First-line chemotherapy in metastatic small-cell lung cancer (SCLC)

The overall treatment results in metastatic small-cell lung cancer have not been changed in the last decades. The prognosis of the disease is still poor with median survival times of less than one year and nearly no chance of cure. This article intends to summarize the current status of treatment in m-SCLC and especially focuses on the aspects of choice of drugs and efforts of treatment intensification either by dose escalation or shortening of treatment intervals. Furthermore the currently available data about the activity of newer drugs, including taxanes and topoisomerase I inhibitors are reported. These cytostatic agents widen the therapeutic options in the treatment of SCLC and will hopefully improve the outcome of the patients in the next years.     

Epirubicin + G-CSF as peripheral blood progenitor cells (PBPC) mobilising agents in breast cancer patients

BACKGROUND:: In an attempt to mobilise peripheral blood progenitor cells(PBPC) from patients with breast cancer, Epirubicin supportedwith G-CSF was tested. Another aim of the study was also tooptimize the procedure so that the number of leukapheresis procedurescould be reduced. These cells were subsequently reinfused ashematologic rescue after high-dose chemotherapy programs. PATIENTS AND METHODS:: Twenty-nine patients received Epirubicin 150 mg/sqm + G-CSFat the dose of 5 µg/kg/bw s.c. daily, starting 24 hoursafter chemotherapy. Twelve had metastatic, eight inflammatoryor locally advanced disease, and nine were treated in an adjuvantsetting. RESULTS:: The median numbers of CD34+ cells and CFU-GM collected were12.9 x 10Vkg/bw and 111.7 x 104/kg/bw, respectively. The meannumber of leukapheresis procedures per patient was 1.8 ±0.3(range 1–3), and the mean day of the first procedure wasthe tenth ± 1 (range 8–13) after Epirubicin. Theminimum required target for one high-dose procedure was collectedin a single leukapheresis in 13 patients. Moreover, in 9 casesone procedure was adequate for two high-dose courses (i.e. >10x 10Vkg/bw CD34+ cells). Response to Epirubicin was evaluablein 14/20 cases, with a response rate of 50%. CONCLUSIONS:: Epirubicin delivered at 150 mg/sqm is a very effective mobilisingagent for breast cancer patients; to ameliorate the responserate other active drug(s) should be added. breast cancer, epirubicin, high-dose, peripheral blood progenitor cells     

Chemotherapy for small-cell lung cancer (SCLC) patients with renal failure

We administered chemotherapy in three cases of small-cell lung cancer (SCLC) with renal failure under different situations. Hemodialysis (HD) was used in 2 out of the 3 cases. Case 1 was complicated by acute renal failure from extensive bilateral tumor invasion. After chemotherapy (CBDCA + ETP) under HD, renal metastases regressed and renal function improved, although the final response was PD. In case 2, HD had been introduced for diabetic nephropathy. After 2 cycles of chemotherapy (CBDCA + ETP) under HD, the patient attained a PR. Case 3 is an example of paraneoplastic nephrotic syndrome with renal failure. Chemotherapy including CBDCA or CDDP was performed and the QOL of the patient improved. Pro-GRP and serum creatinine changed in parallel during the clinical course of 6 admissions. In conclusion, individualized therapy is necessary to increase survival time of SCLC patients with renal failure. Although chemotherapy is useful, further study is needed for the selection of suitable chemotherapeutic regimens, optimal dosage of each drug and the timing of HD.     

SEOM clinical guidelines for the treatment of small-cell lung cancer (SCLC) (2019)

Small-cell lung cancer (SCLC) accounts for 15% of lung cancers. Only one-third of patients are diagnosed at limited stage. The median survival remains to be around 15–20 months without significative changes in the strategies of treatment for many years. In stage I and IIA, the standard treatment is the surgery followed by adjuvant therapy with platinum–etoposide. In stage IIB–IIIC, the recommended treatment is early concurrent chemotherapy with platinum–etoposide plus thoracic radiotherapy followed by prophylactic cranial irradiation in patients without progression. However, in the extensive stage, significant advances have been observed adding immunotherapy to platinum–etoposide chemotherapy to obtain a significant increase in overall survival, constituting the new recommended standard of care. In the second-line treatment, topotecan remains as the standard treatment. Reinduction with platinum–etoposide is the recommended regimen in patients with sensitive relapse (≥ 3 months) and new drugs such as lurbinectedin and immunotherapy are new treatment options. New biomarkers and new clinical trials designed according to the new classification of SCLC subtypes defined by distinct gene expression profiles are necessary.     

小细胞肺癌的治疗现状及进展

小细胞肺癌是一种恶性程度较高的肿瘤,具早期发生远处转移的倾向。因绝大多数患者于确诊时已伴有淋巴结或远处转移且无手术治疗的指征,小细胞肺癌的分期很少采用TNM分期法,而根据病灶范围简单地分为局限期与广泛期。不利的预后因素包括广泛期疾病、LDH值升高、不良的行为状态评分体重下降与男性性别。局限期小细胞肺癌的治疗应采用4—6个周期EP方案[（依托泊苷VP-16）＋顺铂（DDP）]化疗联合同期胸部放射的治疗方案。广泛期疾病以全身化疗为主,方案多采用VP-16联合顺铂或卡铂。即便对于老年或行为状态评分较差的患者,联合化疗仍值得推荐。治疗后肿瘤达完全缓解者应接受预防性全颅放疗,以降低颅脑转移率。     

G-banded chromosome analysis of bone marrow and peripheral blood cells from small cell lung cancer (SCLC) patients

Detailed G-banded chromosome analysis was carried out on the bone marrow and/or PHA-stimulated peripheral blood cells from 17 SCLC patients (14 males and 3 females), who were diagnosed cytologically or pathologically or both. Twelve of them had no prior treatment and 16 had a heavy smoking history. High chromosome aberration rates were found in the bone marrow (31% for average structural aberration rate and 63% for numerical aberration rate) and peripheral blood cells (37% for average structural aberration rate and 49% for numerical aberration rate). The smoking index, as a whole, was positively correlated to the structural chromosome aberration rate, indicating that smoking is one of the most important environmental factors in causing chromosome aberrations. But some patients gave a high aberration rate dis-proportional to their smoking index, suggesting that genetically determined susceptibility to smoking or even other factors also play an important role. The structural chromosome aberrations in the bone marrow and peripheral blood cells were mainly clustered on chromosome 3 and chromosomes 1, 9 and 11, respectively. The aberration types were manifold and complicated. No consistent or specific aberration as del 3p14-23 for SCLC was found in this study.     

外周血干细胞支持合并大剂量化疗对12例小细胞肺癌的疗效

目的 探讨高剂量化疗用外周血干细胞支持提高小细胞肺癌的疗效、可行性、安全性.方法 小细胞肺癌首先采用常规化疗后取得病灶缩小者,动员外周血干细胞后用血细胞分离仪采取外周血干细胞后,再用高剂量化疗CVpP方案,化疗后24～48小时干细胞回输.观察白细胞变化,当白细胞＜1.5×109/L时进入层流室保护,直到白细胞＞1.5×109/L时出层流室,转普通病房.3周后胸片复查,达CR或PR者.有手术指征者予以切除,其中1例高剂量衡量后达PR,子手术切除,术后标本仅残留少量癌细胞,无手术指征者再进行放疗.结果 近期疗效有效率达100%(CR 27%,PR 73%),白细胞在第10～12天恢复正常,血小板在第13～14天恢复正常.主要不良反应为Ⅳ度骨髓抑制,仅1例有皮肤感染,未发生与治疗有关的死亡.结论 外周血干细胞支持合并高剂量化疗在肺癌治疗中有效、安全、可行.     

Myelo-ablative therapy with peripheral blood progenitor cell (PBPC support in patients with haematological malignancy

BACKGROUND: Myelo-ablative therapy with peripheral blood progenitor cell(PBPC) support is increasingly being used in patients with haematologicalmalignancy considered to be at high risk for recurrence. Theresults of this approach, in comparison with the previous experienceat St. Bartholomew's Hospital (SBH) using autologous bone marrowtransplantation form the basis of this report. PATIENTS AND METHODS: 42 patients (age range 18–63 years, median 42 years),deemed to have a poor prognosis with conventional therapy receivedmyelo-ablative therapy with PBPC support. Diagnoses comprised:non-Hodgkin's lymphoma (NHL): 16 patients, Hodgkin's disease(HD): 9, Multiple Myeloma (MM): 12, and solid tumours (ST):5. PBPC were mobilised using adriamycin: 35 mg/m² i.v. on day1 and etoposide 100 mg/m² orally, days 1–5, followed byG-CSF: 5 ng/kg, subcutaneously, for a median of 7 days (range6–9 days). RESULTS: A total of 67 PBPC collections were performed, 1 being ‘sufficient’(i.e. mononuclear cells > 1.5x10⁸/g and CD34+ cells >1x10⁶/kg)in 21 of the 42 patients. The median time to haematologicalrecovery following reinfusion of PBPC was 13 days for both neutrophils>0.5x10⁹/I and platelets >20x10⁹/I (ranges: 8–27,and 8–48 days, respectively) which is significantly shorterthan for patients in the historical control group. Supportivecare requirements were also significantly reduced, as was theduration of hospital stay i.e., median 19 days (range 12–73days) compared with 29 days (range 9–180 days). CONCLUSION: These results confirm rapid blood count recovery following myelo-ablativetherapy with PBPC support and the feasibility of this approach. myelo-ablative therapy, peripheral blood progenitor cells, haematological malignancy     

Long-term survivors of small-cell lung cancer (SCLC): A French multicenter study

Background: The aim of this study was to analyze SCLC patients beyond 30 months, particularly their outcome, their way of life, and factors which could influence relapses, second-primary cancers and death.Patients and methods: Between January 1986 and May 1995, 263 SCLC patients who survived longer than 30 months were included from 52 French institutions. The analysis was performed on the 155 cases confirmed by a pathologic review.Results: Physical, mental and psychological states were considered as normal at 30 months in respectively 70.3%, 87.7% and 67.7% of patients, not influenced by prophylactic cranial irradiation, number of chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30 months. Return to work was possible for 40% of patients in the first two years following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line treatment. Their median survival was 12 months since retreatment, and seven patients have survived again longer than 30 months. Age >60 at the time of diagnosis was found as an independent factor increasing the risk of relapse beyond 30 months (OR = 2.46, IC 95% (1.16–5.26), P = 0.01). The risk of relapse became less than 10% beyond five years. Twenty patients (13%) developed a second primary cancer in a mean time of 58.6 months. The risk of second primary cancer was increased by a number of chemotherapy cycles >6 (OR = 3.25, IC 95% [1.08-9.8] P = 0.02) and by an age >60 (OR = 2.92, IC 95% (1.07–7.97), P = 0.03). Five- and 10-year survival rates were respectively 68% and 44%. In these patients having reached a 30-month survival, three independent factors were predictive of a survival longer than five years: age 60 at the time of diagnosis (OR = 2.85, IC 95% (1.23–6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28–7.69), P = 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75–12.5), P = 0.002). This study suggests that: 1) therapeutic sequelae are rather mild, allowing return to work in 40% of patients; 2) relapsing 30-month survivors can benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year follow-up.     

Detection at diagnosis of tumor cells in bone marrow aspirates of patients with small-cell lung cancer (SCLC) and clinical correlations

BACKGROUND: Immunocytochemistry has often been used to identify tumor cellsin bone marrow aspirate (BMA) of SCLC patients in order to improvethe results of conventional histomorphology. However, whetherthe detection of bone marrow microlocalisation at diagnosishad implications for prognosis has not been clear. PATIENTS AND METHODS: Eighty-four slides (44 patients) and 66 bone marrow biopsies(from 42/44 patients) were evaluated. Cytospins of BMA wereincubated wih the monoclonal antibody (MAb) NCC-LU-243, recognisingthe cluster 1 antigen (NCAM) and then stained by the APAAP (alkalinephosphatase-anti-alkaline phosphatase) method. The relationshipamong BMA and PS (performance status), NSE (neuron-specificenolase), stage, survival was also studied. RESULTS: 33/84 (39%) BMA were positive for NCAM, compared with 8/66 (12%)bone marrow biopsies (p     

Prevalence of the Rhesus-negative phenotype in Caucasian patients with small-cell lung cancer (SCLC).

We report that the Rhesus (Rh)-negative phenotype is more prevalent in patients with small-cell lung cancer (SCLC) than in the normal Caucasian population (SCLC: 25% Rh-negative vs. 15% expected, p less than 0.0001). This finding has been validated for a Central and a Northern European population (Switzerland and UK). In contrast, the Rh-negative phenotype is no more frequent in non-small-cell lung cancer patients or in heavy smokers with coronary heart disease than in the general population. There was a normal distribution of the ABO blood group phenotype in all patients studied. Whilst the significance of this observation is unclear, we hypothesize that a genetic predisposition to the development of SCLC may be linked to a hitherto unidentified gene on chromosome 1p near the Rh locus. Our observation may perhaps allow further progress to be made in understanding genetic mechanisms of SCLC carcinogenesis.     

Paclitaxel in combination with carboplatin as salvage treatment in refractory small-cell lung cancer (SCLC): A multicenter phase II study

Purpose:The activity and toxicity of paclitaxel plus carboplatincombination in patients with disease progression after initial chemotherapyfor small-cell lung cancer (SCLC) was investigated in a multicenter phase IIstudy. Patients and methods:Thirty-two patients (twenty-seven men) withextensive stage refractory SCLC after EP or CAV front-line chemotherapywere treated with paclitaxel 200 mg/m² on day 1 andcarboplatin 6 AUC on day 2 in a four-week schedule. The patients' medianage was 60 years and the performance status (WHO) was 0 for 9, 1 for 20 and2 for 3 patients. All patients were evaluable for toxicity and 29 forresponse. Results:Complete response was observed in one (3%) andpartial response in seven (22%) for an overall response rate of25% (95% confidence interval (CI): 10%–40%).Seven (22%) patients had stable disease and seventeen (53%)progressive disease. All but one of the responders had been previously treatedwith EP combination and three of them had failed to respond. The medianduration of response and the median TTP were 3 and 5.5 months, respectively.The median overall survival was seven months. Grade 3–4 neutropenia wasobserved in 12 (37%) patients and in 2 of these it was associated withinfection. There were no toxic deaths. Grade 4 anaemia was observed in one(3%) patient and grade 3 thrombocytopenia in three (9.4%).Non-hematologic toxicity was very mild with grade 2–3 asthenia occurringin 10 (25%) patients; asthenia was the reason for treatmentdiscontinuation in 3 patients. Conclusions:The combination of paclitaxel and carboplatin is arelatively active and well-tolerated regimen as salvage treatment in patientswith refractory SCLC.     

Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.

The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.     

Determining carboplatin/etoposide dosage in extensive stage small-cell lung cancer (SCLC).

In order to define the maximum tolerance level of combined carboplatin/etoposide dosage, patients with extensive stage small-cell lung cancer (SCLC) were treated with a fixed dose of carboplatin (300 mg/m2 iv on day 1) and escalating doses of etoposide starting with 80 mg/m2 iv on days 1-3. Five patients were given this starting and every following dose level. The daily dose of etoposide was increased in increments of 20 mg/m2 iv until severe myelosuppression occurred in 3 of 5 patients. Leuko- or thrombocytopenia WHO grade 3 or 4 occurred in 0/5 of the patients at the dose levels of 80 and 100 mg/m2, in 1/4 of the patients at the level of 120 mg/m2, in 2/5 of the patients at a level of 140 mg/m2, and 3/5 patients at a level of 160 mg/m2. Thus, increase in dosage was stopped at an etoposide dose of 160 mg/m2. Other side effects were mild and consisted predominantly of nausea and vomiting in 14/25 of the patients. The overall response rate was 40% with a 12% complete remission rate, median survival was 9.3 months and median progression-free survival totalled 4.3 months. These results indicate that combined carboplatin/etoposide is a well tolerated regimen in extensive-stage SCLC, with response rates comparable to those of other standard protocols. Using treatment intervals of 4 weeks the recommended dose of etoposide in combination with 300 mg/m2 carboplatin was identified as 140 mg/m2 iv for 3 consecutive days.     

Report from the International Atomic Energy Agency (IAEA) consultants' meeting on elective nodal irradiation in lung cancer: small-cell lung cancer (SCLC)

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients.     

Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small-cell lung cancer (SCLC)

In this study, we evaluated the clinical usefulness of ProGRP and NSE for diagnosis and prognosis of small-cell lung cancer (SCLC). Serum levels of ProGRP and NSE were determined in 108 healthy subjects, 103 patients with benign pulmonary diseases, 142 with non-small cell lung cancer (NSCLC), and 114 with SCLC. Sensitivity of ProGRP in diagnosis of SCLC was significantly higher than that of NSE (64.9 vs. 43.0%, P < 0.001). The difference was substantial in patients with limited disease (56.5 vs. 20.3%, P < 0.001). However, 11 of 40 SCLC patients with normal levels of serum ProGRP (27.5%) showed elevated levels of serum NSE. In the SCLC patients receiving chemotherapy, the CR rate in patients with elevated NSE levels was significantly lower than in patients with normal levels of NSE (18.5 vs. 61.7%, P < 0.001). Elevation of both ProGRP and NSE was a poor prognostic factor, and patients with elevated levels of either ProGRP or NSE showed shorter survival than those without. From multivariate analysis, NSE was found to have a greater effect on survival of SCLC patients than ProGRP. These findings indicate that ProGRP is more sensitive than NSE for diagnosis of SCLC, while NSE is superior to ProGRP as a prognostic factor. In conclusion, both ProGRP and NSE are useful tumor markers and they have a complementary role for each other in diagnosis and prognosis of SCLC.     

Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro

We examined the relationship between (18)F- labeled 2-fluro-2-deoxy-d-glucose (FDG) uptake, and expression of glucose transporters (GLUTs) in two human small-cell lung cancer (SCLC) lines CPH 54A and CPH 54B. Changes in the expression of GLUTs and vascular endothelial growth factor (VEGF) during 12-, 18-, and 24 hours of severe hypoxia in vivo (xenografts) and in vitro (cell cultures) were recorded for both tumor lines. The two SCLC lines are subpopulations of the same patient tumor. In spite of their common genomic origin they represent consistently different metabolic and microenvironmental phenotypes as well as treatment sensitivities. There were higher levels of Glut-1 protein in 54B and a correspondingly higher FDG uptake in this tumor line (P<.001). During hypoxia a significant upregulation of in VEGF mRNA, GLUT-1 mRNA, and Glut-1 and -3 protein occurred with a distinctly different time course in the two cell lines. A similar co-upregulation of GLUT and VEGF was seen in hypoxic tumors of both lines. There were no significant changes of HIF-1alpha mRNA during hypoxia in either of the cell lines. A more detailed understanding of such correlations between glucose metabolism, angiogenesis, and microenvironmental phenotype of tumors, by positron emission tomography (PET) and molecular techniques might further sophisticate our interpretation of glycolytic predominance in tumors as seen by 18FFDG PET.     

Small steps of improvement in small-cell lung cancer (SCLC) within two decades: A comprehensive analysis of 484 patients

Background

It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade.

Methods

All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol.

Results

A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age <70 years and absence of LDH elevation in the palliative setting.

Conclusions

In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.