Gregory A. Curt

The Pharmacology and Clinical Use of Methotrexate

METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkins lymphoma, oste...

Cancer-Related Fatigue: Prevalence of Proposed Diagnostic Criteria in a United States Sample of Cancer Survivors

PURPOSE To evaluate the proposed cancer-related fatigue (CRF) diagnostic criteria in a sample of cancer survivors. More accurate prevalence estimates of CRF may result in improved diagnosis and management of one of the most common symptoms associated with cancer and its treatment. METHODS Three hundred seventy-nine individuals who had been treated with chemotherapy, either alone or in combination with radiation therapy, were surveyed. Patients were asked background questions about their current condition, their medical history, and the frequency of fatigue during their chemotherapy. Additionally, patients who reported experiencing fatigue at least a few days each month during treatment were asked a series of questions about the impact of fatigue on their daily functioning. RESULTS One hundred forty-one (37%) individuals reported at least 2 weeks of fatigue in the previous month. Of the respondents who had received their last treatment more than 5 years ago, 33% still reported at least a 2-week period of fatigue in the month before the interview. Evaluation of the proposed criteria revealed that 17% of respondents met at least two criteria for CRF. CONCLUSION The prevalence of diagnosable CRF in the individuals in this sample, most of whom had completed treatment more than 1 year ago, was 17%-lower than expected based on previous reports that have used less-strict criteria. In a sizable number of people, CRF persists well beyond active treatment and should be a focus of intervention. Although they will require replication in other samples and clinical validation, these formal diagnostic criteria can be a step toward common language and a better understanding of the severity range and persistence of CRF.

High-dose carboplatin in refractory ovarian cancer patients.

Thirty previously treated refractory ovarian cancer patients, all of whom received prior therapy with cisplatin, were treated in a phase II trial with high-dose carboplatin (800 mg/m2 per cycle with cycles administered every 35 days). Patients were treated with high-dose carboplatin when they were no longer responding to prior therapy or had relapsed after an initial response. Objective responses were achieved in eight of 30 patients (27%) while ten patients had minor responses or stable disease. No responses were observed from high-dose carboplatin in patients who had progressive disease during prior therapy with a cisplatin-based regimen. The primary toxicity of high-dose carboplatin was myelosuppression with a median WBC nadir of 0.6 and a median platelet nadir of 6,500 after the first cycle of therapy. Myelosuppression was not particularly cumulative as 78% of patients were able to receive either 100% or 75% of the projected dose even with the fourth cycle of high-dose carboplatin. The gastrointestinal (GI) toxicity of carboplatin was mild and there was no clinically apparent nephrotoxicity or neurotoxicity. These results demonstrate that: there is marked cross-resistance between cisplatin and carboplatin, and high-dose carboplatin may be a potential alternative to high-dose cisplatin in the treatment of ovarian cancer patients.

Formation of methotrexate polyglutamates in purified myeloid precursor cells from normal human bone marrow.

Immature myeloid precursor cells were preferentially selected from normal human bone marrow by using immune rosette techniques that employed monoclonal antibodies against mature granulocytes, monocytes, T and B lymphocytes, and erythroid precursors (Mo5, M3, OKT3, B1, and EP1, respectively). We examined the formation, retention, and cytotoxic effects of methotrexate (MTX) polyglutamates (MTX-PGs) in these purified myeloid precursor cells. After 1- and 24-h exposures to MTX, with thymidine and deoxyinosine as rescue, the intracellular MTX-PG profile was examined by high-pressure liquid chromatography. Efflux patterns of MTX-PGs were also studied after additional 1- and 24-h incubations in drug-free media. Cytotoxic effects of retained MTX-PGs on bone marrow myeloid precursors were examined by colony formation in drug-free semisolid agar. Normal myeloid precursor cells converted MTX to MTX-PGs in a concentration- and time-dependent manner, preferentially retaining MTX-PGs with three to five glutamyl moieties. At low concentrations of MTX (1 microM), MTX-PG formation was insufficient to maintain saturation of the target enzyme dihydrofolate reductase after removal of drug from the incubation medium, and there was no decrease in myeloid colony formation. At higher concentrations of MTX (10 microM), formation of higher molecular weight polyglutamates was sufficient to allow for 24-h saturation of intracellular binding capacity after removal of extracellular drug and resulted in a 35% reduction in the formation of colony-forming units in culture. Comparison of MTX metabolism in normal bone marrow cells and the MTX-sensitive HL-60 human leukemia cell line showed twofold greater PG formation by these tumor cells after 24-h exposure to 1 or 10 microM MTX, and a marked (greater than 30-fold) increase in cytotoxicity for the HL-60 cells as compared with normal myeloid precursors, suggesting that the MTX polyglutamation may be important to its selective antitumor action.

Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics.

PURPOSE COL-1 is a high-affinity murine monoclonal antibody (MAb) specific for carcinoembryonic antigen (CEA). A phase I trial was conducted in which a uniform quantity of antibody labeled with escalating doses of iodine 131 (131I) was administered to patients with advanced gastrointestinal (GI) malignancies to evaluate tolerance and pharmacokinetics. PATIENTS AND METHODS Eighteen patients with advanced, assessable GI malignancies (16 colon, one pancreas, and one gastric) previously treated with conventional chemotherapy (but no pelvic radiation) received 20 mg of COL-1 labeled with 131I, with doses from 10 mCi/m2 to 75 mCi/m2. In this cohort, the baseline serum CEA level ranged from 6 to 2,739 ng/mL (mean +/- SD, 500 +/- 639). RESULTS Nuclear imaging detected at least one tumor site in all 18 patients; 82% of all tumor involved organs were positive and 58% of all lesions > or = 1.0 cm were detected. Immune complexes were detected in 89% of patients 5 minutes after completion of infusion, and levels correlated with CEA levels (r = .71). Elevated CEA (> 500 ng/mL) and tumor bulk (total tumor area > 150 cm2) correlated directly with clearance of serum radioactivity and inversely with serum half-life and cumulative serum radioactivity parameters. Nonhematologic toxicity was mild and non-dose-limiting. Hematologic toxicity, particularly thrombocytopenia, was both dose-related and dose-limiting. The maximal-tolerated dose is 65 mCi/m2. The correlation between dose (millicuries per square meter) and thrombocytopenia was made stronger, by accounting for either variation in pharmacokinetics, or variation in serum CEA and tumor bulk. CONCLUSION 131I-COL-1 is well tolerated, except for hematologic toxicity. These data suggest that patients with highly elevated circulating CEA levels and/or increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the circulation and experience less myelosuppression.

Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate.

We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.

Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs.

Calcium channel blockers (CCBs) such as verapamil and nitrendipine are capable of increasing drug sensitivity in resistant murine and human tumor cells. This finding has potential value in the treatment of acquired drug resistance in human malignancies. Thus, we tested the ability of CCBs of two different structural classes to enhance the toxicity of doxorubicin (DOX), vinblastine (VBL), and vincristine (VCR) for normal myeloid and macrophage colony formation (marrow colony forming units-granulocyte-monocyte [CFU-GM]). Drug effects on colony formation from 35 normal volunteer marrows and from seven patient marrows in the recovery phase after cytotoxic chemotherapy were determined. No enhancement of toxicity was mediated by verapamil or nitrendipine when these drugs were co-incubated with the cytotoxic drugs for one hour or 24 hours before plating marrow cells in a semisolid agar system.

Skin reactions induced by trimetrexate, an analog of methotrexate.

We have observed three forms of skin toxicity induced by the new antifol trimetrexate in a Phase I trial. They are: radiation recall, cellulitis at the infusion site, and generalized skin eruptions with erythroderma. A total of 25 episodes of some form of skin reaction occurred in 31 patients. The generalized eruption began about four days after drug administration and cleared within a week. The mechanism of skin toxicity of trimetrexate and other antifols is unknown.

Cancer chemotherapy: Progress and expectations, 1984

Progress in the treatment of cancer with drugs has radically altered the clinical approach to patients with malignancy. Not only have new drugs produced promising results in hitherto untreatable tumors, but they have extended and enhanced the effectiveness of other modalities, including surgery and radiotherapy. In this article, the authors consider avenues of research that likely to aid in the discovery of new anticancer drugs and improve the effectiveness of established agents. Promising new efforts in drug development include the use of new screening systems, particularly those employing human tumor materials; the development of improved analogs of existing active agents particularly those of the anthracycline and platinum complex types; and the search for agents that which promote differentiation or prevent metastasis. In an effort to improve the effectiveness of established agents, the authors consider the application of pharmacokinetic principles in developing regional perfusion routes, intraperitoneal chemotherapy, and central nervous system penetration. Finally, the contribution of biochemical pharmacology to the current understanding of drug action, mechanisms of resistance, and drug interactions are considered, and the impact of this knowledge on clinical protocol design is assessed.

One in Five Cancer Clinical Trials Is Published: A Terrible Symptom—What's the Diagnosis?

There was a time in the history of science when publications represented a completed body of knowledge that took many years (sometimes a lifetime), often by a single person, to compose. Newton’s Principia [1] and Copernicus’ On the Revolutions of the Heavenly Spheres [2] come to mind. Indeed, the idea of publishing incremental scientific observations, something which we would call journal articles today, only began when letters between scientists began to be reproduced in the press. Today’s world of scientific publication is entirely different. It is increasingly difficult for medical oncologists to keep current with the generally incremental advances published regularly by well-known and well-respected medical journals. And yet, as Ramsey and Scoggins point out in this edition of The Oncologist, we may be struggling to keep up with information that represents only “the tip of the iceberg” [3]. Slipping beneath the surface is a wealth of unpublished data that might prove valuable to the cancer research community. We can only guess at its content. While there are inherent methodologic limitations to the analysis undertaken by Ramsey and Scoggins, the possibility that fewer than one in five cancer clinical trials find their way to the peer-reviewed literature is thought-provoking and disturbing. Obviously a variety of reasons may underlie the failure to publish: flawed trial design, a failure to reach endpoints because of any number of problems (including inadequate accrual), negative results, and simple neglect on the part of the trial sponsor and the principal investigator. These problems, individually or in combination, may contribute to the failure to submit a manuscript for publication. Ramsey and Scoggins hypothesize that a major reason for failure to publish is selection bias against trials that do not meet their endpoints and, indeed, the majority (57%– 90%) of the published trials are positive [3]. But other factors aside from a negative result may defeat a trial and its publication. Among these most prominently is the failure to accrue patients. So, while about one in five cancer trials is eventually published, equally sad is the fact that half of the unpublished trials have failed to accrue and reach endpoints; this finding represents an indictment of the review process that allows poorly designed or low-priority trials to be initiated, or delays them past their point of relevance. The latter consideration is particularly relevant to the National Cancer Institute (NCI) Cooperative Groups, which routinely take 2 years or more to bring a trial from concept to active accrual. Dilts and Sandler have studied accrual patterns in four NCI-designated Comprehensive Cancer Centers and have made some remarkable conclusions [4]. Nearly 60% of trials opened for 5 years had fewer than five patients enrolled at each site, and, for 20% of studies, not a single subject had been accrued. Looking at the bigger picture, of all NCI phase I, II, and III trials opened and closed between 2000 and 2007, only 50%–60% achieved minimal stated accrual goals. So, while perhaps only one in five cancer clinical trials is ever published, of those unpublished, a significant percentage probably died for lack of accrual. Which potential statistic is the sadder, the low publication rate or the low accrual rate? In truth, they both are, as neither should be true. We should also acknowledge that investigators and sponsors also face the hurdle of finding a journal willing