Susan Groshen

Primary osteogenic sarcoma: Eight-year experience with adjuvant chemotherapy

SummarySince October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.

Improved control of cisplatin‐induced emesis with high‐dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients

A series of consecutive trials were undertaken to determine whether higher doses of intravenous metoclopramide and combinations of metoclopramide, dexamethasone, and diphenhydramine would improve antiemetic control or decrease treatment‐related side effects in patients receiving cisplatin at 120 mg/m2. Metoclopramide and dexamethasone were studied because of their proven efficacy as single agents and their differing mechanisms of action and side effects. Diphenhydramine was used because of its possible antiemetic properties and its ability to control acute dystonic reactions. Two hundred fifty‐five patients who had never received chemotherapy or antiemetics were observed in the hospital for the 24 hours following cisplatin administration. The addition of dexamethasone or dexamethasone plus diphenhydramine to intravenous metoclopramide 2 mg/kg produced both improved antiemetic control and a decrease in treatment‐associated diarrhea (P = 0.002). The use of metoclopramide alone at a dose of 3 mg/kg for only two doses appeared as effective as 2 mg/kg for five doses. When dexamethasone and diphenhydramine were given with metoclopramide 3 mg/kg for two intravenous dosages, 81% of patients experienced no emesis and 93% had two or fewer vomiting episodes. The antiemetic results of this 2‐hour “short‐course” regimen were superior to metoclopramide 2 mg/kg, with (P = 0.002) or without (P = 0.0001) dexamethasone and diphenhydramine. It was concluded that combinations of metoclopramide plus dexamethasone plus diphenhydramine improve antiemetic control, facilitate the usage of higher doses of metoclopramide, and decrease the incidence of treatment‐related side effects.

Antiemetic control and prevention of side effects of anti‐cancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone. A double‐blind, randomized trial

Combinations of metoclopramide and dexamethasone given intravenously control vomiting caused by high doses of cisplatin. Lorazepam and diphenhydramine are useful adjuncts to antiemetics. In a double‐blind trial, 120 patients receiving high‐dose cisplatin (120 mg/m2) for the first time were randomly assigned to receive either lorazepam (1.5 mg/m2) or diphenhydramine (50 mg) intravenously, 45 minutes prior to cisplatin. In addition, all patients received intravenous dexamethasone (20 mg) 40 minutes prior to chemotherapy along with metoclopramide (3 mg/kg) 30 minutes before and 90 minutes after cisplatin. Patients were directly observed in the hospital after cisplatin administration and completed a subjective assessment questionnaire. Overall, 60% of patients experienced no vomiting, and 83% had two or fewer emetic episodes during the study. There were no significant differences in objective antiemetic control between the two regimens. Only 3% of patients receiving lorazepam experienced treatment‐related restlessness as opposed to 19% given diphenhydramine (P = 0.007). Less recall of chemotherapy administration (P < 0.001), more sedation (P = 0.003), and transient enuresis while sedated (P = 0.0002) were characteristic of patients receiving lorazepam. Patient‐generated ratings revealed less anxiety (P = 0.0001) for those individuals given the lorazepam‐containing combination. Both regimens were well accepted, with 89% of patients receiving the lorazepam combination and 83% of those given the diphenhydramine regimen wishing to receive the same drugs in the future. Some degree of delayed vomiting occurred in 85% of patients during the 4‐day period following this study. During the time that patients are at the greatest risk for emesis, the 24 hours immediately following cisplatin, three drug antiemetic combinations of either lorazepam or diphenhydramine with metoclopramide plus dexamethasone stopped cisplatin‐induced emesis for the majority of patients and lessen other treatment‐related side effects. Less restlessness and anxiety were observed among individuals receiving the lorazepam‐containing combination.

Subject-reported compliance in a chemoprevention trial for familial adenomatous polyposis.

A high level of compliance with an assigned treatment regimen is fundamental to accurate assessment of treatment effectiveness in any clinical trial. If compliance is poor, an effective treatment may be confounded by inadequate delivery of the regimen. Although much research has focused on broad aspects of compliance dealing with clinical therapeutic situations, there was a need for further research dealing specifically with adherence issues in a long-term chemoprevention trial since subject motivation in the latter is likely to differ from that of the former. Examining subject-reported compliance over the first 2-year treatment periods of a long-term chemoprevention trial for familial adenomatous polyposis, it was found that (1) compliance decreased over time, (2) fiber compliance was lower than vitamin compliance, and (3) four explanatory variables which may be amenable to individualized study-team interventions emerged as useful prognosticators of fiber compliance.

Ferritin in Neuroblastoma. Impact of Tumor Load and Blood Transfusions

Serial serum ferritin (SF) levels were measured in 36 patients with neuroblastoma seen at Memorial Sloan-Kettering Cancer Center (MSKCC) between January 1981 and December 1982. The significance of the associations among SF, stage and extent of disease, number of blood transfusions, liver function, serum iron (Fe), total iron-binding capacity (TIBC), and transferrin saturation was investigated. Although a dominant statistical correlation was found between SF and number of blood transfusions, the results suggest that amount of disease contributes to increasing SF levels. Serum ferritin levels increased on average in a linear fashion with number of blood transfusions in patients free of disease or with minimal disease. In patients with bulky disease, this increase was exponential (p value less than 0.01). Application of a reverse hemolytic plaque assay to the analysis of ferritin secretion by cells demonstrates that tumor cells do secrete ferritin in vitro.

Blood transfusion and lung cancer recurrence

Recent reports have suggested that perioperative blood transfusions may adversely affect prognosis after resection of non-small cell lung cancer (NSCLC). To determine the impact of perioperative transfusion on the recurrence-free interval, the status of 352 patients who underwent pulmonary resection for pathologic Stages I and II NSCLC was investigated. Transfused patients were significantly older than untransfused patients (P = 0.0009) but were not significantly different in sex distribution (P = 0.12) or tumor stage (P = 0.09). Recurrence was not significantly different in transfused patients when compared with patients who received no blood (P = 0.23) even when stratified for stage (Stage I, P = 0.58; Stage II, P = 0.14). Furthermore, the number of units transfused was not associated with time to tumor recurrence (P = 0.58). Contrary to other reports, these results do not support the contention that perioperative blood transfusion is significantly associated with decreased recurrence-free survival.

Chemoprevention Studies in Familial Polyposis

Familial polyposis is a classic prototype of hereditary human precancer. Patients with polyposis coli were chosen for our studies of chemoprevention because the precursors and histology of sporadic large bowel cancer are mirrored and truncated in time by polyposis. One of several clearly defined precancerous lesions of genetic origin, polyposis, is characterized by the development of numerous adenomas of the large bowel at a young age, with a risk approaching 100% of eventually developing single or multiple adenocarcinomas (1). Familial polyposis is transmitted as an autosomal-dominant disorder with a high degree of penetrance (2), and occurs at an expected frequency of 1 in 6850 to 1 in 23,790 live births (2,3). The study of environmental factors in the more dynamic setting provided by polyposis may identify modes of chemoprevention relevant to sporadic large bowel cancer, as well as provide this information in less time. Thus, it is hypothesized that the important genetic mutational event requires subsequent promotional events for the induction of adenomas and cancer and that these promotional events can be blocked by chemopreventive agents.

Clinically Significant Correlations between Blood Transfusions, Ferritin and Prognosis in Neuroblastoma

Abstract The significance of the correlations among serum ferritin (SF), stage, extent of disease and number of blood transfusions was investigated in 36 patients with neuroblastoma seen at MSKCC between January 1981 and December 1982. Although a dominant statistical correlation was found between SF and number of blood transfusions, the results suggest that amount of disease contributes to increasing SF levels. Application of a reverse hemolytic plaque assay to the analysis of ferritin secretion by cells demonstrates that tumor cells do secrete ferritin in vitro .