Search

BACKGROUD: The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS). METHODS: Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count

Fatigue is a common side effect of interferon (IFN) therapy, reported in 70-100% of patients treated with IFN. The etiology of IFN-mediated fatigue (IMF) is multifactorial, with endocrine failure, neuropsychiatric disturbance, autoimmunity, and cytokine dysregulation potentially being contributors. Thyroid dysfunction, associated with the development of autoantibodies, is seen in 8-20% of patients receiving IFN-alpha. IFN-alpha also suppresses the hypothalamic-pituitary-adrenal axis. In addition, IFN-alpha therapy leads to depression and cognitive slowing, and depressed patients are predisposed to develop fatigue. Clinical management of IMF is challenging because the syndrome is variable in onset and severity and the pathophysiology is poorly understood. Current management typically centers on dose reduction, but ancillary nonpharmacologic measures may help improve symptoms. Other strategies include antidepressant or anxiolytic therapy and treatment of coexisting hypothyroidism. Future studies utilizing IFN should include quantitative guidelines for grading and managing IMF.

BACKGROUND Recent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS The combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.

Background Second-line therapy of patients with colorectal cancer metastatic to the liver is unsatisfactory. One alternative to systemic treatment is therapy directed locoregionally. Methods Twenty-four patients with unresectable colorectal cancer with bulky liver metastases who had failed prior systemic therapy were randomized to treatment with either embolization or chemoembolization. For the embolization group, particulate transcatheter polyvinyl alcohol (PVA) (150-250-microns particles) mixed with full-strength iodinated radiographic contrast was administered under direct fluoroscopic control. In patients randomized to chemoembolization, 5-fluorouracil (750 mg/m2) and recombinant alpha-2a-interferon (Roche Laboratories, Nutley, NJ) (9-MU) were thoroughly mixed into the PVA contrast suspension. Study end points were response to therapy and survival. Results Of 24 patients, 13 were randomized to chemoembolization and 11 to embolization therapy. All were assessable for toxicity, response, and complications. Among the first 13 patients treated initially, a suppurative abscess developed in one patient, who died. Eleven subsequent patients were pretreated with oral and intravenous antibiotics without further infectious complications. Five patients had hemorrhagic complications, two of which were serious. The treatment was otherwise well tolerated, with most patients experiencing transient pain, fevers, and elevations in leukocyte counts and liver enzymes, which resolved spontaneously. Computed tomography scans of the liver were used to assess patient response to therapy. There were 6 responders (25%) among the 24 patients treated. No differences in response to treatment or survival between the embolization and chemoembolization groups were noted. With a median follow-up of more than 12 months, the median survival was 9.3 months from the time of embolization therapy. Conclusions Embolization and chemoembolization therapy appear to have antitumor activity as second-line therapy in patients with colorectal carcinoma with bulky liver metastases. Although generally well tolerated, complications of this therapy may be severe. The addition of further patients to this trial will allow a rigorous comparison of embolization alone versus embolization with chemotherapy.

Background. Anatomic barriers to the spread of laryngeal cancer include the conus elasticus, the quadrangular membrane, and the thyroid cartilage. It has been speculated that an elastic barrier surrounds and protects the ventricle. Methods. The authors studied the microanatomic patterns of spread of 17 cases of patients who had laryngeal cancer with paraglottic disease and confirmed their findings by examining normal autopsy specimens. Results. Five patients of the seventeen cases showed no ventricular mucosal involvement despite extensive paraglottic disease. Both an inner, central, subepithelial periventricular elastic barrier, and a more peripheral periventricular elastic membrane barrier were identified; the latter was in continuity with the conus elasticus and quadrangular membrane

Background Combinations of 5-fluorouracil (5FU) and recombinant alfa-2a-interferon (IFN) are synergistic in vitro and have demonstrated activity in colorectal carcinoma, renal cell carcinoma, and urothelial tumors. Methods A Phase II trial of the combination of 5FU, 750 mg/m2 daily x 5 followed by weekly bolus therapy, and IFN, 9 MU subcutaneously three times per week, was initiated in patients with esophageal carcinomas. Patients were required to have biopsy-proven squamous cell or adenocarcinoma of the esophagus, locally advanced or metastatic disease beyond the scope of surgical resection, and adequate performance status, renal, hepatic, and bone marrow function. Results Twenty-one patients were enrolled; one patient was inevaluable for response because he had received prior chemotherapy, but was evaluated for toxicity. Eleven patients had metastatic disease, and 10 had locally advanced disease. Thirteen patients had squamous cell carcinoma and 8 adenocarcinoma. Toxicities were acceptable with no serious diarrhea and only two cases of serious stomatitis, although a greater than expected incidence of neurologic toxicity was observed. There were five responders (25%) including two patients with advanced or locally advanced disease rendered pathologically free of disease. One patient, initially considered surgically unresectable, was able to undergo a total thoracic esophagectomy after responding to treatment with 5FU/IFN, at which time only a single microscopic focus of carcinoma in situ was found. She remains alive and free of disease at 18+ months. A second patient who presented with metastatic disease and nearly complete obstruction of the esophagus regained normal swallowing function after treatment with 5FU/IFN; rebiopsy of all lesions revealed the patient to be pathologically free of disease. He survived over 2 years. Conclusions This regimen employing a single cytotoxic agent has activity in esophageal carcinoma. Strategies employing biochemical modulation deserve additional investigation in the treatment of esophageal carcinoma.

Adenocarcinoma of the pancreas is an extremely malignant neoplasm with a particular propensity to spread to the liver. In an effort to combine chemotherapy with high-dose local irradiation plus a modest dose of irradiation to suspected (subclinical) hepatic metastasis, patients with unresectable pancreatic carcinomas with no known distant metastasis were treated on a prospective multi-institutional Radiation Therapy Oncology Group (RTOG) Phase I/II trial. High total dose continuous radiation therapy to the pancreas (6120 cGy in 34 fractions over 7 weeks) and simultaneous prophylactic hepatic irradiation (PHI, 2340 cGy in 13 fractions for the last 2.5 weeks) were combined with administration of 5-fluorouracil 1000 mg/m2/day (maximum, 1500 mg) by intravenous continuous infusion for 5 days starting on day 1 and repeated on day 30 for 5 days, followed by a dose of 600 mg/m2 as a weekly bolus injection starting during week 9 for 6 months. In 18 months, 81 patients were enrolled in the study; 79 were evaluable with a minimum potential follow-up of 8.2 months. The patients ranged in age from 32 to 75 years (median, 64 years). Karnofsky performance status was 80 to 100 in 74% of patients. The tumor was confined to the head of the pancreas in 72% of patients. The planned radiation therapy for the pancreas was completed in 87% of patients, 80% received the planned PHI, and 85% completed the first two cycles of chemotherapy. Seventy-five percent of patients completed both treatments according to the protocol. Most patients who did not complete both treatments had tumor progression or refused additional therapy. During all cycles of chemotherapy and radiation therapy, 2 patients died of complications (Grade 5, 1 hepatic and 1 infection), 9 had life-threatening reactions (Grade 4, 7 hematologic, 1 neurologic, and 1 mucositis), and 31 patients had severe effects (Grade 3) according to the RTOG toxicity scale. Overall hepatic metastasis was documented in 32% (13% as the first site of failure), persistent or progressive pancreatic tumor was evident in 73%, and abdominal and extra-abdominal spread were reported in 27% and 8% of patients, respectively. Eighty percent (63 patients) died (median survival, 8.4 months). Although this study suggests that PHI may reduce the frequency of hepatic metastasis, failure to control the primary tumor and intraabdominal spread remain overwhelming.

BACKGROUND: Based on evidence of activity in preclinical and Phase I studies, the authors undertook a study of bortezomib, a reversible proteasome inhibitor, for patients with metastatic sarcomas. METHODS: Two arms were opened, each using a Simon two-stage design. Arm A included patients with osteogenic sarcoma, Ewing sarcoma, and rhabdomyosarcoma. Arm B accrued patients with other types of soft tissue sarcomas. Patients were not allowed to have received previous chemotherapy for metastatic disease. The initial dose of bortezomib was a 1.5 mg/m2 intravenous push twice weekly followed by a rest week. The dose was escalated to 1.7 mg/m2 if patients tolerated Cycle 1 well. The dose escalation was eliminated due to toxicity observed in the first six patients. RESULTS: Painful neuropathy, myalgias, and asthenia were the most significant observed toxicities. The most frequent toxicities included fatigue, diarrhea, constipation, and nausea. Pharmacodynamic data from 18 patients with complete data collection did not show consistent differences between patients with or without Grade 2 or Grade 3 neuropathy (toxicity graded according the National Cancer Institute Common Toxicity Criteria). Arm A had low accrual and was closed. One confirmed partial response among 21 evaluable patients was observed on Arm B in a patient with leiomyosarcoma. Due to the inactivity of this agent, the study was closed after the first stage of accrual. CONCLUSIONS: Bortezomib has minimal activity in soft tissue sarcoma as a single agent. If studied further in sarcomas, bortezomib should be investigated in combination with agents with demonstrated preclinical synergy.

BACKGROUND Following surgical debulking, most patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV carcinoma of the ovary receive treatment with combination chemotherapy. However, the optimal postsurgical therapy for ovarian carcinoma remains to be defined. METHODS To define better the role of initial therapy with a cisplatin-based chemotherapy regimen, the Eastern Cooperative Oncology Group (ECOG) initiated a randomized, Phase III trial, EST 2878, comparing initial therapy with a single, orally administered alkylating agent, melphalan, versus a complex regimen employing cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD). Women who failed treatment with melphalan were crossed-over to treatment with CHAD minus the cyclophosphamide (HAD). Study endpoints included response to therapy, time to treatment failure, and overall survival. RESULTS Between October, 1978, and November, 1980, EST 2878 accrued 253 patients with advanced epithelial carcinoma of the ovary. There were 118 eligible patients initially treated with melphalan and 126 with CHAD. Two patients experienced lethal toxicities, including gastrointestinal hemorrhage (1 patient) and neutropenic sepsis (1 patient), and 22 patients experienced life-threatening toxicities, including hematologic toxicity (21 patients) and anaphylaxis (1 patient). Response to treatment and clinical complete response rates were higher in women receiving CHAD (60% and 38%, respectively) versus melphalan (42% and 21%, respectively) (P = 0.037 and P = 0.024, respectively), but these differences were confined to women older than 50 years of age. Likewise, time to treatment failure was significantly longer in women receiving CHAD (P = 0.014), but the difference was again confined to women older than 50 years of age and to women suboptimally debulked at the time of surgery. Survival did not differ between the two arms (median survivals of 17.5 months with initial melphalan therapy and 19.5 months with CHAD), probably because women treated initially with melphalan received salvage therapy with HAD. Twenty-three patients survived longer than 10 years. Among 18 long term survivors who had retrospective pathologic review, 8 had borderline tumors of the ovary. CONCLUSIONS In women with advanced ovarian cancer, initial therapy with a cisplatin-based combination chemotherapy regimen resulted in higher clinical complete response rates and longer time to failure compared with initial therapy with a single, oral alkylating agent; however, the benefits of this approach were confined to women older than 50 years of age at diagnosis, and there was no significant difference in survival. Cancer 1996;77:733-42.

Many patients with diffuse malignant pleural mesothelioma have dyspnea or chest pain. Cardiac symptomatology is frequently difficult to differentiate from symptoms of pleuropulmonary disease. To better define the clinical characteristics of cardiac involvement in patients with mesothelioma, the electrocardiographic (EKG) and echocardiographic findings in 64 patients with biopsy-proven malignant pleural mesothelioma were reviewed. A total of 19/64 (30%) patients had autopsy studies available for review. The EKG was abnormal in 55 patients (89%). Over half (60%) had an arrhythmia, including sinus tachycardia (42%), premature atrial and ventricular contractions (13%), atrial fibrillation (3%), and atrial flutter (1%). Over one third (37%) had a conduction abnormality, including bundle branch block (13%), hemiblock (8.5%), and incomplete right bundle branch block (13%). Echocardiography revealed a total of 13 patients with pericardial effusions, two with pericardial thickening, and one with an anterior sonolucent space. Of 19 autopsies, cardiac invasion was found in 14 (74%), with more than half to the pericardium and more than one quarter to the myocardium. It is concluded that: clinical cardiac abnormalities occur in the great majority of patients with malignant pleural mesothelioma, pathologic cardiac invasion occurs in the great majority of patients with pleural mesothelioma, and the EKG and echocardiogram are helpful in differentiating cardiac involvement from progressive pulmonary disease in patients with pleural mesothelioma.