Practical guidelines for routine intensity-modulated radiotherapy verification: pre-treatment verification with portal dosimetry and treatment verification with in vivo dosimetry.

The purpose of this work is to provide guidelines for the routine use of portal dosimetry and in vivo diode measurements to verify intensity-modulated radiotherapy (IMRT) treatments. To achieve tolerance levels that are sensitive enough to intercept problems, both the portal dosimetry and the in vivo procedure must be optimised. Portal dosimetry was improved by the introduction of an optimised two-dimensional (2D) profile correction, which also accounted for the effect of backscatter from the R-arm. The scaled score, indicating the fraction of points not meeting the desired gamma evaluation criteria within the field opening, was determined as the parameter of interest. Using gamma criteria of a 3% dose difference and 3 mm distance to agreement, a "scaled score" threshold value of 1.5% was chosen to indicate excessive tongue and groove and other problems. The pre-treatment portal dosimetry quality assurance (QA) does not encompass verification of the patient dose calculation or position, and so it is complemented by in vivo diode measurements. Diode positioning is crucial in IMRT, and so we describe a method for diode positioning at any suitable point. We achieved 95% of IMRT field measurements within ±5% and 99% within ±8%, with improved accuracy being achieved over time owing to better positioning. Although the careful preparation and setup of the diode measurements can be time-consuming, this is compensated for by the time efficiency of the optimised procedure. Both methods are now easily absorbed into the routine work of the department.

Patients' pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea.

Based on extensive research with animals, classical conditioning theorists have come to regard contingency as the primary factor in the development of conditioned responses. However, recent experimental work with humans has suggested the possibility that participant expectations may also directly contribute to the development of conditioned responses. To date, this phenomenon has not been investigated in clinical settings. Anticipatory nausea (AN) in chemotherapy patients, widely viewed as the best established example of classical conditioning in clinical medicine, provides an opportunity to examine the contributions of patient expectations to the development of a conditioned response outside the laboratory. The present study of 59 breast cancer patients supported the hypothesis that pretreatment patient expectations make a significant (p < .03) contribution to the development of AN after statistically controlling for the strongest conditioning predictor, contingency. These data imply that patient expectations should be considered when evaluating conditioned responses to aversive medical treatments.

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients.

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.

The combined use of radiation therapy and lonidamine in the treatment of brain metastases.

Lonidamine is an indazole carboxylic acid that has been shown to be synergistic with radiotherapy (RT) in tissue culture and animal models. Clinical experience has shown that lonidamine is well-tolerated, and appears to potentiate the activity of conventional chemotherapy in the treatment of brain metastases. A prospective randomized trial was undertaken to evaluate the use of lonidamine in combination with RT in the treatment of brain metastases. All patients received 3000 cGy of whole brain radiotherapy (WBRT). Fifty eight patients were enrolled; 31 received lonidamine plus WBRT and 27 received WBRT alone. There was no significant difference in response rate or survival between the treatment groups. Lonidamine blood levels were measured in 30 of the 31 patients who received the drug, and were therapeutic (greater than or equal to 15 micrograms/ml) in 50%. Survival and response rate were unaffected by the presence or absence of a therapeutic lonidamine level. The most common side-effects of lonidamine were myalgia, testicular pain, anorexia, and ototoxicity; however, only 2 patients had to discontinue the drug because of intolerable myalgias. No serious organ toxicity or myelosuppression was observed.

Prevalence, predictors, and course of anticipatory nausea in women receiving adjuvant chemotherapy for breast cancer.

Factors related to the prevalence, prediction, and course of anticipatory nausea (AN) in women (n = 77) receiving adjuvant chemotherapy for breast cancer were examined. Using a prospective longitudinal research design, patients were interviewed both before and after each chemotherapy infusion. Fifty-seven percent of the patients developed AN. These patients were characterized by more severe gastrointestinal side effects following the initial infusion and greater expectations for experiencing chemotherapy-related nausea. A more rapid development of AN was related to a history of experiencing nausea across a greater variety of situations, higher IV drug doses, and less infusion-related anxiety at the initial infusion. Although AN occurred intermittently across treatment sessions, severity was constant. Results provided strong support for the hypothesis that classical conditioning processes are instrumental in AN acquisition. The role of anxiety in the development of AN is considered as are clinical implications for the prevention of AN and recommendations for future research.

Nonpharmacologic factors in the development of posttreatment nausea with adjuvant chemotherapy for breast cancer.

A prospective, longitudinal design was used to determine the role of nonpharmacologic factors in the development of posttreatment nausea (PTN). Forty-five women with no previous chemotherapy experience who were receiving a single regimen of adjuvant chemotherapy for breast cancer were interviewed before and after their first six infusions. Seventy-one percent of patients developed PTN. The PTN was related to the following: patients' physical status at the onset of treatment; heightened anxiety during infusions; susceptibility to nausea and vomiting after eating certain foods; and expectations of developing chemotherapy-related nausea. Anxiety during infusions, susceptibility to nausea and vomiting, and expectations of side effects also accounted for differences in the frequency, intensity, and severity of PTN. These findings offer strong support for the view that nonpharmacologic factors contribute to individual differences in gastrointestinal responses to chemotherapy.

Phase I and clinical pharmacologic evaluation of Lonidamine in patients with advanced cancer.

Lonidamine was studied in 31 patients with different types of advanced cancer. With one exception, patients were pretreated. Lonidamine was given at 6 dosage levels from 180 to 520 mg/m2 for at least 28 days. No toxicity on hematopoietic function was observed. Side effects consisted mostly in musculoskeletal discomfort, testicular pain in males and a reversible ototoxicity. In 2 patients conjunctivitis and photophobia occurred. Plasma Lonidamine levels were measured in 14 patients. Peak concentrations were observed from 1 to 2 h after administration and ranged from 3 to 35 micrograms/ml. Objective antitumoral effects were observed in only 2 patients with mycosis fungoides; a 3rd patient with mycosis fungoides was considered to have stable disease.

Phase II evaluation of m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) in patients with adenocarcinoma of the pancreas.

m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide, a substituted acridine derivative, was administered to 27 patients with adenocarcinoma of the pancreas. The dose ranged from 90-210 mg/m2/course. The toxic effects were primarily hematologic. Twenty-four of the patients were evaluable for response. These patients received a median of 2 doses (range 1-7). The median time from diagnosis to therapy was 2 months (range 0-16). Two patients achieved an MR lasting 4 and 2 months, respectively. Two patients had stabilization for 6 and 3 months. The median survival for all patients was 3 months. Survival distribution for patients with prior chemotherapy versus no previous therapy was not significantly different (p = 0.5). This study suggests that m-AMSA has little value as a single agent in the treatment of adenocarcinoma of the pancreas.

Phase II trial of 10-deaza-aminopterin in patients with advanced colorectal cancer.

Twenty-two patients with advanced colorectal cancer were treated with 10-deaza-aminopterin given intravenously twice weekly for four doses beginning at 15 mg/m2. Twelve patients had no prior chemotherapy. Dose-limiting toxicity was mucositis. Tumor regression was not seen in any patient.

Endocrine consequences of CMF adjuvant therapy in premenopausal and postmenopausal breast cancer patients.

The effect of CMF adjuvant therapy (cyclophosphamide, methotrexate, and 5-fluorouracil) on endocrine function was investigated in breast cancer patients. CMF therapy resulted in suppression of ovarian function in some premenopausal patients but pituitary function and adrenal function were unaffected. There was an inverse relation between age and duration of treatment required to induce ovarian suppression. Although amenorrhea was achieved within 2-4 months in patients aged 40 years or older, younger women required larger cumulative doses of cytotoxic drugs to induce ovarian dysfunction. Patients younger than 30 years of age continued to menstruate with no major alteration in hormonal levels resulting from the cytotoxic drugs. CMF therapy had no significant effect on hormonal levels in postmenopausal patients indicating that in this group therapeutic response is not mediated via the endocrine system.

Phase I trial of 10-deaza-aminopterin in patients with advanced cancer.

The clinical effects of 10-deaza-aminopterin, an inhibitor of dihydrofolate reductase with a better therapeutic index against several murine tumors than that of methotrexate, were examined during the course of a phase I study in patients with advanced malignant neoplasms. Three escalating dose schedules were explored: single iv injections once daily, single iv injections twice weekly, and continuous infusion. The maximum tolerated doses were: single injections at a dose of 7 mg/m2/day for 5 days; single injections at a dose of 15 mg/m2 twice weekly for four to six doses; and continuous infusion at a dose of 3 mg/m2/day for 5-6 days in patients with solid tumors and until bone marrow hypoplasia in patients with leukemia. Mucositis was dose-limiting in all schedules. Occasionally, mild leukopenia, thrombocytopenia, and skin rash were noted. A minor antitumor response was seen in a patient with gallbladder carcinoma. Marked leukemic cell kill was observed in several patients with acute leukemia or blastic phase of chronic myelogenous leukemia. Disease-oriented phase II trials are planned at this Center for several tumor varieties.

A clinical trial of amygdalin (Laetrile) in the treatment of human cancer.

One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a "metabolic therapy" program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.

A phase II evaluation of m-AMSA, 4'-(9-acridinylamino) methanesulfon-m-anisidide, in patients with breast cancer.

A phase II study of m-AMSA, 4'-(9-acridinylamino) methanesulfon-m-anisidide was carried out in 40 patients with metastatic carcinoma of the breast. The drug, at a dose of 120 mg/m2, was given as a single intravenous injection every 3 weeks. One patient achieved a partial remission of 4 months duration; three patients experienced minor response. This study suggests that the true major response rate of advanced breast cancer to m-AMSA given in this manner is less than 13% at the 95% confidence level.

Phase I trial of metoprine in patients with advanced cancer.

The effects of metoprine administered orally every 2 weeks were studied in 71 evaluable adult patients with advanced malignant tumors. Two escalating dose schedules were explored in this phase I evaluation: (a) doses ranging from 20 to 65 mg/m2 without scheduled leucovorin, and (b) doses ranging from 100 to 300 mg/m2 with scheduled iv leucovorin. Thrombocytopenia was dose-limiting at 65 mg/m2 in the low-dose schedule; CNS toxicity was dose-limiting at 300 mg/m2 in the high-dose schedule. Occasionally leukopenia and mild nausea or vomiting were noted. Therapeutic responses were observed in patients with mycosis fungoides, non-Hodgkin's lymphoma, and adenocarcinoma of unknown origin. Phase II (disease-oriented) studies can appropriately be initiated with fortnightly metoprine at 50 mg/m2 without leucovorin. In the high-dose schedule, 225 mg/m2 of metoprine with 75 mg/m2 of iv leucovorin at 24 hours appears appropriate for good-risk patients; in marginal-risk patients, two doses of leucovorin should be given: 75 and 37.5 mg/m2 at 24 and 96 or 168 hours, respectively.

Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside.

In conventional clinical use, cytosine arabinoside (ara-C) is rapidly deaminated by pyrimidine nucleoside deaminase to the nontoxic compound uracil arabinoside. Tetrahydrouridine (THU) effectively inhibits this enzymatic degradation but is by itself nontoxic. This study demonstrates that concomitant administration of THU markedly increases the myelosuppressive potency of ara-C. When 25 or 50 mg/kg of THU iv and 0.1--0.2 mg/kg of ara-C iv are given daily x 5 days, they produce moderate-to-severe leukopenia and mild-to-moderate thrombocytopenia. A dose of 25 mg/kg of THU with 0.1 mg/kg of ara-C iv daily x 5 days appears appropriate for phase II studies; it produces myelosuppression equivalent to that produced by 3 mg/kg/day x 5 days of ara-C alone. No toxicity occurred with this combination that would not have been expected from ara-C given alone in an equitoxic dose. Although THU and ara-C produced a reduction in peripheral blood and bone marrow blast cells in eight of nine patients with acute leukemia, bone marrow remission did not occur in any of these heavily pretreated patients.

Phase I trial of vindesine in patients with advanced cancer.

A phase I evaluation of vindesine was carried out in 69 adult patient with advanced malignancies. Two escalating dose schedules were explored: (a) a single dose every 7--14 days, and (b) daily injections X 5--10 days as tolerated. The main toxic effects were myelosuppression, alopecia, paresthesia, asthenia, myalgia, and hyporeflexia. Antitumor activity was seen during this phase I study in patients with leukemia, lymphoma, and testicular neoplasms. Disease oriented phase II trials of 3--4 mg/m2 every 7--14 days or 1.3--2.0 mg/m2/day X 5--7 days every 3 weeks would be appropriate.