Phase I-II study of multiple daily fractions for palliation of advanced head and neck malignancies

PURPOSE: To assess palliation of advance head and neck malignancies with the use of rapid hyper fractionation studies similar to the RTOG 85-02. MATERIALS AND METHODS: 37 patients with 39 lesions were entered into the non-randomized Phase I-II protocol, between 1984 and 1991. Previously untreated malignancies were present in 24 lesions, primary recurrent diseases in six patients, metastasis to the head and neck in five patients and skin primaries in the remaining two cases. At presentation 15 of 37 patients (or 17 of 39 lesions) were in operable due to poor medical status, eight patients were considered technically in operable due to extent of disease, 10 patients had distant metastasis and four patients refused surgery. The protocol uses twice a day fraction (370 cGy per fraction) for 2 consecutive days totalling 1,480 cGy per course. Three courses were given at 3-week intervals for a final tumor dose of 4,440 cGy in twelve fraction over 8-9 weeks. RESULTS: Eleven of 39 lesions had complete response; 19 lesions had partial response; 4 lesions had no response; 3 lesions progressed under treatment. Response could not be assessed in two patients. The average survival after completion of therapy was 4.5 months ranging from 2 weeks to 31 months. Palliation was achieved in 33 of 39 lesions. The acute reactions were minimal and no late or long term complications were noted. CONCLUSION: The absence of significant complications with reasonable response in the high rate of palliation suggests that this rapid hyper fractionation palliation study should be studied for further evaluation.     

Phase II trial of vindesine in advanced head and neck cancer

Twenty-one patients with advanced epidermoid carcinoma of the head and neck region were treated with vindesine. Therapy was started at a dose of 3 mg/m2. Dose escalation by 0.5 mg/m2 weekly to a maximum of 4.0 mg/m2 was permitted when no toxicity was seen. Major dose-limiting toxic effects were neutropenia and peripheral neuropathy. Objective responses were seen in five patients: three partial responses lasting 2, 2, and 3 months, and two minor responses lasting 2 and 5 months.     

Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas

A significant link between 5-fluorouracil (5FU) plasma concentration and its therapeutic activity has been demonstrated in colon and head and neck cancer patients for 5FU used as a continuous infusion. Dose adjustment based on pharmacokinetic follow-up has been proposed to decrease hematological and digestive toxicities, but the clinical impact of this approach has not yet been demonstrated. A randomized multicentric study was conducted to evaluate the clinical interest of 5FU dose adaptation guided by pharmacokinetics. One hundred twenty-two head and neck cancer patients were randomly assigned to receive induction chemotherapy with cisplatin (100 mg/m2, day 1) and 5FU (96-h continuous infusion), either at standard dose (St-arm; 4 g/m2) or at a dose adjusted according to the 5FU area under the curve (AUC0-48h; PK-arm). In total, 106 patients were evaluable for toxicity and response. In the PK-arm (n = 49), 5FU doses and area under the curve were significantly reduced during cycle 2 and cycle 3 (P < 0.001) as compared with the St-arm (n = 57). Grade 3-4 neutropenia and thrombopenia were significantly more frequent in the St-arm as compared with the PK-arm (17.5% versus 7.6%, respectively; P = 0.013). No grade 3-4 mucositis occurred in the PK-arm, whereas 5.1% was observed in the St-arm (P < 0.01). The objective response rate was comparable in the two treatment arms: 77.2% in the St-arm versus 81.7% in the PK-arm. The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement.     

Quality of life in advanced prostate cancer: results of a randomized therapeutic trial

BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.     

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study

PURPOSE: A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION: Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.     

Recent randomized trials of chemoradiation in the management of locally advanced head and neck cancer

Arsenic and antimony are two semimetals sharing some chemical as well as toxicological properties. Both elements are clastogenic but not point mutagenic in their trivalent state of valency. Environmental exposure to arsenic was proven to be associated with increased rates of various types of cancers. Antimony is suspected to be carcinogenic to humans. Arsenic and antimony can be found as environmental co-contaminants resulting in co-exposure to man. However, in most regions where arsenic was found in elevated environmental amounts, it was not investigated whether an additional exposure to antimony was predominating. In this study, the chromosome mutagenicity induced by arsenic(III) was significantly suppressed by antimony(III) in the micronucleus test with V79 cells. The results demonstrate the necessity to identify putative environmental co-contaminations of antimony in the regions contaminated with arsenic and to determine the impact of antimony co-exposure on arsenic genotoxicity and carcinogenicity in man in vivo.     

Fluorodeoxyglucose imaging of advanced head and neck cancer after chemotherapy

Acetyl- and butyrylcholinesterase have 51-54% sequence identity in mammalian species; they exhibit distinct substrate and inhibitor specificities. The crystal structure of acetylcholinesterase enables one to predict folding of related esterases as well as assign residues responsible for differences in substrate specificity. These predictions were tested by expression of esterase chimeras and site-specific mutants using mouse acetylcholinesterase as a template. Chimeras of acetylcholinesterase in which the amino-terminal 174 and the carboxyl-terminal 88 amino acids have been converted to the butyrylcholinesterase sequences still exhibit acetyl-like substrate specificity. Four nonconserved amino acids which are within the central sequence and appear to surround the acyl pocket, F295, R296, F297, and V300, have been mutated alone and in combination to the corresponding residues found in butyrylcholinesterase, L286, S287, I288, and G291. The V300 and R296 mutants slightly enhance butyrylthiocholine hydrolysis while the F295 and F297 mutants, alone and in combination, confer butyrylcholinesterase character by enhancing activity to butyrylthiocholine, and diminishing activity to acetylthiocholine. The F297 mutation eliminates substrate inhibition. F295 and F297 may form a clamp around the acetoxy methyl group. They have distinctive roles in affecting catalysis of the two acylcholines and precisely control acyl ester specificity. Comparison of the susceptibilities of the chimeras and site-specific mutants to cholinesterase-specific inhibitors isoOMPA, ethopropazine, and BW284c51 suggests that inhibitor selectivity for isoOMPA is attributable to residues limiting the size of the acyl pocket, while residues in the amino-terminal domain presumably near the lip of the gorge affect BW284c51 selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial

Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by its unresponsiveness to chemo- and/or radiotherapy. Therefore, many patients demand alternative drug therapy such as mistletoe treatment. However, there are no controlled data available analyzing the effect of mistletoe treatment in pancreatic cancer. In the present phase I/II study we evaluated the effect of mistletoe (Eurixor) treatment in 16 patients (7 women, 9 men) with histologically verified ductal pancreatic carcinoma. At the time when the patients were enrolled nine patients had lymph node metastases (stage III), and in 7 patients distant metastases (stage IV) were present. Mistletoe was administered twice a week by subcutaneous injection in a dosage of 1 ng per kg body weight. Monthly follow-ups included clinical status, multidimensional evaluation of quality of life, contrast enhanced computed axial tomography scan (CT scan) or ultrasonography, and determination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Apart from one anaphylactic reaction, which necessitated suspension of treatment for a few days, no severe side effects were observed. No partial or complete remission was seen. Eight patients (50%) showed a CT-verified status of "no change" according to World Health Organization criteria for at least 8 weeks. Median survival time in all patients was 5.6 months (range 1.5 to 26.5 months). Analysis of multidimensional evaluation of quality of life showed a stable course of disease in 7 patients. All except two patients claimed that mistletoe had a positive effect on their quality of life, with an obvious decline only during the last weeks of life. These results indicate that mistletoe is not able to significantly influence tumor growth in advanced pancreatic carcinomas. However, mistletoe treatment can stabilize quality of life, and therefore may help patients to maintain adequate life quality in their few remaining months.     

Management of the clinically positive neck in organ preservation for advanced head and neck cancer

An 82-year-old man was treated with isoniazid (INH) because of a low-grade fever. On the 9th day of treatment, dry coughing and general malaise developed. On the 30th day, he was admitted to our hospital. A chest-X ray film showed infiltrative shadows in the right middle and lower lung fields, but a chest CT scan showed an abnormal lung density in the right lower lobe. Abnormal laboratory findings included leucocytosis, liver dysfunction, hypoxemia, low vital capacity, low diffusing capacity and a high level of C-reactive protein. A differential cell count of the bronchoalveolar lavage fluid (BALF) showed many neutrophils and lymphocytes; examination of a specimen obtained by transbronchial lung biopsy (TBLB) revealed edema of alveolar walls, lymphocyte infiltration, and proliferation of type II alveolar epithelial cells. A drug lymphocyte stimulation test (DLST) against INH was positive. After discontinuation of INH, symptoms resolved, laboratory findings became normal, and the infiltrative shadows in the right middle and lower lung fields disappeared. The clinical course and the findings of BALF, TBLB, and DLST suggested the diagnosis of pneumonitis caused by INH.     

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer

BACKGROUND: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.     

Concurrent Taxol and split-course accelerated radiotherapy for advanced head and neck cancer

AIM: The aim of this study was to investigate feasibility and toxicity of fractionated paclitaxel administration concurrently with accelerated radiotherapy in the treatment of advanced head and neck cancer. PATIENTS AND METHODS: Patients with a proven histology of inoperable head and neck carcinoma were eligible for this study. Between July 1994 and August 1995, 12 patients with stage IV (UICC) tumors were treated. Patients were required to have normal end-organ function. Exclusion criteria included: age > 70 years, metastatic disease, performance status (Karnofsky < 70), major intercurrent medical disorders, and previous chemotherapy. External radiation was delivered twice a day at 1.5 Gy per fraction, specified to the reference point (ICRU 50), with a minimum interfraction interval of 6 hours. The accelerated scheme was split into 2 courses by a rest period of 9 days (including weekends) after administration of 30 Gy within 2 weeks. After 39 days a total dose of 72 Gy was reached. Paclitaxel (30 mg/m2/d) was administered as a continuous intravenous infusion over a period of 3 hours on days 1 to 5 and 29 to 33 of radiation therapy. All patients received premedication to avoid allergic reactions and circulatory monitoring was used routinely. RESULTS: Radiochemotherapy was completed in 10 patients with 8 complete and 2 partial remissions. Most important toxicity was a short period of neutropenia, which occurred 3 to 6 days after chemotherapy and was associated with fever in 9 cases. During paclitaxel infusion there was a significant but clinically not relevant increase in blood pressure and a decrease in heart rate. No acute cardiac effects occurred and no hypersensitivity reaction was seen. CONCLUSIONS: This regimen demonstrates a high activity in locally advanced head and neck cancer. Neutropenia associated with fever was the major dose limiting toxicity.     

Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck

BACKGROUND: To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks. RESULTS: Twenty-four patients with a median age of 59 years (range 42-74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%-42%). The main toxicity was hematological: neutropenia grade 3-4 in 28% of the cycles and thrombocytopenia grade 3-4 in 16%. The most significant non-hematological toxicity was asthenia grade 2-3 in 24% of the cycles. CONCLUSIONS: This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.     

Control of advanced chemodectomas of the head and neck with irradiation

Long-term follow-up of 15 patients treated with definitive radiotherapy for advanced glomus tumors of the head and neck is presented. Disease was locally controlled in all patients. A prescribed dose above 4,500 cGY did not improve treatment results. Radiation therapy remains the treatment of choice for advanced glomus tumors.     

Immunotherapy of head and neck cancer

Understanding the mechanisms responsible for photodamage to the skin is most important for dermatology. 3-D cultures have been used as tools to mimic the in vivo situation for several years. We irradiated such a system containing human dermal fibroblasts cultured in collagen gels, a well-known model considered to be a dermal equivalent, which reproduces the interaction between cells and the surrounding extracellular matrix. The effects of solar irradiation (315-800 nm) on the steady-state levels of the mRNAs of extracellular matrix components (type I and III collagens) and their degrading enzymes (interstitial collagenase, MMP-1 and stromelysin 1, MMP-3) were measured. Exposure to low levels of solar radiation (0-10 J cm-2 in the UVA, i.e. suberythemal UVA doses) caused a transient decrease in type I procollagen mRNA, an increase in MMP-mRNA, and no change in type III procollagen mRNA steady-state levels. These results describe the early changes in the connective tissue of the skin following exposure to low-level solar stimulation, and may help explain the long-term changes in photodamaged skin.     

Chemoprevention of head and neck cancer

The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of exocrine and endocrine pancreas was investigated in conscious sheep. Intravenous infusions of PACAP-27 and PACAP-38 (1, 3, and 10 pmol/kg/min) for 10 min during phase II of the duodenal migrating myoelectric complex accelerated pancreatic protein and amylase outputs dose-dependently. The responses in enzyme secretion to both PACAPs at the highest doses were inhibited significantly by atropine infusion (14.4 nmol/kg/min). Vasoactive intestinal polypeptide (VIP) at 3 pmol/kg/min significantly accelerated protein but not amylase outputs, although the response to the highest dose was not significantly influenced by atropine. PACAP-27 and VIP increased pancreatic juice flow and bicarbonate output dose-dependently; however, the responses to the highest dose were not altered significantly by atropine. On the other hand, intravenous injection of PACAP-38 (100 pmol/kg) did not influence basal plasma concentration of insulin, glucagon, and glucose. Moreover, PACAP-38 (1-100 pmol/kg) altered neither pancreatic endocrine response to intravenous infusion of glucose (20 mumol/kg/min) not that to n-butyric acid (33 mumol/kg/min). These results suggest that PACAP contributes to the regulation of exocrine secretion of the ovine pancreas but not to endocrine secretion. PACAP appears to accelerate pancreatic enzyme secretion mostly via the cholinergic nerves.     

Amifostine: a radioprotector in locally advanced head and neck tumors

Patients with locally advanced head and neck tumors were treated +/-amifostine (200 mg/m2, i.v.) before radiotherapy (5x 2 Gy, for 6 weeks). A significant decrease in side effects (p=0.034) using the oral assessment score and duration of mucositis (p=0.02) in the amifostine group was observed. Amifostine is feasible and effective, decreasing acute and late side effects in patients with head and neck tumors.     

Chemoprevention in head and neck cancer: basic science and clinical application

As cure rates in childhood acute lymphoblastic leukemia edge toward 80%, the focus of research is shifting to better means of identifying and treating resistant cases. This new emphasis has stimulated progress in several areas. Recent findings suggest that poor early responses to therapy and detection of minimal residual disease at the postremission induction period by immunologic methods are reliable indicators of an adverse prognosis warranting modification of treatment. In this regard, timely administration of intensified chemotherapy, including a second reinduction/intensification phase, may nullify the adverse prognosis conferred by a delayed response to induction therapy. Comparative analysis of survival outcomes in T-cell patients who received chemotherapy or cranial irradiation (12 Gy) to prevent overt leukemia in the central nervous system suggests that the latter modality should be retained for cases with leukocyte counts > 100 x 10(9)/L. Recent innovations in histocompatibility matching, prevention of graft-versus-host disease, and antiviral prophylaxis have enhanced the applicability of hematopoietic stem cell transplantation, making this procedure available to candidates lacking matched sibling donors. Finally, demonstration that acute lymphoblastic leukemia has an angiogenic phase in bone marrow raises the possibility of effective treatment with antiangiogenic agents, such as endostatin. Remaining challenges in the treatment of childhood leukemia include 1) the development of specific and more effective therapy for high-risk cases and 2) the reduction of long-term complications associated with intensive chemotherapy and cranial irradiation.