Faculty Publications

Given high rates of smoking among cancer patients, smoking cessation treatment is crucial; yet limited data exist to guide integration of such trials into the oncologic context. In order to determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Out of 14,514 screened patients, 263 (< 2%) were eligible; 43 (16%) refused enrollment. Among the eligible patients, 220 (84%) enrolled. Enrollment barriers included smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (> 30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about seven alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. About 52 (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant's depressive symptoms is critical for promoting cessation.

Given high rates of smoking among cancer patients, smoking cessation treatment is crucial; yet limited data exist to guide integration of such trials into the oncologic context. In order to determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Out of 14,514 screened patients, 263 (<2%) were eligible; 43 (16%) refused enrollment. Among the eligible patients, 220 (84%) enrolled. Enrollment barriers included smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (>30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about seven alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. About 52 (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant's depressive symptoms is critical for promoting cessation.

Objectives: To compare the results of clinical and pathological staging for a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) and to examine patterns and ramifications of the disparity between staging methods. Design: Prospective inception cohort (median follow-up, 7 years). Setting: Multi-institutional cooperative group study (Eastern Cooperative Oncology Group 4393/Radiation Therapy Oncology Group 9614) involving 17 academic medical centers. Patients: A total of 560 patients with new-onset or recurrent HNSCC enrolled during a 7-year period. Interventions: Surgical resection with curative intent with or without adjuvant or previous radiotherapy or chemotherapy. Main Outcome Measures: Clinical staging and pathological staging and the component TN tumor categorieswere compared with overall and disease-specific Survival. Association of survival With staging was derived by means Of the proportional hazards model. Results: Of the 501 cases in which both clinical and pathological staging was available, a disparity was found between at least 1 component tumor category assigned by the 2 methods in almost 50% of cases. Both methods showed a strong association of stage with overall survival for the cohort at large. However, pathological nodal category was a superior predictor (P<.001 vs P=.005), whereas there was an advantage to pathological tumor category in predicting disease-specific survival (P=.01). Conclusions: Both staging methods are useful in predicting survival, whereas information gained at neck dissection regarding nodal metastases provides some refinement in prognostic results. These findings demonstrate the need for enhanced methods of tumor assessment and apparent benefit of data gathered at neck dissection for accurate disease assessment and stratification.

No method reliably detects residual low-volume nodal disease in a patient with a complete response (CR) to treatment. Control of the N0-1 neck is to be expectd after CR; no treatment is needed. Positron emission tomography (PET) may improve patient selection, but neck dissection should still be performed for patients with good performance status and residual masses. Neck dissection reduces the incidence of regional recurrence, although the impact on survival is small. Whether the risk of tumor recurrence or the morbidity of neck dissection should be of greater concern for patients with N2-3 disease in CR is a matter of individual judgment. Combined modality therapy will control most nodal metastases (even for patients with advanced nodal disease). Neck dissection in patients presenting with bulky nodal disease who achieve a CR after combined modality therapy will diminish the regional recurrence rate by about 15%. Nowadays, patients with N3 disease and CR often still have residual neck tumor. Node dissection is to be advised. Neck dissection should still be considered an important treatment modality for patients who undergo combined modality therapy with advanced nodal disease, even if they have achieved a CR.

Background The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospective clinical trial. Methods We prospectively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group (ECOG) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and standard fractionation radiation therapy. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis. The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age, ECOG performance status, stage, and other covariables was estimated by use of a multivariable Cox proportional hazards model. All sta! Results Genomic DNA of oncogenic HPV types 16, 33, or 35 was located within tumor cell nuclei of 40% (95% confidence interval [CI] = 30% to 50%) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR. Compared with patients with HPV-negative tumors, patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%, difference = 27%, 95% CI = 9.3% to 44.7%, P = .01) and after chemoradiation treatment (84% vs 57%, difference = 27%, 95% CI = 9.7% to 44.3%, P = .007). After a median follow-up of 39.1 months, patients with HPV-positive tumors had improved overall survival (2-year overall survival = 95% [ 95% CI = 87% to 100%] vs 62% [ 95% CI = 49% to 74%], difference = 33%, 95% CI = 18.6% to 47.4%, P = .005, log-rank test) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression (hazard ratio [HR] = 0.27, 95% CI = 0.10 to 0.75), and death from any cause (HR = 0.36, 95% CI! Conclusion For patients with HNSCC of the oropharynx, tumor HPV status is strongly associated with therapeutic response and survival.

BACKGROUND: We analyzed the variability and accuracy of sentinel lymph node (SLN) identification by lymphoscintigraphy performed preoperatively and repeated on the day of operation in patients with melanoma or Merkel cell cancer. METHODS: Twenty-five prospectively studied patients had lymphoscintigraphy prior to and on the day of operation. Discordance between lymphoscintograms was defined as change in location of SLN or failure to identify a SLN by one of the studies. RESULTS: In 22 of 24 assessable cases (92%), SLNs were excised. Preoperative lymphoscintigraphy was correct in 19 of 22 (86%) cases. Day of operation lymphoscintigraphy was correct in 20 of 22 (91%) cases. SLN location was as classically described in 24 of 25 (96%) cases. Discordance between lymphoscintigraphy studies was 32% (8/25 patients). Half with discordant migration (8%) yielded metastases in basins not identified by day of operation lymphoscintigraphy but demonstrated by preoperative lymphoscintigraphy. CONCLUSIONS: Head and neck lymphatic drainage patterns not only vary between patients but also can vary with time for a single patient.

Background We aimed to examine deficiencies in established methods of summarising adverse events, and to create a new reporting system (TAME) for summarising the toxicity burden of cancer treatment. TAME consolidates traditional adverse-event data into three risk domains: short-term (acute) Toxicity (T), Adverse long-term (late) effects (A), and Mortality risk (M) generated by a treatment programme (E=End results); and assigns treatments to risk classes for each risk domain. Methods We examined formally an established method for summarising adverse events (the max-grade method) in five trials of patients with head and neck cancer done between September, 1991, and August, 2000, by the Radiation Therapy Oncology Group (RTOG) that involved 13 treatment groups (2304 patients). We calculated TAME summary metrics that included time and multiplicity factors in the same patient groups. We compared relative T values with relative values for toxic effects from the max-grade approach. We also calculated the range of individual patient T scores in two groups from one of the trials (the laryngeal-preservation trial). Results The max-grade method systematically excluded 29-70% of total reported high-grade (grade 3-4) acute adverse events, contained progressive bias, and favoured higher toxicity programmes. Relative T values in the 13 treatment programmes tested showed an increase of almost 500% in acute toxicity burden (100-590) between treatment groups compared with a 170% increase (100-270) between treatment groups by use of the max-grade method. The difference between these two summary systems was statistically significant (mean difference -102 [95% CI -167 to -37], p=0.005, t test for paired differences). Four risk classes were designated for acute and relative late effects: low (100-140), moderate (150-390), high (400-490), and extreme (>= 500). The distribution of individual patient T scores showed that 82 (60%) patients who received concurrent platinum-radiotherapy for larynx preservation reported two or more high-grade events, and 34 (20%) reported four or more high-grade events; these findings differed significantly from the distribution of individual patient T scores for patients who received radiotherapy alone, in which 32 (19%) reported two or more high-grade events and 3 (3%) reported four or more high-grade events (p<0.0001). The max-grade method also systematically excluded 26-48% of high-grade (grade 3-4) late adverse events. However, less variation was noted in the relative risk of late events (100-270) by the TAME method for late effects. Interpretation Traditional methods for summarising adverse events systematically exclude important data, giving an inaccurate impression of the toxicity burden in complex multimodality trials. By contrast, T values use data on all high-grade adverse events. T values are proportional to the intensity of treatment, showing a 500% increase between treatment groups in acute toxicity burden in RTOG trials of head and neck cancer done during this study interval. TAME reporting provides a concise and uniform method to compare relative risk among treatment options. Future studies should include testing the performance of the TAME system in additional datasets (from different research organisations and disease sites), prospective correlation of TAME endpoints with predefined outcome measures, and assessment of its usefulness in clinical decision making.

Background: The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck. Methods: A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome. Results: TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003). Conclusions: Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.

Purpose: Phase I study to determine the maximally tolerated dose (MTD) of cisplatin (cDDP), paclitaxel (P), and concurrent split course hyperfractionated (BID) RT in advanced squamous cell carcinoma of the head and neck (SCCHN) and other upper aerodigestive tumors. Materials and Methods: Eligibility stipulated ECOG performance status 0-2 and either Tx-naive, locally advanced, or locally recurrent, previously radiated, surgically unresectable upper aerodigestive cancer. Metastases were permitted if disease was predominantly locoregional. RT-naive patients received 150 cGy bid x 5 d Q 2 wks x 4. Previously radiated patients received 150 cGy bid x 5, wk 1; then 120 cGy bid x 5 Q 2 wk x 3 (later increased to 150 cGy BID for the entire treatment). Treatment fields included recurrent tumor only with 2 cm margins. Whenever possible, conventional and 3-D conformal techniques were used. Elective nodal radiation was not administered. Starting doses of cDDP and P were 12 mg/m(2)/d x 5 and 15 mg/m(2)/d x 5, respectively, Q 2 wk x 4, each given on RT days only. At dose level 2, cDDP was increased to 15 mg/m(2)/d x 5. At dose level 3, P was increased to 20 mg/m(2)/d x 5. Granulocyte colony stimulating factor (G-CSF) days 6-12 (off treatment week) was added if cumulative neutropenia precipitated treatment delays. Results: Thirty-one patients (21 men, 10 women) were treated. Eight had received prior chemotherapy, 27 prior RT. At dose level three, regular treatment delays of =1 week due to slow neutrophil recovery occurred. Addition of G-CSF (dose level 3b) reduced treatment delays from 100 percent to 28 percent and decreased the incidence of Grade =2 neutropenia and mucositis. Six of 7 patients at this dose level completed all 4 cycles of treatment and all received full dose RT (60 Gy). No other dose-limiting toxicities occurred. Of 22 assessable patients with locally recurrent SCCHN, 12 (55 percent) responded. Median time to progression in this group was 6 months, with median and one-year survival of 9.5 mos and 41 percent, respectively. Conclusion: Concurrent daily cisplatin/paclitaxel and split course hyperfractionated RT (60 Gy) is feasible in previously radiated patients. G-CSF, administered between each cycle, reduces the incidence of treatment delays. Activity is promising and toxicity acceptable.

SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA

Background. Patients with local recurrences or new head and neck primary tumors in previously irradiated tissues have few options for salvage treatment. One option for select patients is to undergo reirradiation with concurrent chemotherapy. The purpose of this study is to report the initial clinical results of the Fox Chase phase I and II prospective reirradiation and chemotherapy studies. Methods. Between July 1996 and January 2002, 38 patients with locally recurrent unresectable squamous cell carcinoma of the head and neck were treated with concurrent chemotherapy and reirradiation on two prospective trials. All patients had received prior radiation therapy to the head and neck region (median dose, 64.2 Gy). Patients received cisplatin and paclitaxel along with hyperfractionated external beam radiation therapy to the site of recurrence. Results. The median follow-up was 10 months. The median survival was 12.4 months, with actuarial rates of overall survival of 50% and 35% at 1 and 2 years, respectively. During follow-up, 63% of patients experienced local progression of disease, all in the irradiated field. Actuarial progression-free survival at 1 year was 33%, with a median time to progression of 7.3 months. Acute grade 3 to 4 toxicity included neutropenia, nausea, emesis, and mucositis. Conclusions. Hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy demonstrates durable locoregional control in select patients, although late toxicity may occasionally be significant. Only sites of disease recurrence need to be covered in the reirradiation fields. © 2005 Wiley Periodicals, Inc.