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Purpose: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer., Methods and Materials: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine. Capecitabine dose was increased from 650 mg/m(2) to 825 mg/m(2) orally twice daily on the days of radiation therapy; erlotinib dose was increased from 50 mg orally daily in weeks 1 to 3, to 50 mg daily in weeks 1 to 6, to 100 mg daily in weeks 1 to 6. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab., Results: A total of 19 patients were enrolled, and 18 patients were considered evaluable. No patient had grade 4 acute toxicity, and 1 patient had grade 3 acute toxicity (hypertension). The MTD was not reached. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 4 patients (22%), posterior pelvic exenteration in 1 (6%), and abdominoperineal resection in 6 (33%). Of the 18 patients, 8 (44%) had pathologic complete response, and 1 had complete response of the primary tumor with positive nodes. Three patients (17%) had grade 3 postoperative complications (ileus, small bowel obstruction, and infection). With a median follow-up of 34 months, 1 patient developed distant metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 94%., Conclusions: The combination of preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib was well tolerated. The pathologic complete response rate appears promising and may warrant further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Venous resection may be required to achieve complete resection of pancreatic cancers. We assessed the ability of radiographic criteria to predict the need for superior mesenteric-portal vein (SMV-PV) resection and the presence of histologic vein invasion., Methods: All patients who underwent pancreaticoduodenectomy from 2004 to 2011 at the authors' institution were identified. Preoperative pancreatic protocol CT images were re-reviewed to characterize the extent of tumor-vein circumferential interface (TVI) as demonstrating no interface, ≤ 180° of vessel circumference, >180° of vessel circumference, or occlusion. Findings were correlated with the need for venous resection, histologic venous invasion, and survival., Results: A total of 254 patients underwent pancreaticoduodenectomy and met inclusion criteria; 98 (39.6 %) required SMV-PV resection. In our cohort, 76.4 % of patients received neoadjuvant chemoradiation. The TVI classification system predicted with fair accuracy both the need for SMV-PV resection at the time of surgery and histologic invasion of the vein. In particular, 89.5 % of patients with TVI > 180° or occlusion required SMV-PV resection. Of those, 82.4 % had documented histologic SMV-PV invasion. TVI ≤ 180° was associated with favorable overall survival compared to a greater circumferential interface., Conclusions: A tomographic classification of the tumor-SMV-PV interface can predict the need for venous resection, pathologic venous involvement, and survival. To assist in treatment planning, a standardized assessment of this anatomic relationship should be routinely performed.

Importance: There is growing interest in reducing the variations and deficiencies in the multidisciplinary management of gastric cancer., Objective: To define optimal treatment strategies for gastric adenocarcinoma (GC)., Design, Setting, and Participants: RAND/UCLA Appropriateness Method involving a multidisciplinary expert panel of 16 physicians from 6 countries., Interventions: Gastrectomy, perioperative chemotherapy, adjuvant chemoradiation, surveillance endoscopy, and best supportive care., Main Outcomes and Measures: Panelists scored 416 scenarios regarding treatment scenarios for appropriateness from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate; 4 to 6, uncertain; and 7 to 9, appropriate. Agreement was reached when 12 of 16 panelists scored the scenario similarly. Appropriate scenarios agreed on were subsequently scored for necessity., Results: For patients with T1N0 disease, surgery alone was considered appropriate, while there was no agreement over surgery alone for patients T2N0 disease. Perioperative chemotherapy was appropriate for patients who had T1-2N2-3 or T3-4 GC without major symptoms. Adjuvant chemoradiotherapy was classified as appropriate for T1-2N1-3 or T3-4 proximal GC and necessary for T1-2N2-3 or T3-4 distal GC. There was no agreement regarding surveillance imaging and endoscopy following gastrectomy. Surveillance endoscopy was deemed to be appropriate after endoscopic resection. For patients with metastatic GC, surgical resection was considered inappropriate for those with no major symptoms, unless the disease was limited to positive cytology alone, in which case there was disagreement., Conclusions and Relevance: Patients with GC being treated with curative intent should be considered for multimodal treatment. For patients with incurable disease, surgical interventions should be considered only for the management of major bleeding or obstruction.

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.

Objective: Defining processes of care, which are appropriate and necessary for management of gastric cancer (GC), is an important step toward improving outcomes., Methods: Using a RAND/UCLA Appropriateness Method, an international multidisciplinary expert panel created 22 statements reflecting optimal management. All statements were scored for appropriateness and necessity., Results: The following tenets were scored appropriate and necessary: (1) preoperative staging by computed tomography of abdomen/pelvis; (2) positron-emission tomographic scans not routinely indicated; (3) consideration for adjuvant therapy; (4) further clinical trials; (5) multidisciplinary decision making; (6) sufficient support at hospitals; (7) assessment of 16 or more lymph nodes (LNs); (8) in metastatic disease, surgery only for palliation of major symptoms; (9) surgeons experienced in GC management; (10) and surgeons experienced in both GC management and advanced laparoscopic surgery for laparoscopic resection. The following were scored appropriate, but of indeterminate necessity: (1) diagnostic laparoscopy before treatment; (2) a multidisciplinary approach to linitis plastica; (3) genetic assessment for diffuse GC and family history, or age less than 45 years; (4) endoscopic removal of select T1aN0 lesions; (5) D2 LN dissection in curative intent cases; (6) D1 LN dissection for early GC or patients with comorbidities; (7) frozen section analysis of margins; (8) nonemergent cases performed in a hospital with a volume of more than 15 resections per year; and (9) by a surgeon with more than 6 resection per year., Conclusions: The expert panel has created 22 statements for the perioperative management of GC patients, to provide guidance to clinicians and improve the care received by patients.

Background: The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer., Methods: The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and < 50% residual cancer cells; and minor, ≥ 50% residual cancer cells. The reproducibility of quantified pathologic response between 2 pathologists was assessed using tumors from 55 randomly selected patients who did not demonstrate a complete response., Results: Pathologic response was complete in 21% of patients, near-complete in 20% of patients, major in 37% of patients, and minor in 22% of patients. Nineteen percent of patients had ypT0N0 disease, 27% had ypT1-2N0 disease, 21% had ypT3-4N0 disease, and 33% had N+ disease. The 5-year RFS rates by category of quantified pathologic response were as follows: complete, 95%; near-complete, 88%; major, 69%; and minor, 61% (P < .001). Major and minor response, high histologic grade, and perineural invasion were found to be significant predictors of decreased RFS on multivariate analysis. The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near-complete response (94%) compared with those with a major (64%) or minor (61%) response (P < .02). Moderate to substantial agreement was observed between the 2 pathologists (κ = 0.72)., Conclusions: Quantified pathologic response is a predictor of RFS in patients with rectal adenocarcinoma and stratifies patients with high pathologic stage disease., (© 2013 American Cancer Society.)

Background: In treating pancreatic cancer, there is no clearly defined optimal sequence of chemotherapy, radiation therapy and surgery. Therefore, cost-effectiveness should be considered. The objective of this study was to compare cost and outcomes between a surgery-first approach versus neoadjuvant chemoradiation followed by surgery for resectable pancreatic head cancer., Methods: A decision analytic model was constructed to compare the 2 approaches. Data from the National Cancer Database, National Surgical Quality Improvement Program, and literature populated the surgery-first arm. Data from our prospectively maintained institutional pancreatic cancer database populated the neoadjuvant arm. Costs were estimated by Medicare payment (2011 U.S. dollars). Survival was reported in quality-adjusted life-months (QALMs)., Results: The neoadjuvant chemoradiation arm consisted of 164 patients who completed preoperative therapy. Of these, 36 (22 %) did not proceed to surgery; 12 (7 %) underwent laparotomy but had unresectable disease; and 116 (71 %) underwent definitive resection. The surgery-first approach cost $46,830 and yielded survival of 8.7 QALMs; the neoadjuvant chemoradiation approach cost $36,583 and yielded survival of 18.8 QALMs. In the neoadjuvant arm, costs and survival times for patients not undergoing surgery, those with unresectable disease at laparotomy, and those completing surgery were $12,401 and 7.7 QALMs, $20,380 and 7.1 QALMs, and $45,673 and 23.4 QALMs, respectively., Conclusions: Neoadjuvant chemoradiation for pancreatic cancer identifies patients with early metastases or poor performance status, who can be spared an ineffective or prohibitively morbid operation, and is associated with improved survival at significantly lower cost than a surgery-first approach. Neoadjuvant chemoradiation followed by surgery is a strategy that provides more cost-effective care than a surgery-first approach.

Background: Weekly or daily cisplatin and 5-fluorouracil (5-FU)-based chemoradiation was evaluated for patients with locally advanced squamous cell carcinoma (SCC) of the anal canal treated at a single institution over a 20-year period., Methods: A retrospective, single-institution analysis was conducted of patients receiving concurrent 5-FU/cisplatin and radiotherapy for locally advanced SCC from 1989 to 2009. Endpoints included clinical complete response rate, local recurrence rate, colostomy-free survival, disease-free survival (DFS), overall survival, and treatment-related toxicity., Results: A total of 197 patients were evaluable. The majority had American Joint Committee on Cancer stage II (41%) or stage III (46%) disease; most were T2 (44%) or T3 (27%); bulky nodal disease (N2-N3) was noted in 24% of patients. Patients received weekly (20 mg/m2) or daily (4 mg/m2) cisplatin during radiotherapy. Median radiation dose was 55 Gy. Clinical complete response was observed in 185 patients (94%). After a median follow-up of 8.6 years, local recurrence rate was 11%. Sixteen patients (8%) developed distant metastases. The 5-year DFS was 81%, the 5-year overall survival was 86%, and the 5-year colostomy-free survival was 88%. By univariate analysis, N-stage was a poor prognostic indicator for 5-year DFS (P = .02, 95% confidence interval = 1.17-2.01) and distant metastases (P = .046, 95% confidence interval = 1.09-2.13). Increased T-stage correlated with the necessity for salvage surgery (P = .01)., Conclusions: The combination of weekly/daily cisplatin and 5-FU-based chemotherapy with concurrent radiotherapy is an effective regimen, and our long-term results indicate that cisplatin is an alternative to mitomycin C and may be considered for the treatment of locally advanced SCC of the anal canal., (© 2013 American Cancer Society.)

Background: A relationship between higher volume providers and improved outcomes has been suggested by some studies and has been used to construct guidelines for many diseases. For gastric cancer (GC), however, optimal volume cutoffs are not clear., Methods: A multidisciplinary expert panel of 16 physicians from 6 countries scored 120 scenarios regarding provider characteristics for gastric resections for GC. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed on were scored subsequently for necessity., Results: Surgeon and hospital practice volume scenarios were evaluated. The panel felt it was inappropriate for surgeons doing ≤2 GC cases per year to perform a multivisceral resection (MVR), D2 lymphadenectomy (D2-LND), or laparoscopic total gastrectomy, and ≤6 GC cases per year for an MVR involving a pancreatoduodenectomy (MVR-PD), or endoscopic mucosal resections (EMR). It was considered appropriate for surgeons doing ≥11 GC cases per year to perform open gastrectomy or D2-LND, and ≥20 GC cases per year for any MVR, laparoscopic gastrectomy, or EMR. For hospitals, it was considered inappropriate for hospitals managing ≤4 GC cases per year to perform D2-LND or laparoscopic total gastrectomy, and ≤10 GC cases per year, for MVR-PD or EMR. Hospital volumes ≥21 cases per year was considered appropriate for any GC procedure. It was inappropriate for an MVR to be performed in a hospital without interventional radiology services and for a MVR-PD in a hospital with no level I intensive care unit., Conclusion: Appropriate and inappropriate provider volumes for a variety of gastric procedures have been defined by an international expert panel., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Purpose: The goal of this study was to determine the incidence and risk factors associated with gastric bleeding in patients treated with radiation therapy for intrahepatic cholangiocarcinoma., Methods and Materials: Between November 2002 and December 2008, 33 patients with intrahepatic cholangiocarcinoma were treated with radiation therapy to the primary site. Twenty-nine (88%) patients were previously treated with chemotherapy, including gemcitabine and cisplatin in 19 patients. The median dose of radiation therapy was 50.4 Gy (range, 35-70 Gy). Twenty-seven (82%) patients received concurrent therapy, with capecitabine in 26 and bevacizumab in 1 patient., Results: Nine of the 33 patients developed gastric bleeding, with a 1-year actuarial rate of 36%. Of these 9 patients, 7 presented with bleeding symptoms and 2 presented with anemia. All 9 patients were documented to have gastritis on endoscopy. The absolute and percent volumes of stomach receiving 40 and 50 Gy were significantly associated with the risk of gastric bleeding., Conclusions: Patients with intrahepatic cholangiocarcinoma have a significant risk of developing gastric bleeding after radiation therapy. Hence, the volume of stomach exposed to radiation therapy should be minimized in patients receiving radiation therapy for intrahepatic cholangiocarcinoma., (Copyright © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Improving local control is critical to improving survival and quality of life for patients with locally advanced unresectable pancreatic cancer (LAPC). However, previous attempts at radiation dose escalation have been limited by duodenal toxicity. In order to guide future studies, we analyzed the clinical and dosimetric factors associated with duodenal toxicity in patients undergoing fractionated chemoradiation for LAPC., Methods and Materials: Medical records and treatment plans of 106 patients with LAPC who were treated with chemoradiation between July 2005 and June 2010 at our institution were reviewed. All patients received neoadjuvant and concurrent chemotherapy. Seventy-eight patients were treated with conventional radiation to 50.4 Gy in 28 fractions; 28 patients received dose-escalated radiation therapy (range, 57.5-75.4 Gy in 28-39 fractions). Treatment-related toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to assess prognostic influence of clinical, pathologic, and treatment-related factors by using Kaplan-Meier and Cox regression methods., Results: Twenty patients had treatment-related duodenal toxicity events, such as duodenal inflammation, ulceration, and bleeding. Four patients had grade 1 events, 8 had grade 2, 6 had grade 3, 1 had grade 4, and 1 had grade 5. On univariate analysis, a toxicity grade ≥2 was associated with tumor location, low platelet count, an absolute volume (cm(3)) receiving a dose of at least 55 Gy (V(55 Gy) > 1 cm(3)), and a maximum point dose >60 Gy. Of these factors, only V(55 Gy) ≥1 cm(3) was associated with duodenal toxicity on multivariate analysis (hazard ratio, 6.7; range, 2.0-18.8; P=.002)., Conclusions: This study demonstrates that a duodenal V(55 Gy) >1 cm(3) is an important dosimetric predictor of grade 2 or greater duodenal toxicity and establishes it as a dosimetric constraint when treating patients with unresectable pancreatic cancer with concurrent chemoradiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Locally advanced rectal cancer is commonly treated with chemoradiation prior to total mesorectal excision (TME). Studies suggest that metformin may be an effective chemopreventive agent in this disease as well as a possible adjunct to current therapy. In this study, we examined the effect of metformin use on pathologic complete response (pCR) rates and outcomes in rectal cancer. The charts of 482 patients with locally advanced rectal adenocarcinoma treated from 1996 to 2009 with chemoradiation and TME were reviewed. Median radiation dose was 50.4 Gy (range 19.8-63). Nearly, all patients were treated with concurrent 5-fluorouracil-based chemotherapy (98%) followed by adjuvant chemotherapy (81.3%). Patients were categorized as nondiabetic (422), diabetic not taking metformin (40), or diabetic taking metformin (20). No significant differences between groups were found in clinical tumor classification, nodal classification, tumor distance from the anal verge or circumferential extent, pretreatment carcinoembryonic antigen level, or pathologic differentiation. pCR rates were 16.6% for nondiabetics, 7.5% for diabetics not using metformin, and 35% for diabetics taking metformin, with metformin users having significantly higher pCR rates than either nondiabetics (P = 0.03) or diabetics not using metformin (P = 0.007). Metformin use was significantly associated with pCR rate on univariate (P = 0.05) and multivariate (P = 0.01) analyses. Furthermore, patients taking metformin had significantly increased disease-free (P = 0.013) and overall survival (P = 0.008) compared with other diabetic patients. Metformin use is associated with significantly higher pCR rates as well as improved survival. These promising data warrant further prospective study.

Background: Hereditary diffuse gastric cancer (HDGC) represents a minority of gastric cancer (GC) cases. The goal of this study is to use a RAND/University of California Los Angeles (UCLA) appropriateness methodology to examine indications for genetic referral, CDH1 testing, and consideration of prophylactic total gastrectomy (PTG)., Methods: A multidisciplinary expert panel of 16 physicians from six countries scored 47 scenarios. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) of 1-3 were considered inappropriate, 4-6 uncertain, and 7-9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed upon were subsequently scored for necessity., Results: The panel felt that patients with family history of diffuse gastric cancer (DGC), lobular breast cancer, or multiple family members with GC should be referred for genetic assessment and multidisciplinary decision-making. The panel felt that it is appropriate for patients with DGC to have CDH1 mutation testing in a family with (1) ≥2 cases of GC, with at least one case of DGC diagnosed before age of 50 years; (2) ≥3 cases of GC diagnosed at any age, one or more of which is DGC; (3) a patient diagnosed with DGC and lobular breast carcinoma; or (4) patients diagnosed with DGC under age of 35 years. The panel felt that PTG should be offered to CDH1 mutation carriers 20 years or older., Conclusions: Identification of genetic mutations in patients at risk for hereditary GC is important, and criteria for testing are suggested.

Background: Experience with preoperative therapy for other cancers has led to an assumption that borderline resectable pancreatic cancers can be converted to resectable cancers with preoperative therapy. In this study, the authors sought to determine the rate at which neoadjuvant therapy is associated with a reduction in the size or stage of borderline resectable tumors., Methods: Patients who had borderline resectable pancreatic cancer and received neoadjuvant therapy before potentially undergoing surgery at the authors' institution between 2005 and 2010 were identified. The patients' pretreatment and post-treatment pancreatic protocol computed tomography images were rereviewed to determine changes in tumor size or stage using modified Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) and standardized anatomic criteria., Results: The authors identified 129 patients who met inclusion criteria. Of the 122 patients who had their disease restaged after receiving preoperative therapy, 84 patients (69%) had stable disease, 15 patients (12%) had a partial response to therapy, and 23 patients (19%) had progressive disease. Although only 1 patient (0.8%) had their disease downstaged to resectable status after receiving neoadjuvant therapy, 85 patients (66%) underwent pancreatectomy. The median overall survival duration for all 129 patients was 22 months (95% confidence interval, 14-30 months). The median overall survival duration for the patients who underwent pancreatectomy was 33 months (95% confidence interval, 25-41 months) and was not associated with RECIST response (P = .78)., Conclusions: Radiographic downstaging was rare after neoadjuvant therapy, and RECIST response was not an effective treatment endpoint for patients with borderline resectable pancreatic cancer. The authors concluded that these patients should undergo pancreatectomy after initial therapy in the absence of metastases., (Copyright © 2012 American Cancer Society.)

Background: For ampullary carcinoma (AC), the lymph node ratio (LNR) has been associated with overall survival. However, the use of the LNR to predict distant recurrence risk remains unknown. The purpose of this study was to determine if the LNR is associated with distant recurrence risk., Methods: One hundred forty three patients with AC who underwent pancreaticoduodenectomy between 1989 and 2011 were identified from a single-institution prospective database. Data on clinicopathologic factors and recurrence were analyzed., Results: At a median follow-up of 43 months (62 months for survivors), 55 patients (38 %) had developed recurrent disease, with a median time to recurrence of 13 months. Patients with a LNR ≥ 0.15 were more likely to have T3/4 tumors, advanced stage lymphovascular (LVI), or perineural invasion (PNI) and develop recurrent disease. Univariate analysis demonstrated that T-stage, lymph node status, AJCC stage, LVI, PNI, and LNR were significantly associated with decreased time to distant recurrence (TTDR). In multivariate stepwise regression, only LNR and LVI were significantly associated with decreased TTDR., Conclusions: A high positive LNR is associated with distant recurrence after surgical resection of AC. Given the high risk of disease recurrence, consideration for adjuvant therapy is warranted in patients with a LNR ≥ 0.15.

Background: This report analyzes the adherence to radiation therapy protocol guidelines in contemporary Radiation Therapy Oncology Group (RTOG) gastrointestinal trials. We aim to provide insight into current standards and compliance of radiation therapy field design and administration., Methods: From 1994 to 2006, the Gastrointestinal Cancer Committee of the RTOG initiated and completed 15 phase I-III clinical trials utilizing radiation therapy in the multimodality treatment of gastrointestinal cancers. In each protocol, details for planning and executing radiation therapy were outlined and each protocol contained scoring criteria for these components of radiation therapy, characterized according to per-protocol, variation acceptable and deviation unacceptable. Review of treatment planning and implementation was performed in all studies following therapy completion., Results: Radiation therapy planning and implementation was reviewed in 2309 of 2312 (99.9%) patients. The mean rate of compliance over all for the 15 protocols was 65% (total of the 2309 analyzed patients). The mean variation acceptable rate was 21% whereas the mean deviation unacceptable rate was 5%. The mean "other" rate (no RT given or incomplete RT due to death, progression or refusal) was 8%. Two of the 15 trials (13%) had deviation unacceptable rates >10%. In four studies incorporating pre-treatment review of radiation therapy planning and treatment, compliance with protocol therapy was enhanced., Conclusions: The fidelity of radiation planning and execution detailed in protocol to actual therapy is heterogeneous, with a mean per-protocol rate of 65%. As clinical trials evolve, available technology should permit efficient pre-treatment review processes, thus facilitating compliance to protocol therapy. These analyses should also permit prospective analysis of outcome measures by compliance to therapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Acute vulvitis, acute urethritis, and permanent sexual dysfunction are common among patients treated with chemoradiation for squamous cell carcinoma of the anal canal. Avoidance of the genitalia may reduce sexual dysfunction. A vaginal dilator may help delineate and displace the vulva and lower vagina away from the primary tumor. The goal of this study was to evaluate the positional reproducibility and vaginal sparing with the use of a vaginal dilator., Materials and Methods: Ten female patients treated with IMRT for anal cancer were included in this study. A silicone vaginal dilator measuring 29 mm in diameter and 114 mm in length was inserted into the vagina before simulation and each treatment. The reproducibility of dilator placement was investigated with antero-posterior and lateral images acquired daily. Weekly cone beam CT (CBCT) imaging was used to confirm coverage of the GTV, which was typically posterior and inferior to the dilator apex. Finally, a planning study was performed to compare the vaginal doses for these 10 patients to a comparable group of 10 female patients who were treated for anal cancer with IMRT without vaginal dilators., Results: The absolute values of the location of the dilator apex were 7.0 ± 7.8mm in the supero-inferior direction, 7.5 ± 5.5 mm in the antero-posterior, and 3.8 ± 3.1mm in the lateral direction. Coverage of the GTV and CTV was confirmed from CBCT images. The mean dose to the vagina was lower by 5.5 Gy, on average, for the vaginal dilator patients, compared to patients treated without vaginal dilators., Conclusion: The vaginal dilator tended to be inserted more inferiorly during treatment than during simulation. For these ten patients, this did not compromise tumor coverage. Combined with IMRT treatment planning, use of a vaginal dilator could allow for maximum sparing of female genitalia for patients undergoing radiation therapy for anal cancer., (Published by Elsevier Ireland Ltd.)

Background: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy., Methods: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded., Results: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22)., Conclusions: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.

Purpose: The goal of this study was to evaluate dosimetric parameters, acute toxicity, pathologic response, and local control in patients treated with preoperative intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy for localized gastric adenocarcinoma., Methods: Between November 2007 and April 2010, 25 patients with localized gastric adenocarcinoma were treated with induction chemotherapy, followed by preoperative IMRT and concurrent chemotherapy and, finally, surgical resection. The median radiation therapy dose was 45 Gy. Concurrent chemotherapy was 5-fluorouracil and oxaliplatin in 18 patients, capecitabine in 3, and other regimens in 4. Subsequently, resection was performed with total gastrectomy in 13 patients, subtotal gastrectomy in 7, and other surgeries in 5., Results: Target coverage, expressed as the ratio of the minimum dose received by 99% of the planning target volume to the prescribed dose, was a median of 0.97 (range, 0.92-1.01). The median V(30) (percentage of volume receiving at least 30 Gy) for the liver was 26%; the median V(20) (percentage of volume receiving at least 20 Gy) for the right and left kidneys was 14% and 24%, respectively; and the median V(40) (percentage of volume receiving at least 40 Gy) for the heart was 18%. Grade 3 acute toxicity developed in 14 patients (56%), including dehydration in 10, nausea in 8, and anorexia in 5. Grade 4 acute toxicity did not develop in any patient. There were no significant differences in the rates of acute toxicity, hospitalization, or feeding tube use in comparison to those in a group of 50 patients treated with preoperative three-dimensional conformal radiation therapy with concurrent chemotherapy. R0 resection was obtained in 20 patients (80%), and pathologic complete response occurred in 5 (20%)., Conclusions: Preoperative IMRT for gastric adenocarcinoma was well tolerated, accomplished excellent target coverage and normal structure sparing, and led to appropriate pathologic outcomes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy., Patients and Methods: All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression., Results: In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v 1.4% v 4.4%; P = .002)., Conclusion: Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies.

Objectives: Carcinoma of unknown primary (CUP) in the abdomen and pelvis is a heterogeneous group of cancers with no standard treatment. Considered by many to be incurable, these patients are often treated with chemotherapy alone. In this study, we determined the effectiveness of radiation therapy in combination with chemotherapy in patients with CUP in the abdomen and pelvis., Patients and Methods: Medical records were reviewed for 37 patients with CUP treated with radiation therapy for disease located in the soft tissues and/or nodal basins of the abdomen and pelvis at the University of Texas M.D. Anderson Cancer between 2002 and 2009. All patients underwent chemotherapy, either before or concurrent with radiation therapy. Patients were selected for radiation therapy on the basis of histologic type, disease extent, and prior therapy response. Twenty patients underwent definitive radiation therapy (defined as radiation therapy targeting all known disease sites with at least 45 Gy) and 17 patients underwent palliative radiation therapy. Only 6 patients had surgical resection of their disease. Patient and treatment characteristics were extracted and the endpoints of local disease control, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity incidence were analyzed., Results: The 2-year PFS and OS rates for the entire cohort were 32% and 57%, respectively. However, in patients treated with definitive radiation therapy, the rates were 48% and 76%, and 7 patients lived more than 3 years after treatment with no evidence of disease progression. Nevertheless, radiation-associated toxicity was significant in this cohort, as 40% experienced Grade 2 or higher late toxicities., Conclusions: The use of definitive radiation therapy should be considered in selected patients with CUP in the soft tissues or nodal basins of the abdomen and pelvis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy is not clear. In this study, we performed a detailed examination of neural invasion in pancreaticoduodenectomy specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and in 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in the untreated group (80%, 48/60) than in the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extratumoral PNI, intratumoral PNI, intrapancreatic PNI only, extrapancreatic PNI, and intraneural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 cases (28.5%), respectively. The presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor, and American Joint Committee on Cancer stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared with tumors with PNI involving nerves ≤0.8 mm but not with other clinicopathologic parameters and survival. In the treated group, the presence of PNI or intraneural invasion correlated significantly with shorter disease-free survival and overall survival compared with no PNI or PNI only, respectively. PNI was an independent prognostic factor for both disease-free survival and overall survival in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Objectives: To determine the influence of neoadjuvant chemoradiation and standardized dissection of the superior mesenteric artery upon the oncologic outcome of patients with localized pancreatic adenocarcinoma., Methods: One hundred ninety-four patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy between 2004 and 2008 were evaluated. The retroperitoneal dissection was performed directly along the superior mesenteric artery in all cases. A standard histopathologic protocol that measured the "superior mesenteric artery (SMA) margin distance" between cancer cells and the superior mesenteric artery was employed., Results: Seventy-six percent of patients received neoadjuvant chemoradiation. The SMA margin was positive in 4% of patients but an additional 22% of patients with a negative margin had a SMA margin distance of ≤1 mm. Preoperative CT images overestimated the SMA margin distance in 73% of cases. Patients who received chemoradiation had longer SMA margin distances than those who did not. Patients who received chemoradiation and had a SMA margin of >1 mm had the lowest recurrence rates. Administration of neoadjuvant chemoradiation and lower estimated blood loss were independently associated with longer progression-free survival on multivariate analysis., Conclusions: Preoperative chemoradiation and meticulous dissection of the superior mesenteric artery maximize the distance between cancer cells and the SMA margin and may influence locoregional control.

Purpose: We conducted a phase II trial to assess the survival duration and quality of life of patients who received adjuvant interferon-based chemoradiation for pancreatic adenocarcinoma after pancreaticoduodenectomy., Methods: Patients with a performance status of 0 or 1 were enrolled to receive interferon-alfa-2b (3 million units MWF), cisplatin (30 mg/m(2), 6 doses) and 5-fluorouracil (5-FU; 175 mg/m(2)/day), concurrent with external-beam radiation (50.4 Gy) and followed by 2 courses of systemic 5-FU. The protocol was modified to include an optional 9 day break in the middle of chemoradiation. Quality of life was assessed by use of validated instruments., Results: Twenty-eight patients were eligible for analysis. The operation of 15 (54%) patients was performed at other institutions. All patients had T3 tumors, 22 (79%) had positive lymph nodes and 4 (14%) had positive (R1) margins. 24 (86%) patients completed therapy. In all, 25 (89%) patients experienced grade 3 toxicity and 3 (11%) patients were hospitalized. The most common grade 3 events were leukopenia (15, 54%) and neutropenia (12, 43%). No grade 4 toxicity occurred. Overall quality of life decreased during chemoradiation but returned to baseline thereafter and was stable throughout surveillance. 19 patients have died; the median follow-up of the 9 survivors is 62 months. The median OS duration of treated patients was 42.3 (95% confidence interval 30.5-54.2) months., Conclusions: Adjuvant interferon-based chemoradiation can be delivered safely and tolerably-though with substantial reversible toxicity-to patients of good performance status at an experienced cancer center. Therapy may be associated with an improvement in overall survival.

Purpose: The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer., Patients and Methods: Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m(2)/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m(2)/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m(2) for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire was also performed., Results: Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test)., Conclusion: This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.

Background: Hepatocellular carcinoma is one of the most common cancers worldwide. Data regarding the use of radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with radiotherapy in the modern era at a single institution., Material and Methods: A total of 29 patients with localized hepatocellular carcinoma treated from 2000-2010 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30 to 75 Gy) with a median biologically effective dose of 80.6 (range 60 to 138.6). Median tumor size at the time of radiation was 5.2 cm (range 2 to 25 cm)., Results: Eighty three percent of all patients had either stable disease or a partial response to radiation, based on RECIST criteria. Median change in tumor size following radiation was -17% (range -73.5 to 177.8%). Estimated one-year overall survival and in-field progression-free survival rates for the study population were 56% and 79%, respectively. One-year overall survival in patients treated to a biologically effective dose <75 was significantly lower than in patients treated to a biologically effective dose ≥75 (18% vs. 69%). One-year in-field progression-free survival rate (60% vs. 88%) and biochemical progression-free survival duration (median 6.5 vs. 1.6 months) were also significantly improved in patients treated to a biologically effective dose ≥75. Grade 3 toxicity was seen in 13.8% of patients., Discussion: In a population without endemic viral hepatitis, unresectable hepatocellular carcinoma demonstrates significant response to radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased biologically effective dose is associated with improved survival and local tumor control.

Purpose: The benefit of adjuvant radiotherapy (RT) after surgical resection for extrahepatic cholangiocarcinoma has not been clearly established. We analyzed survival outcomes of patients with resected extrahepatic cholangiocarcinoma and examined the effect of adjuvant RT., Methods and Materials: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2003. The primary endpoint was the overall survival time. Cox regression analysis was used to perform univariate and multivariate analyses of the following clinical variables: age, year of diagnosis, histologic grade, localized (Stage T1-T2) vs. regional (Stage T3 or greater and/or node positive) stage, gender, race, and the use of adjuvant RT after surgical resection., Results: The records for 2,332 patients were obtained. Patients with previous malignancy, distant disease, incomplete or conflicting records, atypical histologic features, and those treated with preoperative/intraoperative RT were excluded. Of the remaining 1,491 patients eligible for analysis, 473 (32%) had undergone adjuvant RT. After a median follow-up of 27 months (among surviving patients), the median overall survival time for the entire cohort was 20 months. Patients with localized and regional disease had a median survival time of 33 and 18 months, respectively (p<.001). The addition of adjuvant RT was not associated with an improvement in overall or cause-specific survival for patients with local or regional disease., Conclusion: Patients with localized disease had significantly better overall survival than those with regional disease. Adjuvant RT was not associated with an improvement in long-term overall survival in patients with resected extrahepatic bile duct cancer. Key data, including margin status and the use of combined chemotherapy, was not available through the SEER database., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Preoperative chemoradiation for rectal cancer can decrease the number of evaluable lymph nodes. Hence, the prognostic role of lymph node evaluation in patients with rectal cancer who receive preoperative chemoradiation is unclear. The authors of this report evaluated the prognostic impact of the number of lymph nodes examined in patients with rectal cancer who had negative lymph nodes based on the pathologic extent of disease (ypN0) after they received preoperative chemoradiation., Methods: Between 1990 and 2004, 372 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation followed by mesorectal excision and had ypN0 disease. The median radiation dose was 45 gray, and 68% of patients received adjuvant chemotherapy., Results: Patients had a median of 7 lymph nodes examined after preoperative chemoradiation. Compared with patients who had ≤7 lymph nodes examined, patients who had >7 lymph nodes had higher 5-year rates of freedom from relapse (86% vs 72%; log-rank P = .005) and cancer-specific survival (95% vs 86%; log-rank P = .0004), but no significant difference was observed in the overall survival rate (87% vs 81%; log-rank P = .07). Multivariate Cox proportional models demonstrated that patients who had >7 lymph nodes examined had a significantly lower risk of relapse (hazard ratio [HR], 0.39; P = .003) and death from rectal cancer (HR, 0.45; P = .04) but a similar risk of all-cause mortality (HR, 0.75; 95% CI, 0.46-1.20; P = .23) compared with patients who had ≤7 lymph nodes examined., Conclusions: The number of lymph nodes examined was associated independently with disease relapse and cancer-specific survival in patients with rectal cancer who had ypN0 disease after receiving preoperative chemoradiation. Hence, the authors concluded that the number of negative lymph nodes examined may be a prognostic factor in patients with rectal cancer who receive preoperative chemoradiation., (Copyright © 2011 American Cancer Society.)

Purpose: This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC)., Patients and Methods: Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression., Results: Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016)., Conclusion: This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

Objective: To study the behavior of hypoattenuating liver lesions, deemed too small to characterize at baseline scanning with multidetector computed tomography (CT), in patients with rectal cancer., Methods: Retrospective review of locally advanced rectal cancer patients from a radiation oncology therapy database was conducted. Patients who presented before neoadjuvant chemoradiation without metastases at baseline CT and with follow-up scans for at least 1 year after therapy were evaluated. CT studies were reviewed for the presence and change in size of hypoattenuating liver lesions (<15 mm) at baseline and follow-up., Results: A total of 616 consecutive patients from the radiotherapy database were reviewed. Of these, 70 patients with a total of 163 hepatic lesions met the selection criteria. The mean patient age was 62.4 years (range, 26-85 years). All patients subsequently underwent surgery and adjuvant chemotherapy. The mean time of radiographic imaging from baseline CT to most recent surveillance CT was 3.3 years (range, 1.1-7.4 years). Two radiologists independently reviewed the CTs. The lesions were stable in 56 of 70 (80.0%, 95% confidence interval: 69%, 89%) patients. Of 163 lesions, 148 (90.8%) were stable, 8 (4.9%) regressed, and 7 (4.3%) progressed in size. No significant difference in results was found for patients stratified according to T-stage (P = 0.41) and N-stage (P > 0.99)., Conclusion: In patients with rectal cancer, majority of small hypoattenuating liver lesions remain stable and are treated as benign lesions, at multidetector CT follow-up of more than a year. Nevertheless, hepatic lesion stability during systemic therapy should still be interpreted with caution and closely followed for at least 1 year after completion of therapy.

Purpose: Volumetric modulated arc therapy (VMAT), an evolution of intensity modulated radiation therapy (IMRT), utilizes the dynamic modulation of angular dose rate through changes in gantry speed, linear accelerator dose rate, and multileaf collimator motion to deliver a treatment fraction in rotational fashion with improved efficiency and in shorter time. In general, target coverage relative to adjacent organ-at-risk sparing is highly dependent on the complexity of the treatment site. Therefore, we critically evaluated VMAT compared to IMRT for definitive treatment of anal carcinoma with respect to dosimetry and efficiency., Methods and Materials: Using SmartArc (Philips Healthcare, Andover, MA), VMAT treatment plans were generated for 10 patients treated at our institution for anal carcinoma, and compared to the IMRT plans used for clinical treatment. The patients were all female, had T classification TX/1 (n = 5), T2 (n = 3) or T3 (n = 2), were node-negative (n = 6) or node-positive (n = 4), and were treated to a total dose of 50 to 58 Gy. Pairwise comparisons were made between VMAT and IMRT plans with respect to dose-volume histogram parameters relating the dose received by target volumes, relevant organs at risk, and normal tissues. The plans were machine-delivered, with actual beam delivery times measured., Results: VMAT plans had superior planning target volume coverage and dose homogeneity, with improved conformality in treatment of the elective nodal volume, in comparison to IMRT. Mean dose to the small bowel, genitalia, and femoral heads were significantly lower with VMAT, and similar with respect to bladder, pelvic bones, and normal tissues. Integral dose was comparable between the 2 techniques. VMAT plans required 36.8% fewer monitor units, and beam delivery time was shorter by 9 minutes., Conclusions: Our results indicate that VMAT represents an ideal treatment modality for anal carcinoma, generating plans with excellent target coverage, lower doses to organs at risk, and shorter treatment times, in comparison to IMRT., (Copyright © 2011 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer., Methods: Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters., Results: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk., Conclusions: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus.

It is well established that the development of distant metastatic disease represents the dominant pattern of tumor recurrence/progression among patients with operable and locally advanced pancreatic cancer. However, the contribution of localized or locoregional tumor burden to pancreatic cancer-associated morbidity and mortality may be underappreciated, and therefore balancing competing considerations of systemic versus local disease control becomes important in therapeutic decision-making. The role of local therapies, particularly radiation therapy, has remained somewhat controversial in this disease context. Several phase II and III trials have sought to address the relative importance and role of radiation in both the localized and locally advanced settings, including the sequencing of this modality relative to systemic therapy and its optimal means of administration. However, differences and limitations in study design have produced mixed results, particularly in terms of the contribution of radiation to overall survival benefit. An emerging paradigm that makes conceptual sense and remains the subject of active investigation is to start with a defined period of systemic treatment, thus limiting radiation to the subset of patients who do not manifest with metastatic disease during initial therapy and are therefore most likely to benefit from local control.

Purpose: The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials., Patients and Methods: We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level., Results: We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74)., Conclusions: Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.

Purpose: To retrospectively determine rates of toxicity, freedom from local progression, and survival in rectal cancer patients treated with reirradiation., Methods and Materials: Between February 2001 and February 2005, 50 patients with a history of pelvic radiotherapy were treated with hyperfractionated accelerated radiotherapy for primary (n = 2 patients) or recurrent (n = 48 patients) rectal adenocarcinoma. Patients were treated with 150-cGy fractions twice daily, with a total dose of 39 Gy (n = 47 patients) if the retreatment interval was >or=1 year or 30 Gy (n = 3) if the retreatment interval was <1 year. Concurrent chemotherapy was administered to 48 (96%) patients. Eighteen (36%) patients underwent surgical resection following radiotherapy., Results: Two patients had grade 3 acute toxicity and 13 patients had grade 3 to 4 late toxicity. The 3-year rate of grade 3 to 4 late toxicity was 35%. The 3-year rate of freedom from local progression was 33%. The 3-year freedom from local progression rate was 47% in patients undergoing surgery and 21% in those not undergoing surgery (p = 0.057). The 3-year overall survival rate was 39%. The 3-year overall survival rate was 66% in patients undergoing surgery and 27% in those not undergoing surgery (p = 0.003). The 3-year overall survival rate was 53% in patients with a retreatment interval of >2 years and 21% in those with a retreatment interval of

Large primary tumor and clinical nodal involvement in patients with anal carcinoma treated with chemoradiation are associated with poor disease-free survival (DFS). However, the outcome in individual patient is unpredictable. We hypothesized that biomarkers related to chemotherapy and/or radiation resistance would be associated with DFS. We analyzed clinical and biomarker data in 30 patients with anal carcinoma who had chemoradiation. Patient selection was based on the availability of untreated cancer for biomarkers, completion of prescribed chemoradiation, and patient outcomes (~50% disease-free) nonrepresentative of published cohorts but conducive to biomarker discovery. Ten biomarkers, Ki67, human telomerase (hTERT), epidermal growth factor receptor (EGFR), p53, p16, Bcl-2, vascular endothelial growth factor (VEGF), nuclear factor kappa-B (NF-kappaB), SHH, and Gli-1, were studied. Raw data as continuous variable (only EGFR was trichotomized) were analyzed. Univariate and multivariate Cox models were utilized to assess relationship between DFS and biomarkers. Twenty-three of 30 patients were women, tumor diameter was >5 cm in 30, and 37% had clinically positive nodes. Fourteen (30%) patients had a DFS event after chemoradiation. In univariate analysis, NF-kappaB (P = 0.01), SHH (P = 0.02), Gli-1 (P = 0.02), and tumor diameter (P = 0.03) were significantly associated with DFS, and Ki67 (P = 0.07) was marginally significant. In multivariate analysis, tumor diameter (P = 0.003), Ki67 (P = 0.005), NF-kappaB (P = 0.002), SHH (P = 0.02), and Gli-1 (P = 0.02) were significantly associated with DFS. Our data, albeit preliminary, suggest that several biomarkers (Ki67, NF-kappaB, SHH, and Gli-1) are associated with DFS. Upon further expansion and validation, these results may provide a biomarker-based understanding of heterogeneous clinical biology of patients with anal carcinoma.

Purpose: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer., Methods: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m(2) orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later., Results: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences., Conclusions: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Radiotherapy is the current standard of care for patients with localized squamous cell cancer of the anal canal. The goal of the current study was to evaluate long-term quality of life (QoL) in patients after this treatment., Methods: Questionnaires were mailed to 80 patients treated with definitive radiotherapy, with or without concurrent chemotherapy, for anal cancer, with a minimum 2-year interval after the completion of radiotherapy. The questionnaire included the Functional Assessment of Cancer Therapy-Colorectal (FACT-C), the Medical Outcomes Study (MOS) Sexual Problems Scale, and questions regarding demographic characteristics and comorbidities., Results: A total of 32 (40%) patients completed the questionnaire. There were no significant differences noted with regard to clinical and demographic characteristics between the survey responders and nonresponders. Among the 32 responders, the median dose of radiotherapy was 55 Grays (Gy), and 97% had received concurrent chemotherapy. The median interval between radiotherapy and survey participation was 5 years (range, 3-13 years). The median total FACT-C score was 108 (range, 47-128), of a maximum (best possible) score of 136. Patients who reported depression or anxiety and younger patients were found to have significantly lower total FACT-C scores. The median scores on the Physical, Social/Family, Emotional, Functional, and Colorectal subscales of the FACT-C were 20, 23, 21, 22, and 21, respectively, of maximum (best possible) scores of 28, 28, 24, 28, and 28, respectively. The median score on the MOS Sexual Problems Scale was 67 (range, 0-100), of a maximum (worst possible) score of 100., Conclusions: Patients treated with radiotherapy for anal cancer reported acceptable overall QoL scores, but poor sexual function scores. Investigations are warranted into more modern radiation techniques that could potentially reduce late toxicity from radiotherapy.

Background: We previously reported 26 patients who underwent preoperative chemoradiotherapy (CXRT) for T3 rectal cancer and were subsequently offered full-thickness local excision (LE) as an alternative to total mesorectal excision (TME). At nearly 4 years' follow-up, no difference in outcome was observed. This study compares outcomes in a larger cohort of patients and reevaluates the original 26 patients after longer follow-up., Methods: Retrospective review was performed of patients who underwent preoperative CXRT (radiation doses of 45, 50.4, or 52.5 Gy with concurrent 5-fluorouracil-based chemotherapy) followed by surgery for T3 rectal cancer. Forty-seven patients underwent LE (Kraske [n = 6] or transanal excision [n = 41]). 473 patients underwent TME (abdominoperineal resection [n = 141] or low anterior resection [n = 332]). Local recurrence, disease-free survival (DFS), disease-specific survival, and overall survival (OS) rates were compared., Results: Median follow-up was 63 months for the LE group and 59 months for the TME group. Twenty-three LE patients (49%) had a complete response to CXRT, 17 (36%) had microscopic residual disease, and 7 (15%) had gross residual disease, compared with 108 (23%), 89 (19%), and 276 (58%) TME patients, respectively. There was no significant difference between the 10-year actuarial local recurrence rate for the LE group versus the TME group (10.6% and 7.6%, respectively; P = .52), and no significant difference in DFS, disease-specific survival, or OS rates between groups., Conclusions: In selected patients who demonstrate an excellent response to preoperative CXRT for T3 rectal cancer, full-thickness LE offers comparable local control, DFS, and OS to that achieved with proctectomy and TME.

We previously demonstrated that select cytokine gene polymorphisms in interleukin (IL)-8 are a significant predictor of pain and analgesia in patients with lung cancer. This study explores the role of 13 potentially functional polymorphisms in cytokine genes, including IL-1beta, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-alpha, and nuclear factor kappa-B subunit 1, in pain severity in patients with pancreatic cancer. We evaluated a series of patients with histologically confirmed adenocarcinoma of the pancreas (n=484), who had completed a self-administered survey of pain before initiating any cancer treatment. DNA (n=156) available for a subset of white patients was assayed and assessed for association with pain severity. Results showed that 26% (128 of 484) reported experiencing severe pain (score of >7 on a 0-10 scale). Severe pain varied by the stage of disease (odds ratio [OR] Stage II=4.02, 95% confidence interval (CI)=1.07, 15.07; Stage III=5.02, 95% CI=1.28, 19.61; Stage IV=6.90, 95% CI=1.96, 24.29), ethnicity (OR non-Hispanic blacks=3.67; 95% CI=1.44, 9.38), reports of depressed mood (OR=1.94; 95% CI=1.09, 3.43), and female sex (OR=1.78; 95% CI=1.04, 3.05). Controlling for these covariates, IL8-251T/A (OR=2.43, 95% CI=1.3, 4.7, P<0.009) significantly predicted severe pain in a subset of white patients. When we adjusted for reported analgesic use, we found that IL8-251T/A persisted as a predictor for severe pain, with carriers of TT and AT genotypes having more than a threefold risk (OR=3.23, 95% CI=1.4, 4.7) for severe pain relative to the AA genotypes. We provide preliminary evidence of the role of IL-8 in the severity of pain in pancreatic cancer patients. Additional studies are needed in larger cohorts of patients.

Background: Reirradiation to the abdomen could potentially play a role in palliation of symptoms or local control in patients with gastrointestinal malignancies. Our goal was to retrospectively determine rates of toxicity, freedom from local progression and overall survival in gastrointestinal cancer patients treated with reirradiation to the abdomen., Methods: Between November 2002 and September 2008, 13 patients with a prior history of abdominal radiotherapy (median dose 45 Gy) were treated with reirradiation for recurrent or metastatic gastrointestinal malignancies. The median interval between the two courses of radiotherapy was 26 months. Patients were treated with a hyperfractionated accelerated regimen, using 1.5 Gy fractions twice daily, with a median dose of 30 Gy (range 24-48 Gy). Concurrent chemotherapy was administered to 8 (62%) patients., Results: The 1-year rate of freedom from local progression was 50%, and the median duration of freedom from local progression was 14 months. The 1-year rate of overall survival was 62%, and the median duration of overall survival was 14 months. One patient developed grade 3 acute toxicity (abdominal pain and gastrointestinal bleeding), requiring hospitalization during radiotherapy; subsequently, that patient experienced a grade 4 late toxicity (gastrointestinal bleeding). No other patients developed grade 3-4 acute or late toxicity or required hospitalization during radiotherapy., Conclusion: Hyperfractionated accelerated reirradiation to the abdomen was well-tolerated with low rates of acute and late toxicity. Reirradiation could play a role in providing a limited duration of local control in gastrointestinal cancer patients with a history of prior abdominal radiotherapy.

Purpose: To determine the rates of toxicity, locoregional control, distant control, and survival in anal cancer patients with para-aortic nodal involvement, treated with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy at a single institution., Methods and Materials: Between 2001 and 2007, 6 patients with squamous cell anal cancer and para-aortic nodal involvement were treated with IMRT and concurrent infusional 5-fluorouracil and cisplatin. The primary tumor was treated with a median dose of 57.5 Gy (range, 54-60 Gy), involved para-aortic, pelvic, and inguinal lymph nodes were treated with a median dose of 55 Gy (range, 50.5-55 Gy), and noninvolved nodal regions were treated with a median dose of 45 Gy (range, 43.5-45 Gy)., Results: After a median follow-up of 25 months, none of the patients had a recurrence at the primary tumor, pelvic/inguinal nodes, or para-aortic nodes, whereas 2 patients developed distant metastases to the liver. Four of the 6 patients are alive. The 3-year actuarial locoregional control, distant control, and overall survival rates were 100%, 56%, and 63%, respectively. Four of the 6 patients developed Grade 3 acute gastrointestinal toxicity during chemoradiation., Conclusions: Intensity-modulated radiotherapy and concurrent chemotherapy could potentially serve as definitive therapy in anal cancer patients with para-aortic nodal involvement. Adjuvant chemotherapy may be indicated in these patients, as demonstrated by the distant failure rates. These patients need to be followed carefully because of the potential for treatment-related toxicities.

Purpose: To investigate whether symptom burden before and during preoperative chemoradiation therapy (CRT) for rectal cancer predicts for pathologic tumor response., Methods and Materials: Fifty-four patients with T3/T4/N+ rectal cancers were treated on a Phase II trial using preoperative capecitabine and concomitant boost radiotherapy. Symptom burden was prospectively assessed before (baseline) and weekly during CRT by patient self-reported questionnaires, the MD Anderson Symptom Inventory (MDASI), and Brief Fatigue Inventory (BFI). Survival probabilities were estimated using the Kaplan-Meier method. Symptom scores according to tumor downstaging (TDS) were compared using Student's t tests. Logistic regression was used to determine whether symptom burden levels predicted for TDS. Lowess curves were plotted for symptom burden across time., Results: Among 51 patients evaluated for pathologic response, 26 patients (51%) had TDS. Fatigue, pain, and drowsiness were the most common symptoms. All symptoms increased progressively during treatment. Patients with TDS had lower MDASI fatigue scores at baseline and at completion (Week 5) of CRT (p = 0.03 for both) and lower levels of BFI "usual fatigue" at baseline., Conclusion: Lower levels of fatigue at baseline and completion of CRT were significant predictors of pathologic tumor response gauged by TDS, suggesting that symptom burden may be a surrogate for tumor burden. The relationship between symptom burden and circulating cytokines merits evaluation to characterize the molecular basis of this phenomenon.

Purpose: The purpose was to determine the optimal radiation therapy modality (three-dimensional conformal photon-radiation therapy [3DCRT], intensity-modulated photon-radiation therapy [IMRT], or passive-scattering proton therapy [PT]) for safe dose escalation (72Gy) in pancreatic tumors in different positions relative to organs at risk (OAR) anatomy., Methods and Materials: A 3-cm pancreatic tumor was virtually translated every 5mm over 5cm laterally. We generated two plans for each of the three techniques (3DCRT, IMRT, and PT), one that adhered to target coverage objectives and another to meet OAR sparing constraints with best coverage. We evaluated distances between gross tumor volumes and isodoses and compared dose-volume histograms., Results: IMRT was more conformal in higher gradient dose regions circumferentially, but tumor positions with anteriorly located small bowel benefited more from PT. 3DCRT plans resulted in inadequate target coverage. The V(15Gy) (mean+/-SD) were as follows for the IMRT and PT plans, respectively: stomach, 48%+/-4% vs 5%+/-3% (p<0.0001); and small bowel, 61%+/-8% vs 9%+/-4% (p<0.0001)., Conclusions: Our study showed that the optimal radiation therapy modality for safe dose escalation depends on pancreatic tumor position in relation to OAR anatomy.