Genetic code: aspects of organization.

The pattern of organization of the genetic code decreases to a minimum the phenotypic effects of mutation and of base-pairing errors in protein synthesis. Single base changes, especially transitions, usually cause either no amino acid change or the change to a chemically similar amino acid. The degree of degeneracy of the codons for an amino acid is correlated with their guanine-cytosine content. The code gives greater protection (by both degeneracy and guaninecytosine content of codons) to those amino acids that appear more frequently in proteins. Increased reliability of the protein-synthesis system afforded by this pattern of organization nay have determined the fitness of the present code.

An information-intensive approach to the molecular pharmacology of cancer.

Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI50) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI50 values encode unexpectedly rich, detailed information on mechanisms of drug action and drug resistance. Each compound's pattern is like a fingerprint, essentially unique among the many billions of distinguishable possibilities. These activity patterns are being used in conjunction with molecular structural features of the tested agents to explore the NCI's database of more than 460,000 compounds, and they are providing insight into potential target molecules and modulators of activity in the 60 cell lines. For example, the information is being used to search for candidate anticancer drugs that are not dependent on intact p53 suppressor gene function for their activity. It remains to be seen how effective this information-intensive strategy will be at generating new clinically active agents.

The role of methotrexate in osteosarcoma.

High-dose methotrexate (MTX) is one of the agents currently used in intensive adjuvant chemotherapy regimens for nonmetastatic osteosarcoma. To elucidate the role of high-dose MTX in this disease, we present the history of trials conducted with MTX from the first single-agent studies through progressively complex combination regimens. With this background, some of the basic issues concerning MTX therapy in osteosarcoma are discussed.

Pentostatin in hairy cell leukemia: treatment by the special exception mechanism.

An analysis of the clinical outcomes in 66 patients with hairy cell leukemia treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, National Cancer Institute, between 1983 and 1987 has revealed a favorable balance of risk and benefit. Hematologic parameters and performance status were improved in most patients treated outside the clinical trials mechanism. The treating physicians considered 37 patients (56%) to be complete responders and 15 patients (23%) to be partial responders. Four patients (6%) died while receiving pentostatin. Life-threatening leukopenia (wbc count, less than 1,000/mm3) was reported in 24% of patients, and severe or life-threatening infection occurred in 11%. The experience gained with these patients supplements the information presently being collected from the controlled clinical trials and supports the development of a group C treatment protocol.

4-Ipomeanol: a novel investigational new drug for lung cancer.

4-Ipomeanol (IPO) is the first agent to undergo preclinical development at the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agent targeted against lung cancer. This disease-specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, preferentially within the mammalian lung, specifically within bronchiolar Clara cells, and that its predominant toxicity was to the lung in most species. IPO is inactive or only minimally active against most conventional antitumor test systems. However, some human lung cancer cell lines, as well as a variety of fresh human lung tumor biopsy specimens, have been shown to be capable of mediating the in situ biotransformation of IPO to a potentially cytotoxic intermediate. In this report, the biochemistry, metabolism, preclinical pharmacology, and toxicology of IPO are reviewed and the clinical development plans for this unique and challenging new agent are presented.

Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer.

4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

Phase I and clinical pharmacological evaluation of 4'-deoxydoxorubicin in patients with advanced cancer.

We have conducted a Phase I and initial clinical pharmacological evaluation of 4'-deoxydoxorubicin (4'-DXDX), administering the drug i.v. on an every 21-day schedule to 60 patients with advanced cancer. Patients were treated at six dosage levels ranging from 10 to 35 mg/sq m. Leukopenia was the dose-limiting toxic effect, and no cardiac, renal, or hepatic toxicity was observed; stomatitis was not seen; and there were no drug-related deaths. Significant alopecia was rare at doses less than 35 mg/sq m, mild nausea and vomiting occurred in one-third of patients at myelosuppressive doses; 12 patients had a transient local urticarial reaction. In the 30 patients with measurable disease, two partial remissions were seen, lasting 5 months in a patient with a nasopharyngeal adenocarcinoma, and 7 months in a patient with endometrial adenocarcinoma. The recommended dose of 4'-DXDX for Phase II studies is 30 mg/sq m in good-risk patients and 25 mg/sq m in moderate-risk or heavily pretreated patients. Pharmacokinetic studies were carried out in ten patients, four of whom received 4'-DXDX at a dose of 10 mg/sq m and six at 30 mg/sq m. Disappearance of 4'-DXDX from plasma was triphasic with a rapid initial phase clearance showing a t1/2 alpha of 1 to 2 min and a prolonged terminal phase with a median t1/2 gamma in excess of 90 h in patients receiving 30 mg/sq m.

Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant.

PURPOSE: Bone marrow transplant (BMT) can cure recurrent Hodgkin's disease, but more than half of patients will progress and require additional treatment. When this occurs, there are no curative options and palliative therapy is usually indicated. In such patients, we have routinely used long-term vinblastine therapy because of its relatively low toxicity and high activity. PATIENTS AND METHODS: We retrospectively reviewed the charts of all patients with Hodgkin's disease who relapsed after autologous BMT since 1991. Of 23 patients, 16 received vinblastine; we also include our index case, who began vinblastine following relapse in 1987. Patients received vinblastine 4 to 6 mg/m2 every 1 to 2 weeks, and continued until evidence of disease progression. RESULTS: The 17 patients in this report had a median age of 31 years, performance status of 2, had received a median of three prior regimens, and 12 (71%) patients were advanced stage. Ten (59%) patients had objective responses, of which two (12%) were complete (CR) and eight (47%) were partial (PR). Two additional patients without measurable disease clinically improved for more than 6 months, and 1 patient had stable disease for more than 18 months. With a median follow-up of 20.4 months, the median event-free (EFS) and overall survival were 8.3 and 38.8 months, respectively. The two complete responders remain in remission at 4.6+ and 9+ years. Vinblastine was well tolerated with 3% of cycles associated with fever and neutropenia, and no cumulative or chronic toxicity. CONCLUSION: Vinblastine provides effective palliation with low toxicity in recurrent Hodgkin's disease following transplant. These results suggest that long-term vinblastine therapy may be potentially curative and should be considered as initial therapy for such patients.

A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma.

The palliative role of nonhormonal cytotoxic chemotherapy in the treatment of endocrine-resistant prostatic carcinoma has not been established. Conventional means of quantifying tumor response are most frequently not applicable in this disease because of the lack of measurable objective parameters to allow for a reliable estimation of antitumor effects. While this problem is not unique to prostatic carcinoma, this review illustrates its magnitude in this disease. Only approximately 5% of patients studied fulfill the various criteria for complete response (CR), partial response (PR), or both, while the vast majority of patients reported as responders are actually in the stable disease category. Stable disease is highly questionable as an indicator of antitumor response and should not be used as a criterion for response in conventional phase II studies unless it is convincingly demonstrated that it occurs as a result of treatment. A study design that may allow a more reliable assessment of the value of the stable disease category is described in the text. More effective means for assessing tumor responses and better instruments to measure aspects of quality of life are needed. Review of several prospective randomized clinical trials showed that no treatment program tested during the last decade resulted in a survival advantage when compared with a concurrently treated control group. Furthermore, in two such trials, four different single chemotherapeutic agents widely used in the treatment of this disease (cyclophosphamide, 5-fluorouracil, estramustine phosphate, and streptozocin) either alone or in combination, did not produce any prolongation of survival when compared to a no chemotherapy (standard treatment) control arm. Survival curves for endocrine-resistant patients fall within a relatively narrow and possibly predictable range that may be used as an additional endpoint in conjunction with response (CRs and PRs only) in phase II trials. More definitive evidence of therapeutic efficacy in this disease should derive from phase III trials using survival as one of the major endpoints. Because of the poor results observed with chemotherapy thus far, we suggest that the appropriate control arm for phase III testing in endocrine-resistant patients continues to be a no chemotherapy control arm consisting of a best symptomatic care or a uniformly applied second-line endocrine manipulation.

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma.

PURPOSE: Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. PATIENTS AND METHODS: This is a phase II study of etoposide, vincristine, and doxorubicin, administered as a 96-hour continuous infusion, with intravenous (IV) bolus cyclophosphamide and oral prednisone (EPOCH) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule. Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. RESULTS: Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. CONCLUSION: EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

PURPOSE: A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS: In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS: Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION: The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.

Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy.

PURPOSE: Overexpression of the multidrug resistance gene (mdr-1) is present in up to 60% of relapsed lymphomas. To study its role in lymphomas, we conducted a controlled trial of dexverapamil, an inhibitor of the mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS: Eligible patients had recurrent Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stable tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR). RESULTS: Of 154 patients entered onto the trial, 109 had NHL and 45 had HD. The median age was 44 years, 67% had stage IV disease, and the median number of prior regimens was two (range, one to 12) in NHL and one (range, one to four) in HD. Sixty-four patients (42%) crossed over, of which eight were not assessable. The maximum-tolerated dose of dexverapamil was 900 mg/m2/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs. The mdr-1 level was measured in 44 biopsies from 19 patients. Pretherapy, mdr-1 was low (median, 2.5 U) but increased (median, 12.2 U) at crossover. Of six patients with mdr-1 levels greater than 15 U, three responded to dexverapamil, while only one of eight patients with mdr-1 levels less than 15 U responded. EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity. CONCLUSION: These results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pgp are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier intervention with dexverapamil may be more effective and warrants further study.

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE: High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS: Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS: Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION: High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy.

PURPOSE: To review the efficacy of cyclophosphamide, doxorubicin, etoposide, methotrexate with leucovorin, and prednisone (ProMACE)-based combination chemotherapy programs in the treatment of patients with diffuse small noncleaved-cell non-Burkitt's lymphoma. PATIENTS AND METHODS: Thirty-three patients with diffuse small noncleaved-cell non-Burkitt's lymphoma were accrued: eight with localized disease were treated with modified ProMACE-mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) plus involved-field radiation therapy, and 25 with advanced-stage disease were treated with ProMACE/MOPP flexitherapy (n = 8), ProMACE-MOPP (n = 9), or ProMACE-cytarabine, bleomycin, vincristine, and methotrexate with leucovorin (CytaBOM) (n = 8). The median follow-up duration is 10 years. RESULTS: All eight patients with localized disease achieved a complete response, none have relapsed, and one died of intercurrent illness. Among patients with advanced-stage disease, five of eight (63%) flexitherapy-treated patients, six of nine (67%) ProMACE-MOPP-treated patients, and eight of eight (100%) ProMACE-CytaBOM-treated patients achieved a complete response. If the two ProMACE-MOPP-based groups are considered together, disease-free and overall survival rates at 15 years are projected at 61% and 35%, respectively. In contrast, only one patient has relapsed from a ProMACE-CytaBOM-induced complete remission, and overall survival of ProMACE-CytaBOM-treated patients (88%) is significantly higher than that for flexitherapy and ProMACE-MOPP (P2 = .04). CONCLUSION: Adult patients with diffuse small non-cleaved-cell non-Burkitt's lymphoma may be effectively treated with regimens that are effective in other aggressive lymphomas (eg, diffuse large-cell lymphoma).

Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy.

PURPOSE: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux pump, a potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. RESULTS: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 mumol/L, respectively. Dexverapamil did not affect the steady-state concentration (Css) of etoposide, but increased the Css of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. CONCLUSION: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.

Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease.

PURPOSE: To evaluate the efficacy and toxicity of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy plus mantle-field radiation therapy in the treatment of patients with massive mediastinal Hodgkin's disease of any stage. PATIENTS AND METHODS: Eighty patients presented with Hodgkin's disease and a mediastinal mass greater than one third the greatest chest diameter on chest radiograph. Patients were staged and treated with MOPP alternated with ABVD chemotherapy for a total of six cycles. Patients then received 10 Gy mantle-field radiation therapy delivered to the original extent of disease followed by 25 to 35 Gy to the residual abnormalities. RESULTS: The complete response (CR) rate was 89%. With a median follow-up duration of 10 years, disease-free survival of the complete responders is 78% at 15 years and overall survival is 75% at 15 years. For patients with stage I or II disease, disease-free survival was 76% at 15 years and overall survival was 79%; for those with stage III or IV disease, disease-free survival was 82% at 15 years and overall survival was 64%. Age, stage, sex, B symptoms, number of extranodal sites, lactate dehydrogenase (LDH) levels, erythrocyte sedimentation rate, and platelet count did not influence treatment outcome. Treatment-related pneumonitis was noted in 16% of patients (fatal in one), mainly in those older than age 35 years who received total doses of radiation therapy greater than 42 Gy. Fertility is more often preserved with MOPP/ABVD therapy than with MOPP chemotherapy and there appears to be less pulmonary and cardiac disease than with ABVD chemotherapy. Two patients have developed second solid tumors within radiation ports and one relapsed patient developed acute leukemia after MOPP salvage therapy. CONCLUSION: MOPP/ABVD followed by mantle-field radiation therapy is an effective treatment for all stages of Hodgkin's disease that present with a large mediastinal mass. Our data suggest that the large mediastinal mass is a more dominant determinant of prognosis than Ann Arbor stage or other clinical prognostic factors.

From research to approved treatment: overcoming the obstacles.

The translation of promising early clinical results into approved therapy for cancer patients is often very difficult. To gain Food and Drug Administration approval, a new agent must be shown to be safe and effective, but the accepted endpoints for demonstrating efficacy, such as improved patient survival, are frequently inappropriate to clinical trials in oncological research. An examination of recent bases for granting FDA approval suggests that changes in research strategies that would allow, eg, the inclusion of improved quality of life and quantified and possibly descriptive data from phase II trials as demonstrations of an agent's efficacy would facilitate the licensing procedure. Additionally, the approaches used by insurance companies to control costs increasingly result in denial of coverage for patients in clinical trials. This problem may stem in part from a general lack of understanding of the nature of investigative therapy and the importance of clinical trials in delivering state-of-the-art care to cancer patients. It is up to all oncologists to promote a better understanding of the procedures and benefits of clinical research, particularly in regard to reimbursement policies.

Alternating combination chemotherapy regimens in small-cell lung cancer.

Although many combination chemotherapy regimens are capable of inducing rapid tumor regression and improved survival in patients with small-cell lung cancer (SCLC), death from recurrent chemotherapy-resistant disease remains the inevitable outcome in over 90% of cases. There have been several attempts to overcome this problem of drug resistance by the administration of two or more combination regimens in various types of alternating schedules. However, this treatment strategy has not achieved the kind of success observed in other tumor types. Several factors may account for this failure. The regimens employed may have lacked sufficient non-cross resistance and relative efficacy. Furthermore, consideration of the biologic processes involved in the regulation of tumor cell growth, heterogeneity, and drug resistance suggests that the time interval between alternating combinations should be as short as possible. Data indicate that combination cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV), and combination cisplatin and VP-16 (PVP) are highly active and not totally cross resistant in patients with SCLC. An induction regimen consisting of CAV rapidly alternating with PVP has been studied in 44 patients. Treatment was well tolerated and the regimens could be alternated at intervals of less than 3 weeks. A 95% objective response rate and 67% complete response rate was achieved. These results appear to be better than previous results with CAV or PVP used alone as induction therapy. A randomized trial is required to confirm this impression.