Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292).

BACKGROUND: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. PATIENTS AND METHODS: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy. RESULTS: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

A Coala-T-Cannabis Survey Study of breast cancer patients' use of cannabis before, during, and after treatment.

BACKGROUND: The goal of this study was to characterize cannabis use among patients with breast cancer, including their reasons for and timing of use, their sources of cannabis information and products, their satisfaction with the information found, their perceptions of its safety, and their dialogue about cannabis with their physicians. METHODS: United States-based members of the Breastcancer.org and Healthline.com communities with a self-reported diagnosis of breast cancer within 5 years (age ≥ 18 years) were invited to participate in an anonymous online survey. After informed consent was obtained, nonidentifiable data were collected and analyzed. RESULTS: Of all participants (n = 612), 42% (n = 257) reported using cannabis for relief of symptoms, which included pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea/vomiting (46%). Furthermore, 49% of cannabis users believed that medical cannabis could be used to treat cancer itself. Of those taking cannabis, 79% had used it during treatment, which included systemic therapies, radiation, and surgery. At the same time, few (39%) had discussed it with any of their physicians. CONCLUSIONS: A significant percentage of survey participants (42%) used cannabis to address symptoms; approximately half of these participants believed that cannabis could treat cancer itself. Most participants used cannabis during active cancer treatment despite the potential for an adverse event during this vulnerable time. Furthermore, most participants believed that cannabis was safe and were unaware that product quality varied widely and depended on the source. This study reviews the research on medicinal cannabis in the setting of these findings to help physicians to recognize its risks and benefits for patients with cancer. LAY SUMMARY: Almost half of patients with breast cancer use cannabis, most commonly during active treatment to manage common symptoms and side effects: pain, anxiety, insomnia, and nausea. However, most patients do not discuss cannabis use with their physicians. Instead, the internet and family/friends are the most common sources of cannabis information. Furthermore, most participants believe that cannabis products are safe and are unaware that the safety of many products is untested.

Preliminary evaluation of a predictive blood assay to identify patients at high risk of chemotherapy-induced nausea.

PURPOSE: The aim of this study was to test a new blood-based assay for its ability to predict delayed chemotherapy-induced nausea. METHODS: Blood drawn from consented patients prior to receiving their first platinum-based therapy was tested for glutathione recycling capacity and normalized to total red cell numbers. This number was used to predict nausea and then compared to patient reported outcomes using the Rotterdam Symptom Check List and medical records. RESULTS: We show that the pathways involved in the glutathione recycling are stable for at least 48 h and that the test was able to correctly classify the risk of nausea for 89.1 % of the patients. The overall incidence of nausea was 21.9 % while women had an incidence of 29.6 %. CONCLUSIONS: This might be the first objective test to predict delayed nausea for cancer patients receiving highly emetogenic chemotherapy. We believe that this assay could better guide clinicians in their efforts to provide optimal patient-oriented care.

Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Chemotherapy-induced peripheral neuropathy is frequently a dose-limiting factor in cancer treatment and may cause pain and irreversible function loss in cancer survivors. We tested whether alpha-lipoic acid (ALA) could decrease the severity of peripheral neuropathy symptoms in patients undergoing platinum-based chemotherapy. METHODS: Cancer patients 18 years or older were randomly selected to receive either 600 mg ALA or a placebo three times a day orally for 24 weeks while receiving chemotherapy regimens including cisplatin or oxaliplatin. Neuropathy was measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale and the NCI Common Toxicity Criteria for Adverse Events neurotoxicity grades. Results from timed functional tests and the Brief Pain Inventory (BPI) were secondary endpoints. RESULTS: Seventy of 243 (29 %) patients completed the study (24 weeks). Both the ALA and the placebo arms had a comparable drop-out rate. No statistically significant differences were found between the ALA and the placebo groups for FACT/GOG-Ntx scores, BPI scores, and patients' functional outcomes. CONCLUSION: This strategy of oral ALA administration was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. High attrition rates due to poor patient compliance and manner of dosage administration in this trial demonstrated a lack of feasibility for this intervention. Future studies to explore ALA as a neuroprotective agent should take heed of the barriers confronted in this study.

A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11.

PURPOSE: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. PATIENTS AND METHODS: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). RESULTS: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. CONCLUSIONS: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.

The symptom burden of cancer: Evidence for a core set of cancer-related and treatment-related symptoms from the Eastern Cooperative Oncology Group Symptom Outcomes and Practice Patterns study.

BACKGROUND: A set of common cancer-related and treatment-related symptoms has been proposed for quality of care assessment and clinical research. Using data from a large, multicenter, prospective study, the authors assessed the effects of disease site and stage on the percentages of patients rating these proposed symptoms as moderate to severe. METHODS: The severity of 13 symptoms proposed to represent "core" oncology symptoms was rated by 3106 ambulatory patients with cancer of the breast, prostate, colon/rectum, or lung, regardless of disease stage or phase of care; 2801 patients (90%) repeated the assessment 4 to 5 weeks later. RESULTS: At the time of the initial assessment, approximately 33% of the patients reported ≥ 3 symptoms in the moderate-to-severe range; 11 of the 13 symptoms were rated as moderate to severe by at least 10% of all patients and 6 were rated as moderate to severe by at least 20% of those receiving active treatment. Fatigue/tiredness was the most severe symptom, followed by disturbed sleep, pain, dry mouth, and numbness/tingling. More patients with lung cancer and patients receiving active treatment reported moderate to severe symptoms. Percentages of symptomatic patients increased by disease stage, less adequate response to therapy, and declining Eastern Cooperative Oncology Group performance status. The percentages of patients reporting moderate to severe symptoms were stable across both assessments. CONCLUSIONS: The results of the current study support a core set of moderate to severe symptoms that are common across outpatients with solid tumors, that can guide consideration of progression-free survival as a trial outcome, and that should be considered in clinical care and in assessments of quality of care and treatment benefit.

Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial.

IMPORTANCE: There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy. OBJECTIVE: To determine the effect of duloxetine, 60 mg daily, on average pain severity. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment. INTERVENTIONS: The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks. MAIN OUTCOME MEASURES: The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form "average pain" item with 0 representing no pain and 10 representing as bad as can be imagined. RESULTS: Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount. CONCLUSION AND RELEVANCE: Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00489411.

Full-term pregnancy and vaginal delivery after treatment for non-Hodgkin's lymphoma of the cervix and lower uterine segment: a case report.

BACKGROUND: Primary gynaecologic non-Hodgkin's lymphomas are rare. We present a case of primary large B-cell lymphoma localized to the lower uterine segment and endocervical stroma that was successfully treated with chemotherapy and immunotherapy. Treatment was followed by a disease-free interval and successful term vaginal delivery. CASE: A 21-year-old nulliparous woman presented with dysfunctional uterine bleeding. Radiologic assessment of a posterior lower uterine segment mass and pathologic evaluation of cervical biopsies demonstrated diffuse large B-cell lymphoma involving the endocervical stroma. The patient was treated with chemotherapy and immunotherapy. She had a normal, uncomplicated full-term pregnancy and spontaneous vaginal delivery six years after treatment. CONCLUSION: Aggressive diagnosis and treatment of primary non-Hodgkin's lymphomas of the cervix do not preclude the possibility of a successful pregnancy and term vaginal delivery.

Effect of Taxane Chemotherapy With or Without Indoximod in Metastatic Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. OBJECTIVE: To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. INTERVENTIONS: A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and ß = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. RESULTS: Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01792050.

Cancer genetics evaluation: barriers to and improvements for referral.

Despite the availability of cancer susceptibility testing, little information exists regarding physicians' selection and referral of eligible patients. This study provides insight into whom, why, and when physicians refer for cancer genetics evaluation, as well as their comfort level within this role. Eighty-two physicians (51 primary care, 15 gynecology, 11 surgery and 5 oncology) completed a survey (response rate: 34%) regarding cancer genetics referral practices. Of these, 59% reported an awareness of the hospital's cancer genetics program. Program awareness was greater among oncologists, surgeons, and gynecologists than among primary care physicians (p < 0.0001). Patients were referred for enhanced risk assessment (88%), improved medical management (85%), and concern for family members (83%). Patient eligibility was based on family cancer history (96%), patient cancer history (83%), and patient request (73%). Patients were not referred mainly due to patient disinterest (54%) or physician concern about either insurance coverage (44%) or insurance discrimination (31%). Primary care physicians were less comfortable with identifying patients for referral (p < 0.001) and with discussing genetics (p < 0.002) than specialists. The largest barriers to referral were lack of program awareness and limited knowledge regarding patient eligibility, improved insurance coverage, and antidiscrimination legislation. Physician-targeted marketing and education may improve the referral process.

Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer.

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Basics of asset protection.

Asset protection has become a hot topic for physicians because of the risk of high judgments in medical malpractice cases-judgments that often exceed their policy limits and can force a physician into bankruptcy. In this article we describe some of the background and basics of asset protection. In future articles we will detail some of the protection strategies that can be used.

Characterization of the apoptotic response induced by the cyanine dye D112: a potentially selective anti-cancer compound.

Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation.

Motivations and concerns of women considering genetic testing for breast cancer: a comparison between affected and at-risk probands.

Since the discovery of the BRCA1 and BRCA2 genes, there has been an increasing demand for breast cancer risk assessment programs. In an effort to understand and serve the population such programs target better, several studies have identified factors influencing high-risk women to pursue breast cancer risk assessment and genetic testing services; none, however, has focused on how the motivations and concerns of at-risk women may differ from their previously affected counterparts, who are typically the initial members of their families to undergo genetic testing. The majority of both previously affected and unaffected women felt that preventative surgery decisions, surveillance practices, the assessment of children's risks, and increased breast cancer anxiety were "more important" or "very important" issues regarding their thoughts about genetic testing. Significantly more affected women deemed family members' opinions "more" or "very important" (p < 0.01). Opinions concerning insurance and employment discrimination did not vary significantly between groups; however, a larger percentage of affected women felt this issue was of importance. Although all issues above should be addressed with women seeking cancer risk assessment and genetic testing, this research may help health care providers to gain a greater understanding of how the motivators and concerns of high-risk women can differ with personal cancer status so that referral, counseling, and education can be executed optimally.

Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma.

BACKGROUND: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). METHODS: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks × 2 -3 cycles. RESULTS: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. CONCLUSIONS: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC.

Ecological risk assessment issues identified during the U.S. Environmental Protection Agency's examination of risk assessment practices.

Recently, the U.S. Environmental Protection Agency examined its current risk-assessment principles and practices. As part of the examination, aspects of ecological risk-assessment practices were reviewed. Several issues related to ecological risk assessment were identified, including the use of organism-level versus population-level attributes to characterize risk, the possible opportunities associated with the increased use of probabilistic approaches for ecological risk assessment, and the notion of conservatism in estimating risks. The agency examination provides an understanding of current practices and is intended to begin a dialogue in which the risk assessment community can engage in addressing the identified issues to improve and enhance ecological risk assessment.

Combined therapy with topotecan and gemcitabine in patients with inoperable or metastatic non-small cell lung cancer.

PURPOSE: We conducted a phase I/II trial of topotecan combined with gemcitabine in patients with metastatic or unresectable non-small cell lung cancer (NSCLC) based on preclinical data showing in vitro synergy against an established lung adenocarcinoma cell line. The aim was to determine the maximally tolerated dose (MTD) of topotecan when the gemcitabine dose is held constant, as well the dose limiting toxicity (DLTs) of this combination in NSCLC patients. PATIENTS AND METHODS: Twenty-four patients with stage IIIB or IV NSCLC were treated weekly times 3 with a week break with gemcitabine (1250 mg/m2 over 30 minutes) and topotecan (30 minutes) at varying doses. The starting dose of topotecan was 1.0 mg/m2 and doses were escalated in 0.25-mg/m2 increments until the MTD was achieved. RESULTS: The MTD of gemcitabine/topotecan was 1250 mg/m2 of gemcitabine and 2.00 mg/m2 of topotecan (level 5). Neutropenia was the DLT. Few nonhematologic toxicities were observed. There were 5 (21%) partial responses among 24 patients. The median survival was 22 weeks. Two patients have had prolonged (> 2 year) survival. CONCLUSION: The combination of gemcitabine and topotecan seems to be active against NSCLC with acceptable hematologic toxicity and minimal nonhematologic toxicity. The recommended dose for further study is 1250 mg/m2 of gemcitabine (days 1, 8, 15) and 2.0 mg/m2 of topotecan (days 1, 8, 15) administered every 28 days.