Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients.

BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas. METHODS: Patients with resected clinical American Joint Committee on Cancer TNM stage II or III adenocarcinomas of the stomach or GEJ from 2004 through 2013 were identified utilizing the National Cancer Data Base. Hazard ratios (HRs), 95% confidence intervals, and P values were computed using a Cox proportional hazards procedure. Multivariable models were adjusted for treatment regimen, age, race, ethnicity, tumor size, TNM stage, Charlson comorbidity index, and tumor grade. RESULTS: Patients receiving PECT had a 72% survival advantage compared with those treated with POCRT (5058 patients; HR, 0.58 [adjusted P<.0001]). The 5-year actuarial survival rate for PECT was 44% compared with 38% for POCRT. A statistically significant survival advantage for PECT also was observed when the analysis was stratified by clinical stage of disease (stage II [3192 patients]: adjusted HR, 0.79 [P = .041]; and stage III [1866 patients]: adjusted HR, 0.49 [P<.0001]). This benefit was greatest among patients with lymph node-positive disease who converted to lymph node-negative status with PECT. CONCLUSIONS: In this large series of patients with stage II/III resected gastric/GEJ adenocarcinomas from >1500 American College of Surgeons Commission on Cancer-accredited facilities, patients receiving PECT were shown to survive longer than those receiving POCRT. Cancer 2017;123:2909-17. © 2017 American Cancer Society.

Identification of prognostic and predictive markers in pancreatic adenocarcinoma. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

Pancreatic cancer remains a significant cause of morbidity and mortality. While increasing treatment options have improved outcomes for many patients, they have also complicated decision-making for treatment. Unfortunately, most patients with pancreatic cancer die from their disease. Prognostic and predictive markers could play a role to improve treatment by identifying patients who may or may not require a given therapy, and determining those most likely to benefit from a therapy. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium held in San Francisco, January 2011, several interesting abstracts were presented that focused on prognostic and predictive markers associated with pancreatic adenocarcinomas. These abstracts discuss progress made in identifying molecular subtypes of pancreatic cancers that may provide insight into selection of patients likely to benefit from certain therapies.

Intensity modulation with respiratory gating for radiotherapy of the pleural space.

We wanted to describe a technique for the implementation of intensity-modulated radiotherapy (IMRT) with a real-time position monitor (RPM) respiratory gating system for the treatment of pleural space with intact lung. The technique is illustrated by a case of pediatric osteosarcoma, metastatic to the pleura of the right lung. The patient was simulated in the supine position where a breathing tracer and computed tomography (CT) scans synchronized at end expiration were acquired using the RPM system. The gated CT images were used to define target volumes and critical structures. Right pleural gated IMRT delivered at end expiration was prescribed to a dose of 44 Gy, with 55 Gy delivered to areas of higher risk via simultaneous integrated boost (SIB) technique. IMRT was necessary to avoid exceeding the tolerance of intact lung. Although very good coverage of the target volume was achieved with a shell-shaped dose distribution, dose over the targets was relatively inhomogeneous. Portions of target volumes necessarily intruded into the right lung, the liver, and right kidney, limiting the degree of normal tissue sparing that could be achieved. The radiation doses to critical structures were acceptable and well tolerated. With intact lung, delivering a relatively high dose to the pleura with acceptable doses to surrounding normal tissues using respiratory gated pleural IMRT is feasible. Treatment delivery during a limited part of the respiratory cycle allows for reduced CT target volume motion errors, with reduction in the portion of the planning margin that accounts for respiratory motion, and subsequent increase in the therapeutic ratio.

Stereotactic body radiotherapy for pancreatic cancer: recent progress and future directions.

Despite advances in surgical, medical, and radiation therapy for pancreatic cancer, the prognosis remains poor. At this time, the only chance for long-term survival is surgical resection. More challenging is the optimal management of unresectable locally advanced pancreatic cancer, which has historically been treated with concurrent chemoradiation or chemotherapy alone. However, the survival and local control benefit of conventional radiotherapy in addition to chemotherapy was unclear. More recently, stereotactic body radiotherapy (SBRT) is emerging as a viable approach to maximizing local tumor control with a tolerable side effect profile. SBRT achieves sharp dose fall-off facilitating safe delivery of highly focused radiation to the tumor over 1-5 days. Although the optimal regimen of pancreas SBRT has not yet been established, its short treatment course limits the delay of additional. Future directions involve prospective study of pancreas SBRT and exploration of biomarkers and imaging technology in order to adopt a personalized management paradigm.

Gastrointestinal bleeding associated with concurrent capecitabine and radiotherapy in patients with pancreatic cancer.

CONTEXT: Capecitabine is currently being evaluated for the treatment of a variety of gastrointestinal malignancies. OBJECTIVE: The aim of this study is to report on the incidence of late gastrointestinal bleeding in patients with pancreatic cancer who received concurrent capecitabine and abdominal irradiation followed by prolonged capecitabine therapy. PATIENTS: We reviewed the medical records of 24 patients (13 female, 11 males; median age of 64.5 years): 22 cases of adenocarcinoma and 2 cases of neuroendocrine carcinoma. Initially, 4 patients underwent surgical resection. Median follow-up was 10.3 months. INTERVENTIONS: Patients received capecitabine (600-800 mg/m2 orally twice daily) with concurrent radiation (50.4-54.0 Gy). Patients who were resected received an additional 2-4 cycles of capecitabine; otherwise, capecitabine was given indefinitely until disease progression occurred. MAIN OUTCOME MEASURE: Incidence of late gastrointestinal bleeding. RESULTS: Three patients developed gastro-intestinal bleeding after concurrent capecitabine and irradiation and 2 of these patients died as a result of this toxicity. CONCLUSIONS: Our study indicates that serious gastrointestinal bleeding is a possible late complication associated with concurrent capecitabine and irradiation therapy for pancreatic cancer followed by additional capecitabine therapy. Caution and close monitoring should therefore be used when continuing capecitabine therapy in this setting.

The multidisciplinary approach to the treatment of rectal cancer: 2015 update.

The multidisciplinary approach to the management of rectal cancer continues to evolve with developments in surgery, radiation therapy as well as systemic chemotherapy. Refinement of surgical techniques to improve organ preservation, selective use of neoadjuvant (or adjuvant) therapies, improvements in staging modalities and emerging criteria for the selection of tailored therapies are some of the advancements made over the last three decades. In addition, neoadjuvant treatment alternatives, multimodality sequencing and adaptive therapies based on treatment response continue to be a subject of clinical investigation. The current article reviews the salient topics related to the multidisciplinary treatment of resectable rectal cancer.

Capecitabine as a Radiosensitizer in Adjuvant Chemoradiotherapy for Pancreatic Cancer: A Retrospective Study.

AIM: Pancreatic cancer remains one of the deadliest cancer diagnoses and is the fourth leading cause of cancer-related deaths in the U.S. Surgery is the mainstay of treatment for the 20% for whom the tumor is resectable, however, controversy exists over the appropriate adjuvant therapy where local recurrence rates remain strikingly high (50-85%). We aimed to evaluate the safety and efficacy of adding capecitabine (a known radiosensitizer by direct and abscopal effects) to concurrent radiation in the adjuvant setting after resection of pancreatic adenocarcinoma. PATIENTS AND METHODS: We conducted a retrospective study of 63 patients diagnosed from 2004-2013 with histopathologically-confirmed stage I/II pancreatic cancer treated with a surgical resection followed by adjuvant concurrent chemoradiation to at least 45 Gy using 3D planning and capecitabine at 1,600 mg/m(2)/day (Monday-Friday) for 6 weeks. This was combined with either 4 months of gemcitabine at 1,000 mg/m(2) weekly for 3 out of 4 weeks or capecitabine at 2,000 mg/m(2) for 14 days every 3 weeks for a total of 4 months. RESULTS: The majority of patients were over 65 years old (71%), male (60%), had negative surgical margins (79%), had pancreatic head or neck involvement (71%), Eastern Cooperative Oncology Group performance score of 1 (71%), and a cancer antigen 19-9 in the range of 11-100 U/ml at the time of diagnosis (51%). Of the 63 patients reviewed, 61 patients (97%) completed concurrent chemoradiotherapy. Treatment was halted in one patient due to gastritis and a second for gastrointestinal bleeding. Otherwise, adverse reactions during concurrent chemoradiotherapy were well-tolerated and the majority were Common Terminology Criteria for Adverse Events grades 1 and 2. Grade 3 toxicity was anorexia (n=2) and hand and foot syndrome (n=2) and GI bleeding (n=1). The only grade 4 toxicities were anorexia (n=1) and fatigue (n=1). The median follow-up of patients at the time of analysis was 36 months. The median survival of the entire cohort was 23.5 (range=8.5-42) months. The 1-, 2- and 3-year survival rates were 80%, 35% and 25%, respectively. CONCLUSION: Concurrent chemoradiation using capecitabine as a radiosensitizer in the adjuvant setting for pancreatic cancer was completed by the vast majority of patients in this series. Treatment was relatively well-tolerated, and its efficacy seems comparable to that for historical controls. This study probably represents the largest yet reported using capecitabine in this setting. Future studies including an increased sample size are required.

Anti-EGFR-mediated radiosensitization as a result of augmented EGFR expression.

PURPOSE: Elevated epidermal growth factor receptor (EGFR) expression has correlated with a poor prognosis after standard treatment of several malignancies. However, it is not clear whether the absolute level of EGFR expression affects the radiosensitizing properties of anti-EGFR treatments. A better understanding of this question would be helpful for the design of protocols that deliver these treatments. To explore this question, cells (LS174T) that did not display inherent anti-EGFR treatment-induced radiosensitization were selected for studies that could potentially enhance EGFR expression. MATERIALS AND METHODS: Human colon carcinoma cells (LS174T), which did not show radiosensitization by anti-EGFR treatments, were employed for these studies. (Also, these cells were not responsive to the antiproliferative effects of anti-EGFR treatment.) Using standard transfection techniques (eukaryotic expression vector) as well as an adenoviral construct to enhance EGFR expression, LS174T cells were transduced in a manner that resulted in enhanced expression of EGFR. Subsequently, standard proliferation studies were performed to test the radiosensitizing properties of anti-EGFR treatment (an anti-EGFR monoclonal antibody: IMC-C225). RESULTS: Studies were undertaken to stably transfect LS174T cells with EGFR. The stable transfectants, LS174T.EGFR cells, were responsive to the antiproliferative effects of anti-EGFR treatment, in contrast to the parent LS174T cells. Similar results were demonstrated when the cells were infected with AdEGFR. Additionally, the LS174T.EGFR cells were responsive to the radiosensitizing properties of anti-EGFR treatment (IMC-C225), whereas the parent cells were not. CONCLUSIONS: Although the level of EGFR expression is of prognostic significance in many tumor models, the response of cells to anti-EGFR treatment alone, or combinations of this treatment with radiation or chemotherapy, depends upon many factors that are not necessarily related to the inherent EGFR expression of the tumor cells. However, the studies reported herein, demonstrate that when LS174T cells were transduced to show increased EGFR expression, they became responsive to the radiosensitizing properties of anti-EGFR treatments.

Variation of neck position with image-guided radiotherapy for head and neck cancer.

PURPOSE: An understanding of the setup variation of the low neck in relation to the upper neck is necessary to define appropriate planning margins, while treating the full neck with intensity-modulated radiotherapy (IMRT) technique. MATERIALS AND METHODS: The setup of 20 sequential head and neck cancer patients was studied. Daily position verification was performed with a computed tomography (CT) on rails. An upper neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which both styloid processes are visible. A low neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which the thyroid gland was visible bilaterally. This procedure was carried out on the planning CT and on each daily treatment CT. The variation of the low neck was analyzed, assuming perfect alignment of the upper neck anatomy. RESULTS: Daily treatment CT of upper neck anterior cervical spine points were normalized to the planning CT. Relative to this coordinate system, the low neck cervical spine point was displaced an average of 3.08 mm anteriorly, ±0.17 mm. There was no systematic lateral or craniocaudal displacement. Random setup errors resulted in low neck standard deviations of 3.9 mm (anteroposterior), 3.3 mm (lateral), and 2.6 mm (craniocaudal). CONCLUSIONS: Position variation in the low neck varied in excess of the planning margins. There was a systematic anterior displacement. Random setup error was greater than expected. The results suggest that the neck volumes located distant from the region of fusion should be drawn with larger planning margins.

ACR Appropriateness Criteria: local excision in early-stage rectal cancer.

Low anterior resection or abdominoperineal resection is considered standard treatment for early rectal cancer. These procedures, however, carry a risk of morbidity and mortality that may not be warranted for early distal lesions, which may be treated with local excision. Emerging data has investigated the efficacy of local excision in patients with early stage rectal cancers. An expert panel designated by the American College of Radiology has reviewed supporting data, from a few prospective multi-institutional trials and a number of single-institution, retrospective reviews. The consensus recognizes the importance of accurate staging to identify patients who may be candidates for a local excision approach. Optimal candidates for local excision alone include small, low-lying T1 tumors, without adverse pathologic features. A number of procedures may be safely used including transanal, posterior trans-sphincteric, posterior proctotomy, transanal excision, or transanal microsurgery. It is important to note that none of these include lymph node evaluation, and depending on the risk of lymph node metastases, adjuvant radiation with or without chemotherapy may be warranted. Patients with positive margins or T3 lesions are at high risk of local recurrence and should be offered immediate APR or LAR. However, patients with high-risk T1 tumors, T2 tumors, or those who are not amenable to more radical surgery may benefit from adjuvant treatment. Data have also reported excellent local control rates for neoadjuvant radiation +/- chemotherapy followed by local excision in higher risk patients, but it is not yet clear if this approach reduces recurrence rates over surgery alone.

Multidisciplinary treatment of resectable rectal cancer.

This review identifies evidence that influences current practices in the multidisciplinary treatment and shapes future directions in the treatment of resectable rectal cancer. Recent advances in surgery, radiotherapy and systemic chemotherapy have provided measurable improvements in disease control, functional outcomes and quality of life for patients with rectal cancer. However, controversies remain regarding the optimum delivery of adjuvant therapies. Preoperative radiation either with or without concurrent chemotherapy demonstrates lower recurrence, with minimal survival benefit. Currently, the use of neoadjuvant standard fractionation chemoradiation versus short-course radiation without chemotherapy is controversial and under investigation. New combinations of chemotherapeutic agents and targeted therapies are also being evaluated. In addition, criteria for patient selection are being re-evaluated to determine the relative benefit of modern treatments, so that we may better tailor adjuvant therapy recommendations to be patient-specific. Recommendations for adjuvant treatments of rectal cancer are continuing to evolve; however, survival has been only marginally affected despite low incidence of local recurrence. Future trials should aim to address the role of adjuvant therapies utilizing new criteria, such as function, quality of life and impact on development of metastatic disease.

Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and concurrent 5-fluorouracil, cisplatin and radiotherapy for patients with esophageal cancer: a phase I study.

This phase I trial investigates the safety of combining radiation, 5-fluorouracil (5-FU) and cisplatin with the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, in patients with esophageal carcinoma. From April 2000 to January 2005, 11 patients with squamous or adenocarcinoma of the esophagus were enrolled. Patients received either 50, 100 or 150 mg oral erlotinib/day beginning on the first day of radiation (three patients in each dose cohort). Concurrent cisplatin (75 mg/m2 i.v., days 8 and 36) and 5-FU (1000 mg/m2 i.v., days 8-11 and 36-39) were also given with 50.4 Gy thoracic radiation, delivered at 180 cGy/day, 5 days/week. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria (version 3.0). Erlotinib with concurrent 5-FU, cisplatin and thoracic radiation was well-tolerated at 50, 100 and 150 mg/day. The major toxicities were diarrhea (grade 1=18%, grade 2=18%), skin rash (grade 4=54.5%), nausea (grade 1=18%, grade 2=54%, grade 3=9%) and dehydration (grade 3=27%). All patients experienced esophagitis during treatment (grade 1=55%, grade 2=32%, grade 3=9%, grade 4=9%). Two patients were discontinued from the study secondary to non-erlotinib-related toxicities. We conclude that the phase I study demonstrates the safety and tolerability of erlotinib delivered at 150 mg/day with concurrent 5-FU, cisplatin and thoracic radiation. The major toxicities encountered were grade 1-2 diarrhea, grade 1 skin rash, grade 1-3 nausea and grade 3 dehydration. A phase II study is planned.

Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPSs) are rare tumors with poor survival rates due to difficult resectability and high local and distant recurrence rates. Preoperative radiation therapy appears to have dosimetric advantages to utilize the tumor as a tissue expander to limit exposure of small bowel to higher radiation doses. METHODS: Between June 1999 and December 2003, 16 consecutive patients with biopsy-proven RPS were treated with preoperative radiation with selective dose escalation. This included 45 grays (Gy) in 25 fractions to the entire tumor plus margin and a boost dose of 57.5 Gy to the volume predicted as high risk for positive surgical margins. Treatment toxicity and local control were evaluated prospectively as primary endpoints. The secondary goal was the theoretical calculation of future dose escalation and feasibility. Each patient underwent laparotomy. Tumor response was judged using computed tomography (CT) scan and by necrosis on final pathology. Theoretical treatment plans evaluated the potential for additional radiation dose escalation. RESULTS: All patients completed the radiation protocol. The most common acute side effects were nausea/vomiting, which affected 4 patients (25%), with only 1 patient requiring inpatient intravenous hydration. There was no severe late postoperative morbidity or mortality. Twelve tumors (75%) decreased in maximum dimension, with a median decrease of 9.4%. Fourteen of 16 patients (88%) underwent complete macroscopic resection. With a median follow-up of 28 months (range, 7-52 months), there were only 2 local recurrences. The actuarial 2-year local control rate was 80%. Theoretical treatment plans suggest that significant dose escalation (up to 80 Gy) may be possible. CONCLUSIONS: Preoperative radiation therapy with selective dose escalation to the margin at risk is tolerable and allows higher radiation dose to the volume judged to be at greatest risk for local tumor recurrence.

Molecular targets as therapeutic strategies in the management of breast cancer.

Although the molecular and genetic determinants of most sporadic breast cancers remain unknown, increasing understanding of molecular and genetic events affecting breast carcinogenesis has provided information about the potential roles of specific biomarkers in tumour development and spread. It is now recognised that mutations of some tumour suppressor genes appear to play important early roles in the formation of some breast cancers. In addition, alterations in proto-oncogenes may contribute to the development of some breast cancers. The study of breast tumour biology at the molecular level has led to the development of targeted drug design, which provides a variety of agents targeted at specific molecules for the prevention, diagnosis and treatment of breast cancer. This review will describe the recognised molecular targets in breast cancer.