Prognostic value of circulating tumor cells’ reduction in patients with extensive small-cell lung cancer

Objectives

Circulating tumor cells (CTCs) have been hypothesized to be a prognostic factor in small-cell lung cancer (SCLC), and different cutoffs have been proposed to identify patients at high risk. We assessed the prognostic value of CTCs in patients with extensive SCLC.

Materials and methods

CTCs were assessed with the CellSearch system in 60 extensive SCLC patients. CTC count at baseline or after one cycle of chemotherapy (cycle-1) or as change after chemotherapy were analyzed separately. Primary outcome was overall survival. The accuracy of prognostic role was assessed by Harrell's c-index. “Optimal” cutoffs were derived by bootstrap resampling to reduce the overfitting bias; accuracy improvement was estimated by calculating the difference of c-indexes of models including clinical variables with or without CTCs.

Results

CTCs were identified in 90% (54/60) of patients at baseline, in which CTC count ranged from 0 to 24,281. CTC count was strongly associated with the number of organs involved. The prognostic accuracy was only marginally increased by the addition to clinical information of “optimal” CTC cutoffs at baseline and after cycle-1. Conversely, a reduction of CTC count higher than 89% following chemotherapy significantly improved prognostic accuracy (bootstrap p-value = 0.009) and was associated with a lower risk of death (HR 0.24, 95% CI 0.09–0.61). When previously proposed cutoffs were applied to our cohort, they showed only marginal improvement of the prognostic accuracy.

Conclusion

CTCs have useful prognostic role in extensive SCLC, but only the change of CTC count after the first cycle of chemotherapy provides clinically relevant information. Previously reported CTC cutoffs were not prognostic in our cohort of patients.     

Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer

Background

We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC).

Prognostic classification with laboratory parameters or imaging techniques in small-cell lung cancer

PURPOSE: Our aim in this study was to compare prognostic models based on laboratory tests with a model including imaging information in small-cell lung cancer. PATIENTS AND METHODS: A retrospective analysis was performed on 156 consecutive patients. Three existing models based on laboratory tests and performance status (PS) and a model based on disease stage assessed by imaging techniques and PS were tested with Cox regression analysis. RESULTS: The 3 laboratory-based models and the imaging-based model were significant in predicting prognosis in our patient group, with hazard ratios of 1.6-3 for medium prognosis groups and 2.6-6.1 for poor prognosis groups compared with good prognosis groups. Models based on laboratory tests appear to predict survival probabilities at least as well as a model with information from imaging techniques. CONCLUSION: Prognostic models using PS and laboratory tests provide a similar estimation of survival of patients with small-cell lung cancer as the combination of PS and disease stage assessed by imaging tests.     

Survival of patients with disseminated small-cell lung cancer

The kinetics of survival in patients with small-cell lung cancer was studied versus the effectiveness of treatment. Survival in localized carcinoma was found to be significantly higher than that in extended tumor. The study of 54 patients given nitrosomethylurea-based combination chemotherapy showed survival in chemotherapy responders to be significantly higher than in cases of resistant tumors. The results of treatment as far as survival is concerned did not differ from those generally reported.     

The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer.

Pretreatment serum lactate dehydrogenase (LDH) levels were assayed in 288 patients presenting with small-cell lung cancer (SCLC) between 1976 and 1985. Patients were routinely staged by physical examination, chest x-ray, bone, brain, and liver scans, and bone marrow evaluation. Clinical response and survival were assessed following treatment with combination chemotherapy as part of four clinical trials. Patients with extensive disease (ED) presented with a higher incidence (108 of 147, 73%) of abnormally elevated LDH (greater than 193 IU/L) than those (65 of 141, 46%) with limited disease (LD) (P = 2 x 10(-6)). Forty percent of patients had an initial normal LDH level and a higher response rate (89 of 108, 82%; complete response [CR], 47%) than those with elevated values of LDH (119 of 156, 76%; CR, 29%). The CR rate varied inversely with the level of LDH in patients with LD (P = .026) but not in those with ED (P = .300). The median survival time and 1-year and 2-year survival rates for patients with elevated LDH were 39 weeks and 33% and 6%, respectively, whereas for those with a normal LDH level these were 53 weeks and 54% and 16%, respectively. Patients with LD and elevated levels of LDH manifested a higher relative death rate (1.63:1) when compared with patients with LD and LDH in the normal range (P = .0083). The survival of patients with ED did not differ between those with normal and elevated levels of LDH (P = .273). A significant survival advantage persisted for patients with LDH in the normal range following adjustments for extent of disease, performance status (PS), and treatment protocol (P = .044, log-rank analysis). In conclusion, serum LDH appears to be a significant independent pretreatment prognostic factor in patients with SCLC that correlates with stage of disease, response to treatment, and survival.     

Single-agent gemcitabine in patients with resistant small-cell lung cancer

Objective:This study was conducted to assess the activity and toxicity of gemcitabine in patients with resistant small-cell lung cancer (SCLC). Patients and methods:Forty-one patients with limited- or extensive-stage SCLC, who were previously treated with at least one chemotherapeutic regimen and progressed during or within three months of finishing the last regimen, were treated with 1000 mg/m² gemcitabine on days 1, 8, and 15 of a four-week cycle. Results:Thirty-eight patients were evaluable for response. Five partial and no complete responses were seen, for an overall response rate of 13% (95% confidence interval (CI): 6%–27%). Time to progression varied from 4 to 20 weeks, with a median of 8 weeks. Median survival was 17 weeks (range 4–84 weeks). Hematological toxicity mainly consisted of NCI–CTC grade 3 thrombocytopenia (29% of patients) and, to a lesser extent, grade 3 leukopenia (18% of patients). Non-hematological toxicity was mild, with nausea being the most commonly reported event. Conclusions:Gemcitabine has modest activity in patients with resistant SCLC. There is some non-cross resistance to most agents against SCLC.     

Sequential chemotherapy in good-prognosis patients with small-cell lung cancer

Summary A sequential combination chemotherapy regimen was evaluated in 23 patients with small-cell lung cancer (16, limited disease; 7, extensive disease). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal serum sodium and albumin levels and alkaline phosphatase values of <1.5 times the upper limit of normal. Treatment comprised ifosfamide and either vindesine or vincristine given on weeks 0, 2 and 4; cisplatin and etoposide given on weeks 6, 9 and 12; and doxorubicin and methotrexate given on weeks 15 and 17. The overall response rate at the end of chemotherapy was 91% and the complete response rate was 43%. Treatment was generally well tolerated and the delivered dose intensity was 83% of that projected. Median survival was 54 weeks, with 4 patients (17%) being alive 2 years after the completion of therapy.This work was supported by the Cancer Research Campaign     

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride

Amrubicin (AMR) is one of the most active chemotherapeutic agents for small-cell lung cancer (SCLC). Previous phase II studies reported on its effectiveness and severe hematological toxicities. However, AMR has yet to be approved outside Japan. Subsequently, no extensive evidence of its effects exist. Between January 2004 and October 2009, 69 patients received AMR for relapsed SCLC at our hospital. We reviewed these patients, and analyzed the efficacy and hematological toxicities of AMR. There were 27 sensitive relapses (S) and 42 refractory relapses (R). Patients received platinum agents, and 43 and 71% of the patients received etoposide and irinotecan, respectively. The median number of treatment cycles was 3 (range 1-14), and the response rate was 51% (70% in the S and 38% in the R cases, respectively). In patients administered with AMR as second-line therapy, the response rate was 55% and as third-line therapy, 39%. Median progression-free survival time was 3.2 months in the S and 1.9 months in the R patients (p=0.1071). Median survival time from the start of AMR was 6.2 months in the S and 4.8 months in the R cases (p=0.0045). The frequency of grade ≥3 hematological toxicities was leukopenia (41%), neutropenia (51%), anemia (14%), thrombocytopenia (17%) and febrile neutropenia (12%). No treatment-related death was observed. Although hematological toxicities, particularly neutropenia, were severe, AMR showed excellent anti-tumor activity, not only in the S, but also in the R cases, as shown in previous phase II studies. These results warrant further evaluation of AMR in the second-line setting, and also in the first-line setting in both limited- and extensive-stage disease. We conducted a phase II study to assess the efficacy of consolidation chemotherapy with AMR after standard chemoradiation in limited-stage SCLC.     

Irinotecan plus carboplatin in patients with extensive-disease small-cell lung cancer

This study was designed to evaluate the efficacy and safety of irinotecan in combination with carboplatin in previously untreated, extensive-disease small-cell lung cancer (ED-SCLC). Patients with histologically or cytologically confirmed ED-SCLC received irinotecan (60 mg/m² on days 1, 8, and 15) plus carboplatin (AUC 5 on day 1) every 4 weeks. Treatment was repeated until disease progression, unacceptable toxicity, or up to 6 cycles. Forty-four patients were enrolled. In an intent-to-treat analysis, the overall response rate (RR) was 75% (8 complete responses and 25 partial responses). The median progression-free (PFS) and overall survival (OS) were 5.6 and 8.7 months, respectively. The principle toxicities were neutropenia and diarrhea. Grade 3–4 neutropenia occurred in 30% of the patients and 7% of patients presented with febrile neutropenia. Grade 3–4 diarrhea occurred in 21% of the patients. A subgroup consisting of patients ≥65 years of age had outcomes similar to the younger group <65 years of age. The objective RR was 72% in the patients <65 years of age and 77% in the patients ≥65 years of age (P = .738). The median PFS and OS (<65 years vs. ≥65 years) were 5.3 vs. 5.6 months (P = .835) and 9.0 vs. 8.7 months (P = .648), respectively. The combination of irinotecan and carboplatin is active and tolerable in patients with ED-SCLC. This regimen could be considered as a treatment option for patients of advanced age.     

Prognostic significance of pleural lavage cytology in patients with lung cancer: a meta-analysis

OBJECTIVE: Cytologic approaches such as pleural lavage cytology (PLC) are considered as possible aids to assessing prognosis of lung cancer patients. We aimed to comprehensively review the evidence for use of PLC to predict prognosis of lung cancer. METHODS: Fifteen studies, including 6391 patients, were found to be eligible for the present meta-analysis. A meta-analysis was done on the log hazard ratios and their variances in these studies. RESULTS: Four studies dealt with pleural lavage before lung resection, six studies dealt with pleural lavage after lung resection, and five studies had PLC data from both before and after lung resection examination. For before lung resection studies, combined hazard ratios showed that positive PLC results had an unfavorable impact on survival: 3.96 (95% confidence interval 2.48-6.33), 4.55 (2.95-7.04), 5.00 (3.39-7.36), 5.67 (3.81-8.43), and 7.06 (5.04-9.90), for 1-, 2-, 3-, 4- and 5-year, respectively. For after lung resection studies, combined hazard ratios showed that positive PLC results had an unfavorable impact on survival: 6.02 (3.74-9.71), 6.64 (4.53-9.72), 7.06 (4.93-10.12), 7.29 (5.18-10.25), and 8.47 (6.12-11.73), for 1-, 2-, 3-, 4- and 5-year, respectively. Totally, the combined hazard ratio was 5.61 (3.98-7.90), showing a worse survival when PLC was positive. These findings could be overestimated because of publication and reporting bias. CONCLUSIONS: PLC is a strong prognostic factor for survival in patients with lung cancer.     

Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer.

PURPOSE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in tumor development and progression. MMP expression has been correlated with advanced clinical stage and poor survival in some tumors, but data for small-cell lung cancer (SCLC) are lacking. The aim of this study was to assess the expression of MMPs and TIMPs in SCLC and to evaluate their importance relative to standard prognostic factors. PATIENTS AND METHODS: Expression of MMP-1, -2, -3, -9, -11, -13, and -14 and TIMP-1, -2, -3, and -4 was evaluated by immunohistochemistry (IHC). In situ hybridization was used to confirm expression of specific mRNAs. Clinical data collected included sex, tumor stage, performance status, weight loss, hematology (hemoglobin, WBC, platelets) and biochemistry (sodium, albumin, alkaline phosphatase, lactate dehydrogenase), treatment, and survival. RESULTS: Samples from 46 patients were evaluated: 30 males, 16 females; 29 limited, 17 extensive stage; 35 Eastern Cooperative Oncology Group performance status 0-1. Positive IHC staining was evident for MMP-1 and -9 in 60% to 70% of tumor cells, and for MMP-11, -13, and -14 and TIMP-2 and -3 in 70% to 100% of tumor cells. Stromal staining of TIMP-1 to -3 was present in less than 30% of specimens. On multivariate analysis, only stage and decreased tumoral expression of TIMP-1 were significant for response (P =.043). Significant factors for survival were tumor stage (P =.0021); weight loss (P =. 013); and high tumor cell expression of MMP-3 (P =.077), MMP-11 (P =. 031), and MMP-14 (P =.019). MMP and TIMP expression did not differ significantly between stages. CONCLUSION: MMPs and TIMPs are widely expressed in SCLC. Increased tumoral expression of MMP-3, -11, and -14 were independent negative prognostic factors for survival. The results support the evaluation of synthetic MMP inhibitors in patients with SCLC.     

Prognostic significance of micrometastasis in non-small-cell lung cancer

Accurate staging of non-small-cell lung cancer (NSCLC) determines prognosis and facilitates decisions regarding treatment options. Unfortunately, even after an apparently complete resection in patients with stage I disease, the recurrence rates range from 25% to 50%, and overall survival is not encouraging. One possible reason for this may be that those patients with a poor outcome actually have more extensive disease, with occult locoregional and/or distant metastasis than originally identified by routine pathologic staging techniques. There is now a sizable body of literature on the detection and possible prognostic role of occult disease in lung cancer. The majority of these studies are based on immunohistochemical analysis of lymph nodes and/or bone marrow, but a handful of studies use molecular approaches. The purpose of this review is to summarize and critique the current literature on occult tumor cell spread to lymph nodes and bone marrow in patients with NSCLC. Based on this literature, we believe that the prognostic significance of bone marrow micrometastasis remains unclear. However, the majority of studies indicate that occult lymph node disease is associated with a poor outcome. Thus, our ability to detect individual tumor cells could result in more accurate staging of NSCLC in patients and would potentially lead to the development of novel therapies, as well as influence decisions regarding the use of appropriate multimodality treatment strategies, the choice of surgical technique, and extent of dissection. As data accumulate, the presence or absence of occult nodal involvement should probably be considered at the next revision of the staging system for NSCLC.     

Selective suppression of cytokine secretion in patients with small-cell lung cancer

BACKGROUND: Whether or not cytokine secretion is impaired in patients withsmall-cell lung cancer (SCLC), is unknown. We therefore investigatedwhether cytokine secretion by immunocompetent cells may be suppressedin patients with SCLC PATIENTS AND METHODS: We determined cytokine secretion by lymphocytes and monocytesin whole blood cell cultures from 58 patients with SCLC, 95patients with non-small-cell lung cancer (NSCLC), 10 patientswith nonmalignant lung disease and from 44 normal healthy individualsby using an enzyme-linked immunosorbent assay (ELISA) specificfor the different cytokines measured. RESULTS: Compared to normal controls, immunocompetent cells from patientswith SCLC secreted significantly lower amounts of IL-2, IFN     

Prognostic significance of serum p53 antibodies in patients with limited-stage small cell lung cancer

p53 tumour suppressor gene alterations are one of the most frequent genetic events in lung cancer. A subset of patients with p53 mutation and cancer exhibited circulating serum anti-p53 self-antibodies (p53-Ab). The prevalence of these antibodies in lung cancer is currently being analysed in a multicentric study. In a group of homogeneous SCLC patients, p53-Ab were detected in 20/97 (20.6%) individuals. In this group of patients, Cox's multivariate analysis identified disease extent (p = 0.022), WHO initial performance status greater than 0 (p = 0.005), and the absence of a complete response after 6 months of treatment (p < 0.0001) as independent prognostic variables, with p53-Ab being of borderline significance (p = 0.051). In the subset of limited-stage SCLC patients, Cox's multivariate analysis found p53-Ab (p = 0.033), WHO initial performance status greater than 0 (p = 0.028), and absence of a complete response (p < 0.001) to be independent prognostic variables. Thus, actuarial analysis showed that patients with limited-stage SCLC and p53-Ab had a median survival time of 10 months, whereas limited-stage SCLC patients without p53-Ab had a 17-month median survival time (p = 0.014).Therefore, serum assay of p53-Ab could help to identify a population of SCLC patients with an especially poor prognosis. This population could represent patients with tumours harboring aggressive p53 mutations.     

Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel

The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration‐resistant prostate cancer (mCRPC) previously treated with a docetaxel‐containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20‐25 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression‐free survival (PFS). An upfront dose‐reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G‐CSF was prescribed to all the patients. Grade ≥3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1‐17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9‐21.2), respectively. Waterfall plot analysis revealed that a prostate‐specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil‐lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects.