Kasi S. Sridhar

A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma.

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.

Review of tests for monitoring doxorubicin-induced cardiomyopathy.

The objective of this review is to make physicians aware of new radionuclide methods to detect cardiac effects of chemotherapeutic drugs. This knowledge is important because of the limitations of the physical examination and the electrocardiogram for detecting early reversible cardiac damage. Presently left ventricular ejection fraction (LVEF) is routinely used to screen for cardiotoxicity. Since LVEF obtained by radionuclide angiocardiography is more accurate than the LVEF estimated by echocardiography, serial radionuclide LVEF monitoring is most commonly used to monitor cardiotoxicity. Diastolic measurements of left ventricular function (such as peak filling rate) are now being added to routine LVEF measurements to enhance standard radionuclide evaluation. This screening test should be done prior to beginning therapy and at appropriate points based on the baseline study, therapy scheme and the patients clinical status. At some centers, exercise LVEF methods are being used to determine if cardiac reserve is adequate for the patient to tolerate additional chemotherapy when cardiac injury may be present. Previously, endomyocardial biopsy was needed to detect and confirm early anthracycline cardiotoxicity. This invasive test may be replaced by a new noninvasive in vivo method using radioactive monoclonal antibodies against cardiac muscle (indium-111-antimyosin). Because cardiac failure has been associated with adrenergic neuron injury, it has been proposed that radioactive methyliodobenzylguanine may detect the adrenergic abnormality which may predict future development of congestive heart failure or sudden death months after therapy is discontinued. Advantages and disadvantages of these methods in evaluating cardiotoxicity, and an algorithm to optimally monitor antitumor therapy-induced cardiomyopathy are discussed.

Skeletal muscle metastases from lung cancer

Hematogenous metastases to the limb skeletal muscles are extremely rare. Better understanding of the mechanisms resulting in the relative resistance of skeletal muscle to metastases could have bearing on therapeutic interventions for prevention of metastases. Three patients with non‐small cell lung cancer and metastases in the proximal limb muscles are presented. Skeletal muscle metastases may present as painful masses in the proximal skeletal muscles. Subcutaneous and osseous metastases which are more frequent must be excluded by careful physical examination, bone scan and x‐rays. Computed tomography (CT) can confirm the location of the tumor within the fascial planes of skeletal muscles and may help in the accurate delineation of the radiation portal. The tumor can be diagnosed and more common causes, such as hematoma or abscess, can be excluded by thin needle aspiration with cytologic examination. Clinical recognition of metastases in this unusual site is important based on our report that total tumor dose of 3600 to 4200 cGy of radiation in fractions of 300 cGy, 5 days a week, is effective in palliation of swelling and pain.

Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas

Six men with either recurrent (n = 4) or unresectable (n = 2) squamous cell carcinoma of the penis (n = 5) and urethra (n = 1) received chemotherapy with cisplatin intravenously at a dose of 100 mg/m2. This was followed 24 hours later by a continuous intravenous infusion of 5‐fluorouracil (5‐FU) at a dose of 960 mg/m2/d for five days every 3 to 4 weeks. There was universal alopecia. The other toxicities were mild and consisted of mucositis, nausea, vomiting, reversible creatininemia, and transient azotemia. After chemotherapy, five patients had a clinical partial response and one had a complete response. Of the five patients with no metastases, three had residual unresectable tumors. These three patients received radiation and survived for 6,8, and 20 months after the start of chemotherapy. The other two patients were rendered disease‐free by surgery. The first patient, who was a partial responder to chemotherapy, survived for 26 months. The second patient, who was a clinical complete responder, had excision of microscopic disease and is disease‐free at 32+ months after the start of chemotherapy. This is the first article to report that the combination of cisplatin and 5‐FU is active in penile and urethral carcinomas. After chemotherapy, surgery may be useful in selected patients to accurately assess response and excise localized residual tumors. Patients rendered tumor‐free may achieve long‐term survival.

New strategies are needed in diffuse malignant mesothelioma

Background. Medical records of 50 patients with malignant mesothelioma were reviewed to determine the clinical features and factors influencing survival.

Allogeneic Vaccination With a B7.1 HLA-A Gene-Modified Adenocarcinoma Cell Line in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE To determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease. PATIENTS AND METHODS We treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100. RESULTS Four patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response. CONCLUSION Minimal toxicity and good survival in this small population suggest clinical benefit from vaccination.

Detection of early anthracycline cardiotoxicity by monitoring the peak filling rate.

Three patients developed clinical congestive heart failure after cumulative doxorubicin doses of 264, 440, and 450 mg/m2, respectively, despite serial monitoring of systolic cardiac function by resting gated radionuclide scanning. All three patients had depressed diastolic function, as shown by a decreased peak filling rate preceding a change in systolic function, which was assessed by left ventricular ejection fraction prior to the development of clinical congestive heart failure. We recommend serial monitoring of the peak filling rate, in addition to left ventricular ejection fraction. If broader experience confirms our impression that the peak filling rate is more sensitive than the current standard assessment of left ventricular ejection fraction, new guidelines may need to be drawn to monitor cardiotoxicity of anthracyclines and anthraquinones.

Combination antiemetics for cisplatin chemotherapy

Nausea and vomiting occur in a majority of patients receiving cisplatin chemotherapy despite prophylactic single agent antiemetic therapy. Three potent antiemetics, metoclopramide, droperidol and dexamethasone, and diphenhydramine to prevent potential extrapyramidal reactions, were combined in prophylaxis of 67 patients receiving cisplatin chemotherapy. Of the patients studied, 76.1% experienced complete protection from both nausea and vomiting in their first course and 62.7% in all their courses of treatment. In 73.3% of 161 evaluable courses, there was neither nausea nor vomiting. Vomiting did not occur in 79.5% of courses. There was no evidence to suggest tachyphylaxis. The efficacy in preventing nausea and vomiting was independent of primary disease site, age, sex, performance status, prior chemotherapy, and prior vomiting. Toxicities were mild and infrequent. Reversible transient extrapyramidal reactions, sweating or twitches occurred in 5.6% of courses. The combination of metoclopramide, diphenhydramine, droperidol and dexamethasone was highly efficacious in preventing nausea and vomiting in moderate or high‐dose cisplatin chemotherapy with little toxicity.

Hyperfractionated radiation therapy and 5-fluorouracil, cisplatin, and mitomycin-C (+/- granulocyte-colony stimulating factor) in the treatment of patients with locally advanced head and neck carcinoma.

The authors had previously reported preliminary results of a treatment regimen of concurrent hyperfractionated radiation therapy and chemotherapy in patients with locally advanced head and neck carcinoma that demonstrated both feasibility and high local control. In an attempt to reduce acute mucosal and hematologic toxicity, granulocyte‐colony stimulating factor (G‐CSF) was added during the second phase of this study.

Response of eccrine adenocarcinoma to tamoxifen

One of two patients with systemic metastases from a poorly differentiated eccrine adenocarcinoma of the scalp was found to have a tumor positive for estradiol receptors. In the receptor positive patient, after tamoxifen therapy, the lymph node metastasis regressed completely and was associated with full relief of pain from osseous metastases for nearly 3 years. Subsequently, progressive painful osseous metastases in the spine, skull, pelvis, and femur were palliated for shorter periods with sequential systemic therapy with megestrol acetate and fluoxymesterone. Osseous metastases were also palliated with external radiation therapy. In contrast, despite external radiation therapy, brain metastases proved fatal. Tamoxifen was ineffective in the estradiol receptor negative patient. Based on this report, it may be valuable to determine the presence of estradiol receptor protein in eccrine carcinoma as a predictor of response to hormonal therapy.