Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma.

PURPOSE: To evaluate the activity and toxicity of carmustine (BCNU) and cisplatin administered as a 72-hour continuous intravenous infusion before radiation in adults with newly diagnosed high-grade astrocytomas. PATIENTS AND METHODS: Fifty-two patients with a Karnofsky performance status greater than 60 and no prior antineoplastic therapy entered this protocol. The median age of the patients was 55 years. Eighty-eight percent had glioblastoma multiforme and 12% had anaplastic astrocytomas. BCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) were administered concurrently as a 72-hour infusion every 3 to 4 weeks. Radiation was begun 4 weeks after the third cycle of chemotherapy or earlier for progressive disease. Responses required a > or = 50% reduction in contrast-enhancing volume. RESULTS: Forty patients (77%) completed three chemotherapy infusions, five (10%) received two infusions, and seven (13%) received only one. Fifty-one patients completed radiation. Seventeen (42%) patients with measurable disease had a partial response (PR) to chemotherapy, 23 (53%) had stable disease (SD), and two (4%) had progressive disease (PD) on chemotherapy. The median survival time for all patients was 13 months. Survival rates at 1, 2, 3, and 5 years were 62%, 19%, 12%, and 5%, respectively. Grade III to IV leukopenia occurred in 32% of patients; 63% received platelet transfusions and 58% required RBCs. Neutropenic fevers were rare and no intracranial hemorrhages or treatment-related deaths were noted. Nausea, vomiting, peripheral neuropathy, hearing loss, and thromboembolic events were relatively common. CONCLUSION: This chemotherapy regimen appears to have significant activity and may prolong survival in adults with newly diagnosed high-grade astrocytoma.

Does intravenous methadone provide longer lasting analgesia than intravenous morphine? A randomized, double-blind study.

A prospective, randomized, double-blind trial was designed to compare the duration of analgesia produced by intravenous morphine and methadone. Patients with intractable cancer-related pain were studied for 5-6 days. One-eighth of the patient's daily opiate requirement was supplied as an i.v. infusion of either morphine or methadone over a period of 15 min. when initiated by the patient using a patient-controlled analgesia device. Dosing intervals, pain intensity assessments and toxicity were evaluated. Twenty-three patients were randomized; 18 were fully evaluable. Ten of the evaluable patients received morphine, 8 received methadone. Dosing intervals did not change over the 5 days for either group. The mean dosing interval for the last 10 doses was 3.9 +/- 0.85 h for patients receiving morphine and 3.9 +/- 1.6 h for patients receiving methadone (P = NS). One patient receiving morphine and one taking methadone required only 2-3 doses/day for pain control. Pain intensity and relief were similar for both groups. All patients had adequate analgesia as determined by at least a 50% difference in pain intensity at peak relief. The duration of pain relief when repeated intravenous doses of these analgesics were given was similar throughout the entire study period although morphine and methadone have different serum half-lives (3 vs. 25 h). Parenteral methadone does not offer a clinically significant increase in the duration of analgesia in patients with severe pain secondary to cancer.

Decreased phenytoin levels in patients receiving chemotherapy.

PURPOSE AND METHODS: Seizures and unexpectedly low phenytoin levels prompted a retrospective review of phenytoin doses and serum levels in patients with primary brain tumors following the administration of cisplatin and carmustine (BCNU) chemotherapy. RESULTS: All patients who received three or more cycles of this chemotherapeutic regimen required an increase in their maintenance phenytoin dose to maintain therapeutic phenytoin levels. The average increase in the daily phenytoin dose was 41% (range, 20% to 100%). In addition, 17 of 26 (65%) assessable chemotherapy cycles were accompanied by a greater than 20% decrease in phenytoin levels or an increase in phenytoin requirements. Significant changes in phenytoin levels occurred as early as two days after administration of chemotherapy and were seen exclusively in treatment cycles that contained cisplatin. Five additional cases were found in the literature in which serum phenytoin concentrations decreased after the administration of antineoplastic agents. CONCLUSIONS: These observations are important to physicians treating patients who are receiving phenytoin. Serious consequences can be avoided by expecting changes in phenytoin dosage requirements after the administration of chemotherapy, monitoring serum levels frequently, and making appropriate adjustments in phenytoin dosages. Prospective evaluations are needed to confirm these observations, to define the chemotherapeutic agents that predispose patients to these alterations in phenytoin's pharmacology, and to determine if drugs other than phenytoin are affected by the administration of chemotherapy.

Double-blind multiple-dose crossover study of the antiemetic effect of intramuscular levonantradol compared to prochlorperazine.

Twenty cancer patients who received chemotherapy were entered into a double-blind crossover design antiemetic study comparing 1 mg levonantradol, an investigational synthetic cannabinoid, to 10 mg prochlorperazine. Sixteen patients completed the crossover. For each antiemetic course, four doses of each study medication were given intramuscularly 2 hours before chemotherapy and then 2, 6, and 10 hours after chemotherapy administration. There were no statistical differences in patients' responses to levonantradol and prochlorperazine. The frequency of side effects was greater with levonantradol than with prochlorperazine. The most common side effect of levonantradol were somnolence, dry mouth, dizziness, tachycardia, postural hypotension, and blurred vision, while those for prochlorperazine were somnolence, dry mouth, and tachycardia.

Correlation of patient and caregiver ratings of cancer pain.

Undertreatment of cancer pain is widely recognized. This study sought to determine if inadequate communication about pain intensity between health care providers and their patients could represent a significant factor interfering with the control of cancer pain. One hundred and three consecutive patients with solid tumors and normal mental status examinations were screened within 48 hr during two study periods. The intensity of patient pain was assessed using a visual analogue scale (VAS) which was given to the patient, his/her primary care nurse, house officer and medical oncology fellow. Sixty-three percent of the patients were taking narcotic analgesics on admission to the hospital. Although there was a correlation between patient and health care provider ratings for the entire group, no statistically significant correlation between the patient's VAS pain score and that of his/her nurse, house officer, or oncology fellow was present in the 44 patients with VAS greater than or equal to 4.0. Agreement between patient and caregiver VAS scores was also examined. When patients rated their pain from 7-10 on the VAS scale, nurses, house officers, and oncology fellows would place their rating of the patient's pain in this range 7%, 20%, and 27% of the time, respectively. Improved correspondence was noted with lower patient VAS scores. This study demonstrates that health care provider impressions of patient pain are often quite different than those of the patient and that these discrepancies are most pronounced in patients with significant pain. The routine use of pain assessment tools, such as the VAS, could enhance patient-caregiver communication and improve care for patients with cancer pain.

A comparison of the Hopkins Pain Rating Instrument with standard visual analogue and verbal descriptor scales in patients with cancer pain.

A self-contained, portable, pain rating instrument that provides an immediate result for documentation purposes was developed to improve pain assessment in cancer patients. The Hopkins Pain Rating Instrument (HPRI) is a 5 x 20 cm plastic visual analogue scale (VAS) with a sliding marker that moves within a groove that measures 10 cm. The side facing the patient resembles a traditional VAS while the opposite side is marked in cm to quantify pain intensity. This psychometric study, which employed a descriptive correlational design, evaluated the reliability and validity of the HPRI by comparing it with a traditional VAS and verbal descriptor scale (VDS). Outpatients with and without pain and inpatients with pain rated their major pain site with the three instruments, which were presented in random order. This was followed by a mental status exam and re-rating of pain with the same instruments to assess test--retest reliability. Completing the study were 71 patients with a variety of cancers and a mean age of 52.8 years. Of these patients, 68% had pain and 54% were receiving opioid analgesics. The most common pain sites were the back, leg, and epigastric areas. On initial and repeat testing, there were high correlations between the HPRI and the VAS (r = 0.99, P less than 0.0001) and the VDS (r = 0.85, P less than 0.0001). The correlation coefficients for test--retest reliability for the HPRI, VAS, and VDS were 0.97, 0.97, and 0.94 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesic decision-making skills of nurses.

Administration of analgesics is a common nursing intervention for providing pain relief to patients with cancer. A sample of 177 nurses participated in a study to examine their decision-making skills when analgesic orders were changed. Nurses were given four clinical vignettes and reference materials to assist them in responding to the vignettes. Twenty-six percent of 708 responses provided by the nurses were answered correctly. Twenty-nine percent of the sample answered all four vignettes incorrectly. The majority (44%) answered only one vignette correctly. No statistically significant differences were found between correct answers and type of work setting, academic preparation, number of patients with cancer cared for per week, number of years employed as a nurse, recent clinical experience with the analgesics used in the vignettes, or the use of reference materials. These findings raise concerns that patients requiring analgesics may not receive an amount that adequately relieves their pain or avoids unnecessary toxicity.

Skills of medical students and house officers in prescribing narcotic medications.

Eighty-eight medical students and house officers were given patient management questions to assess their ability to convert from one narcotic regimen to an approximately equal analgesic dose of a second regimen. Only 8 percent of their answers were within the correct range, even though commonly used reference material was supplied to assist them in answering the questions. There were no significant differences in the responses of house officers from different medical specialties or among all the individuals at different educational levels. Correct answers to the patient management questions markedly increased after instruction on the use of a narcotic equivalency table. More emphasis on the importance of adequate pain control, better teaching of the pharmacology of narcotic analgesic drugs, and additional instruction on the use of narcotic equivalency tables are needed in medical school and house staff training programs.

Anticipatory nausea and vomiting: does it remain a significant clinical problem?

A study performed 5 years ago in our clinic revealed a prevalence rate of 31% for anticipatory symptoms. This finding is consistent with other investigations. It was hypothesized that more effective management of postchemotherapy nausea and vomiting and briefer chemotherapy regimens since the previous study would decrease the prevalence of anticipatory symptoms. The study reported in this article assessed the prevalence of anticipatory symptoms in 121 patients receiving parenteral chemotherapy over a 7-week period. The overall prevalence rate of 33% for anticipatory symptoms was not significantly different from the previous study or other investigations. Length of postchemotherapy nausea was significantly related to the report of anticipatory symptoms. However, the severity of symptoms reported in the investigation was mild. The prevalence in patients on adjuvant therapy for breast cancer was also significantly reduced from the previous investigation. It is concluded that although anticipatory symptoms commonly occur they are only rarely clinically significant.

Clonidine for anticipatory nausea and vomiting: a pilot study examining dose-toxicity relationships and potential for further study.

In preparation for studies of noradrenergic activity in anticipatory nausea and vomiting, we performed an open-dose study of clonidine to examine dose-toxicity relationships and indications of antiemetic activity. Nine patients, three each at 0.1, 0.2, and 0.4 mg/day, received clonidine twice a day for 5 days before chemotherapy. Unwanted effects, principally blood pressure reduction, dry mouth, and sedation, accumulated between 4 and 5 micrograms/kg/day. Four of eight evaluable patients had no anticipatory symptoms on clonidine. It is concluded that clonidine, at a dose of 4 micrograms/kg/day, might safely probe the role of noradrenergic activity in anticipatory nausea and vomiting.

Antiemetic efficacy of dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy.

We conducted a randomized, double-blind, crossover study comparing the antiemetic efficacy of dexamethasone and prochlorperazine in 42 patients with cancer who were receiving outpatient chemotherapy, mainly without cisplatin. Patients experienced significantly less nausea and vomiting with dexamethasone than with prochlorperazine (P less than 0.02 and less than 0.03, respectively). Twenty-five patients experienced no nausea with dexamethasone, as compared with 14 patients taking prochlorperazine (P less than 0.001). Similarly, 29 patients receiving dexamethasone did not vomit, as compared with 18 receiving prochlorperazine (P less than 0.001). Somnolence was the most frequent side effect, occurring in 60 per cent of patients receiving prochlorperazine and in 12 per cent of those receiving dexamethasone (P less than 0.001). Patients also experienced less suppression of appetite while receiving dexamethasone (P less than 0.02). We conclude that dexamethasone is an effective and safe antiemetic in patients receiving cancer chemotherapy without cisplatin.

Familial clustering of malignant astrocytomas.

Three of 32 consecutive patients with astrocytomas enrolled in an experimental chemotherapy protocol had at least one first degree relative with an astrocytoma. These patients did not have family members with an excess of malignancies, known exposure to a specific environmental factor, or a recognized neurocutaneous syndrome. In all three families, the illnesses temporally overlapped and the age of the patients affected in the second generation was less than those in the first generation. An estimation of the probability of developing astrocytomas in families with one affected individual strongly suggests a familial effect. Our observations, coupled with other cases reported in the literature, suggest that familial astrocytomas occur more frequently than is currently recognized. Identification and careful study of such families may provide important clues to the etiology of these malignancies.

Noradrenergic activity in anticipatory nausea.

Two studies were conducted to examine the hypothesis that noradrenergic activity is a cause of the anticipatory nausea associated with cancer chemotherapy. In the first study concentrations of plasma 3-methoxy-4-hydroxyphenyl-glycol (MHPG) on day 1 of cycle 5 of initial chemotherapy were significantly higher in patients with than without anticipatory nausea. To determine whether elevated MHPG reflected a clinically significant causative role for noradrenergic activity in anticipatory nausea, we conducted a randomized, double-blind, placebo-controlled, crossover trial of clonidine for anticipatory nausea. At a dose of clonidine that produced significant side effects and reductions of plasma MHPG, anticipatory nausea was improved only marginally. These studies do not support a causative role for noradrenergic activity in anticipatory nausea that can be reduced by clonidine with an acceptable therapeutic index.

Anticipatory nausea and vomiting in an ambulatory medical oncology population.

We studied the prevalence of anticipatory nausea (AN) and anticipatory nausea and vomiting (ANV) in an ambulatory medical oncology population by self-report questionnaire over 7 weeks. Thirty-eight of 123 (31%) patients receiving parenteral chemotherapy reported anticipatory symptoms (AN or ANV). Twenty-one (17%) patients reported ANV and 17 (14%) reported AN only. Patients receiving parenteral chemotherapy (N = 123) with anticipatory symptoms (N = 38) were younger (45.1 +/- SE 1.9 vs 55.5 +/- 1.45, P less than 0.001) and more likely to be female (82% vs 61%, P = 0.04), unmarried (47% vs 26%, P = 0.03), and receiving adjuvant chemotherapy for breast cancer (42% vs 7% P less than 0.001) than patients without anticipatory symptoms (N = 85). A greater proportion of patients with both postchemotherapy nausea and vomiting and anticipatory symptoms reported greater than 12 hours of postchemotherapy nausea (65% vs 39%, P = 0.01) and postchemotherapy nausea and vomiting (37% vs 12%, P = 0.01) after their most recent cycle of chemotherapy than did patients with postchemotherapy symptoms only. In structured interviews with 23 patients with anticipatory symptoms, 16 identified specific stimuli associated with AN or ANV, taste being the most frequently mentioned (ten of 16 patients) sensory modality. In our clinic, patients receiving adjuvant chemotherapy for breast cancer develop anticipatory symptoms frequently and represent a relatively homogenous sample for further studies.

Tastes associated with parenteral chemotherapy for breast cancer.

We employed a structured interview to retrospectively study tastes and vomiting associated with the parenteral components of cyclophosphamide, methotrexate, and 5-FU in 45 patients with stage II-IV breast cancer. Sixteen patients (36%) reported tastes which generally occurred in each cycle within 30 minutes of parenteral drug administration, lasted less than or equal to 1 hour, and were bitter. Five patients recalled that tastes seemed to produce vomiting. Tasting was significantly associated with postchemotherapy (P less than 0.01) but not anticipatory vomiting. Employing logistic regression techniques, tasting did not significantly improve prediction of anticipatory vomiting by postchemotherapy vomiting. Tastes may be produced by the action of plasma or salivary cyclophosphamide, methotrexate, and 5-FU on taste buds. While tastes might cause some vomiting, they are not necessary for it. Because this was a retrospective study with a small sample, these findings require confirmation.