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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., (Copyright 2005 American Cancer Society.)

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., (Copyright 2001 American Cancer Society.)

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: Recombinant interferon-alpha (IFN) augments the cytotoxicity of both 5-fluorouracil (5-FU) and cisplatin in vitro. A phase II study of 5-FU and IFN resulted in response rates of 25-27% in patients with metastatic esophageal carcinoma., Methods: A Phase II trial was initiated to determine the clinical utility of a three-drug combination (FIP) in patients with regionally advanced or metastatic esophageal carcinoma. Eligibility included biopsy-proven Stage III or IV squamous cell carcinoma or adenocarcinoma of the esophagus with no prior chemotherapy, adequate performance status, nutritional status, bone marrow, hepatic and renal function, and signed informed consent. Patients were treated in the exact sequence of IFN==>cisplatin==>5-FU. Patients received 5-FU, 750 mg/m2/day for 5 days followed by weekly bolus therapy at the same dose; cisplatin, 100 mg/m2 on Day 1, followed by weekly therapy, 25 mg/m2 over the course of 1 hour; and IFN, 10 MU subcutaneously 3 times/week beginning on Day 1. All patients received sargramostim (granulocyte-macrophage colony-stimulating factor, Escherichia coli-derived), 5 micrograms/kg subcutaneously 5 times/week. No patients received radiotherapy., Results: Twenty-four patients were enrolled; 23 were eligible, and 1 was excluded on pathology review (patient was found to have a leiomyoblastoma). The demographics of the population were: median age, 63 years (range, 43-73 years); 18 male patients; squamous cell carcinoma: adenocarcinoma ratio, 22:1, and Stage III:IV ratio, 10:13. Grade 3-4 National Cancer Institute Common Toxicity Criteria toxicities included: leukopenia (13), thrombocytopenia (14), and infection (9). Grade 3 diarrhea, mucositis, and vomiting occurred in 6 patients, 4 patients, and 1 patient, respectively. There were two instances of sudden death, likely related to tumor progression. Major responses occurred in 15 of 23 patients (65%; 95% confidence interval, 43%, 85%) (1 complete response, 14 partial responses). The median survival was 8.6 months; with a median follow-up of 26 months, estimated 30-month survival was 31%., Conclusions: This regimen, although moderately toxic, has substantial activity in metastatic and regionally advanced squamous cell carcinoma of the esophagus. Further investigations should be conducted to determine the role of IFN in the treatment of esophageal carcinoma.

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.

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 membrane barrier were identified; the latter was in continuity with the conus elasticus and quadrangular membrane., Conclusions: Two weak fibroelastic barriers surround the ventricle. The outer, peripheral, fibroelastic membrane is contiguous with the conus elasticus and the quadrangular membrane. Therefore, ventricular involvement is not a sensitive indicator of paraglottic spread. Squamous cell cancer may grow around the periventricular barriers to involve both the true and false cords but may spare the ventricle. The prognostic significance of the violation or preservation of the periventricular elastic barriers is unknown.

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.

Background: Originally described as antiviral agents, interferons (IFN) were investigated as potential anticancer agents because of their antiproliferative and cytotoxic effects, their ability to activate specific components of the immune system, and their relatively modest toxicities. Interest intensified when durable complete remissions were observed in patients with hairy cell leukemia after IFN treatment; modest, but reproducible activity also was found against tumors such as melanoma and renal cell carcinoma which are unresponsive to conventional chemotherapy. Observations of synergy between IFN and cytotoxic drugs in vitro and in vivo suggested that IFN may have additional utility as modulating agents., Methods: Reports of major clinical trials using IFN either alone or in combination with other agents were reviewed. Activity was identified by disease site. Correlations were made with important preclinical studies., Results: IFN has reproducible, but modest, single-agent activity against melanoma, renal cell carcinoma, and acquired immune deficiency syndrome-related Kaposi sarcoma. IFN may be useful in the treatment of a number of benign, in situ, or low-grade tumors. IFN in combinations with cytotoxic agents have demonstrated activity in solid tumors. Clinical trials using combinations of IFN and 5-fluorouracil or dacarbazine suggested a potential benefit for the combination compared with single-agent chemotherapy. These are preliminary findings that require confirmation, but they suggest that combination therapy should be investigated further. In early preclinical and clinical studies, combinations of IFN and other biologic agents, hormonal agents, and radiation therapy appear to be interesting., Conclusions: The role of IFN in the treatment of solid tumors may be evolving from that of single-agent therapy to combination therapy with other active agents. Additional studies are required to determine the optimal doses, schedules, and sequencing of these combination therapies.

Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose-dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross-resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin-resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross-resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.

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.

Cisplatin is a chemotherapeutic coordination complex that has been evaluated extensively. It is particularly active against testicular cancer, but carcinomas of the ovary, bladder, cervix, and head and neck are also responsive. To increase efficacy and decrease toxicity, a number of platinum analogues have been developed and tested. One of these, carboplatin, is of particular interest. In clinical trials, it has demonstrated antitumor activity comparable to that of cisplatin, without evidence of significant renal toxicity or neurotoxicity. A second interesting platinum analogue is iproplatin. Preliminary phase I studies suggest reduced adverse renal and neurologic effects similar to those seen with carboplatin, with efficacy comparable to cisplatin. Attempts to overcome the dose-limiting toxicity of cisplatin by administering high-dose cisplatin (40 mg/m2/d for five days) in hypertonic saline or with thiosulfate protection are also reviewed. These techniques have eliminated nephrotoxicity as the dose-limiting toxicity of cisplatin. However, nonrenal toxicity, especially neurotoxicity, remains substantial. The extent to which high-dose cisplatin-based chemotherapy should be used in routine clinical practice has not been determined.