David S. Ettinger

Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data

Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21–77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (<65 or >65 years) versus dose delivered [< the maximum tolerated dose (MTD) vs ≥ the MTD] or toxicity (< grade 3 vs ≥ grade 3). Of 344 patients, 81 (23.5%) were >65 years old, 34 (9.9%) were ≥70 years old, and 5 (1.5%) were ≥75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged ≥75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.

Biological markers and small cell carcinoma of the lung. A clinical evaluation of urinary ribonucleosides

Five minor base ribonucleosides, primarily degradation products of transfer ribonucleic acid (tRNA), were evaluated as potential biological markers for patients with small cell carcinoma of the lung. The urinary concentration for pseudouridine, 1‐methyladenosine, 1‐methylinosine, N2‐methylguanosine, and N2,N2‐dimethylguanosine was determined by means of reversed‐phase high performance liquid chromatography and quantitatively expressed as a function of creatinine excretion. Comparisons were made with carcinoembryonic antigen (CEA) plasma levels. The total frequency of elevated values for the five nucleosides in pretreatment urine samples was directly related to stage of disease with 24/60 (40%) determinations increased in 12 patients with limited disease and 69/85 (81%) in 17 patients with extensive disease. For these same patients, CEA levels were elevated respectively in 2/11 (18%) of the former and 9/17 (53%) of the latter group. The frequency and degree of elevation of the nucleoside/creatinine ratios in pretreatment samples from patients with extensive disease was correlated directly with increasing number of metastatic sites. Of the five nucleosides, the mean number elevated was two for limited disease, 3–4 for extensive disease with one metastatic site, 4 for two or three, and 5 for four or more sites of metastases. Based on a summation of pretreatment nucleoside/creatinine ratios, a discriminant for survival was derived giving curves separating patients (P = 0.086) similar to the discriminant based on stage of disease. Although discordant results were noted, an overall correlation of 75% agreement with clinical assessment was estimated in response categories when monitoring changes associated with therapy.

Chemotherapy for lung cancer: the state of the art in 2009

Lung cancer remains the most common cause of cancer-related death among men and women worldwide. Incremental and significant advances in available systemic treatments, however, have taken place in the last decade to provide improved survival rates and better palliation for patients with non-small-cell and small-cell lung cancer. Superior imaging techniques have enabled the detection of early-stage disease and adjuvant chemotherapy has earned a place for select patients following resection of their tumors. Perhaps the largest growth has been in the area of advanced non-small-cell lung cancer, in which multiple new combination and single-agent systemic therapies have become standard where previously only ‘best supportive care’ was thought appropriate. In concert with broader applicability of chemotherapy, translational studies have provided the rationale for using molecular markers to identify the patients most likely to benefit from biological and targeted therapies. This review will discuss the current role of chemotherapy in both early and advanced non-small-cell and small-cell lung cancer. Novel targeted systemic therapies and the appropriate selection of treatments for patients based on their tumors’ molecular phenotypes and histologies will also be reviewed.

Emerging profile of cetuximab in non-small cell lung cancer

This paper summarizes the phase II and III clinical trial experience with cetuximab in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Single-arm and randomized phase II studies show that adding cetuximab to platinum-based doublets has favorable efficacy compared to chemotherapy alone or historical control groups that did not receive cetuximab. Two phase III studies have been conducted with different primary endpoints: overall survival in the pivotal FLEX trial, and progression-free survival (PFS) as assessed by an independent radiologic review committee in the supportive BMS 099 trial. FLEX shows that adding cetuximab significantly prolongs survival compared to chemotherapy alone. BMS 099 did not meet its primary objective, but did show that adding cetuximab significantly prolongs PFS as assessed by investigators. Across all studies, the safety and tolerability of adding cetuximab was predictable and manageable, and did not exacerbate the toxicity associated with chemotherapy. These trials enrolled a broad population of NSCLC patients regardless of histological subtype or comorbid cardiovascular disease, populations that have been underrepresented in clinical trials of other biologics. Cetuximab does not carry restrictions in use due to safety, and therefore it may be a particularly valuable option for patients who are not eligible for other biologics.

Double‐Blind Multiple‐Dose Crossover Study of the Antiemetic Effect of Intramuscular Levonantradol Compared to Prochlorperazine

Abstract: Twenty cancer patients who received chemotherapy were entered into a double‐blind crossover design antiemetic study comparing 1 mg levonantradol, an investigational synthetic cannabinoid, to 10 mg prochlorperazine. Sixteen patients completed the crossover. For each antiemetic course, four doses of each study medication were given intramuscularly 2 hours before chemotherapy and then 2,6, and 10 hours after chemotherapy administration. There were no statistical differences in patients responses to levonantradol and prochlorperazine. The frequency of side effects was greater with levonantradol than with prochlorperazine. The most common side effect of levonantradol were somnolence, dry mouth, dizziness, tachycardia, postural hypotension, and blurred vision, while those for prochlorperazine were somnolence, dry mouth, and tachycardia.

Evaluation of the relative importance of chemotherapeutic and antiemetic efficacy in various oncologic settings

Goals of workThis study investigated physician’s attitudes toward the relative importance of chemotherapeutic and antiemetic efficacy in different clinical scenarios.Materials and methodsOncologists in the USA and four European countries completed an online stated-choice survey consisting of three hypothetical treatment choices for each of two patient types. Each hypothetical treatment alternative included both chemotherapy and antiemetic regimens. The two hypothetical patient types were (1) a 48-year-old woman with locoregional infiltrating ductal carcinoma of the breast and (2) a 78-year-old man with squamous cell carcinoma of the lung and multiple liver metastases. In each choice question, oncologists were asked to select the better combination of chemotherapy and antiemetic prophylaxis between two treatment alternatives.Main resultsFive hundred fifty-seven oncologists completed the survey. For the adjuvant breast cancer patient, the most aggressive chemotherapy is consistently the most important treatment consideration in all countries. For the advanced lung cancer patient, the most aggressive chemotherapy, the less aggressive chemotherapy, and the most aggressive antiemetic prophylaxis are of similar importance in most countries.ConclusionsPhysicians appear more likely to prescribe a more aggressive chemotherapy regimen for a younger patient with a perceived curable tumor, regardless of the emetogenic properties of the chemotherapy. Symptom management is more of a concern and chemotherapeutic efficacy relatively less of a priority in an older patient with advanced disease for whom chemotherapy is not curative.

Serum protein-bound carbohydrates and small cell carcinoma of the lung. Correlations with extent of disease, tumor burden, survival, and clinical response categories

The levels for serum protein bound neutral carbohydrates (fucose, mannose, and galactose) were determined at specific intervals for 40 patients with small cell carcinoma of the lung and compared to the corresponding carcinoembryonic antigen (CEA) levels. In pretreatment samples, the frequency of elevation was 92.5% for fucose and 77.5% each for mannose and for galactose. CEA determined in these same samples was elevated (>5 ng/ml) in 45.0%. One or more of the three carbohydrate levels were elevated in pretreatment serum of 95.0% of the patients. The individual frequency of elevation for each carbohydrate was significantly related to initial stage of disease (P < 0.01). Median survival was significantly longer for patients based on a discriminant of <3 carbohydrates elevated in pretreatment samples (25 months) to all 3 elevated (11 months) with P = 0.0302. A single value, termed the biomarker index, was calculated to represent the summation of the individual carbohydrate levels per individual serum sample. The biomarker index was found to be directly correlated with extent of primary disease, number of metastic sites, tumor burden, and clinical response categories assessed at serial time points. For patients with both low Biomarker Index values and normal CEA levels in pretreatment samples, an initial rise in both determinations occurred frequently corresponding to partial or complete tumor response. The occurrence of such discordant results must be considered as a likely possibility for those patients with low or normal pretreatment biological marker levels and subsequent response to primary chemotherapy. Cancer 52:131‐139, 1983.

New drugs in the treatment of non-small cell lung cancer

Lung cancer is the most common malignancy and cause of death due to cancer in the United States. It is estimated that in 1990,157,OOO new cases will have been diagnosed and 142,000 individuals will have died from lung cancer [l]. Non-small cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers [23. The overall cure rate for patients with NSCLC is less than 10%. The poor survival rates reflect the advanced stage of the disease at diagnosis, high recurrence rates associated with surgery and radiation therapy and the inability of combination chemotherapy to significantly prolong survival. There are several single-agents in the treatment of NSCLC that produce response rates of 20% or less [3]. Usually only partial responses are seen in the patients treated and the duration of the responses are short. Combination chemotherapeutic regimens utilizing the drugs that have demonstrated activity as single agents in the treatment of NSCLC have usually improved the response rates including a small percentage of complete responses. In single institution studies, the response rates to combination chemotherapy is usually higher than that reported in randomized studies utilizing similar drug regimens conducted by the cooperative groups [4]. The Eastern Cooperative Oncology Group (ECOG) comparing four commonly used combination chemotherapeutic regimens demonstrated responses of 17-3 1% [5]. Despite the increase in responses with multi-drug regimens, the overall survival rate remains poor. To improve the response rates and duration of responses of the systemic treatment of NSCLC and ultimately increase survival of patients treated, the identification of new drugs with significant activity against NSCLC is needed. The following is an overview of some of the studies evaluating these drugs in the treatment of NSCLC.

Sequential methotrexate and 5-Fluorouracil in advanced ovarian carcinoma

Experimental studies have demonstrated that the combined effects of methotrexate and 5-FU may be optimized in schedules of administration where the antifolate is administered prior to the fluoropyrimidine. Seventeen patients with ovarian carcinoma refractory to standard chemotherapy were treated with a sequence of moderate dose MTX (200 mg/m2) and 5-FU. No responses were seen, although the hematologic and gastrointestinal toxicity which was observed was very mild. Because of prior nephrotoxic chemotherapy and the frequent presence of large amounts of third space fluid in the form of malignant ascites, patients with ovarian cancer are at high risk for MTX toxicity. In this study, eight patients with significant ascites had higher plasma MTX concentrations measured at 48 and 72 hr following drug administration than nine similar patients without ascites. This suggested delayed excretion of MTX in patients with ascites although this difference was not statistically significant. MTX concentrations in ascites exceeded those in plasma between 6 and 12 hr and remained near 1 microM for 24 hr. Although the lack of response is disappointing, the modest toxicity encountered with the careful drug level monitoring and the favorable pharmacologic findings suggest that this combination of drugs each with established activity in untreated ovarian cancer deserves further study in primary treatment.

Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors

ABSTRACT Checkpoint inhibitor pneumonitis (CIP) is an immune‐related adverse event that can occur after initiation of anti–programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial‐enrolled and non–trial‐enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti–programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%–5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher‐grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life‐threatening complication of ICI therapy.