Using flattening filter free beams in electronic tissue compensation whole breast irradiation with deep inspiration breath hold.

PURPOSE: In order to reduce heart dose, DIBH has become a common practice in left-sided whole breast irradiation. This technique involves a significant strain on patients due to the breath-hold requirements. We hereby investigate the dosimetric and delivery feasibility of using flattening filter free (FFF) energies with electronic tissue compensation (ECOMP) planning technique to reduce the required breath-hold lengths and increase patient compatibility. METHODS: Fifteen left-sided, postlumpectomy patients previously receiving DIBH whole-breast radiotherapy (266cGy x 16fx) were retrospectively planned using ECOMP for both 6X and 6X-FFF. A dosimetric comparison was made between the two plans for each patient using various dosimetric constraints. Delivery feasibility was analyzed by recalculating the 6X ECOMP plan with 6X-FFF without replanning (6X-FFF QA) and delivering both plans for a one-to-one comparison using Gamma analysis. Beam-on times for the 6X and 6X-FFF plans were measured. For all tests, Wilcoxon signed-rank test was used with P < 0.05 as significant. RESULTS: No statistical difference was observed between 6X and 6X-FFF plans for most dosimetric endpoints except contralateral breast Dmax (P = 0.0008) and skin Dmax (p = 0.03) and Dmin (P = 0.01) for which 6X-FFF showed favorable results when compared with 6X. 6X-FFF significantly reduced beam-on times for all patients by 22%-42% (average 32%). All plan QAs passed departmental gamma criteria (10% low-dose threshold, 3%/3mm, >95% passing). CONCLUSION: ECOMP planning with FFF was found feasible for left-sided breast patients with DIBH. Plan quality is comparable, if not better, than plans using flattened beams. FFF ECOMP could significantly reduce beam-on time and required breath-hold lengths thereby increasing patient compatibility for this treatment while offering satisfactory plan quality and delivery accuracy.

Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

Can the Student Outperform the Master? A Plan Comparison Between Pinnacle Auto-Planning and Eclipse knowledge-Based RapidPlan Following a Prostate-Bed Plan Competition.

PURPOSE: Pinnacle Auto-Planning and Eclipse RapidPlan are 2 major commercial automated planning engines that are fundamentally different: Auto-Planning mimics real planners in the iterative optimization, while RapidPlan generates static dose objectives from estimations predicted based on a prior knowledge base. This study objectively compared their performances on intensity-modulated radiotherapy planning for prostate fossa and lymphatics adopting the plan quality metric used in the 2011 American Association of Medical Dosimetrists Plan Challenge. METHODS: All plans used an identical intensity-modulated radiotherapy beam setup and a simultaneous integrated boost prescription (68 Gy/56 Gy to prostate fossa/lymphatics). Auto-Planning was used to retrospectively plan on 20 patients, which were subsequently employed as the library to build an RapidPlan model. To compare the 2 engines' performances, a test set including 10 patients and the Plan Challenge patient was planned by both Auto-Planning (master) and RapidPlan (student) without manual intervention except for a common dose normalization and evaluated using the plan quality metric that included 14 quantitative submetrics ranging over target coverage, spillage, and organ at risk doses. Plan quality metric scores were compared between the Auto-Planning and RapidPlan plans using the Mann-Whitney U test. RESULTS: There was no significant difference between the overall performance of the 2 engines on the 11 test cases ( P = .509). Among the 14 submetrics, Auto-Planning and RapidPlan showed no significant difference on most submetrics except for 2. On the Plan Challenge case, Auto-Planning scored 129.9 and RapidPlan scored 130.3 out of 150, as compared with the average score of 116.9 ± 16.4 (range: 58.2-142.5) among the 125 Plan Challenge participants. CONCLUSION: Using an innovative study design, an objective comparison has been conducted between 2 major commercial automated inverse planning engines. The 2 engines performed comparably with each other and both yielded plans at par with average human planners. Using a constant-performing planner (Auto-Planning) to train and to compare, RapidPlan was found to yield plans no better than but as good as its library plans.

Accelerated partial breast radiotherapy: a review of the literature and future directions.

Breast conservation therapy exemplifies the tailoring of medicine in the care of patients with cancer. Akin to improvements in surgical approaches, accelerated partial breast irradiation (APBI) tailors the treatment volume and duration to the needs of well selected patients. Here, we examine the evidence supporting APBI as well as the lessons in patient selection, dose and delivery techniques. Examination of historical techniques and their associated outcomes will support more correct patient selection and treatment delivery in an era where we await the reports of several large prospective trials.

Discovery and characterization of small molecule Rac1 inhibitors.

Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1. Fluorescence polarization studies indicate that these compounds target the nucleotide-binding site of Rac1. In cells, both compounds blocked Rac1 binding to its effector PAK1 following EGF-induced Rac1 activation in a dose-dependent manner, while showing no inhibition of the closely related Cdc42 and RhoA activity. Furthermore, functional studies indicate that both compounds reduced cell proliferation and migration in a dose-dependent manner in multiple pancreatic cancer cell lines. Additionally, the two compounds suppressed the clonogenic survival of pancreatic cancer cells, while they had no effect on the survival of normal pancreatic ductal cells. These compounds do not share the core structure of the known Rac1 inhibitors and could serve as additional lead compounds to target pancreatic cancers with high Rac1 activity.

Prostate bed target interfractional motion using RTOG consensus definitions and daily CT on rails : Does target motion differ between superior and inferior portions of the clinical target volume?

PURPOSE: Using high-quality CT-on-rails imaging, the daily motion of the prostate bed clinical target volume (PB-CTV) based on consensus Radiation Therapy Oncology Group (RTOG) definitions (instead of surgical clips/fiducials) was studied. It was assessed whether PB motion in the superior portion of PB-CTV (SUP-CTV) differed from the inferior PB-CTV (INF-CTV). PATIENTS AND METHODS: Eight pT2-3bN0-1M0 patients underwent postprostatectomy intensity-modulated radiotherapy, totaling 300 fractions. INF-CTV and SUP-CTV were defined as PB-CTV located inferior and superior to the superior border of the pubic symphysis, respectively. Daily pretreatment CT-on-rails images were compared to the planning CT in the left-right (LR), superoinferior (SI), and anteroposterior (AP) directions. Two parameters were defined: "total PB-CTV motion" represented total shifts from skin tattoos to RTOG-defined anatomic areas; "PB-CTV target motion" (performed for both SUP-CTV and INF-CTV) represented shifts from bone to RTOG-defined anatomic areas (i. e., subtracting shifts from skin tattoos to bone). RESULTS: Mean (± standard deviation, SD) total PB-CTV motion was -1.5 (±â€¯6.0), 1.3 (±â€¯4.5), and 3.7 (±â€¯5.7) mm in LR, SI, and AP directions, respectively. Mean (±â€¯SD) PB-CTV target motion was 0.2 (±1.4), 0.3 (±2.4), and 0 (±3.1) mm in the LR, SI, and AP directions, respectively. Mean (±â€¯SD) INF-CTV target motion was 0.1 (±â€¯2.8), 0.5 (±â€¯2.2), and 0.2 (±â€¯2.5) mm, and SUP-CTV target motion was 0.3 (±â€¯1.8), 0.5 (±â€¯2.3), and 0 (±â€¯5.0) mm in LR, SI, and AP directions, respectively. No statistically significant differences between INF-CTV and SUP-CTV motion were present in any direction. CONCLUSION: There are no statistically apparent motion differences between SUP-CTV and INF-CTV. Current uniform planning target volume (PTV) margins are adequate to cover both portions of the CTV.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

Proton radiotherapy for gynecologic neoplasms.

BACKGROUND: Proton beam therapy (PBT) is increasingly being used globally to treat a variety of malignancies. This is the first review assessing PBT for gynecologic neoplasms. Dose distribution to organs-at-risk (OARs), particularly bone marrow (BM), is addressed. Clinical outcomes and toxicity data are detailed. MATERIAL AND METHODS: Systematic searches of PubMed, EMBASE, abstracts from meetings of the American Society for Radiation Oncology, Particle Therapy Co-Operative Group, and American Society of Clinical Oncology were conducted for publications. There were no restrictions on publication dates. Sixteen original investigations were identified and analyzed for this review. RESULTS: The available evidence for PBT in treating gynecologic cancers is of both low quantity and quality. The most studied scenarios for PBT include treatment of para-aortic lymph nodes, re-irradiation, and as an alternative to brachytherapy, and these also represent indications with the greatest opportunity for demonstrating as yet unproven toxicity reductions. Dosimetric studies have shown significantly decreased dose to OARs, such as the rectum, bladder, bowel, kidneys, BM, and femoral heads. This dose reduction to OARs with PBT is more pronounced within the low-dose volumes than the higher dose volumes, which radiobiologically could be expected to lower second malignancy rates. Clinical data, though no level 1 evidence, show appropriate stage-specific tumor control and outcomes with PBT treatment, along with low toxicity rates. CONCLUSION: The existing data, albeit limited, warrant and can help guide larger scale and higher quality studies addressing whether PBT could provide clinically meaningful differences in toxicities and outcomes in women with gynecologic neoplasms.

ACR Appropriateness Criteria® Management of Recurrent Endometrial Cancer.

OBJECTIVES: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. RESULTS: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. CONCLUSIONS: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.

ACR Appropriateness Criteria® Adjuvant Therapy in Vulvar Cancer.

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

ACR appropriateness Criteria® advanced stage endometrial cancer.

OBJECTIVES: Patients with advanced stage endometrial carcinoma constitute a heterogeneous group of patients with different stages, tumor histologic types, and involved sites. Hysterectomy, bilateral salpingo-ophorectomy, and surgical staging are the cornerstone of surgical management in these patients. The optimal adjuvant therapy is yet to be established. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: Four clinical variants were developed to address common scenarios in the management of women with advanced-stage endometrial carcinoma. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. CONCLUSIONS: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with advanced-stage endometrial carcinoma.

ACR Appropriateness Criteria® pretreatment evaluation and follow-up of endometrial cancer.

Endometrial cancer is the most common gynecologic and the fourth most common malignancy in women in the United States. Cross-sectional imaging plays a vital role in pretreatment assessment of endometrial cancers and should be viewed as a complementary tool for surgical evaluation and planning of these patients. Although transvaginal US remains the preferred examination for the screening purposes, MRI has emerged as the modality of choice for the staging of endometrial cancer and imaging assessment of recurrence or treatment response. A combination of dynamic contrast-enhanced and diffusion weighted MRI provides the highest accuracy for the staging. Both CT and MRI perform equivalently for assessing nodal involvement or distant metastasis. PET-CT is more appropriate for assessing lymphadenopathy in high-grade FDG-avid tumors or for clinically suspected recurrence after treatment. An appropriate use and guidelines of imaging techniques in diagnosis, staging, and detection of endometrial cancer and treatment of recurrent disease are reviewed.The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® management of locoregionally advanced squamous cell carcinoma of the vulva.

OBJECTIVES: Locoregionally advanced vulvar cancer (LRAVC) is a rare disease that presents many challenging medical decisions. An expert panel was convened to reach consensus on the most appropriate pretreatment assessment and therapeutic interventions in LRAVC patients. METHODS: The American College of Radiology Appropriateness Criteria are evidenced-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journal and the application of a well-established consensus methodology (modified Delphi) to rate appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to formulate recommendations. RESULTS: Three clinical variants were developed to address common scenarios in the management of LRAVC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches, with numerical ratings and descriptive commentary. CONCLUSIONS: In combining available medical literature and expert opinion, this manuscript may serve as an aid for other practitioners in the appropriate management of patients with LRAVC.

Acr appropriateness Criteria management of vaginal cancer.

Due to its rarity, treatment guidelines for vaginal cancer are extrapolated from institutional reports and prospective studies of cervical and anal cancer. An expert panel was convened to reach consensus on the selection of imaging and therapeutic modalities. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) used by the panel to rate the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four variants were developed to represent clinical scenarios in vaginal cancer management. Group members reached consensus on the appropriateness of the pretreatment evaluation and therapeutic interventions. This article represents the consensus opinion of an expert panel and may be used to inform clinical recommendations in vaginal cancer management.

ACR Appropriateness Criteria® definitive therapy for early-stage cervical cancer.

OBJECTIVES: The definitive treatment of early-stage cervical cancer involves multidisciplinary decision making. This expert panel was convened to reach consensus on the selection of appropriate therapies based on patient and disease characteristics at presentation. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or the treatment. RESULTS: Three clinical variants were developed to represent common scenarios in the treatment of early-stage cervical cancer. Group members reached consensus on the appropriateness of therapeutic options. This process yielded numerical ratings and descriptive commentary. CONCLUSIONS: This manuscript represents the consensus opinion of an expert panel based on a survey of all available medical literature. This manuscript may be used to inform the clinical decision making of physicians involved in the treatment of early-stage cervical cancer.

Multi-institutional review of repeat irradiation of chest wall and breast for recurrent breast cancer.

PURPOSE: To review the toxicity and clinical outcomes for patients who underwent repeat chest wall or breast irradiation (RT) after local recurrence. METHODS AND MATERIALS: Between 1993 and 2005, 81 patients underwent repeat RT of the breast or chest wall for locally recurrent breast cancer at eight institutions. The median dose of the first course of RT was 60 Gy and was 48 Gy for the second course. The median total radiation dose was 106 Gy (range, 74.4-137.5 Gy). At the second RT course, 20% received twice-daily RT, 54% were treated with concurrent hyperthermia, and 54% received concurrent chemotherapy. RESULTS: The median follow-up from the second RT course was 12 months (range, 1-144 months). Four patients developed late Grade 3 or 4 toxicity. However, 25 patients had follow-up >20 months, and no late Grade 3 or 4 toxicities were noted. No treatment-related deaths occurred. The development of Grade 3 or 4 late toxicity was not associated with any repeat RT variables. The overall complete response rate was 57%. No repeat RT parameters were associated with an improved complete response rate, although a trend was noted for an improved complete response with the addition of hyperthermia that was close to reaching statistical significance (67% vs. 39%, p = 0.08). The 1-year local disease-free survival rate for patients with gross disease was 53% compared with 100% for those without gross disease (p < 0.0001). CONCLUSIONS: The results of our study have shown that repeat RT of the chest wall for patients with locally recurrent breast cancer is feasible, because it is associated with acceptable acute and late morbidity and encouraging local response rates.

Inoperable pancreatic cancer: standard of care.

Inoperable pancreatic adenocarcinoma is a dilemma that oncologists frequently encounter. Only 15% to 20% of patients are diagnosed when cancer of the pancreas is still surgically resectable. However, pancreaticoduodenectomy is the only curative option for this disease and should be offered to all patients who meet resection criteria and do not have significant comorbidities. For inoperable pancreatic cancer, the goals of treatment are to palliate symptoms and prolong life. Improved survival in locally advanced disease has been demonstrated with chemoradiation plus fluorouracil or with gemcitabine (Gemzar) alone. In metastatic disease, single-agent gemcitabine has been associated with improvement in symptoms and survival. Trials combining various chemotherapeutic agents with gemcitabine have not had a significant impact on overall survival, although meta-analyses suggest a small benefit. The targeted agent erlotinib (Tarceva) has shown a modest improvement in overall survival in combination with gemcitabine. This combination is another option for first-line therapy in patients with locally advanced or metastatic disease. Despite these recent advances, survival for patients with inoperable pancreatic cancer continues to be poor. Future investigations need to focus on understanding the molecular nature of this malignancy, with the goal of developing interventions based on this knowledge.

Radiotherapy for rejection of renal transplant allografts refractory to medical immunosuppression.

OBJECTIVE: To evaluate the outcome and prognostic factors of patients who underwent local graft irradiation for acute renal allograft rejection refractory to modern immunosuppressive medications. METHODS: From 1996 to 2005, 33 patients received local graft irradiation (LGI), with 3 patients receiving 2 courses of radiation. Graft rejection was diagnosed when a rise in creatinine prompted a renal biopsy that demonstrated acute allograft rejection. Upon failure of medical immunosuppresion to resolve rejection, patients were then referred by the organ transplant team for LGI. The median dose was 800 cGy (range, 600-800 cGy), and was given in 200 cGy fractions generally using AP/PA fields. A retrospective review was conducted to determine dialysis-free survival, defined as the date from initiation of radiation therapy to date of hemodialysis placement, and to analyze potential factors that may predict dialysis free survival. RESULTS: Median follow-up from date of radiation therapy to date of last follow-up was 25 months (range, 0.9-99.4 months). The median time between allograft transplantation and radiation therapy was 17.8 months. For the entire group of patients, 20.6% were alive with a functioning graft. The median dialysis-free survival for the entire group was 3.8 months. The median dialysis-free survival for those patients not on dialysis at time of irradiation versus those patients on dialysis was significantly different (5.6 versus 0 months, P = 0.02). CONCLUSION: In renal allograft transplant recipients who experienced acute rejection episodes refractory to modern chemical immunosuppression, LGI was well tolerated and remains a viable salvage treatment option.

The current status of combined radiotherapy and chemotherapy for locally advanced or resected pancreas cancer.

Pancreas cancer is the fourth most common cause of cancer deaths. Even for the small percentage of patients who can undergo surgical resection of the primary tumor, the risk of recurrence remains unacceptably high. For patients with localized disease that is not amenable to surgical resection, pain related to the primary tumor can significantly impair quality of life. Attempts to improve the duration and quality of life for these patients have included both chemotherapy and radiotherapy. The addition of chemotherapy to radiation may enhance the local effects of radiation or provide treatment of disease outside the radiation field. The results of clinical trials evaluating the appropriate therapy for locally advanced or resected disease have been inconsistent. In some instances, the methods used in these studies became outdated before the results were available. Hopefully, advances in radiation techniques and systemic drug therapy will provide more durable and clinically relevant results. Meanwhile, treatment decisions should be tailored to the clinical situation, including consideration of treatment toxicity and therapy goals. Recognizing which patients are likely to benefit from combination therapy or systemic therapy alone is a subject of future and ongoing clinical trials.