Quality of life among long-term survivors of head and neck cancer treated by intensity-modulated radiotherapy.

IMPORTANCE: Radiation therapy to the head and neck has traditionally been associated with adverse effects that can affect oral health and physical functioning. Although intensity-modulated radiotherapy (IMRT) has been widely adopted as a means of decreasing toxic effects, limited clinical data exist on its potential effect on long-term quality of life. OBJECTIVE: To analyze quality of life among long-term survivors of head and neck cancer treated with IMRT. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis studied 50 consecutive long-term survivors of head and neck cancer from a comprehensive cancer center who had previously undergone IMRT that required bilateral neck irradiation for locally advanced disease. All patients were clinically without evidence of recurrent disease and had at least 5 years of follow-up. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life (UW-QOL) scores were reviewed for all study participants. The UW-QOL questionnaire consists of 12 domains that pertain to the degree of quality of life in the categories of pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. RESULTS: Five years after completion of IMRT, 42 patients (84%) reported that their health-related quality of life was "much better" or "somewhat better" than at the time of cancer diagnosis. With respect to recent health-related quality of life during the preceding 7 days at the time of completing the UW-QOL questionnaire, 40 patients (80%) treated with IMRT reported "outstanding" or "very good" levels of functioning. Five years after completion of treatment, 41 (82%) rated their overall quality of life as "outstanding" or "very good." The lowest domain score on the UW-QOL questionnaire at 5 years pertained to salivary dysfunction. However, 42 patients (84%) reported saliva "of normal consistency" or "less saliva than normal but enough" compared with 8 (16%) reporting "too little saliva." No patient reported having "no saliva." CONCLUSIONS AND RELEVANCE: Our findings add to the body of literature that supports the acceptance of IMRT as standard treatment for head and neck cancer. The fact that most 5-year survivors were satisfied with their quality of lives points to the ability of IMRT to preserve long-term functioning.

A Pilot Study (SWOG S0429) of Weekly Cetuximab and Chest Radiotherapy for Poor-Risk Stage III Non-Small Cell Lung Cancer.

PURPOSE: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT). METHODS: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0-1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400 mg/m(2)) was delivered week 1, followed by weekly cetuximab (250 mg/m(2))/RT to 64.8 Gy in 1.8 Gy daily fractions, and maintenance weekly cetuximab (250 mg/m(2)) for 2 years or until disease progression. H-score for EGFR protein expression was conducted in available tumors. RESULTS: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14 months and median progression-free survival was 8 months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3-4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients. CONCLUSION: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.

Feasibility and toxicity of concurrent chemoradiation for elderly patients with head and neck cancer.

OBJECTIVES: Although concurrent chemoradiation is increasingly used for patients with locally advanced head and neck cancer, many elderly patients receive radiation alone due to toxicity concerns. We evaluate acute and late toxicity among patients age ≥ 65 who received concurrent chemoradiation for head and neck cancer. DESIGN: Retrospective review. SETTING: Tertiary care center. PARTICIPANTS: Between 6/2003 and 8/2011, 40 consecutive patients age ≥ 65 underwent combined chemoradiation for head and neck cancer. Ten patients were treated in the postoperative setting and 30 underwent definitive chemoradiation. Twenty-eight patients received concurrent platinum-based chemotherapy and 12 received concurrent weekly paclitaxel. Treatment plans were designed to provide a dose of 66-72 Gy at 2-2.12 Gy/fraction to >95% of the gross tumor volume in the definitive setting or for positive margins and 60-66 Gy at 2 Gy/fraction post-operatively. Median follow-up was 23.2 months (range: 0-94.4 months). MAIN OUTCOMES MEASURES: Acute skin and mucosal toxicity, unplanned treatment interruptions, and chronic treatment related toxicity including gastrostomy tube dependence as graded by the CTCAE v3.0. RESULTS: Eight patients (20%) required a radiation treatment break of ≥ 3 days. Thirteen (33%) required unplanned hospitalization during or immediately following treatment. No grade 4+ skin or mucosal toxicity was noted. Five patients remained PEG tube dependent at >1 year. One patient developed non-healing mandibular osteoradionecrosis >3 years following chemoradiation. The 2-year Kaplan-Meier estimate of overall survival was 55%. CONCLUSION: Higher-than-expected rates of in-patient hospitalization with significant acute toxicity were noted in this cohort with a correspondingly high rate of radiation treatment breaks. Late toxicity rates were similar to those observed in historical controls with younger patients. Careful patient selection criteria should be employed for elderly patients considering concurrent chemoradiation for head and neck cancer.

Southwestern oncology group phase II trial (S0526) of pemetrexed in bronchioloalveolar carcinoma subtypes of advanced adenocarcinoma.

BACKGROUND: Pemetrexed, a multitargeted antifolate drug, is an active agent in non-small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m(2), administered intravenously every 21 days. RESULTS: Of 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively. CONCLUSION: Pemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.

Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer.

OBJECTIVES/HYPOTHESIS: To evaluate the responsiveness of human papillomavirus (HPV) -positive and HPV-negative oropharyngeal cancer to intensity-modulated radiotherapy (IMRT), using axial imaging obtained daily during the course of image-guided radiotherapy (IGRT). STUDY DESIGN: Observational cohort study with matched-pair analysis of patients irradiated for HPV-positive and HPV-negative oropharygeal cancer. METHODS AND MATERIALS: Ten patients treated by IMRT to 70 Gy for locally advanced, HPV-positive squamous cell carcinoma of the oropharynx were matched to one HPV-negative control subject by age, gender, performance status, T-category, tumor location, and the use of concurrent chemotherapy. The gross tumor volume (GTV) was delineated on daily IGRT scans obtained via kilovoltage cone-beam computed tomography (CBCT). Mathematical modeling using fitted mixed-effects repeated measure analysis was performed to quantitatively and descriptively assess the trajectory of tumor regression. RESULTS: Patients with HPV-positive tumors experienced a more rapid rate of tumor regression between day 1 of IMRT and the beginning of week 2 (-33% Δ GTV) compared to their counterparts with HPV-negative tumors (-10% Δ GTV), which was statistically significant (p<0.001). During this initial period, the average absolute change in GTV was -22.9 cc/week for HPV-positive tumors and -5.9 cc/week for HPV-negative tumors (p<0.001). After week 2 of IMRT, the rates of GTV regression were comparable between the two groups. CONCLUSIONS: HPV-positive oropharyngeal cancers exhibited an enhanced response to radiation, characterized by a dramatically more rapid initial regression than those with HPV-negative tumors. Implications for treatment de-intensification in the context of future clinical trials and the possible mechanisms underlying this increased radiosensitivity will be discussed.

Brachial plexus-associated neuropathy after high-dose radiation therapy for head-and-neck cancer.

PURPOSE: To identify clinical and treatment-related predictors of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer. METHODS AND MATERIALS: Three hundred thirty patients who had previously completed radiation therapy for head-and-neck cancer were prospectively screened using a standardized instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from completion of radiation therapy was 56 months (range, 6-135 months). One-hundred fifty-five patients (47%) were treated by definitive radiation therapy, and 175 (53%) were treated postoperatively. Radiation doses ranged from 50 to 74 Gy (median, 66 Gy). Intensity-modulated radiation therapy was used in 62% of cases, and 133 patients (40%) received concurrent chemotherapy. RESULTS: Forty patients (12%) reported neuropathic symptoms, with the most common being ipsilateral pain (50%), numbness/tingling (40%), motor weakness, and/or muscle atrophy (25%). When patients with <5 years of follow-up were excluded, the rate of positive symptoms increased to 22%. On univariate analysis, the following factors were significantly associated with brachial plexus symptoms: prior neck dissection (p = 0.01), concurrent chemotherapy (p = 0.01), and radiation maximum dose (p < 0.001). Cox regression analysis confirmed that both neck dissection (p < 0.001) and radiation maximum dose (p < 0.001) were independently predictive of symptoms. CONCLUSION: The incidence of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer may be underreported. In view of the dose-response relationship identified, limiting radiation dose to the brachial plexus should be considered when possible.

Intensity-modulated radiotherapy is associated with improved global quality of life among long-term survivors of head-and-neck cancer.

PURPOSE: To compare the long-term quality of life among patients treated with and without intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: The University of Washington Quality of Life instrument scores were reviewed for 155 patients previously treated with radiation therapy for locally advanced head-and-neck cancer. All patients were disease free and had at least 2 years of follow-up. Eighty-four patients (54%) were treated with IMRT. The remaining 71 patients (46%) were treated with three-dimensional conformal radiotherapy (3D CRT) by use of initial opposed lateral fields matched to a low anterior neck field. RESULTS: The mean global quality of life scores were 67.5 and 80.1 for the IMRT patients at 1 and 2 years, respectively, compared with 55.4 and 57.0 for the 3D CRT patients, respectively (p < 0.001). At 1 year after the completion of radiation therapy, the proportion of patients who rated their global quality of life as "very good" or "outstanding" was 51% and 41% among patients treated by IMRT and 3DCRT, respectively (p = 0.11). At 2 years, the corresponding percentages increased to 73% and 49%, respectively (p < 0.001). On multivariate analysis accounting for sex, age, radiation intent (definitive vs. postoperative), radiation dose, T stage, primary site, use of concurrent chemotherapy, and neck dissection, the use of IMRT was the only variable independently associated with improved quality of life (p = 0.01). CONCLUSION: The early quality of life improvements associated with IMRT not only are maintained but apparently become more magnified over time. These data provide powerful evidence attesting to the long-term benefits of IMRT for head-and-neck cancer.

Feasibility study of intra-patient sorafenib dose-escalation or re-escalation in patients with previously treated advanced solid tumors.

PURPOSE: To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies. METHODS: An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3. RESULTS: Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia. CONCLUSIONS: Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.

A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study.

BACKGROUND: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. METHODS: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. RESULTS: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. CONCLUSIONS: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

Voice quality after organ-preservation therapy with definitive radiotherapy for laryngeal cancer.

BACKGROUND: The purpose of this study was to analyze voice quality among patients treated by definitive radiotherapy for laryngeal cancer. METHODS: Ten patients with laryngeal cancer who had completed radiotherapy were involved in this pilot study. A standardized protocol was administered assessing: (1) sustained vowel production following maximal inspiration, (2) sustained vowel production for a 7-second duration repeated 5 times, and (3) spontaneous speech for 10 seconds. RESULTS: The acoustic parameters among patients with early-stage cancer were not statistically different from healthy age-corresponding controls, except for shimmer (0.20 vs 0.16 dB, ρ = 0.01) and maximum phonation duration (24.37 vs 30.10 seconds, ρ = 0.04). For patients with locally advanced cancer, differences with controls were observed with shimmer (2.29 vs 0.16 dB, ρ = 0.01), jitter (7.49% vs 1.04%, ρ = 0.01), harmonics-to-noise ratio (2.67 vs 9.22, ρ = 0.01), and maximum phonation duration (14.12 vs 30.10 seconds, ρ = 0.01). CONCLUSIONS: Despite the subtle differences in voice quality that existed, radiotherapy as a curative treatment for laryngeal cancer allows maintenance of a functional voice.

Randomized phase II trial of concurrent versus sequential bortezomib plus docetaxel in advanced non-small-cell lung cancer: a California cancer consortium trial.

BACKGROUND: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. PATIENTS AND METHODS: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m² intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m² I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. CONCLUSION: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.

Escalating weekly doses of cetuximab and correlation with skin toxicity: a phase I study.

BACKGROUND: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. RESULTS: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. CONCLUSIONS: Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

Radiation therapy in the management of head-and-neck cancer of unknown primary origin: how does the addition of concurrent chemotherapy affect the therapeutic ratio?

PURPOSE: To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin. METHODS AND MATERIALS: The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy. RESULTS: The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both). CONCLUSIONS: Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question.

Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome.

PURPOSE: To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters. METHODS AND MATERIALS: A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria. RESULTS: With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01). CONCLUSIONS: Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.

Primary radiation therapy for head-and-neck cancer in the setting of human immunodeficiency virus.

PURPOSE: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). METHODS AND MATERIALS: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. RESULTS: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. CONCLUSIONS: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

Evaluating the role of prophylactic gastrostomy tube placement prior to definitive chemoradiotherapy for head and neck cancer.

PURPOSE: To determine the effect of prophylactic gastrostomy tube (GT) placement on acute and long-term outcome for patients treated with definitive chemoradiotherapy for locally advanced head and neck cancer. METHODS AND MATERIALS: One hundred twenty consecutive patients were treated with chemoradiotherapy for Stage III/IV head and neck cancer to a median dose of 70 Gy (range, 64-74 Gy). The most common primary site was the oropharynx (66 patients). Sixty-seven patients (56%) were treated using intensity-modulated radiotherapy (IMRT). Seventy patients (58%) received prophylactic GT placement at the discretion of the physician before initiation of chemoradiotherapy. RESULTS: Prophylactic GT placement significantly reduced weight loss during radiation therapy from 43 pounds (range, 0 to 76 pounds) to 19 pounds (range, 0 to 51 pounds), which corresponded to a net change of -14% (range, 0% to -30%) and -8% (range, +1% to -22%) from baseline, respectively (p < 0.001). However, the proportion of patients who were GT-dependent at 6- and 12-months after treatment was 41% and 21%, respectively, compared with 8% and 0%, respectively, for those with and without prophylactic GT (p < 0.001). Additionally, prophylactic GT was associated with a significantly higher incidence of late esophageal stricture compared with those who did not have prophylactic GT (30% vs. 6%, p < 0.001). CONCLUSIONS: Although prophylactic GT placement was effective at preventing acute weight loss and the need for intravenous hydration, it was also associated with significantly higher rates of late esophageal toxicity. The benefits of this strategy must be balanced with the risks.

Late esophageal toxicity after radiation therapy for head and neck cancer.

BACKGROUND: The aim of this study was to determine the incidence of esophageal toxicity after radiation therapy for head and neck cancer. METHODS: The records of 211 patients treated by radiation therapy for head and neck cancer were reviewed to identify those with dysphagia lasting more than 90 days after therapy. Late toxicity criteria established by the Radiation Therapy Oncology Group were used to score the symptoms. RESULTS: The incidence of grade 3+ esophageal toxicity at 3 and 6 months was 30% and 19%, respectively. The rate of gastrotomy-tube dependence at 3 and 6 months was 20% and 11%, respectively. Hypopharyngeal and unknown primary site (p = .01, for both), T4 disease (p = .01), and the use of concurrent chemotherapy (p = .001) were associated with grade 3+ esophageal toxicity and stricture formation. CONCLUSION: A significant proportion of patients exhibit symptoms of esophageal toxicity after radiation therapy for head and neck cancer. Therefore, preventive strategies need further investigation.

Clinical-dosimetric analysis of measures of dysphagia including gastrostomy-tube dependence among head and neck cancer patients treated definitively by intensity-modulated radiotherapy with concurrent chemotherapy.

PURPOSE: To investigate the association between dose to various anatomical structures and dysphagia among patients with head and neck cancer treated by definitive intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy. METHODS AND MATERIALS: Thirty-nine patients with squamous cancer of the head and neck were treated by definitive concurrent chemotherapy and IMRT to a median dose of 70 Gy (range, 68 to 72). In each patient, a gastrostomy tube (GT) was prophylacticly placed prior to starting treatment. Prolonged GT dependence was defined as exceeding the median GT duration of 192 days. Dysphagia was scored using standardized quality-of-life instruments. Dose-volume histogram (DVH) data incorporating the superior/middle pharyngeal constrictors (SMPC), inferior pharyngeal constrictor (IPC), cricoid pharyngeal inlet (CPI), and cervical esophagus (CE) were analyzed in relation to prolonged GT dependence, dysphagia, and weight loss. RESULTS: At 3 months and 6 months after treatment, 87% and 44% of patients, respectively, were GT dependent. Spearman's rho analysis identified statistical correlations (p < 0.05) between prolonged GT dependence or high grade dysphagia with IPC V65, IPC V60, IPC Dmean, and CPI Dmax. Logistic regression model showed that IPC V65 > 30%, IPC V60 > 60%, IPC Dmean > 60 Gy, and CPI Dmax > 62 Gy predicted for greater than 50% probability of prolonged GT dependence. CONCLUSION: Our analysis suggests that adhering to the following parameters may decrease the risk of prolonged GT dependence and dysphagia: IPC V65 < 15%, IPC V60 < 40%, IPC Dmean < 55 Gy, and CPI Dmax < 60 Gy.

Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023.

PURPOSE: Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non-small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. PATIENTS AND METHODS: Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m(2) on days 1 and 8 plus etoposide 50 mg/m(2) on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m(2). Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. RESULTS: Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. CONCLUSION: In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: a California Cancer Consortium Phase I study.

INTRODUCTION: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib. METHODS: Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m2/gemcitabine 800 mg/m2, bortezomib 1.0 mg/m2/gemcitabine 1000 mg/m2, and bortezomib 1.3 mg/m2/gemcitabine 1000 mg/m2, in combination with carboplatin AUC 5.0. RESULTS: Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34-74), and 23 patients were stage IV. The Karnofsky performance score was 80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease. CONCLUSIONS: The combination of bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.