Ifosfamide and vinorelbine as first-line chemotherapy for advanced non-small cell lung carcinoma

We evaluated the efficacy and toxicity of the novel combination of ifosfamide (IFX) and vinorelbine (VNB) as first-line chemotherapy in patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Between March 1993 and November 1994, 44 patients (17 stage IIIB; 27 stage IV) received a regimen consisting of IFX, 2 g/m2 in a 1-h infusion, days 1-3; mesna, 400 mg/m2 in an i.v. bolus at hours 0 and 4 and 800 mg orally at hour 8, days 1-3; and VNB, 35 mg/ m2 in a 20-min infusion, days 1 and 15. During the first course only, a half dose of VNB (17.5 mg/m2) was administered on days 8 and 22. Courses were repeated every 28 days. Forty patients were fully evaluable for response, and 44 were assessable for toxicity. Objective regression was recorded in 13 of 40 patients (33%). No patient achieved a complete response. Thirteen patients presented a partial response (33%); 17 (42%) had no change; and progressive disease was observed in 10 (25%). The median duration of response was 10 months, and the median time to treatment failure for the whole group was 4 months. Median survival was 11 months. The dose-limiting toxic effect was myelosuppression. Leukopenia occurred in 25 patients (57%) and was grade 3 or 4 in 8 patients (18%). Twelve patients (27%) developed peripheral neurotoxicity, while five had mild IFX-induced CNS toxicity. Phlebitis was observed in 15 of 30 patients (50%) who did not have central implantable venous systems. The IFX-VNB combination exhibited an activity against NSCLC that was among the highest reported for non-cisplatin-containing regimens, with a toxicity profile that was easily managed.     

Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain

BACKGROUND: A retrospective study of patients undergoing stereotactic radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma (NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven patients underwent radiosurgery during a 7-year interval; 71 also underwent whole brain radiation therapy. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. RESULTS: The overall median survival was 10 months after radiosurgery, and 15 months from the diagnosis of brain metastases. Five factors significantly affected survival: extent of systemic disease, presence of a neurologic deficit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary tumor of the chest. Median survival time was 26 months in a subgroup of patients with no extracranial metastases, no neurologic deficits, and a small tumor without necrosis. The authors evaluated 91 tumors with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery for NSCLC brain metastases is effective and is associated with few complications. The early detection of brain metastases and treatment with radiosurgery combined with radiation therapy provide the opportunity for extended high quality survival.     

FOLFOX6序贯周剂量多西紫杉醇及顺铂方案一线治疗老年晚期胃癌临床观察

目的:观察FOLFOX6序贯周剂量多西紫杉醇及顺铂方案一线治疗老年晚期胃癌的疗效和安全性.方法:32例晚期胃癌患者先采用FOLFOX6方案化疗.14天为1个周期.FOLFOX6方案化疗3个周期结束后第14天开始给予多西紫杉醇+顺铂方案化疗,每周给药一次,每4周为1 周期,治疗2周期.结果:全组32例均可评价疗效,完全缓解 0例(0%),部分缓解 14例(43.8%),稳定13例(40.6%),进展5例(15.6%),总有效率为43.8% (14/32),临床获益率84.0%(27/32).中位疾病进展时间为7.6个月(95%可信区间,3.6～12.12个月),中位生存期为10.9个月(95%可信区间,5.4～15.5个月),1年生存率为40.6% (13/32).主要毒性反应为骨髓抑制、消化道反应和脱发,多数为1～2度.结论:FOLFOX6序贯周剂量多西紫杉醇及顺铂方案一线治疗老年晚期胃癌疗效较好,毒性反应较轻,耐受性好.     

Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: a meta-analysis of response, toxicity, and survival

Cyclosporin A (CsA) induces osteoporosis but not through direct activation of osteoclasts. CsA also inhibits cell-mediated mineralization in marrow stromal cell culture, whereas the tyrphostin AG-1478 increases mineralization. These antagonistic effects on mineralization were used to discern molecules that underwent phosphorylation changes in association with their opposing effects on mineralization. In parallel, quantitative changes in Src protein were followed. Multiple dexamethasone (DEX)-stimulated stromal cell cultures were grown with and without a mineralization-inhibiting dose (0.1 microM) of CsA and were harvested on different days of DEX stimulation. Immunoblots of gel-fractionated cell extracts showed that the most noticeable changes in tyrosine phosphorylated proteins (TPP) were seen on day 8 of DEX stimulation. At least 15 TPP bands, mostly smaller than 53 kDa, were more prominent in CsA-treated cultures on day 8. Under CsA, Src protein quantity decreased on day 8, but its cleavage product (52/54 kDa) was sixfold more abundant then on day 7. Day 8 was chosen to test the effect of AG-1478 on the CsA-induced TPP changes. Dimethyl sulfoxide (DMSO) alone, the solvent of AG-1478, increased mineralization in CsA-treated versus CsA-untreated cultures and slightly decreased Src and its cleavage product. AG-1478 at 5 microM, in CsA cultures increased the specific alkaline phosphatase activity threefold, with a slight change in mineralization relative to controls grown with DMSO alone. This was accompanied by decreased intensity of several TPP bands smaller than 36 kDa. In contrast, treatment with 50 microM of AG-1478 increased the intensity of TPP bands at the same molecular size range. This high AG-1478 dose decreased cell counts selecting mineralizing cells. The results indicate that increased Src protein cleavage product on day 8 by CsA is associated with mineralization inhibition, which is opposed by DMSO and 50-microM AG-1478, thus antagonizing the effect of CsA on mineralization. Direct or indirect interaction between Src and TPP, antagonistically affected by CsA and AG-1478, is likely to underlay cellular control of mineralization. Changes in p19 and p29 intensity showed association with mineralization that was reflected by a significant direct and inverse correlation, respectively, with calcium precipitation per cell.     

Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated nonsmall cell lung carcinoma

BACKGROUND: Neuroendocrine differentiation can be identified in 10-30% of patients with nonsmall cell lung carcinoma (NSCLC) by immunohistochemical or electron microscopic techniques. However, its clinical significance is not well established. METHODS: Tumors from 107 patients with Stage IIIA, IIIB, and IV NSCLC treated with cisplatin/etoposide with or without hydrazine in the North Central Cancer Treatment Group and Mayo Clinic protocols were analyzed immunohistochemically with antibodies to chromogranin A (CGA), Leu 7 (CD 57), and synaptophysin (SY). These results were compared with clinical outcomes. RESULTS: Keratin AE1/AE3, used as a control, was positive in 99.1% of cases; 34.6% had positive staining for at least 1 neuroendocrine marker, and 11.3% had positive staining for 2 or more markers. CGA was positive in 4.7%, Leu 7 in 18.7%, and SY in 24.3% of cases. A significant increase in survival was seen in patients with tumors expressing any one neuroendocrine marker or any combination of neuroendocrine markers (P < or = 0.01). There was no correlation between the presence of neuroendocrine differentiation and either response to chemotherapy or time to disease progression (P > 0.3), nor was there any correlation between chemotherapy response, time to progression, or survival with staining intensity or percent of cells positive per case. CONCLUSIONS: Neuroendocrine differentiation may be of prognostic significance in patients with advanced stage NSCLC treated with chemotherapy.     

Cytostatic treatment of patients with advanced non-small cell lung cancer

Complications of patellar resurfacing in total knee arthroplasty have rekindled the interest of many surgeons in patellar retention. In a prospective study 20 randomly selected patients of 40 underwent patellar resurfacing in combination with their total knee arthroplasty. The other 20 patients were left with an unresurfaced patella. Within 24 months of follow-up, the advantages of patellar resurfacing could be seen according to the Knee Society Score. Especially in advanced osteoarthritis of the knee joint, the patients achieved better scores in climbing stairs and in function. The superior functional results are arguments for patellar resurfacing, at least in knees with advanced osteoarthritis.     

Energy balance in nonsmall cell lung carcinoma patients before and after surgical resection of their tumors

BACKGROUND: The purpose of this study was to investigate whether surgical removal of a tumor influences energy balance, body weight, and body composition in lung carcinoma patients. METHODS: In 53 nonsmall cell lung carcinoma (NSCLC) patients, resting energy expenditure (REE, measured by ventilated hood), energy intake (EI, determined by diet history), body weight, and body composition (fat free mass [FFM], measured by bioelectrical impedance analysis) were all determined before tumor resection. In 39 of 53 patients, REE, EI, body weight, and body composition were also measured 3, 6, and 12 months after tumor resection. RESULTS: Thirty-six of 53 patients (68%) were found to be hypermetabolic. Fourteen patients were excluded from the repeated measurements. Patients with curative tumor resection (n = 30) showed an increase in body weight over a 1-year period, in contrast to patients with tumor recurrence (n = 9), who lost weight (+3.5 vs. -3.6 kg, P < 0.005). The weight gain was caused predominantly by an increase in fat mass (FM), while the weight loss was caused for more than half by a decrease in FFM. Body weight was increased in hypermetabolic patients (n = 20) as well as patients with normal metabolism (n = 10) 1 year after successful removal of their tumors. However, although EI/REE was significantly increased in hypermetabolic patients (from 106% to 140%, P < 0.05), it was not changed in patients with normal metabolism. CONCLUSIONS: Hypermetabolic NSCLC patients undergoing curative resection show an improvement in energy balance caused by both a decrease in REE and an increase in EI. This positive energy balance results in weight gain, which is caused predominantly by an increase in FM.     

Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival

We report the electrophysiologic findings of myoclonus in a patient with Huntington's disease (HD). This patient was studied postoperatively after a bilateral fetal cell transplant in his striatum. Incomplete transient improvement was seen in the myoclonus, followed by gradual deterioration. The myoclonus itself had a cortical correlate and was associated with an enlarged somatosensory evoked potential (SEP), consistent with the presence of cortical reflex myoclonus. An enlarged SEP has not been previously reported in myoclonus associated with HD. The postulated mechanisms for myoclonus, when it occurs in HD, have differed in the literature. The reason for the transient improvement of the myoclonus following transplantation is unclear, but this case raises the possibility that basal ganglia circuits may modulate cortical myoclonic activity.     

Localization of tumor suppressor activity important in nonsmall cell lung carcinoma on chromosome 11q

Loss of heterozygosity on chromosome 11q23 is observed at high frequency in human nonsmall cell lung carcinomas (NSCLCs), suggesting the presence of a tumor suppressor gene. Previous analysis of DNA from 79 patients identified a commonly deleted segment of 5 centimorgans. Complementation analysis was used to further localize a putative tumor suppressor gene. Three yeast artificial chromosome (YAC) clones spanning the minimal loss of heterozygosity region were modified, and spheroplast fusion was used to transfer them into human A549 NSCLC or murine Lewis lung carcinoma (LLC) cell lines. The resulting yeast x human hybrid cell lines containing an intact copy of a 1.6-Mb YAC, 939b12, showed reduced growth in vitro. Injection of parental A549 cells into athymic (nu/nu) mice resulted in tumor formation at 27 of 28 injection sites. In contrast, two independent 939b12-containing cell lines formed tumors at only 3 of 20 injection sites. 939b12 also suppressed tumor formation by LLC NSCLC cells in nude mice, but YACs 785e12 and 911f2, which flank 939b12, had no suppressor activity. Further localization of tumor suppression activity on 939b12 was accomplished by introduction of defined fragmentation derivatives into A549 cells and by analysis of YACs that were broken on transfer into LLC cells. This complementation approach localized tumor suppression activity to the central 700 kb of 939b12 and provides a functional assay for positional cloning of this tumor suppressor gene.     

The possible advantage of hyperfractionated thoracic radiotherapy in the treatment of locally advanced nonsmall cell lung carcinoma: results of a North Central Cancer Treatment Group Phase III Study

BACKGROUND: A three-arm Phase III randomized trial was performed to compare response rates, time to local or distant progression, and survival for patients with unresectable (Stage IIIA or IIIB) nonsmall cell lung carcinoma treated with standard fractionated thoracic radiotherapy (SFTRT) versus accelerated hyperfractionated thoracic radiotherapy (AHTRT) with or without combination etoposide and cisplatin chemotherapy. METHODS: This trial was initiated in 1992 by the North Central Cancer Treatment Group. Patients with Stage IIIA or IIIB nonsmall cell lung carcinoma were eligible. They were randomly assigned to either SFTRT (6000 centigray [cGy] in 30 fractions) or AHTRT (150 cGy twice daily to a total dose of 6000 cGy, with a 2-week break after the initial 3000 cGy); the AHTRT was given alone or with concomitant cisplatin (30 mg/m2, Days 1-3 and 28-30) and etoposide (100 mg/m2, Days 1-3 and 28-30). RESULTS: A total of 110 patients were entered on study. Eleven patients were declared ineligible or off study on the day of study entry. This analysis was confined to the 99 eligible patients. This article reports mature follow-up, because more than 80% of the patients have died. The median follow-up of living patients was 2.5 years. There were suggestions of improvement in the rates of freedom from local recurrence and survival for patients treated with AHTRT (with or without chemotherapy) as opposed to SFTRT (P = 0.06 and P = 0.10, respectively). The improvement in survival associated with AHTRT (with or without chemotherapy) was statistically significant for the subgroup of patients with nonsquamous cell carcinoma after adjustment for other potentially confounding factors (P = 0.02). No differences in freedom from systemic progression or survival were found in a comparison of AHTRT with chemotherapy and AHTRT without chemotherapy. CONCLUSIONS: These results suggest that treatment of Stage IIIA or IIIB nonsmall cell lung carcinoma with AHTRT with or without chemotherapy may improve freedom from local progression and survival as compared with SFTRT, especially for patients with nonsquamous cell carcinoma. The statistical powers to detect the observed differences in median time to local progression and survival were approximately 55% and 35%, respectively. Therefore, further investigation comparing SFTRT with AHTRT is warranted.     

Complex and controversial issues in locally advanced non-small cell lung carcinoma

Locally advanced non-small cell lung carcinoma (NSCLC) presents enormous challenges to clinicians and researchers. Because of the absence of metastatic disease, it is a potentially curable condition, greatly differentiating it from stage IV NSCLC. The median and actuarial survival rates are poor, though clearly improved in the past decade, and clearly better than several other types of locally advanced malignancies (e.g., pancreatic cancer, glioblastoma). As demonstrated in Table I, the combination of chemotherapy and radiotherapy has earned the designation of "standard of care" for most good-performance-status patients with locally advanced NSCLC. It is likely that improvements in radiotherapy have also contributed to the enhanced survival and local control rates in this disease. With concurrent chemoradiotherapy, the majority of patients can receive a substantial local response (Fig. 1). Many achieve durable local control, only to succumb to eventual distant metastatic failure. There remains much room for improvement, and there are several avenues for clinical and translational research that offer promise. These include new systemic chemotherapy options (and newer ways of combining these drugs with radiotherapy), improvements in radiotherapy fractionation and dose intensity, methods of protection from chemoradiotherapy toxicity, specific therapies to prevent brain metastatic failure, and the integration of biologically targeted molecules into chemoradiation programs. This article summarizes the advances in the treatment of locally advanced NSCLC over the past several decades and explores some of the many remaining controversies and areas for future investigation.     

Autologous tumor killing activity as a prognostic factor in primary resected nonsmall cell carcinoma of the lung

BACKGROUND: Cytotoxic activity of peripheral blood lymphocytes obtained during surgery against autologous fresh tumor cells has been reported. However, the role of lymphocyte autologous tumor killing or natural killer activity during the postoperative period remains obscure. In this article, the authors describe the importance of postoperative autologous tumor killing activity as a prognostic factor in patients with primary resected nonsmall cell lung carcinoma (NSCLC) after long term follow-up. METHODS: Forty-two patients who had resection of NSCLC, with primary culture of autologous tumor cells taken successfully, were studied. Cytotoxic activity against autologous, allogenic NSCLC and K562 leukemia cells was examined using peripheral blood lymphocytes obtained during the 2 weeks immediately following surgery. Factors related to prognosis were analyzed by univariate and multivariate analyses. RESULTS: The overall 5- and 10-year survival rates for the NSCLC patients were 40.5% and 27.5%, respectively. Statistical analysis of survival curves revealed a significant difference with regard to T classification (P = 0.025), N classification (P = 0.0015), stage (P = 0.028), and postoperative autologous tumor killing activity (P = 0.0008); there were no significant differences in relation to age, gender, histology, differentiation, visceral pleural invasion, resectability, surgical method, allogeneic tumor killing activity, or natural killer activity. Multivariate analysis demonstrated a significant correlation between disease recurrence and N classification (P = 0.0003), T classification (P = 0.023), stage (P = 0.001), and autologous tumor killing activity (P = 0.007), indicating independent prognostic significance. The phenotypes of the effector cells involved in autologous tumor killing activity were CD3(+), CD4(-), CD8(+), and CD11b(-). Autologous tumor killing activity was inhibited by competing unlabeled autologous tumor cells. CONCLUSIONS: Autologous tumor killing activity during the 2 weeks immediately following surgery is an important prognostic factor in resected NSCLC.     

A phase I/II study of paclitaxel (TAXOL) and concurrent radiotherapy in advanced nonsmall cell lung cancer

OBJECTIVE: Polymerase chain reaction amplification of a portion of the RhC/c/E/e gene could lead to a rapid, accurate determination of fetal RhC/c/E status. The purpose of this study was to evaluate the accuracy of this technique by testing for the first time a large number of deoxyribonucleic acid samples derived from individuals whose RhC/c/E status was established by standard serologic methods. We also evaluated the potential clinical utility of polymerase chain reaction to ascertain fetal antigen status. STUDY DESIGN: Samples were obtained from Centre d'Etude du Polymorphisme Humain families used for studies of genetic variation (n = 655). Deoxyribonucleic acid was extracted by standard techniques. With few modifications, published primers and reaction conditions were used. Samples were digested with restriction enzymes yielding characteristic electrophoresis patterns for RhC/c/E. Clinical utility was assessed by review of all patients evaluated for erythrocyte sensitization. RESULTS: RhC-positive (n = 479), RhC-negative (n = 176), Rhc-positive (n = 524), Rhc-negative (n = 131), RhE-positive (n = 131) and RhE-negative (n = 524) samples were evaluated. The sensitivity of RhC/ c and E typing by polymerase chain reaction was 98.3%, 98.1%, and 96.9%, respectively. The specificity of polymerase chain reaction for identifying the RhC/c/E antigens was 91.5%, 94.7%, and 99.2%, respectively. CONCLUSIONS: Although it would appear that use of polymerase chain reaction to establish RhC/c/E type could aid in evaluation of RhC/c/E sensitization, we are concerned about the instances of antigen-positive individuals characterized as antigen negative. Further study is necessary to determine if this reflects a polymorphism, mutation, a data coding error, or a combination. The Centre d'Etude du Polymorphisme Humain database is known to contain such errors at a rate that may surpass the error rate of our testing. A second molecular technique could be used to achieve better accuracy in the ascertainment of Rh C/c/E type. On the basis of a review of our patient population, molecular deoxyribonucleic acid techniques now available could aid the management of erythrocyte sensitization in pregnancy in > 96% of cases.     

多西他赛与吉西他滨分别顺泊治疗晚期非小细胞肺癌的临床研究

Objective: The aim of this study was to evaluate the clinical efficacy and side effects of docetaxel/cisplatin regiment and gemcitabine/cisplatin regiment in the patients with advanced non-small-cell lung cancer (NSCLC). Methods: Seventy six patients with advanced NSCLC who were chemotherapy-naive were enrolled in two groups. In docetaxel group (DP group) the patients received docetaxel 75 mg/m2 and cisplatin 60 mg/m2 on day 1. In gemcitabine group (GP group) the patients received gemcitabine 1000 mg/m2 on day 1 and day 8. The dosage of cisplatin was the same as DP group. The two regiments were administrated intravenously every 21 days as a cycle, each patient received 2-4 cycles. All patients were followed up until disease progressed or patients died. Results: The overall response rates were 43.5% in DP group and 45.9% in GP group. The response rate was significantly different between the initial treated group and retreated group in both two groups (53.8% vs 23.0% in DP group and 56% vs 25% in GP group, P < 0.05, respectively). The main side effects were bone marrow suppression and thrombocytopenia. Conclusion: Docetaxel/cisplatin regiment and gemcitabine/cisplatin regiment for the patients with advanced NSCLC were efficient and well-tolerated chemotherapeutic approachs with low toxicity levels. The efficacy and major toxicity in two groups were similar.     

Blood vessel and lymphatic vessel invasion in resected nonsmall cell lung carcinoma. Correlation with TNM stage and disease free and overall survival

BACKGROUND: The objective of this prospective study was to assess in 96 patients with resected nonsmall cell lung carcinoma (NSCLC) the prevalence of both blood and lymphatic vessel invasion (BVI and LVI) according to stage, as well as their prognostic value for disease free and overall survival. METHODS: BVI and LVI were evaluated by hematoxylin and eosin stains on surgical specimens after resection. Associations among variables were tested by Fisher's exact test or the chi-square test; prognostic values on time-failure data were analyzed by the log rank test and the multivariate Cox model. RESULTS: BVI was present in 52% of NSCLC cases and LVI in 59%. Venous but not arterial vascular invasion correlated with the T factor and pTNM, whereas LVI correlated with the N factor and pTNM. In univariate analysis, LVI but not BVI was associated with a short disease free interval (P = 0.0007) and poor survival (P = 0.0001). The estimated relative risk of death in patients with LVI was 3.2 compared with patients without LVI. In multivariate analysis, LVI and pTNM were additional predictors for poor disease free and overall survival. In this series, BVI had no prognostic value. CONCLUSIONS: The prevalence of BVI and LVI appeared high in patients with NSCLC, especially those with advanced pTNM stages. LVI was predictive of poor outcome, both time to recurrence and death.     

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.     

Effect of clarithromycin treatment of natural killer cell activity in patients with advanced non-small cell lung cancer]

The treatment of a 14-membered ring macrolide, clarithromycin (CAM), prolongs the survival time of patients with unresectable nonsmall cell lung cancer, and improves the host factor. As we previously reported, one of the underlying mechanisms is that the treatment of CAM increases the bioactivity of interleukin-12 (IL-12). In the present study, we administered CAM to murine lung cancer treatment models with Lewis lung carcinoma and to 18 patients with unresectable non-small lung cancer whose anticancer treatment had been terminated. The timing of CAM administration was examined and the time course of NK activity was measured. In the murine lung cancer treatment models, administration of CAM 7 days after anticancer chemotherapy more strongly inhibited the tumor growth and more rapidly and significantly increased NK activity, compared to the concomitant use of CAM with an anticancer chemotherapy. In humans, the NK activity which had decreased after anticancer treatment, tended to be increased after one month of treatment with CAM (p = 0.06). One month of treatment with CAM significantly increased the NK activity (p < 0.05) of the following subjects: patients with stage III in the clinical stages, patients with squamous cell carcinoma, patients who had received radiotherapy alone as pretreatment therapy, and patients whose pretreatment therapy effect was partial response (PR). We conjectured that increasing NK activity was one of the underlying mechanisms of the macrobiotic effect of CAM. CAM was especially effective for patients in the early clinical stages and patients who responded well to pretreatment therapy. Murine lung cancer models showed that non-concomitant use of CAM with anticancer chemotherapy was more effective.