John J. Stuart

Written informed consent in patients with breast cancer

One hundred breast cancer patients, 35 adjuvant and 65 advanced, were interviewed 0–24 months after the start of chemotherapy to assess their knowledge and perceptions of the purposes, risks and benefits of treatment. Prior to therapy, all had been given verbal explanations and had signed informed consent forms explicitly detailing drugs, objectives and possible adverse effects of therapy. Seventeen percent of adjuvant and 29% of advanced patients were unable to name any of their drugs. While most patients recognized distressing side effects such as nausea and hair loss, less than 50% were aware of the potentially lethal complications of infection and bleeding. While the purpose of adjuvant therapy was cure, only 29% of the adjuvant patients were aware of this. In contrast, 35% of the advanced patients incorrectly stated that they were told their therapy was potentially curative. Explanations given by a nurse in addition to a physician were better understood than those given by a physician alone. We conclude that, in spite of intensive efforts at improving informed consent procedures, current results are unsatisfactory.

Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial.

Adriamycin is of noteworthy efficacy in the treatment of metastatic breast cancer. Its role in combination regimens is under investigation. One hundred seventy‐five women with advanced breast cancer were entered into a prospectively randomized trial comparing two five‐drug regimens. Regimen CMFVP consisted of cyclophosphamide (C), methotrexate (M), 5‐fluorouracil (F), vincristine (V), and prednisone (P). Regimen CAFVP was identical but substituted Adriamycin (A) for methotrexate. Twenty‐seven patients were disqualified; 148 were evaluable. With CMFVP the complete response rate (CR) was 11%, and the partial response rate (PR) was 46%; with CAFVP, CR was 13% and PR was 45%. Duration of response tended to be slightly longer for patients on the Adriamycin arm. The median survival for CR and PR patients with CMFVP was 20.2 months, which was shorter (p =.07) than the 33 month median survival with CAFVP. Although statistical significance was not reached at the 5% level, the increased survival of responders on the Adriamycin regimen supports the data of other studies which suggest that first line combination chemotherapy in advanced breast cancer should include Adriamycin. Cancer 42:2141–2148, 1978.

A randomized comparative trial of chemotherapy and irradiation therapy for stage ii breast cancer

One hundred fifty‐eight evaluable patients with Stage II carcinoma of the breast with positive lymph nodes were treated either with adjuvant chemotherapy or irradiation therapy followed by chemotherapy. Patients were randomized to test the effectiveness of L‐phenylalanine mustard (L‐PAM) with and without postoperative irradiation therapy (R.T.) against cyclophosphamide, 5‐fluorouracil, and methotrexate (CMF) with and without postoperative irradiation therapy in decreasing the frequency of recurrence. No significant difference was observed between L‐PAM as compared with R.T. plus L‐PAM (P = 0.85). The difference between CMF and R.T. plus CMF was significant in support of CMF alone (P = 0.04). The frequency of recurrence between R.T. plus L‐PAM and R.T. plus CMF showed no difference. A comparison of the chemotherapy only regimens showed an advantage of CMF over L‐PAM (P = 0.05). Both the delay in starting chemotherapy and the significant decrease in percent optimal drug dosage during the first six cycles of therapy are factors that may influence the high frequency of relapse observed in the R.T. plus chemotherapy groups. Of the four treatments, CMF has the lowest frequency of recurrence.

Treatment of advanced non-Hodgkin's lymphoma with vincristine infusion

Twenty‐five patients with a variety of histologic types of advanced non‐Hodgkins lymphoma refractory to previous chemotherapy were entered into a trial of vincristine infusion. Patients received 5‐day courses of vincristine 0.25 mg/m2/day by continuous intravenous infusion after an initial 0.5 mg intravenous bolus injection. Courses were repeated every 3 weeks. Objective responses were observed in nine patients (36%), all of whom had previously received vincristine given by conventional bolus injection. A complete response occurred in a patient with diffuse mixed histiocytic lymphocytic lymphoma, and partial responses were observed in eight patients with the following histologic types: diffuse poorly differentiated lymphocytic (4); nodular poorly differentiated lymphocytic (2); diffuse mixed histiocytic lymphocytic (1); and diffuse histiocytic (1). Duration of response lasted from 1.2 to 16.2 months (mean, 4.4 months). The principal complication of therapy was mild‐to‐moderate neurotoxicity; this occurred in 12 patients (48%) who received a total of 54 courses of vincristine infusion. Hematologic toxicity was minimal and nausea/vomiting did not occur. Vincristine infusion may afford palliation for patients with advanced non‐Hodgkins lymphomas who have become refractory to standard chemotherapeutic regimens even if they have received prior vincristine by conventional bolus injection. These data suggest the possibility of enhancing the therapeutic efficacy of vincristine in the treatment of non‐Hodgkins lymphoma by use of an infusion technique.

Informed consent: patient information forms in chemotherapy trials.

DOCUMENTATION OF INFORMED CONSENT BY patients entering clinical trials is an ethical and legal necessity. Federal regulations and judicial opinions have led to increasingly lengthy, detailed “consent” forms, yet published studies demonstrate that patients remain confused about the nature and anticipated consequences of study entry. It has been suggested that more detail may even alarm or further confuse patients. Seventy-five women undergoing chemotherapy for advanced breast cancer participated in this study which assessed patient preference for long-, medium-, or short-form length, and whether form length preference correlated with patient characteristics or indicators of patient autonomy in decision-making or physician dependency. Patient preferences for information were not predicted by the patient autonomy or physician dependency scores or by age, marital status, or level of education. The majority of patients expressed a preference for more detailed information about their treatment, yet a majority of patients given detailed forms answered questions basic to the study design incorrectly, irrespective of educational level. The increased detail included in the long forms was not reported to increase stress compared to the short forms. Patient information forms are a principal tool for informing patients for consent but if they are to perform their desired function they must be designed more carefully and evaluated more thoroughly than in the past.

Acquired von Willebrand disease associated with an inhibitor to factor VIII antigen and gastrointestinal telangiectasia

A patient with acquired von Willebrand disease and gastrointestinal telangiectasia is described. He presented with the recent onset of spontaneous hemorrhage and demonstrated a prolonged bleeding time, reduced factor VIII coagulant (FVIII:C), and undetectable factor VIII-related antigen (FVIIIR:AG) and ristocetin cofactor (FVIIIR:WF). Following transfusion of cryoprecipitate, there was a smaller than expected immediate increase in FVIII:C, FVIIIR:WF and FVIIIR:AG, with a rapid return to baseline levels and no secondary increase in FVIII:C. An inhibitor could be demonstrated in the patients plasma which markedly decreased the level of FVIIIR:AG in normal plasma whereas it only weakly decreased the activity of FVIIIR:WF and FVIII:C. The inhibitor was contained in the immunoglobulin G(IgG) fraction of plasma and lacked precipitating properties. This inhibitor demonstrates a specificity not previously seen in spontaneous antifactor VIII antibodies. Our report also demonstrates that ristocetin-induced agglutination of platelets is not always the most sensitive method for detecting an inhibitor in acquired von Willebrand disease.

Cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil in advanced prostatic cancer: A randomized trial

Thirty‐two evaluable patients with metastatic carcinoma of the prostate were entered into a prospective randomized trial comparing cyclophosphamide (CYC) with a combination of cyclophosphamide, methotrexate, and fluorouracil (CMF). Progressive disease after endocrine manipulation was noted in 97% (31/32) of patients before entry. Stable disease (S) was observed in 9 of 17 patients treated with CYC. One partial response (PR) and seven stable responses occurred in the 15 CMF patients. Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF. Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months. Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF, respectively. Toxicity was moderate, and no deaths were attributable to sepsis or bleeding. Almost all patients in this study had bone lesions as the dominant site of disease; this made objective assessment of response difficult. There was no significant improvement in response conferred by the combination regimen. Although patients with metastatic prostatic cancer may benefit from chemotherapy, impressive clinical responses are uncommon.

Clinical trial of pyridoxine to reduce vincristine neurotoxicity.

In a murine model system, pyridoxine has demonstrated protective properties during administration of lethal doses of vincristine (VCR). Subsequently, pyridoxine has been evaluated in patients receiving VCR during an adjuvant chemotherapy program for stage II carcinoma of the breast. The toxicities, cumulative VCR dosage, and percentage of ideal dosage observed in 24 patients receiving pyridoxine have been compared to those observed in 88 patients who previously received VCR without pyridoxine in the same chemotherapy program. All patients ideally were to receive VCR 1.0 mg/m2 weekly for 6-weeks with dose modification for neurotoxicity. Treatment patients received pyridoxine 1.5 grams p.o. daily in three divided doses during the 6-week course. The degree of neurotoxic manifestations of VCR was similar in the treatment and comparison patients. Absent to mild neurotoxicity was observed in approximately 70% of patients in both groups; moderate or greater neurotoxicity occurred in about 30% of patients in both groups. Full dosage (6.0 mg/m2) was attained in 8 (33%) treatment patients and 18 (24%) comparison patients (p=0.28). The mean percentage of ideal dosage of VCR was 84.6±10.8 in patients receiving pyridoxine and 81.9±21.6 in those given only VCR (p=0.59). Gastrointestinal and hematologic toxicities were similar in both groups. Pyridoxine in this dose and schedule afforded no protection from the neurotoxic side effects of VCR.

Coagulation studies in children with isolated recurrent epistaxis

IN 1 9 5 9, Schulman I reported on 34 children with recurrent epistaxis. Seventeen of these children had no personal or family history suggestive of a bleeding disorder. No coagulation abnormalities were found in this group. The other 17 children had multisymptomatic bleeding histories, or positive family history for a coagulation disorder, and all but one were shown to have hemorrhagic disorders. Schulman concluded that isolated, recurrent epistaxis was unlikely to be associated with coagulation disorders. In the past 20 years, advances in understanding and technology have increased our ability to identify mild bleeding disorders. We elected to re-evaluate prospectively a gr6up of children specifically referred for evaluation of isolated, recurrent epistaxis, to determine whether or not a significant number of youngsters with this problem have a mild bleeding disorder.

A randomized trial of adjuvant chemotherapy and immunotherapy in stage I and stage II cutaneous melanoma. An interim report

Seventy patients with Stage I and II malignant melanoma were randomized to treatment with either intravenous dacarbazine alone or intravenous dacarbazine plus intradermal injection of the methanol‐extracted residue of bacillus Calmette‐Guerin (BCG). Analysis of treatment failed to reveal a statistically significant difference between these two forms of treatment in Stage I and II patients. It is possible that chemoimmunotherapy may increase survival in Stage II patients, but this possibility should be interpreted with caution.