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Closed Protocol Summaries: 9003
Title: A Phase III Randomized Study to Compare Twice Daily Hyperfractionation, Accelerated Hyperfractionation with a Split and Accelerated Fractionation with Concomitant Boost, to Standard Fractionation Radiotherapy for Squamous Cell Carcinomas of the Head and Neck Patient Population: Patients at least 18 years of age, KPS >60, with histologically proven squamous cell carcinoma or lymphoepithelioma arising in the oral cavity, oropharynx, larynx or hypopharynx, AJC Stage III or IV (Stage II base of tongue) but M0. Patients are to have had no prior radiotherapy, chemotherapy or surgery (other than biopsy). Objectives: To determine whether hyperfractionation and/or accelerated fractionation improves the local-regional control rate of advanced squamous cell carcinoma of the head and neck. Also, to evaluate the disease-free and overall survival rates associated with patients treated by each of the different fractionation schemes, and evaluate associated levels of acute and late treatment toxicities. Schema:
Reference: Ang KK, Berkey B, et al. Impact of Epidermal Growth Factor Receptor Expression on Survival and Pattern of Relapse in Patients with Advanced Head and Neck Carcinoma. Cancer Research, 62 7350-7356, 2002. A correlative study was performed to address the impact of epidermal growth factor receptor (EGFR) overexpression on survival and pattern of failure in patients with advanced head and neck squamous cell carcinomas (HNSCCs) enrolled in a Phase III trial and randomized to receive conventional radiotherapy. The study population comprised 155 of 268 (58%) randomized patients with sufficient pretreatment biopsy specimens for immunohistochemical assay. The specimens were dewaxed and incubated after standard preparation with mouse monoclonal antibodies recognizing the extracellular domain of the EGFR molecule. The catalyzed product was visualized with 3,3'-diaminobenzidine Chromogen Kit and lightly counterstained with Mayer's hematoxylin. Quantitative EGFR immunohistochemistry (IHC) was done with SAMBA 4000 Cell Image Analysis System, without knowledge of the clinical outcome, to yield mean absorbance (MOD), staining index (SI), and quick score (QS). These EGFR IHC parameters were correlated with the T stage, N stage, combined stage grouping, and recursive partitioning analysis classes. Subsequently, the EGFR parameters were correlated with the outcome end points, i.e., overall survival (OS), disease-free survival (DFS), local-regional (LR) relapse, and distant metastasis rates. We found that HNSCCs exhibited a wide variation in EGFR expression (MOD, 0.2-66.0; SI, 0.3-97.0; QS, 0.01-69.9) with a relatively strong but nonlinear correlation between MOD and SI (r = 0.79). There was no correlation between EGFR expression and T stage, N stage, stage grouping, and recursive partitioning analysis classes (r = -0.07 to 0.17). The OS and DFS rates of patients with high EGFR-expressing HNSCCs (>median MOD) were highly significantly lower (P = 0.0006 and P = 0.0016, respectively) and the LR relapse rate was highly significantly higher (P = 0.0031) compared with those of patients with low EGFR-expressing HNSCCs. However, there was no difference in the distant metastasis rate between the two groups (P = 0.96). Significant correlations, although somewhat less robust than MOD, were also observed between SI and QS and the OS, DFS, and LR relapse rates. Multivariate analysis showed that EGFR expression was an independent determinant of survival and a robust independent predictor of LR relapse. In summary, this correlative study in a large series of patients revealed that EGFR expression, which varied considerably among HNSCCs, was a strong independent prognostic indicator for OS and DFS and a robust predictor for LR relapse but not for distant metastasis. The data suggest that EGFR IHC should be considered for selecting patients for more aggressive combined therapies or enrollment into trials targeting EGFR signaling pathways. Reference: Ang KK, Berkey B, et al. Impact of Epidermal Growth Factor Receptor Expression on Survival and Pattern of Relapse in Patients with Advanced Head and Neck Carcinoma. NCI-EORTC Meeting, Washington, DC, Int'l J Bio Markers, [17] (S2) pg. S16-S17, Abs. 2002. Objective: A correlative study was undertaken to assess the impact of epidermal growth factor receptor (EGFR) overexpression on survival of and pattern of failure in patients with stage III-IV head and neck carcinomas (HNC) enrolled into a phase III trial and randomized to receive the standard therapy. Material and Methods: The study population comprised of 155 of 268 patients in whom sufficient pretreatment tumor biopsy specimens were available for immunohistochemical assay (IHC). The paraffin-embedded samples were dewaxed, incubated after standard preparation with mouse monoclonal antibodies that react to the peptide backbone of the extracellular domain of the EGFR molecule and peroxidase. The catalyzed product was visualized with DAB Chromogen Kit and lightly counterstained with Mayer's Hematoxylin. Quantitative EGFR-IHC was done with SAMBA 4000 Cell Image Analysis System, without knowledge of the clinical outcome, to yield mean optical density (MOD), staining index (SI), and quick score (QS). These EGFR-IHC parameters were correlated with the American Joint Committee on Cancer (AJCC) T-stage, N-stage, combined stage grouping, and the previously introduced Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) classes. Subsequently, the EGFR parameters were correlated with the treatment outcome endpoints, i.e., overall survival (OS), disease-free survival (DFS), local-regional (LR) relapse, and distant metastasis rates. Results: There was no difference between patient groups with and without sufficient tumor specimens in the distribution of established prognostic determinants such as T-stage, N-stage, combined stage grouping, KPS and age, and in the therapy outcome. The data revealed that HNC exhibited a wide variation in EGFR expression (MOD: 0.2-66.0, SI: 0.3-97.0, and QS: 0.01-69.9) with a relatively strong correlation between MOD and SI (r: 0.79). There was no correlation between EGFR expression and T-stage, N-stage, combined stage grouping, and RTOG-RPA classes (r: 0.07-0.17). The OS and DFS rates of patients with high EGFR expressing carcinomas (> median MOD) were highly significantly lower (p=0.0006 and p=0.0016, respectively) and the LR relapse rate was highly significantly higher (p=0.0031) than those of patients with lower EGFR expressing HNSCC. However, there was no difference in the distant metastasis rates between the two groups (p=0.96). Significant correlations, though less robust than MOD, were also observed between SI and QS and the overall survival, disease-free survival, LR relapse rates. Multivariate analysis showed that EGFR expression was an independent determinant of survival and a robust independent predictor of LR relapse. Conclusion: This correlative study in a large series of patients revealed that EGFR expression, which varied considerably among HNC, was a strong independent prognostic indicator for overall and disease-free survival and a robust predictor for LR relapse but not for distant metastasis. The data suggest that it is prudent to select patients based on EGFR-IHC for enrollment into trials targeting EGFR signaling pathways. Reference: Eldridge B, Rabinovitch R, Berkey B, et al. The Impact Of Baseline Nutritional Support On Treatment Outcome In Patients With Locally Advanced Squamous Cell Cancer Of The Head And Neck Treated With Definitive Radiotherapy: Report Of The Radiation Therapy Oncology Group (RTOG) Trial 90-03. Proc Am Soc Thera Rad Oncol (ASTRO), New Orleans, LA, Int J Radiat Oncol Biol Phys, [54] (2) pg. 115, Abs. #194, 2002. Purpose/Objective: This analysis was performed to determine whether nutritional support affects treatment related toxicity, local-regional control and overall survival in patients treated with definitive radiotherapy alone for locally advanced squamous cell cancer of the head and neck (HNSCC). Materials/Methods: Data was evaluated on the 1073 patients treated on RTOG 90-03, a randomized trial comparing 4 definitive radiotherapy (RT) fractionation schemes for locally advanced cancer HNSCC (standard fractionation, hyperfractionation, accelerated hyperfractionation with planned split, and accelerated fractionation with concomitant boost). Information retrieved from the database included pretreatment patient characteristics (primary tumor site, weight loss 6 months prior treatment, T, N, and AJCC stage), specific nutrition support (including oral nutrition supplementation and tube feeding use at baseline, during treatment, and 3- and 6-months following treatment), and incidence and severity of dysphagia and KPS (baseline, during treatment, 3- and 6-months follow-up), and incidence and severity of mucositis (during treatment, 3- and 6-months follow-up). Uni- and multivariate analyses were performed to determine if these factors were significantly correlated with treatment outcome. Results: Prior to initiation of RT, 293 patients (27%) were receiving baseline nutritional support (BSN) of some kind (50%-oral supplements alone, 27%-supplementation via tube feeding, and 23%-various combinations of oral+/or tube+/or IV supplementation). During treatment, nearly all patients (86%) required nutritional support. Patients receiving BNS had significantly poorer distributions of KPS, T, N, and overall AJCC stages (all p<0.0001) compared to those patients who did not. BNS patients had significantly increased weight loss in the six months prior to RT than those who did not receive BNS (means of 8kg and 3kg, respectively). Patients with moderate-severe dysphagia at baseline were more likely to require BSN (p<0.0001). Patients with moderate-severe dysphagia at baseline that did not receive BSN were more likely to require nutritional support during treatment (p=0.015) than those who had no-mild dysphagia at study entry, regardless of whether they received standard or altered fractionation. However, dose delivered and overall elapsed days of treatment were not significantly different for BNS patients than others. Patients receiving BNS had a trend toward less Grade 3-4 mucositis (p=0.057) after completion of treatment (adjusting for baseline dysphagia and standard versus altered fractionation). However, patients receiving BNS had a significantly increased actuarial rate of local-regional failure (71% vs. 44%, p<0.0001) and a significantly decreased actuarial rate of overall survivial (16% vs. 39%, p<0.0001) compared to all other patients at 5 years post-randomization. A multivariate analysis demonstrated that T stage, N stage, KPS, weight loss, and BNS were all significant independent predictors of local-regional control and overall survival. Conclusions: Patients with locally advanced HNSCC who receive BNS, despite their associated poorer KPS and increased pre-treatment weight loss, are just as likely to complete a full course of definitive radiotherapy in the prescribed time frame. Patients with BNS have inferior rates of local-regional control and overall survival that is independent of their greatly advanced stage. Further research will be beneficial in identifying the cause of the poorer prognosis for this population, which will lead to improved design and analysis of clinical trials. Conclusions: Laryngectomy following organ preservation treatment is associated with acceptable morbidity. Perioperative mortality is low but up to one third of patients will develop a pharyngocutaneous fistula. Local-regional control is excellent for this group of patients. Survival following salvage TL was not influenced by the initial organ preservation treatment. Reference: Konski A, Berkey B, et al. The Effect of Education Level on Outcome of Patients Treated on Radiation Therapy Oncology Group (RTOG) Protocol 90-03. J Clin Oncol 21: 249a, 2002. Purpose: It has been hypothesized people in lower socioeconomic groups have worse outcomes because they present with more advanced stage cancers or receive inferior treatment. We investigate this hypothesis by using education level as a proxy for income level in patients treated on RTOG protocol 90-03. Methods: RTOG 90-03 was a phase III randomized trial investigating 4 different radiation fractionation schedules in the treatment of locally advanced head and neck cancers. Overall survival and local-regional control rates were analyzed by education level as measured by patient response on the demographic form at study entry. Education level is separated into the following categories: no answer, no school, grade 1-8, some high school, high school graduate/GED, and college/technical. Results: No significant difference existed in the distribution of patients by education level when analyzed by tumor stage, nodal status or primary site. A significant difference was noted in the distribution of patients by education level between the standard fractionated radiation treatment arm and the hyperfractionated radiation treatment arm (p=0.018). No statistical difference was noted in median treatment days or median radiation dose in all four treatment groups when separated by education level. Patients attending college had highly significantly better overall survival and local-regional control outcome than the other groups combined (p=0.0030 and p=0.0052 respectively: from Cox proportional hazards model with educational level, assigned treatment, t-stage, n-stage, KPS, and primary site). Conclusion: Patients attending college or technical school had improved overall survival and local-regional control than those who did not. These differences cannot be explained by differences in tumor stage or treatment. Other possible factors such as poorer overall health or lack of support systems contributing to these results need to be further investigated. Reference: Calvin D, et al. Microvessel Density (MVD) > 60 Does Not Predict for Outcome in Advanced Head And Neck Squamous Cell Carcinoma (HNSCC): Results of A Prospective Study From the RTOG 90-03 Trial. Int J Radiat Oncol Biol Phys 51:41, 2001. Purpose: Tumor vascularity has been associated with increased risks of locoregional failure (LRF), distant metastasis (DM), and poor survival (Sv) in numerous disease sites. This correlative study was designed to assess whether MVD, an immunohistochemical marker for tumor vascularity, predicts for radiotherapy outcome in locally advanced HNSCC patients. Materials and Methods: From September, 1991 until August, 1997, 1,073 patients with locally advanced HNSCC were enrolled onto the RTOG 90-03 trial, a phase III four-arm study comparing hyperfractionation, split-course and concomitant boost accelerated fractionation to standard fractionation radiotherapy (Int J Rad Onc Biol Phys 48:7-16, 2000). Pretreatment paraffin-embedded biopsy specimens were available for MVD analysis in 459 of these patients. Nine patients were deemed ineligible or missing supporting data. 434 (96%) patients were diagnosed with Stage III or IV disease. Disease sites included 49 (11%) oral cavity, 262 (58%) oropharynx, 60 (13%) hypopharynx and 79 (18%) supraglottic larynx patients. Factor VIIIRA monoclonal antibody was used for MVD staining by an immunoperoxidase method. Sections were scanned at high power (200X). The mean number of stained MV profiles from three 400X fields of the tumor specimen containing the highest vessel density (hot spot) was recorded as the MVD. A prestudy MVD of >60 was used as the threshold for high MVD, based on previously published studies. Specimens were analyzed for MVD by a single author (MEH) in a blinded fashion, negating for interobserver variability. Univariate comparisons of disease-free Sv (DFS) and overall Sv (OAS) were done using the Kaplan-Meier method with analysis of differences performed by the log-rank test. Time to locoregional failure (TTLRF) and distant metastasis (TTDM) were analyzed using the method of cumulative incidence employing the Gray's test. Multivariate analysis (MVA) was performed using the Cox proportional hazards model. Results: The median follow-up for enrolled patients with MVD assessment was 22.0 months for all analyzable and 59.5 months for living patients. There were no statistically significant differences in pretreatment characteristics between patients evaluated for MVD and not evaluated for MVD when analyzed for treatment arm, gender, race, age, disease site, performance status, T or N stage, AJCC stage grouping or histology. Also, there were no outcome differences between these two groups when evaluated for TTLRF (p=0.80), TTDM (p=0.67), DFS (p=0.15) and OAS (p=0.11). Reference: Fisher J, et al. Treatment, Patient and Tumor Characteristics Impact Quality of Life (QOL) In Patients With Locally Advanced Head and Neck Cancer: Report of The Radiation Therapy Oncology Group (RTOG) Trial 90-03. Int J Radiat Oncol Biol Phys 51:98, 2001. Purpose: To determine factors that effect QOL in patients with locally advanced squamous cell cancer of the head and neck randomized to standard fractionation radiotherapy (SFX), hyperfractionation (HFX), Accelerated Fractionation with Split (AFX-S) and Accelerated Fractionation with Concomitant Boost (AFX-C). Materials and Methods: RTOG 90-03 used the Head and Neck Performance Status Scale (HNPSS) and the Functional Assessment of Cancer Therapy (FACT-H&N), version 2 to assess QOL. The HNPSS has three components Normalcy of Diet, Eating in Public, and Understandability of Speech. The FACT-H&N has two components: a global QOL questionnaire (FACT-G) consisting of 4 domains; Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and an additional H&N specific questionnaire (AC). Between 3/92 and 8/97, 1113 pts. were randomized; 718 completed a pretreatment FACT-H&N. Pts. completed the HNPSS & FACT-H&N; pretreatment, 4 weeks post-RT, every 3 months for 1year. Results: Prior to the start of radiotherapy (RT) 48% of pts had normal diets, 64% had normal public eating, and 77% had normal speech. Age (<60 vs. > 60), KPS, tumor site (oral cavity vs. other), T-stage (T3+T4 vs. T1+T2+TX), N-stage (N0 vs. other), Race (Non-White vs. White), and marital status (single vs. married), FACT-G, PWB, EWB, FWB, AC, use of oral nutrient supplements, feeding tube, and parenteral nutrition predicted for pretreatment diet, public eating, and speech. During the acute toxicity phase diet, eating, and speech were related to the intensity of RT (HFX or AFX-C), marital status (single), tumor site (oral cavity), use of oral nutrient supplements, and feeding tube. At one-year oral cavity tumors, AFX-C, oral nutrient supplements, feeding tube, and single patients had worse diet, eating, and speech. Conclusion: Pretreatment patient and tumor characteristics impact on QOL prior to the initiation of therapy. Intensification of radiotherapy, marital status, tumor site, and nutritional support all effect QOL during the first year post therapy. These data suggest that interventions prior to the start of therapy may improve QOL in long-term survivors. MVD values ranged from 5-80 (median value of 30). Only 37/450 (8%) patients possessed an MVD > 60. There were no outcome differences for all patients with MVD < 60 and >60 for TTLRF (p=0.86), TTDM (p=0.67), DFS (p=0.70) and OAS (p=0.44). Similar outcome results were seen when analyzed for each of the four head and neck disease sites or for Stage III or Stage IV disease. On MVA, KPS, disease site and N-stage, but not MVD, were independent prognostic factors for TTLRF, DFS and OAS. Conclusions: In this large, prospective study, a MVD >60 did not predict for radiotherapy outcome in advanced HNSCC patients. This contrasts with nasopharyngeal carcinoma reports where MVD is highly predictive of outcome. Further analysis of the data will be presented in detail with findings supporting the design of future clinical trials. Reference: Konski A, et al. Cost-Utility Analysis of RTOG 90-03: Phase III Randomized Study Comparing Altered Fractionation To Standard Fractionation Radiotherapy For Locally Advanced Head And Neck Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys 51:48, 2001. Purpose: To determine the cost-effectiveness using cost-utility analysis of four treatment regimens for locally advanced head and neck cancers. Materials and Methods: Quality adjusted survival was calculated for patients randomized to RTOG 90-03 by Q-TWiST methodology. Determination of toxicity threshold was made by two of the co-authors (AK & CS). Patients were deemed to be in a toxicity state when the recorded toxicity was skin (> grade 2), mucositis (> grade 2), salivary gland (> grade 2), esophageal (> grade 2), larynx (> grade 2), upper GI (> grade 2), spinal cord (> grade 2), bone (> grade 3), joint (> grade 3). Time in toxicity was measured from onset of toxicity to time below toxicity threshold. Patients showing a complete response were considered in relapse at the time of recurrence. Cost were obtained and modeled as previously described by Owen et al.1 The cost-utility analysis was performed comparing the three experimental fractionation schedules to the standard fractionation. Results are reported in $/Quality Adjusted Life Year (QALY). Results: Cost-utility analysis of the entire population assuming a utility of 1 for time spent in toxicity and relapse found accelerated fractionated radiotherapy with concomitant boost the most cost-effective regimen using actual cost data with $14,155.5/QALY. Sensitivity analysis using a utility of .1 for time spent in toxicity, i.e. patients would not like to have any toxicity, found the standard fractionation arm dominated all treatment arms. When the analysis is performed by gender and a utility of .6 was assumed for toxicity, hyperfractionated radiotherapy was the most cost-effective for males while accelerated hyperfractionated radiotherapy with split was the most cost-effective in females. When a utility of 1 was assumed for toxicity, accelerated fractionated radiotherapy with concomitant boost was the most cost-effective in males with the results unchanged in females. Cost-effectiveness acceptability curves will be presented. Conclusions: This analysis finds accelerated fractionated radiotherapy to be the most cost-effective treatment regimen for patients with locally advanced head and neck cancer. The results differ between gender because of the time spent in toxicity and in relapse. The results will differ based on the utility patient's place on time spent in toxicity and relapse. Patients placing a higher utility on any survival will favor the more aggressive regimens. Conversely, patients placing a low utility on time spent in toxicity and relapse and thus not wanting to spend time in these health states, would have lower QALY's and thus treatment which is less cost-effective than standard therapy.
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