Gerald H. Clamon

Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non–Small-Cell Lung Cancer

PURPOSE The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. METHODS Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. RESULTS Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. CONCLUSION Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

Screening for depression and anxiety in cancer patients using the Hospital Anxiety and Depression Scale

Nine hundred and thirty inpatients and outpatients with cancer were approached to complete the Hospital Anxiety and Depression Scale (HADS). Eight hundred and nine (86.9%) of those approached participated in this screening. Using the suggested cutoff score of 8 for the anxiety and depression subscales, we found that 47.6% of this population would warrant further psychiatric evaluation. Twenty-three percent (23.1%) had scores 11 or greater and would be the most likely to have had anxiety (17.7%) or depressive (9.9%) disorders based on DSM-III-R criteria. Patients with active malignant disease and inpatient status were more likely to have higher depression scores. The HADS was an easily administered tool that identified a large proportion of cancer patients as having high levels of anxiety or depression. However, clinical psychiatric interviews were not performed, so it is not possible to determine what proportion of patients would benefit from treatment.

Radiosensitization With Carboplatin for Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: A Phase III Trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group

PURPOSE To determine whether the administration of carboplatin concurrently with radiation treatment improves survival in patients with inoperable stage III non-small-cell lung cancer. PATIENTS AND METHODS Two hundred eighty-three patients with inoperable stage III non-small-cell lung cancer were entered onto a randomized trial by the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. Randomization was performed before initiation of any therapy. All patients received an induction chemotherapy program with vinblastine and cisplatin for 5 weeks, followed by 6,000 cGy of radiation therapy over 6 weeks. One hundred thirty-seven patients were randomized to this therapy regimen alone; 146 patients were randomized to receive carboplatin at 100 mg/m2/wk concurrent with the radiation therapy. RESULTS The complete response was 18% with concurrent carboplatin versus 10% with radiotherapy alone (P = .101). There was no difference with respect to failure-free survival (10% with carboplatin and 9% with radiotherapy alone) or overall survival (13% with carboplatin and 10% with radiotherapy alone) at 4 years. In patients not receiving carboplatin, the relapse rate was 69% within the field of radiation and 53% in the boost volume. In patients receiving carboplatin, the relapse rate was 59% within the field of radiation and 43% in the boost volume. Patients with cancers more than 70 cm2 in size had significantly poorer survival (P = .01). CONCLUSION Carboplatin at the dose and schedule used did not significantly impact on disease control or survival. The relapse rate within the chest remained more than 50%. More effective regimens will be required to impact on local disease control and survival.

Response of intractable pain to continuous intrathecal morphine: a retrospective study

&NA; We have treated 37 patients with intractable pain (35 with cancer‐related pain) by continuous intrathecal morphine infusion via implanted pump. These patients were carefully selected according to specific criteria, and each demonstrated a significant reduction in pain following a test dose of intrathecal morphine. All patients had good pain relief from intrathecal morphine infusion, even with pain located in cervical dermatomes. Systemic narcotics could be withdrawn from most patients. Significant side effects were rare and typically self‐limited. Many patients required gradually increasing doses, seemingly related to disease progression. Two patients with non‐malignant pain have had variable dose requirements over 28 and 44 months without clear tolerance. In these patients we observed a reduction in side effects associated with systemic opioids when continuous intrathecal opioid infusion was instituted. Intrathecal opioid administration may have fewer complications than ablative pain relief procedures. In properly selected patients, this method offers an effective alternative for pain relief.

Adverse Events Associated With Concurrent Chemoradiation Therapy in Patients With Head and Neck Cancer

OBJECTIVE To assess toxicities, functional outcomes, and health-related quality of life associated with concurrent chemoradiation therapy (CRT) in patients with head and neck cancer. DESIGN Prospective and retrospective outcomes study. SETTING Tertiary care institution. PATIENTS Participants in the longitudinal Outcomes Assessment Project whose head and neck cancer was treated with CRT between February 1, 2000, and March 1, 2007 (n = 104). INTERVENTIONS Patients prospectively provided functional and health-related quality of life information, including data from the 1-year and most current follow-up visits. Medical records were reviewed to determine toxicity and survival rates. MAIN OUTCOME MEASURES Well-defined acute and late toxicities; functional outcomes (diet, dentition, tracheostomies); head and neck cancer-specific, general health, and depression outcomes; and survival rates. RESULTS Most patients had oropharyngeal or laryngeal tumors (87.5%) and advanced-stage disease (75.0%). Approximately one-half had hematologic toxicities and toxicity-related treatment delays. Approximately one-quarter had neurotoxicities and/or ototoxicites, moist desquamation, pneumonia, nausea and vomiting requiring hospitalization or intravenous fluids, dehydration or malnutrition requiring hospitalization, and mild or moderate fever. Although patients receiving the current intensity-modulated radiation therapy (IMRT) protocol using the Pinnacle(3) planning system had more toxicity-related treatment delays, they had fewer toxicities and better functional and health-related quality of life outcomes compared with those receiving conventional lateral opposing-field radiation or the initial IMRT protocol using the Best nomos PEACOCK planning system. CONCLUSIONS Patients receiving CRT experience a substantial number of treatment-related adverse events, primarily affecting oropharyngeal and laryngeal function, with improvement noted for the current IMRT protocol. Improving dental prosthetic rehabilitation and including evaluations with speech and swallowing pathologists before and during treatment may enhance patient outcomes.

Distress Associated with Cancer as Measured by the illness Distress Scale

Over 400 cancer patients were given the Illness Distress Scale (IDS), a brief measure of the physical and emotional distress related to serious illness. Physical manifestations of the disease proved to be the source of greatest discomfort among these patients. Greater distress was reported by younger patients and by those who were unmarried. Also, patients with more advanced disease scored higher on the scale. The IDS appeared to measure four dimensions of distress related to the experience of illness, including loss of meaning, physical disease, medical treatment and social isolation. Scores on the instrument correlated highly with a measure of depression, the Beck Depression Inventory. The IDS appears to be a reliable and valid measure of distress associated with serious illness.

Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597

PURPOSE Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non-small-cell lung cancer (NSCLC) receiving selenium supplementation. PATIENTS AND METHODS Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence. RESULTS The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected. CONCLUSION Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC.

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Changing failure patterns in oropharyngeal squamous cell carcinoma treated with intensity modulated radiotherapy and implications for future research.

Objective:Review the University of Iowa experience with intensity modulated radiation treatment (IMRT) in oropharyngeal squamous cell carcinoma. Methods:From January 2000 to July 2004, 66 patients with oropharyngeal cancer were treated with IMRT, 62 with definitive IMRT and 4 postoperative IMRT. Three target volumes (CTV1, CTV2, and CTV3) were defined. The prescribed doses to CTV1, CTV2, and CTV3 were 70 to 74 Gy, 60 Gy, and 54 Gy, respectively, for definitive IMRT, and 60 to 66 Gy, 60 Gy, and 54 Gy, respectively, for postoperative IMRT. Results:Median follow-up was 27.3 months and all living patients had a follow-up of at least 11.5 months. The 3-year estimate of locoregional progression free survival was 98.8%. However, there is a high incidence of distant metastasis with a 3-year estimate of distant metastasis-free survival of 80.4%. In addition, there is a high incidence of second primary tumor. The 3-year overall survival and 3-year disease-free survival were 78.1% and 64.4%, respectively. Treatment was well tolerated with 1 death resulting from treatment toxicity. Conclusions:IMRT offers an excellent locoregional control for oropharyngeal cancer patients. Failure patterns have changed with an increased portion of patients who failed distantly, either with metastasis or second primary tumor. Therefore, survival for these patients is still poor. Future research should focus on identifying patients at high risk of distant diseases and developing effective systemic treatment and prevention for distant diseases.

High-dose paclitaxel plus G-CSF for malignant mesothelioma: CALGB phase II study 9234

BACKGROUND New agents with activity in mesothelioma are sorely needed. The Cancer and Leukemia Group B (CALGB) therefore performed a phase II study of high-dose paclitaxel in patients with malignant mesothelioma who had no prior chemotherapy. PATIENTS AND METHODS Thirty-five patients accrued to this multi-institutional phase II study of paclitaxel given as a 24-hour infusion at 250 mg/m2 every three weeks plus filgrastim (G-CSF) 300 mcg subcutaneously days 3-18. RESULTS There were three (9%) regressions of evaluable disease. The median survival was five months (95% confidence interval (95% CI): 1.9-9.6 months), the one-year survival rate was 14% and the two-year survival rate was 6%. Toxicity was tolerable with one death from pneumonia (without neutropenia) on day 18 and a 23% rate of grade 4 granulocytopenia. CONCLUSIONS The level of activity seen with paclitaxel is similar to that seen in other CALGB trials of the single agents carboplatin, trimetrexate and 5-azacytidine. Future studies of of paclitaxel (at lower doses) in combination with synergistic agents could be considered.