Richard L. Scher

Bio: Richard L. Scher is an academic researcher from Duke University. The author has contributed to research in topics: Zenker's diverticulum & Head and neck cancer. The author has an hindex of 25, co-authored 60 publications receiving 4242 citations. Previous affiliations of Richard L. Scher include University of Virginia & Durham University.

Hyperfractionated Irradiation with or without Concurrent Chemotherapy for Locally Advanced Head and Neck Cancer

Abstract: Background Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. Methods Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. Results Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disea...

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck

Abstract: Purpose: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evalaute the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of th ehead and neck (SCCHN). Methods and Materials: Pretreatment tumor pO2 was assessed polagographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measureemnt taken from locally advanced primaries (T3 or T4) or neck nodes ≥ 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66–70 Gy) or twice daily irradiation 91.25 Gy B.I.D. to 70–75 Gy) +/- planned neck dissection (for ≥N2A disease) according to institutiional treatment protocols. Results: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4–60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tmor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.07). Conclusion: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relatiosnhip between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.

Abstract: Purpose: Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer. Methods and Materials: At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The twodimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (mmol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint. Results: Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n 5 25). Other sites included oropharynx (n 5 5), hypopharynx (n 5 3), and oral cavity (n 5 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 mmol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries ( <0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 mmol/g vs. 4.8 mmol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage. Discussion: Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes. © 2001 Elsevier Science Inc.

Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer

Abstract: Purpose Neck dissection has traditionally played an important role in the treatment of patients with squamous cell carcinoma of the head and neck who present with regionally advanced neck disease (N2-N3). Radiotherapy and concurrent chemotherapy improves overall survival in advanced head-and-neck cancer compared with radiotherapy alone. The necessity for postchemoradiation neck dissection is controversial. The intent of this report was to define the value of neck dissection in this patient population better. Methods and materials Patients with locally advanced squamous carcinoma of the head and neck who also presented with nodal disease and underwent hyperfractionated radiotherapy and concurrent cisplatin/5-fluorouracil chemotherapy constituted the study population. Adjuvant modified neck dissection (MND) was planned 6 to 8 weeks after completion of chemoradiation in those patients who had a biopsy-proven pathologically complete response at the primary tumor site, irrespective of the clinical/radiographic neck response. A cohort of patients underwent electrode assessment of tumor oxygenation. Pathologic findings from the MND were used to compute the negative and positive predictive values and overall accuracy of the clinical/radiographic response (cCR). Regional control, failure-free survival, and survival were compared according to whether patients actually underwent MND. Results A total of 154 patients received concurrent chemoradiation. Of these, 108 presented with nodal disease: N1, n = 30; and N2-N3, n = 78. MND was performed in 65 (60%) of 108 patients, including 13 (43%) of 30 with Stage N1 and 52 (66%) of 78 with Stage N2-N3. For N1 patients, the negative predictive value of a cCR, positive predictive value of less than a cCR, and the overall accuracy for clinical response was 92%, 100%, and 92%, respectively. For N2-N3 patients, the corresponding values were 74%, 44%, and 60%. Patients with poorly oxygenated tumors were more likely to have residual disease at MND. The median follow-up was 4 years. The 4-year disease-free survival rate was 70% for N1 patients, irrespective of the clinical response or whether MND was performed. The 4-year disease-free survival rate was 75% for N2-N3 patients who had a cCR and underwent MND vs. 53% for patients who had a cCR but did not undergo MND ( p = 0.08). The 4-year overall survival rate was 77% vs. 50% for these two groups of patients ( p = 0.04). Conclusion The clinical and pathologic responses in the neck correlated poorly with one another for patients with N2-N3 neck disease undergoing concurrent chemoradiation for advanced head-and-neck cancer. MND still appears to confer a disease-free survival and overall survival advantage with acceptably low morbidity. Tumor oxygenation assessment may be useful in selecting patients who are especially prone to have residual disease. Better tools need to be developed to determine prospectively whether this procedure is required for individual patients.

Endoscopic staple diverticulostomy for Zenker's diverticulum: review of literature and experience in 159 consecutive cases.

Abstract: Objectives/Hypothesis: Several reports since the early 1990s have advocated a minimally invasive technique, endoscopic staple diverticulostomy (ESD), to treat Zenker's diverticulum. However, long-term results and comparisons with the reported experience with external or other endoscopic approaches have been lacking in the literature. We present follow-up on our experience with ESD since 1995 and compare it with the results obtained by other endoscopic or external techniques for treatment of Zenker's diverticulum. Study Design: Retrospective review of 159 consecutive ESD procedures performed on 150 unique patients with Zenker's diverticulum between March 1995 and August 2002. Telephone interviews of patients were conducted to assess long-term treatment outcome. Review of the literature was performed by Ovid MEDLINE search for all reports on the surgical treatment of Zenker's diverticulum in the English language between January 1990 and August 2002. Methods: Data were retrospectively reviewed and information was tabulated for age, sex, size of diverticulum, symptoms, duration of symptoms, operative time, length of hospital stay, time before oral intake, complications, and relief of symptoms at first postoperative visit. Follow-up interviews of patients were conducted to assess current status of symptoms and, if any symptoms returned, how many months after the procedure they recurred. All case series in the literature in the English language since 1990 that were found in the Ovid MEDLINE database and referenced from identified articles were also tabulated for the same information. Results: At the time of initial follow-up after ESD, 98% of patients reported complete or improved symptoms. Average hospital stay was 0.76 days, with a diet started on postoperative day 0.25. There was a 2.0% significant complication rate without mortality. Further follow-up (average, 32.2 mo) identified a recurrence rate of 11.8%. On review of the literature, patients who underwent ESD had shorter perioperative courses, quicker return to diet, and lower complication and mortality rates compared with external procedures. ESD had comparable operative times and mortality rates, but fewer complications and more rapid convalescent times compared with other endoscopic procedures. Recurrence rates were found to be variable. Conclusions: Overall, ESD is an outpatient procedure with few complications. The technique has a faster operative and convalescence period with fewer complication rates compared with other endoscopic or external transcervical approaches. The results in the present study and those reported in the English language literature advocate that ESD be the initial preferred treatment for Zenker's diverticulum.

Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck

Abstract: BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

Why do cancers have high aerobic glycolysis

Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.

Abstract: After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment. conclusions Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.

Postoperative Irradiation With or Without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer

Abstract: background We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. methods After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1 ⁄ 2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. results After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan–Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan–Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. conclusions Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Abstract: Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.