Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck.

BACKGROUND: The objective of this study was to determine prognostic factors for response and survival on three consecutive institutional trials utilizing concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck (SCCHN). METHODS: Since 1985, patients with locally advanced SCCHN at the University of Maryland have been managed with concurrent chemotherapy and radiation therapy (RT). Three consecutive pilot studies have been performed evaluating the utility of weekly chemotherapy with standard fractionated RT. Chemotherapy consisted of carboplatin either alone (28 patients) or in combination with bleomycin (23 patients) or paclitaxel (60 patients). In all three studies, RT was given to 70.2 gray (Gy) at 1.8 Gy/fraction/day to the primary site. All patients had locally advanced SCCHN and were believed to be poor surgical candidates. Sixty-seven percent of patients had T4 disease, and 21% had T3 disease. Seventy-five percent of patients had N2-N3 disease. One hundred eleven patients were examinable for toxicity, response, and survival analysis. Factors including age, race, gender, primary site location, histologic grade, T classification, N classification, and treatment regimen were evaluated to identify predictors of these endpoints. RESULTS: The median follow-up for patients treated on study 1 (carboplatin and RT) and study 2 (carboplatin and bleomycin [C + B]/RT) was 98 months, and it was 30 months for study 3 (carboplatin and paclitaxel [C + P]/RT). The complete response rates were 54%, 52%, and 70% respectively (P = 0.01). Multivariate analysis identified length of treatment break (< 1 week vs. > 1 week) as the only predictor of complete response to therapy. The local control for the entire group was 50%. The local control for C + P/RT was 63%, versus 32% and 36% for C/RT and C + B/RT respectively (P = 0.004). The 2-, 3-, and 5-year disease free and overall survivals for the entire population were 41%, 41%, and 35% and 42%, 36%, and 33%, respectively. The 3-year overall survival rates by treatment regimen were 18% (C/RT), 35% (C + B/RT), and 47% (C + P/RT; P = 0.01). On univariate analysis, age younger than 50 years (P = 0.01), treatment with C + P/RT (P = 0.005), and treatment break of 5 days or fewer (P < 0.05) were also predictive of improved overall survival. On multivariate analysis, only complete response (P < 0.0001) and treatment with C + P/RT (P = 0.02) remained statistically significant. CONCLUSIONS: Chemoradiation provides patients with locally advanced SCCHN the opportunity for long term survival. Among the three chemoradiation regimens studied, C + P/RT was associated with the best complete response and survival rates. Complete response to therapy was the single most important predictor of overall survival. These three consecutive concurrent chemotherapy and radiation trials achieved a 5-year survival of greater than 30% for the entire population. These results support the use of this nonoperative approach for this group of patients with a historically poor prognosis.

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

PURPOSE: Unresectable squamous cell carcinomas of the head and neck (SCCHN) continue to pose a significant therapeutic challenge. This report defines the toxicities, efficacy, and prognostic factors associated with the combination of carboplatin (CBDCA), paclitaxel, and once-daily radiation for patients with locally advanced disease. Additionally, the pharmacokinetics of paclitaxel were investigated. METHODS AND MATERIALS: From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. RESULTS: Sixty patients were evaluable for response and survival with a median follow-up of 30 months (range 7-70). Ninety-eight percent of patients completed prescribed therapy. One patient died after refusing medical management for pseudomembranous colitis and is scored as a Grade 5 toxicity. Two patients suffered Grade 4 leukopenia. Median number of break days was two. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months. Response to therapy and status of the neck at presentation were the only prognostic factors found to influence survival. The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. Plasma paclitaxel concentrations in the range shown to be radiosensitizing were achieved. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

Rodent cell transformation and immediate early gene expression following 60-Hz magnetic field exposure.

Some epidemiological studies suggest that exposure to power frequency magnetic fields (MFs) may be associated with an elevated risk of human cancer, but the experimental database remains limited and controversial. We investigated the hypothesis that 60-Hz MF action at the cellular level produces changes in gene expression that can result in neoplastic transformation. Twenty-four hour 200 microT continuous MF exposure produced negative results in two standard transformation systems (Syrian hamster embryo cells and C3H/10T1/2 murine fibroblasts) with or without postexposure to a chemical promoter. This prompted a reexamination of previously reported MF-induced changes in gene expression in human HL60 cells. Extensive testing using both coded and uncoded analyses was negative for an MF effect. Using the same exposure conditions as in the transformation studies, no MF-induced changes in ornithine decarboxylase expression were observed in C3H/10T1/2 cells, casting doubt on a promotional role of MF for the tested cells and experimental conditions.

Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines.

Norepinephrine (NE) and epinephrine (E) are metabolized extraneuronally by catechol-O-methyl-transferase to the metanephrines (MNs), normetanephrine (NMN) and metanephrine (MN). Subjects in this study received infusions of tritium-labeled NE and E. Concentrations of MNs and catecholamines were measured in plasma flowing into and out of the heart, forearm, lungs, kidneys, mesenteric organs (gastrointestinal tract, spleen, and pancreas), liver, and adrenals to examine the regional production of MNs from circulating and locally released catecholamines. NE spillover from mesenteric organs and kidneys accounted for 64% of the spillover from all tissues. There was detectable spillover of E from most extraadrenal tissues, but 91% was from the adrenals. The production of MNs from locally released and circulating catecholamines varied widely among tissues. The liver made the largest contribution to removal of circulating NE (57%) and E (32%) and the largest contribution to the production of NMN (54%) and MN (37%) from metabolism of circulating catecholamines. In all other tissues more NMN was produced from locally released than from circulating NE. Thus, the metabolism of circulating NE was responsible for only 19% of the total production of NMN. An even smaller portion (6%) of plasma MN was derived from metabolism of circulating E. Most plasma MN (91%) was produced within the adrenals, which also provided the largest single source (23%) of NMN. The regional variation in extraneuronal production of MNs indicates considerable heterogeneity in how circulating and locally released catecholamines are handled by different tissues. The substantial contribution of the adrenals to the production of MNs explains the extraordinary sensitivity of these metabolites for the diagnosis of pheochromocytoma.

Role of radiation therapy in the management of malignant chondroid syringoma.

BACKGROUND: Malignant sweat gland neoplasms are exceedingly rare tumors. Malignant chondroid syringoma (MCS) is one of the rarest subtypes, and as such, still poorly understood. It lacks distinctive clinical features, often delaying initial diagnosis and therapeutic management. OBJECTIVE: A current case and the available literature are reviewed to determine the overall clinical course of the MCS and the potential role of adjuvant therapy. METHODS: A case of MCS was studied by light microscope, immunohistochemistry, and electron microscopy. The clinical data of this case and of other reported cases are summarized and compared. RESULTS: This tumor recurred locally after initial local excision. Subsequent re-excision and radiation therapy rendered the patient without evidence of disease. This case study and the literature review of the 20 reported cases indicate that MCS is highly recurrent with tendency toward metastasis. CONCLUSION: MCS appears to behave in an aggressive manner. An initial treatment modality is aggressive surgery. Adjuvant radiation therapy with or without chemotherapy should be tried in future cases.

Plasma metanephrines in the diagnosis of pheochromocytoma.

OBJECTIVE: To examine whether tests for plasma metanephrines, the o-methylated metabolites of catecholamines, offer advantages for diagnosis of a pheochromocytoma over standard tests for plasma catecholamines or urinary metanephrines. DESIGN: Cross-sectional study. SETTING: 3 clinical specialist centers. PATIENTS: 52 patients with a pheochromocytoma; 67 normotensive persons and 51 patients with essential hypertension who provided reference values; and 23 patients with secondary hypertension and 50 patients with either heart failure or angina pectoris who served as comparison groups. MEASUREMENTS: Plasma concentrations of catecholamines (norepinephrine and epinephrine) and metanephrines (normetanephrine and metanephrine) were measured in all patients. The 24-hour urinary excretion of metanephrines was measured in 46 patients with pheochromocytoma. RESULTS: Pheochromocytomas were associated with increases in plasma concentrations of metanephrines that were greater and more consistent than those in plasma catecholamine concentrations. No patient with a pheochromocytoma had normal plasma concentrations of both normetanephrine and metanephrine. The sensitivity of these tests was 100% (52 of 52 patients [95% CI, 94% to 100%]), and the negative predictive value of normal plasma concentrations of metanephrines was 100% (162 of 162 patients). Tests for plasma catecholamines yielded eight false-negative results and a sensitivity of 85% (44 of 52 patients [CI, 72% to 93%]). The negative predictive value of normal plasma concentrations of catecholamines was 95% (156 of 164 patients). Tests for urinary metanephrines yielded five false-negative results and a sensitivity of 89% (41 of 46 patients [CI, 76% to 96%]). Because no statistical difference was noted in the number of false-positive results between tests for plasma metanephrines (15%) and tests for plasma catecholamines (18%), the specificities of the two tests did not differ. CONCLUSIONS: Normal plasma concentrations of metanephrines exclude the diagnosis of pheochromocytoma, whereas normal plasma concentrations of catecholamines and normal urinary excretion of metanephrines do not. Tests for plasma metanephrines are more sensitive than tests for plasma catecholamines or urinary metanephrines for the diagnosis of pheochromocytoma.

Combined carboplatin plus bleomycin and conventional radiotherapy for advanced carcinomas of the head and neck.

In a previous study, we reported a 72% response rate (CR = 52%) in patients with unresectable head and neck (H&N) carcinomas treated with simultaneous carboplatin (CBDCA) and radiotherapy (RT). Bleomycin (Bleo), a known radiosensitizing agent, has been shown to increase response rates when given together with RT in similar patients. To explore the nonoverlapping toxicities of these two agents, we combined i.v. CBDCA (100 mg/m2/week), Bleo (5 units on day 1 and 4/weekly) and standard doses of RT in patients with unresectable H&N carcinomas. Chemotherapy (CT) was continued until completion of RT. Twenty-three (13 males, 10 females) previously untreated patients with stage IV squamous cell carcinoma of the H&N were treated at the University of Maryland Medical Center: 61% had oropharyngeal cancers; 26%, hypopharynx; 9%, oral cavity; and 4%, an unknown primary. Moderate to severe mucositis developed in 90%, which required RT interruptions of up to 3 weeks. After a median follow-up (FU) of 18 months, 35% achieved a complete response (CR) and 65% died from progressive disease. These preliminary data suggest that the addition of Bleo increases mucosal toxicity substantially and, while a moderate response rate was observed, it is unlikely that the CR rate will be higher than CBDCA/RT, which was also better tolerated and hence more suitable to multimodal approaches.

Effect of chronic smoking on endothelium-dependent vascular relaxation in humans.

1. Cigarette smoking is one of the major risk factors for the development of atherosclerosis. It is not clear, however, whether chronic cigarette smoking impairs the normal physiological function of the endothelium before the development of morphological vascular lesions. To test this, we investigated endothelium-dependent vascular relaxation in young habitual smoking subjects. 2. In 11 non-smokers and 10 habitual smokers we measured the changes in bilateral forearm blood flow, arterial blood pressure and forearm vascular resistance (ratio between mean arterial blood pressure and forearm blood flow) during three interventions: post-occlusive forearm hyperaemia, intrabrachial infusion of methacholine which causes vasodilatation by stimulating the release of endothelium-dependent relaxing factor, and intrabrachial infusion of sodium nitroprusside which causes vasodilatation independently from the endothelium by a direct effect on the vascular smooth muscle wall. 3. During infusion of the highest dose of methacholine, forearm vascular resistance decreased by 91.7 +/- 1.4% in the smokers and by 89.9 +/- 1.8% in the non-smokers. During infusion of sodium nitroprusside, forearm vascular resistance decreased by 80.0 +/- 3.8% in the smokers as compared with 80.7 +/- 6.1% in the non-smokers. There was no difference in basal forearm vascular resistance or in post-ischaemic reactive hyperaemia between smokers and non-smokers. Thus, vasodilatation induced by both methacholine and sodium nitroprusside was not significantly different between smokers and non-smokers. 4. We conclude that in young habitual cigarette smokers the endothelium-dependent vasodilation in the forearm seems to be preserved, suggesting that habitual smoking does not result in permanent endothelial dysfunction in the human forearm.

Carboplatin (CBDCA) and radiotherapy for stage IV carcinoma of the head and neck: a phase I-II study.

The prognosis of patients with squamous cell carcinoma (SQC) of the head and neck (H&N) depends on the primary site and anatomical extent of the disease. Recurrence rates after conventional surgery (S) and/or radiotherapy (RT) remain low for localized tumors, whereas in advanced loco-regional disease they occur in over 60% of all cases. Several combinations of treatment modalities have been attempted in order to improve local control in Stages III and IV. Unfortunately, the recurrence rate remains high with added morbidity when conventional surgery is combined with pre or post-operative radiotherapy. Induction chemotherapy (CT) with Cisplatinum and Bleomycin has resulted in severe toxicities when combined with radiotherapy. To evaluate the toxicity of Carboplatin (CBDCA), a second generation platinum analog, when given simultaneously with conventional doses of radiotherapy, 26 patients with Stage IV SQC of the head and neck were treated at the University of Maryland Medical Systems. There were 23 males and 3 females; median age was 59 years and median Karnofski performance status was 60. Twenty patients had received no prior therapy; six had surgical exploration and excision with measurable residual disease. Anatomically, six patients had tumors of the oral cavity, twelve in the pharynx, one in the nasopharynx, four in the larynx, one in the hypopharynx, one in the maxillary antrum, and one was an unknown primary. These patients were treated as out-patients with weekly injections of Carboplatin. The dose was escalated: two patients received 60 mg/M2, seven received 75 mg/M2, thirteen were treated with 100 mg/M2, and four with 400 mg/M2. The radiotherapy was given daily with conventional fractions of 180 cGy and total tumor doses of 60-75 Gy. Toxicities were mainly hematological with median nadirs decreasing with increasing doses of Carboplatin. Mucositis was seen in over 80% of the patients, but interestingly enough, it has never been more severe than that observed with radiotherapy alone. So far, there has not been any kidney, ear, or neurotoxicities. Of 25 evaluable patients, 19 (76%) responded with 13 (52%) showing complete response. The overall median survival time is 266+ days (324+ for responders and 179+ for non-responders). The follow-up is still short, 10-14 months, but 9 of 13 patients with complete response have not yet progressed.