eight patients underwent laparoscopy or laparotomy to evaluate for resection after neoadjuvant therapy, but only 4 patients underwent surgical resection (one at another institution). Notably, 8 patients progressed locally within the 54 Gy isodose line or below. Furthermore, potential for duodenal toxicity is a substantial concern with dose escalation efforts, and incidence of toxicity demonstrated a dose-volume relationship. Collectively, our data caution against aggressive efforts to downstage locally advanced or borderline resectable tumors by escalating radiation dose solely to the tumor-arterial interface.

Our data add to a growing body of literature exploring this treatment strategy, and the results are mixed. Some recent studies have reported dose escalation strategies resulting in significant downstaging of borderline resectable and locally advanced pancreatic cancer. One retrospective study evaluated outcomes of patients treated with gemcitabine followed by stereotactic body radiotherapy (SBRT) to 30 Gy in 5 fractions, with dose escalation to 35 Gy in the region of vessel abutment/encasement.

Of patients with borderline resectable disease, 77% underwent surgery, with 56% completing resection (97% R0).

 The authors noted a significant radiographic response in most patients, but details of vessel involvement after treatment were not reported. Notably, a large proportion of patients in this study reported initial borderline resectable stage T3 tumors (77%), which by definition did not involve the SMA or CA. Since the analysis did not include changes in radiographic staging, it is unclear if SBRT contributed to downstaging in this study. By comparison, our cohort included 70% of patients with T4 tumors with extensive arterial involvement, who are much less likely to undergo resection.

A recent dose escalation study using gemcitabine with concurrent IMRT for locally advanced pancreatic cancer resulted in a recommended dose of 55 Gy in 25 fractions. Although all patients were initially locally advanced, 12 of the 50 patients (24%) went on to surgical resection (83% R0).10 The authors reported significant radiographic improvement after therapy; however, details of tumor-vessel response were not provided. In our subgroup of patients with locally advanced disease, only 1 of 9 (11%) had radiographic evidence to warrant downstaging (and was later found to have DM at laparoscopy). Similarly, in the aforementioned SBRT study11, only 2 patients (12.5%) with locally advanced disease proceeded to surgery, both of whom were eventually deemed unresectable.

Dose escalation strategies have also demonstrated improved local control rates for pancreatic cancer, but have been limited by higher rates of gastrointestinal toxicity.

In the dose escalation study by Ben-Josef and associates

 patients (17%) progressed locally with a 2-year freedom from local progression (FFLP) of 59%. Of the 20 patients treated to 55 Gy, 6 grade > 3 events occurred, leading to an estimated 24% probability of dose-limiting toxicity. With SBRT

, local failure only occurred in patients who did not undergo resection. Of those patients, local control was 60% at 18 months. Furthermore, only 5.3% experienced late grade 3 toxicity with no grade 4 or 5 events. In our study, 6 patients progressed locally with an estimated 2-year FFLP of 33%. We encountered an overall gross rate of 13% grade > 3 late duodenal toxicity. Interestingly, our pattern of local failure analysis revealed that no patients failed above the 54 Gy isodose line, which may inform future dose escalation strategies.

Our results indicate that the goal of escalated radiation therapy should be shifted away from improving resectability to improving local control in borderline resectable and locally advanced pancreatic cancer. More standardized resection and response criteria are necessary to better compare results within the literature. Similarly, detailed analyses of vessel involvement and local patterns of failure are helpful to further aid the choice of optimal dose, as are toxicity rates to determine the therapeutic ratio. Importantly, DM continues to play a large role in preventing surgical resection and causing death; therefore, escalated radiation doses should be combined with either improved systemic therapies or biomarkers that help predict patterns of failure.

While this study provides some guidance for future efforts of radiation therapy in pancreatic cancer, we acknowledge its limitations. Primarily, this study was retrospective and had a small sample size. Additionally, although radiand treatment courses were not uniform. Finally, there was inherent bias in the selection of the patients for dose escalation. However, it must be noted that the selected patients exhibited favorable tumor characteristics—namely, lack of progression prior to starting chemoradiation&mdash;and yet all had poor outcomes regardless.

In summary, dose escalation to 63 Gy in 28 fractions to the tumor-arterial interface resulted in low rates of tumor resection. In patients with borderline resectable disease, development of DM soon after chemoradiation was the main factor that precluded surgery. In patients with locally advanced disease, lack of tumor response was a major reason patients were not resected. For the 3 patients who underwent surgery for borderline resectable disease, margins were negative, and none experienced a major unexpected complication from the escalated dose of radiation.

Given these results, we have adopted a strategy using ablative doses to the entire tumor in select cases. To avoid the duodenal toxicity we encountered using only orthogonal kV image guidance, we now use strict mucosal dose constraints and daily CT-guided 3D-3D matching for image- guided radiation therapy.

Houston Methodist (MT), Houston, TX. Department of Radiation Oncology (EK, PD, CC), Department of Diagnostic Radiology (PB), Department of Surgical Oncology (MK, JF, JL), Department of Gastrointestinal Medical Oncology (GV, RW), The University of Texas MD Anderson Cancer Center, Houston, TX.

: Christopher H. Crane, MD, MD Anderson Cancer Center, Department of Radiation Oncology, 1515 Holcombe Blvd. MS-97, Houston, TX 77030, Phone: 713-563-2341. Fax: 713-563-2331. E-mail: ccrane@mdanderson.org

: Dr Varadhachary participates in consulting for Celgene. Conflicts of interest: None.

: The authors acknowledge support from the Center for Radiation Oncology Research and the Sheikh Ahmed Center for Pancreatic Cancer Research at The University of Texas MD Anderson Cancer Center. Dr Koay was also supported by NIH’s Physical Sciences Oncology Centers (PS-OCs) U54CA143837 (Center for Transport Oncophysics), the Pancreatic Cancer Action Network (14-20-25-KOAY) and the Radiological Society of North America (RSD1429).

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Articles

Radiation Dose Escalation to the Tumor-Arterial Interface of Locally Advanced and Borderline Resectable Pancreatic Cancer

Department of Radiation Medicine and Applied Sciences

Radiation Oncology and Molecular Sciences

Johns Hopkins University School of Medicine

The utilization of internet-based educational forums has been developing over the last few years for the sharing of information and standardization of practice patterns.

As technical details of treatment planning become more involved and the complexity of treatment planning increases with our ability to deliver higher doses in fewer treatment fractions—and as newer treatment modalities are being developed&mdash;accurate target and organ delineation, and sometimes even the ability to obtain expert opinions, have become even more critical. Numerous reports state inter-observer variability in practice exists not only between experts in our field in each disease site, but especially among trainees and in centers that have lower volumes of certain types of cases. Currently there are limited resources for residents and practitioners to refer to for specific help on contouring both target volumes and organs at risk in the modern era. The utilization of online contouring atlases has started to address this need, but more comprehensive educational materials are an unmet need for this very critical problem.

The e-contouring program documented in this article has a unique niche in this regard, allowing for a novel, web-based, user-friendly, accessible, interactive approach to facilitate interaction between colleagues for decision support. As our field is a dynamically and rapidly changing its practices, we are in great need of these types of innovative educational interventions. Here, the authors present a novel approach to ongoing education and quality improvement. While it is clear that the eContour website is not meant to replace experienced clinician judgment in any case, and that more cases are needed, it represents an excellent innovation that hopefully just represents the beginning of the development of more comprehensive online educational resources for learning residents and continuing-to-learn practitioners.

Target delineation in radiation oncology is critical to delivering safe and effective radiation therapy. Evidence from clinical trials suggests that poor radiation treatment plan quality decreases the rates of overall survival and increases rates of toxicity. The introduction of new technologies in radiation oncology, including intensity-modulated radiotherapy (IMRT), image-guided stereotactic radiosurgery (SRS), and stereotactic body radiation therapy (SBRT) have improved our ability to deliver higher doses of radiation to the tumor and areas at risk while avoiding normal tissues. These highly conformal radiation fields leave little margin for error, highlighting the critical importance of accurate contouring.

There is substantial inter-observer variability among radiation oncologists in target delineation, which is most notable in head-and-neck and lung cancers, although it has also been shown in prostate cancer due to variable definitions of the prostate apex. This variation can be reduced when contouring atlases and consensus guidelines are referenced. Unfortunately, barriers exist that limit clinicians from seeking answers to their clinical questions (such as details of high-risk clinical target volume coverage), which results in decreased adherence to the standard of care. Effective strategies to implement clinical guidelines emphasize intervention at the time of the patient encounter, which is also a recommended approach to motivating adult learning. eContour (eContour.org) is a novel, web-based, interactive contouring resource that aims to facilitate access to decision support through high-yield radiation treatment recommendations that are free and available at the point of care.

Target delineation in radiation oncology—commonly referred to as contouring&mdash;represents the crux of delivering safe and effective radiation therapy. Contours not completely encompassing the tumor or regions at risk of microscopic disease lead to increased rates of disease recurrence and decreased survival.

 On the other hand, contours that are too large have the potential to lead to increased rates of toxicity.

 The introduction of new technologies in radiation oncology, including intensity-modulated radiotherapy (IMRT), image-guided stereotactic radiosurgery (SRS), and stereotactic body radiation therapy (SBRT), has improved our ability to deliver higher doses of radiation to the tumor and areas at risk while avoiding normal tissues.

Poor Contouring Quality Affects Patient Outcomes

Impact of Low-Volume Centers and Geography on Patient Outcomes

These highly conformal radiation fields leave little margin for error, which highlights the critical importance of accurate contouring. Here, we review the potential impact of suboptimal contouring on patient outcomes, currently available educational resources to aid radiation oncology providers in contour delineation, effective strategies to improve access to high-yield information for clinical management, and finally propose a recently released novel, open-access contouring resource called eContour (eContour.org).

There is increasing evidence that a radiation plan of poor quality leads to inferior patient outcomes. A re-analysis of the head-and-neck trial TROG 02.02 found a 20% decrease in overall survival at 2 years (70% vs 50%) for patients with radiation protocol violations compared to compliant treatment plans.

 Likewise, the head-and-neck trial RTOG 0129 found that patients with radiation plan protocol violations had a 22% decrease in survival at 5 years (63% vs 41%) compared to patients receiving protocol compliant treatment plans.

 A third head and neck trial, RTOG 0022, reported a 46% increase in locoregional failure at 2 years (6% vs 50%) in patients with major protocol deviations.

 In pancreatic cancer, RTOG 9704 found a decrease in overall survival (1.74 years vs 1.46 years) as well as a trend toward increasing grade 4/5 non-hematologic toxicity in patients with protocol violations.

 Finally, the HD4 trial of patients with early-stage Hodgkins lymphoma found recurrence- free survival at 7 years was decreased by 12% (84% vs. 72%) in patients with non-compliant treatment plans.

 Multiple aspects of the radiation planning process can lead to protocol violations4, although significant evidence suggests an integral role for contouring. In the TROG 02.02 head-and-neck trial, 25% of deviations were due to “incorrect target definition.”

 In the RTOG 00-22 head and neck trial, 83% of major deviations related to “PTV66 coverage.”

 In the RTOG 9704 pancreas trial, 70% of deviations were due to “field placement or size.”

 This trial also found that 13% of plans identified as “unacceptable” were due to an over-contouring bowel. In the HD4 Hodgkins trial, 29% of protocol deviations were due to “volume too small.”

 Taken together, these findings suggest that radiation plan quality—of which contouring represents a central component&mdash;substantially impacts patient survival.

Multiple studies demonstrate that rates of protocol deviations correlate inversely with the number of patients treated per center.

 For example, TROG 02.02 found that treatment centers enrolling <5 patients had a 30% protocol deviation rate in comparison to 5% in centers enrolling 20 or more patients. RTOG 0129 found a similar result with a cutoff of 13 or more patients, reducing the rate of protocol deviations from 18% to 6%. RTOG 0022 found a cutoff of 20 patients to be significant. Similar patterns have been observed in early-stage Hodgkins (HD4) and breast cancer (NSABP B04).

 A review of clinical trial Q&A by Weber et al raised the provocative and controversial question of whether low-volume treatment centers should be authorized to enroll patients into clinical trials due to the cost for institutional activation and apparent detrimental effect on radiation quality.

 Population-based studies further support the link between center experience and patient health outcomes.

Multiple studies using the National Cancer Data Base (NCDB) have shown decreased survival in patients treated at low-volume centers with chemoradiotherapy for larynx cancer

, definitive chemoradiotherapy for stage III non— small cell lung cancer

, and radiation for high-risk prostate cancer.

 Recently, a Surveillance, Epidemiology, and End Results (SEER)-Medicare study looked specifically at individual provider experience in head-and-neck cancer and found a correlation between provider volume and outcomes.

This study found that the risk of death decreased by 21% for every additional 5 patients treated, with a similar decrease in the risk of aspiration pneumonia.

 Of note, this survival difference was seen in patients treated with IMRT but not 3D-conformal radiotherapy—which emphasizes the need for high-quality radiation delivery, particularly in the current era of advanced radiation technology.

Figure. Screenshot of a representative case in eContour.org

Improving Quality in the Digital Age The Basis of Evidence-Based Medicine

The findings from the clinical trials and population-based studies reviewed above all point to a link between radiation quality and patient health outcomes. While one solution might to be to centralize radiation delivery in high-volume specialty centers, the reality and complexity of cancer care delivery makes this solution difficult. The average course of non-palliative radiation takes weeks or months to deliver, and relocating patients to a high-volume center presents substantial logistical challenges. Personal and socioeconomic strains on patients and caregivers represent clear barriers to either patient relocation or daily travel to tertiary care facilities. Additionally, within the US, distance to radiation presents a clear impediment to delivery of effective radiation. In early-stage breast cancer, rural areas have been found to have the lowest rates of breast-conserving surgery, which is hypothesized to be due to geographic distance from radiation oncology centers, and therefore, access to therapy.

 In stage II/III rectal cancer, a recent population-based study using NCDB data found that patients living a significant distance from a radiation oncology clinic were less likely to receive radiation (OR 0.75 for >50 miles and OR 0.46 for >250 miles).

 The preferred approach in radiation oncology therefore has been to improve quality of care in the community.

Radiation therapy in particular among medical specialties should be conducive to delivering high-quality care remotely in the digital age. Radiation treatment planning is rarely performed emergently, allowing time for physicians to review the literature and ask clinical questions of colleagues. It is unclear, though, how often radiation oncologists ask and seek answers to their clinical questions. Data from general medicine characterizes a phenomenon whereby clinical questions arise frequently at the point of care, but often go unanswered. In a systematic review of 11 studies including direct clinical observation and clinician interviews, Del Fiol et al found that 0.57 clinical questions were asked per patient encounter, of which clinicians pursued answers to questions 50% of the time.

 This percentage has been remarkably stable over time, although the source of where physicians look for answers appears to have shifted. In a seminal study by Covell et al in 1985, 29% of questions were answered by discussing with a colleague

, compared to only 14% in a study from 2007.

 Meanwhile, the use of internet searches such as Google and UpToDate for research have increased to up to 30% of clinical inquiries.

In radiation oncology, peer review commonly takes the form of routine prospective “chart rounds” to review radiation treatment plans. While data linking peer reviews to improved outcomes are lacking, several studies catalog significant rates of plan changes with chart rounds, with one study from British Columbia Cancer Agency reporting that 7% of radiation plans were changed.

 The American Society for Radiation Oncology (ASTRO)’s Target Safely Campaign provides recommendations regarding procedures for routine peer review.

 Peer review, however, is not without limitations. One recent study out of MD Anderson found that 17% of peer-reviewed patient cases still did not meet the standard of care.

 Outside of radiation oncology, the general medical literature suggests that peer review results fall short of literature searches in terms of finding answers to clinical questions

, possibly because colleagues have an equally difficult time keeping up-to-date with the medical literature. A systematic review assessing the relationship between clinician experience and quality of care delivered reported the sobering statistic that over half (52%) of 62 published studies on the subject report that physician knowledge, adherence to standards of practice, and quality of care decline with clinician age and experience.

In radiation oncology, two mechanisms have recently been implemented to facilitate access to expert review. In 2010, Chartrounds.com formed out of a need for decision support among physicians without easy access to peer review. Chartrounds.com is a conferencing website that allows community radiation oncologists to present patient cases (including diagnostic imaging and radiation treatment plans) to disease site specialists on a scheduled basis. Chartrounds.com has reported, in abstract, form outcomes that include broad usership, and user feedback showing the significant impact of the sessions on treatment decisions. 

 In 2012, theMedNet.org was developed to facilitate knowledge sharing through social media in which radiation oncologists ask clinical questions that initiate discussion among academic radiation oncologists. Conference abstracts report responses frequently incorporating new studies into recommendations to guide clinical practice.

When physicians do decide to seek answers to their clinical questions, they are successful an average of 80% of the time.15 With only 50% of questions being pursued, however, the barriers are significant, and most commonly reported to be lack of time. On average, clinicians spend a mean of 2-3 minutes seeking an answer to a specific question. Unanswered questions are viewed as an important opportunity to improve patient outcomes by filling gaps in medical knowledge in the context of clinical decisions.

To help clinicians digest the large quantities of information, which may sometimes even be conflicting, practice guidelines have become increasingly available. However, implementation research demonstrates that practice guidelines rarely translate into real-world clinical practice, primarily due to suboptimal methods of development, delivery, and access.

 In fact, journal publication represents one the least effective mechanisms to change practice, while patient- specific interventions at the time of the encounter are one of the most effective mechanisms.

Enthusiasm in the digital age has built around the potential for electronic clinical knowledge support systems such as Up- ToDate to provide evidence-based decision support at the point of care. Recent evidence from two studies, though retrospective, suggest that use of UpToDate resulted in improved patient outcomes using quality metrics including hospital length of stay and 30-day risk-adjusted mortality in patients presenting with acute myocardial infarction and pneumonia.

 This effect appears to be dose-dependent and most significant in small- to medium-sized non-teaching facilities. In addition to just-in-time answers providing opportunities for improved clinical outcomes for the current patient, educational research supports this as the most effective means of adult learning, and therefore, the ideal focus of continuing medical education.

Contouring provides an ideal point in the radiation oncology care continuum to intervene with high-quality information. Given the impact of contouring on patient outcomes in radiation oncology, many resources have been developed, including consensus guidelines, contouring atlases, and books.

 Numerous studies have demonstrated substantial interobserver variability among radiation providers

, which can be reduced if providers are given access to contouring reference aids.

 However, radiation oncologists routinely report barriers to accessing currently available resources.

First, current contouring atlases are thorough, although they can be cumbersome to use (they are often PDF documents, with some over 100 pages long), requiring considerable study to apply to clinical practice. While the RTOG website includes 10-15 disease-specific visual atlases, the majority of consensus guidelines are available only in the form of journal publication. Another limitation of current contouring resources is that they often focus on normal anatomy, while patient clinical presentations include significant heterogeneity. For example, the consensus guideline for head and neck lymph nodes by multiple cooperative groups (Danish Head and Neck Cancer Group [DAHANCA], European Organisation for Research and Treatment of Cancer [EORTC], Hong Kong Nasopharyngeal Carcinoma Study Group [HKNPCSG], National Cancer Institute of Canada Clinical Trials Group [NCIC CTG], Nakayama Cancer Research Institute [NCRI], Radiation Therapy Oncology Group [RTOG], and Tasman Radiation Oncology Group [TROG])29 includes only to the node-negative neck, which does not translate well to the node-positive patient, highlighting the lack of generalizability of current resources.

Other resources aimed at education and peer review in contouring include live contouring webinars

, which offer a useful educational opportunity, though can be costly and do not serve as an on-demand reference for providers. One interactive website called EduCase (www.educase.com) allows the submission of contours for offline review by a paid expert, but has not attracted high user volume, potentially due to the complexity of the platform, delays in obtaining feedback, or the subscription fee. Lastly, a product called Anatom-e (anatom-e.com) aims to serve as an on-demand resource for providers, although it requires hardware installation, and has a membership fee.

eContour (eContour.org) stands to challenge the existing paradigm in image-based contouring resources. We sought to design a tool that could overcome the limitations of current contouring resources and build on the success of other interactive online medical resources. With eContour, we have constructed a user-friendly, web-based tool that is free and facilitates point-of-care reference using a DICOM- based platform that integrates MRI and PET image overlays and enables active interaction with 3D images, mirroring current radiation-planning software, but in a quickly accessible website (see Figure). This web-based imaging platform style parallels eAnatomy (www.imaios. com), a website that has been shown to be the radiographic anatomy resource most frequently used by radiology residents.

 eContour collects and synthesizes consensus guidelines, recently published protocols, and key publications guiding management decisions around target delineation into an easily digestible resource that physicians can review in a couple minutes. By providing a busy provider with valuable case-specific information critical to safe and effective treatment planning at the point of care, eContour strives to serve as an imaging-based companion to UpTo- Date for radiation oncology providers.

The public release of eContour took place on March 8, 2016. Within one month, the website has gained over 1000 registered users from 50 states and 65 countries, primarily through social media and professional organization newsletters within the United States. In addition to practicing radiation oncologists and resident physicians, there has been significant interest among medical dosimetrists, particularly due to the website’s incorporation of organs at risk and normal anatomy. To address deficiencies in radiographic anatomy identified in radiation oncology training

, each case includes critical normal anatomy to facilitate understanding of the rationale behind treating various at-risk areas. The current library includes a basic set of head-and-neck and lymphoma cases, although we are progressively expanding to multiple disease sites through the solicitation of case submissions from experts that will be peer-reviewed and published electronically to create a comprehensive searchable library of individual patient cases. User feedback will be critical to shaping future directions of eContour to ensure that it develops into a robust resource that meets the needs of radiation oncologists in a health care environment characterized by increasing the complexity of both medical decision- making and technical radiation treatment planning.

Department of Radiation Medicine and Applied Sciences (EG, NP, AM, JM), University of California San Diego, La Jolla, CA. Address correspondence to: Erin F. Gillespie, MD, University of California San Diego, Department of Radiation Medicine and Applied Sciences, 3960 Health Sciences Dr., MC0865, La Jolla, CA 92093-0865, Phone: 858-822-6080. Fax: 858-246-1505. E-mail: efgillespie@ucsd.edu

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eContour is a novel, web-based, interactive contouring resource that aims to facilitate access to decision support through high-yield radiation treatment recommendations that are free and available at the point of care.

June 2016 | Contemporary Radiation Oncology

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eContour: Evidence-Based Interactive Contouring Resources at the Point of Care

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