National Cancer Institute-United States strategy regarding intraperitoneal chemotherapy for ovarian cancer.

On the basis of three large randomized phase III trials, the National Cancer Institute (NCI) issued a Clinical Announcement in January 2006 recommending that women with optimally debulked stage III ovarian cancer and their physicians consider a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. The combination of IV and IP chemotherapy is associated with a clinically significant benefit in survival, although it does also confer an increased risk of toxicity compared to IV chemotherapy alone. The NCI Clinical Announcement was issued as part of a broader educational campaign, designed in conjunction with professional societies, cancer centers, Clinical Trials Cooperative Groups, and cancer advocacy organizations. The further development of IP chemotherapy in ovarian cancer requires additional clinical and translational research.

Accelerated titration designs for phase I clinical trials in oncology.

BACKGROUND: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity. PURPOSE: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained. METHODS: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient. RESULTS: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively. CONCLUSION: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are under-treated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.

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.

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans.

4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemical-biological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that metabolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development. Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominantly alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging from 202 to 826 mg/m2. Although individual plasma drug disposition curves were well described by a two-compartment first order elimination model, The relationship between IPO dose and area under the disposition curve was curvilinear, suggesting saturable elimination kinetics. At the maximum tolerated dose, the mean half-lives (lambda 1 and lambda 2) were 6.7 and 114.5 min, respectively. Renal excretion of parent compound accounted for less than 2% of the administered dose of IPO. An unidentified metabolite was detected in the plasma of patients treated at higher doses. No objective antitumor responses were observed; however, stable disease persisted for at least eight courses in 27% of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiac disturbances during the administration of taxol.

The clinical development of taxol, a new antimicrotubule agent with a unique mechanism of cytotoxic action, has proceeded slowly due to serious hypersensitivity reactions (HSRs) and shortages in its supply. Nevertheless, large-scale phase II trials have been initiated as taxol has recently demonstrated impressive activity in advanced and cisplatin-refractory ovarian carcinoma. Furthermore, the incidence of HSRs has been reduced substantially with premedications and modifications in the administration schedule. However, various manifestations of potential cardiotoxicity have been observed in several patients who participated in four phase I and II studies of taxol. Asymptomatic bradycardia has occurred in a high proportion of patients, including 29% of ovarian cancer patients who were treated with maximally tolerated doses of taxol in a phase II study. More profound cardiac disturbances, including a range of atrioventricular conduction blocks, left bundle branch block, ventricular tachycardia (VT), and manifestations of cardiac ischemia, have been observed in seven of 140 patients (5%) who received taxol. Descriptions of these events are presented in this report to alert investigators to the potential for these adverse effects. Although these disturbances did not result in serious sequelae in most patients, investigators should continue to maintain a high degree of caution until precise risk factors, frequency, and clinical significance of these adverse cardiac effects are determined.

Clinical trial designs for cytostatic agents: are new approaches needed?

Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

PURPOSE: To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. CONCLUSION: Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer.

The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.

Enchondroma of the nasal septum due to Ollier disease: a case report and review of the literature.

BACKGROUND: Morbus Ollier is characterized by the presence of multiple enchondromas (ie, benign intraosseous cartilaginous lesions). Although their manifestation in the limb bones is well described, only a few cases with ear, nose, and throat (ENT) involvement, primarily arising from the skull, have been reported. The malignant transformation toward slowly growing low-grade chondrosarcomas is the most severe form of progression. METHODS: We report a unique case of a 54-year-old patient with Ollier disease with an extensive nasal enchondroma apparently eroding the middle nasal concha and expanding to the lateral nasal wall that raised suspicion of malignant transformation. RESULTS: Radiological and histological features of enchondromas can be controversial and seem to have limited sensitivity to exclude low-grade malignancy. The clinical symptoms play a decisive role in differentiation between enchondromas and low-grade chondrosarcomas. CONCLUSION: Surgery remains the only effective solution in removing an enchondroma and preventing the tendency toward malignant transformation.

Clinical development of Taxol.

Taxol is the first of a novel class of anticancer drugs, the taxanes. Taxol's unique effects include its ability to polymerize tubulin into stable microtubules in the absence of cofactors and to induce the formation of stable microtubule bundles. During its development, formidable challenges were overcome: a suitable formulation was developed, an adequate supply was ensured, severe hypersensitivity reactions were diminished in incidence and severity, and clinical efficacy was demonstrated. Phase II evaluation is still underway; to date, clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancer. Response rates were low in early studies in melanoma, prostate, colon, cervix, and renal cancer, but for these tumors, additional evaluation is ongoing with a higher Taxol dose or different schedule. In December 1992, Food and Drug Administration approval was granted for use of Taxol as second-line therapy in ovarian cancer patients. Nevertheless, important questions regarding optimal use of this important new drug remain. These include determination of optimal dose and schedule and development of suitable combination chemotherapy regimens. The clinical development of Taxol and current status of phase I, II, and III clinical trials are reviewed.

The current status of new platinum analogs.

Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance.

Current dosage and schedule issues in the development of paclitaxel (Taxol).

Basic questions regarding optimal dose and schedule of anticancer drug administration frequently persist long after regulatory approval and commercial availability of a drug. For paclitaxel (TAXOL), these questions were considered early in drug development. This paper reviews the available preclinical studies that assessed different drug concentrations and durations of drug exposure. The current status of clinical trials designed to help resolve these issues is also reviewed.

Promising new agents under development by the Division of Cancer Treatment, Diagnosis, and Centers of the National Cancer Institute.

The Division of Cancer Treatment, Diagnosis and Centers of the National Cancer Institute (NCI) has a large program in clinical cancer therapeutics development. It currently holds investigational new drug applications for nearly 200 agents with which it sponsors clinical trials. In addition, it has a major preclinical development program. With the tremendous advances in our understanding of molecular and tumor biology during the past decade, the NCI's portfolio of agents has expanded beyond classical cytotoxic agents to include a wide variety of new molecular and therapeutic targets. In addition to agents with more conventional mechanisms of action, the NCI has targeted therapeutics programs that focus on tumor vasculature, cell cycle control and cell signaling, mechanisms of apoptosis, invasion and metastasis, and immunological recognition and response. Each of these focused areas includes agents of different classes and modes of action that are all directed at the target of interest. The scope of the NCI's program allows it to respond to incorporate promising new agents or targets as they arise and to prioritize them for use of preclinical and clinical resources. Agents in development through the NCI are derived from a number of diverse sources including its own screening efforts, academia, and numerous collaborations with the pharmaceutical and biotechnology industries. NCI works closely with collaborators to ensure complementary, non-duplicative clinical development and attempts to ensure that the full potential of promising agents is explored. A number of compounds in early clinical development or about to enter the clinic are discussed briefly in this manuscript.

Treatment of platinum-resistant ovarian cancer.

In the United States, almost 70% of the 23,000 women diagnosed annually with epithelial ovarian cancer present with advanced disease (FIGO stages III-IV). Primary therapy for these patients includes surgical cytoreduction and 6-8 courses of platinum- and taxane-based chemotherapy. Although 90% of patients will respond to this multi-modality combination regimen, most patients will experience recurrences. The 5 year survival for women with stage III disease is 15-30% and 0-20% for those with stage IV disease. Medical and gynecological oncologists, therefore, must be prepared to treat many women with recurrent ovarian cancer.

Salvage chemotherapy for epithelial ovarian carcinoma.

Advanced epithelial ovarian cancer is a highly chemosensitive solid tumor with response rates of 70-80% to first-line chemotherapy, including a high proportion of complete responses. The majority of patients, however, eventually relapse and ultimately die of chemoresistant disease. Response rates to salvage agents are modest, and duration of response is relatively short. Important new agents have been identified in the salvage setting, however, and all patients with ovarian cancer recurring or persisting after front-line therapy should be encouraged to enroll in clinical trials. Phase II trials should include multiple adequately sized cohorts, for patients with platinum-sensitive disease and those with platinum-refractory disease. In addition, patients should be stratified by treatment-free interval. An effort should be made to report standard response endpoints, such as median duration of response, median time to progression, and median survival. Retreatment with a platinum-containing compound is appropriate in patients with platinum-sensitive disease. Trials of high-dose chemotherapy with hematologic support may be most appropriate for patients with minimal disease following first-line therapy, but are unlikely to benefit patients with platinum-resistant or bulky disease. Paclitaxel should figure prominently in consideration of salvage therapy for patients with platinum-resistant disease. Responses to other single agents or combination chemotherapy have been modest and generally of short duration. Efforts at hormonal therapy have been disappointing. Promising new agents include topoisomerase I inhibitors, such as topotecan, 9-aminocamptothecin, irinotecan (CPT-11), and pyrazoloacridine. Therapies focusing on novel molecular targets include antiangiogenesis agents, antimetastatic agents, and signal transduction inhibitors. Immunotherapy, including radioimmunotherapy, immunotoxins, and direct antitumor effects of monoclonal antibodies, may be useful. Greater understanding of the molecular pathology of ovarian cancer may help us develop more rational and effective treatment.