Small-cell lung cancer: prognostic factors and changing treatment over 15 years

BackgroundThe incidence of small-cell lung cancer (SCLC) has decreased over several decades. Sixty-eight thousand six hundred eleven patients with SCLC in the National Cancer Data Base (NCDB) were analyzed to describe demographic, treatment, and survival changes between 1992 and 2007.Methods and MaterialsFour patient cohorts—diagnosed in 1992, 1997, 2002, and 2007—were examined. Univariate and multivariate analyses were performed to determine changes in demographic and treatment factors and their effect on survival of limited SCLC (LSCLC) and extensive SCLC (ESCLC).ResultsThe proportion of female patients increased, whereas the proportion of non-Hispanic white patients decreased. Median survival for patients with ESCLC and LSCLC was 6.1 and 12.9 months, respectively, and was not significantly improved between patients diagnosed in 1992 and 2002. Improved survival was associated with female sex, age < 70 years, and receipt of surgery for patients with LSCLC. Radiation therapy decreased the hazard ratio (HR) for patients with stage III LSCLC but not for patients with earlier stage disease. Chemotherapy decreased the HR for all patients with LSCLC. Patients with ESCLC treated with radiation in addition to chemotherapy had better survival than those who received only chemotherapy.ConclusionsDespite changes in demographics and treatment, the median and 5-year survival rates for patients with SCLC have not significantly improved over the past 15 years. Surgery was associated with improved survival in LSCLC. The benefit of chemotherapy and/or radiation therapy was dependent on American Joint Committee on Cancer (AJCC) stage. AJCC staging information had prognostic and treatment ramifications and should be collected in future studies and databases.     

Chemotherapy with concurrent brain and thoracic radiotherapy in brain-only metastases of treatment naive small-cell lung cancer: a phase II study

To study the treatment outcomes of brain-only metastases from small-cell lung cancer (SCLC) at initial diagnose treated by chemotherapy with concurrent brain and thoracic radiotherapy (RT). From Jan 2004 to Jan 2009, 36 treatment-na?ve SCLC patients with brain-only metastases in Sun yat-sen University were enrolled. Treatment contained initial EP chemotherapy with concurrent whole-brain radiotherapy (WBRT). EP regimen consisted of etoposide 100 mg/m(2) IV d1-3, cisplatin 80 mg/m(2) IV d1, repeated every 3 weeks. WBRT with total dose of 30 Gy in 10 fractions was started within 1 week from the beginning of chemotherapy followed by thoracic RT including 2 Gy once daily to a total dose of 60 Gy. Treatment responses were evaluated after 3 cycles of chemotherapy. EP regimen was given totally 6 cycles for no tumor progression. Thirty-four patients were evaluable. All of the 20 CNS symptomatic patients experienced symptoms relief. Objective responses in the brain and primary thoracic lesions were observed in 26 (76.5%, 16CR + 10PR) and 29 (85.3%, 23CR + 6PR) patients, respectively. The median survival time (MST) was 19.2 months, and the 1-and 2-year overall survival rates (OS) were 70.6 and 29.4%, respectively, in all patients. Patients with CR response had the longest MST of 21.9 months and 1-and 2-year OS of 93.8 and 43.8%, respectively. Treatment toxicity profiles were acceptable. The treatment strategy of concurrent chemotherapy with brain and thoracic RT might achieve promising survival outcomes comparable to limited-stage SCLC in initially diagnosed SCLC with brain-only metastases.     

Prophylactic cranial irradiation in small-cell lung cancer: Findings from a North Central Cancer Treatment Group Pooled Analysis

BackgroundThis pooled analysis evaluated the outcomes of prophylactic cranial irradiation (PCI) in 739 small-cell lung cancer (SCLC patients with stable disease (SD) or better following chemotherapy ± thoracic radiation therapy (TRT) to examine the potential advantage of PCI in a wider spectrum of patients than generally participate in PCI trials.Patients and methodsThree hundred eighteen patients with extensive SCLC (ESCLC) and 421 patients with limited SCLC (LSCLC) participated in four phase II or III trials. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. Survival and adverse events (AEs) were compared.ResultsPCI patients survived significantly longer than non-PCI patients {hazard ratio [HR] = 0.61 [95% confidence interval (CI): 0.52–0.72]; P < 0.0001}. The 1- and 3-year survival rates were 56% and 18% for PCI patients versus 32% and 5% for non-PCI patients. PCI was still significant after adjusting for age, performance status, gender, stage, complete response, and number of metastatic sites (HR = 0.82, P = 0.04). PCI patients had significantly more grade 3+ AEs (64%) compared with non-PCI patients (50%) (P = 0.0004). AEs associated with PCI included alopecia and lethargy. Dose fractionation could be compared only for LSCLC patients and 25 Gy/10 was associated with significantly better survival compared with 30 Gy/15 (HR = 0.67, P = 0.018).ConclusionsPCI was associated with a significant survival benefit for both ESCLC and LSCLC patients who had SD or a better response to chemotherapy ± TRT. Dose fractionation appears important. PCI was associated with an increase in overall and specific grade 3+ AE rates.     

Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control

BACKGROUND AND PURPOSE: We analyzed the impact on survival outcomes of treatment interruptions due to toxicity arising during the concurrent phase of chemotherapy/radiotherapy (ChT/RT) for our limited-stage small-cell cancer (LSCLC) population over the past 10 years. MATERIALS AND METHODS: From 1989 to 1999, 215 patients received treatment for LSCLC, consisting of six cycles of alternating cyclophosphamide/doxorubicin or epirubicin/vincristine (CAV; CEV) and etoposide/cisplatin (EP). Thoracic RT was started with EP at either the second or third cycle (85% of patients). RT dose was either 40 Gy in 15 fractions over 3 weeks or 50 Gy in 25 fractions over 5 weeks, delivered to a target volume encompassing gross disease and suspected microscopic disease with a 2 cm margin. Treatment breaks arising during concurrent ChT+RT were used to manage severe symptomatic or hematologic toxicities. We used the interruptions in thoracic RT as the 'marker' for any concurrent break and measured 'break duration' by the total length of time (in days) RT was interrupted, since that also signaled that ChT could be re-initiated. Patient results were analyzed for the impact of interruptions/treatment prolongation on overall and disease-free survival. RESULTS: For all patients, 2-year and 5-year overall and disease-specific survivals were 22.7 and 7.2, 27.6 and 9.3%, respectively; overall and disease-specific median survivals were 14.7 months each. A total of 56 patients (26%) had treatment breaks due to toxicity. Hematologic depression caused the majority of breaks (88%). The median duration of breaks was 5 days (range 1-18). Patients with and without interruptions were compared for a range of prognostic factors and were not found to have any significant differences. Comparing interrupted/uninterrupted courses, median survivals were 13.8 versus 15.6 months, respectively, and 5-year overall survivals were 4.2 versus 8.3%, respectively. There was a statistical difference between overall survival curves which favored the uninterrupted group (P=0.01). When comparing a series of prognostic variables, multivariable analysis found that the most significant factor influencing survival in the present study was the presence of treatment breaks (P=0.006). There was a trend for development of any recurrence in the patients with breaks (P=0.08). When controlling for the use of prophylactic cranial irradiation (PCI) in the two groups, the rate of failure in the chest was higher in the patients with RT breaks (58 vs. 33%). The rate of failure in the brain was dependent on the use of PCI only. CONCLUSIONS: Interruptions in treatment to palliate the toxicity from concurrent chemoradiation result in poorer local control and decreased survival.     

Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival.

PURPOSE: To determine the impact of continued smoking by patients receiving chemotherapy (CHT) and radiotherapy (RT) for limited-stage small-cell lung cancer (LSCLC) on toxicity and survival. PATIENTS AND METHODS: A retrospective review was carried out on 215 patients with LSCLC treated between 1989 and 1999. Treatment consisted of six cycles of alternating cyclophosphamide, doxorubicin, vincristine and etoposide, cisplatin (EP). Thoracic RT was concurrent with EP (cycle 2 or 3) only. Patients were known smokers, with their smoking status recorded at the start of chemoradiotherapy (CHT/RT). RT interruption during concurrent CHT/RT was used as the marker for treatment toxicity. RESULTS: Of 215 patients, smoking status was recorded for 186 patients (86.5%), with 79 (42%) continuing to smoke and 107 (58%) abstaining during CHT/RT. RT interruptions were recorded in 38 patients (20.5%), with a median duration of 5 days (range, 1 to 18 days). Median survival for former smokers was greater than for continuing smokers (18 v 13.6 months), with 5-year actuarial overall survival of 8.9% versus 4%, respectively (log-rank P =.0017). Proportion of noncancer deaths was comparable between the two cohorts. Continuing smokers did not have a greater incidence of toxicity-related treatment breaks (P =.49), but those who continued to smoke and also experienced a treatment break had the poorest overall survival (median, 13.4 months; log-rank P =.0014). CONCLUSION: LSCLC patients who continue to smoke during CHT/RT have poorer survival rates than those who do not. Smoking did not have an impact on the rate of treatment interruptions attributed to toxicity.     

Small cell lung cancer treated in southeast Wales

AimsIn small cell lung cancer (SCLC), consolidation thoracic irradiation (CTI) increases 3-year absolute survival by 5.4% in patients with limited disease and a complete response to chemotherapy. Early concurrent thoracic radiotherapy has been shown to improve local control and prolong survival compared with CTI in some trials. The standard management of patients with SCLC in southeast Wales is CTI in individuals with limited disease and a complete response to chemotherapy. A review of patients with SCLC was carried out to establish whether survival locally is comparable with that reported in published studies, and if patients given CTI have survival comparable with that reported in studies where early concurrent thoracic radiotherapy was used.Materials and methodsBetween January 2000 and December 2002, 303 patients were registered with SCLC in southeast Wales. One hundred and fifteen (47%) patients had limited disease and 60/115 (52%) received CTI.ResultsPatients with limited disease receiving CTI had a median survival of 17.7 months (95% confidence interval: 15–27.9 months). The 2- and 5-year survivals were 38 and 13%, respectively.ConclusionsThese results compare favourably with previously published studies on SCLC. There are no plans to change our current treatment policy for SCLC in southeast Wales.     

胸部放疗在广泛期小细胞肺癌治疗中的价值

目的 探讨胸部放疗在广泛期小细胞肺癌中的应用价值及对患者预后的影响.方法 回顾性分析154例广泛期小细胞肺癌患者的临床资料,化放疗组89例,化疗组65例.放疗采用常规分割1.8～2.0 Gy/次,1次/d,总剂量为40～60 Gy,化疗采用EP方案(顺铂+依托泊甙)、CE方案(卡铂+依托泊甙)或者CAO方案(环磷酰胺+阿霉素+长春新碱).结果 全组中位生存时间为13.7个月,2年和5年生存率分别为27.9%和8.1%,其中化放疗组分别为17.2个月、36.0%和10.1%,化疗组分别为9.3个月、16.9%和4.6%,两组生存率差异有统计学意义(P=0.001).全组中位无进展生存时间为8.0个月,2年和5年无进展生存率分别为13.6%和8.2%,其中化放疗组分别为10.0个月、17.4%和10.5%,化疗组分别为6.2个月、9.8%和4.9%.两组无进展生存率差异有统计学意义(P＜0.001).化放疗组胸内复发率为29.6%(21/89),化疗组胸内复发率为70.0%(42/65),差异有统计学意义(P=0.000).结论 胸部放疗能降低广泛期小细胞肺癌局部失败的发生率,延长患者的总生存时间和无进展生存时间.

Abstract：

Objective To evaluate the effect of thoracic radiation therapy(TRT) on patients with extensive stage small-cell lung cancer(SCLC). Methods One hundred and fifty-four patients with extensive stage SCLC treated in our department between January 2003 and December 2006 were enrolled in this study.Eighty nine patients received chemotherapy and thoracic radiation therapy(ChT/TRT),and 65 patients were treated with chemotherapy alone(ChT without TRT).The chemotherapy was CE(carboplatin and etoposide),PE(cisplatin and etoposide) or CAO(CTX,ADM and VCR) regimens.The total dose of thoracic irradiation was 40-60 Gy with 1.8-2.0 Gy per fraction. Results For the whole group,the median survival time(MST) was 13.7 months,the 2-year and 5-year overall survival rates were 27.9% and 8.1%,respectively.The MST,overall survival rates at 2 years and 5 years in the ChT/TRT group and ChT without TRT group were 17.2 months,36.0%,10.1% and 9.3 months,16.9%,4.6%,respectively(P =0.001).The median progression-free survival(PFS) for all patients was 8.0 months,the 2-year and 5-year PFS were 13.6% and 8.2%,respectively.The median PFS,2-year and 5-year PFS in the ChT/TRT group and ChT without TRT group were 10.0 months,17.4%,10.5% and 6.2 months,9.8%,4.9%,respectively(P ＜0.001).The incidence of intra-thoracic local failure was 29.6% in the ChT/TRT group and 70.0% in the ChT/without TRT group(P = 0.000). Conclusions Chemotherapy plus thoracic radiation therapy can improve the overall survival,progress free survival and reduce local regional failure rate in patients with extensive stage SCLC compared with that by chemotherapy alone.     

Split-course versus continuous thoracic radiation therapy for limited-stage small-cell lung cancer: final report of a randomized phase III trial

The optimal integration of radiation and chemotherapy for limited-stage small-cell lung cancer (SCLC) remains unclear. This phase III trial was conducted to determine whether chemotherapy plus interdigitating split-course thoracic radiation therapy (RT) improved survival compared with standard-dose continuous thoracic RT. One hundred fourteen patients were randomized to receive 50 Gy thoracic RT delivered in 2.0-Gy fractions given continuously (5 weeks) concurrent with the first 2 cycles of chemotherapy (arm A) or 50 Gy delivered via an interdigitating split course in 2.5-Gy fractions (8 weeks) concurrent with the first 3 cycles of chemotherapy (arm B). During the split-course RT, once-daily radiation was delivered on days 8-17 of each of the first two 21-day cycles and days 8-11 of the third 21-day cycle. All patients received the following chemotherapy: cisplatin/etoposide on cycles 1, 2, and 5 and cyclophosphamide/vincristine/doxorubicin on cycles 3, 4, and 6. Prophylactic cranial irradiation was recommended after a complete response to all therapy. One hundred ten eligible patients were randomized. Grade 3/4 esophagitis was reported in 9% of patients receiving continuous thoracic RT versus 4% of patients receiving split-course RT. Grade 3/4 hematologic toxicity was common in both treatment arms. Complete/partial response was observed in 80% of patients on arm A versus 84% on arm B. Overall survival rates at 5 years were 18% and 17% for arms A and B, respectively. Interdigitating split-course thoracic RT delivered in 2.5-Gy fractions was tolerable in patients with limited-stage SCLC but did not provide a survival advantage.     

Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy

Objectives

To determine the rates of loco-regional (LR) failure and toxicity in extensive-stage small cell lung carcinoma (ES-SCLC) patients treated with consolidative thoracic radiotherapy (TRT).

Methods

A retrospective review was conducted on SCLC patients treated from January 2005 to July 2009. Patients with ES-SCLC who received consolidative TRT ≥30Gy were identified. Sites of disease failure, toxicity Common Terminology Criteria for Adverse Events version 3.0, incidence, and cause of treatment delays and vital status were determined. The cumulative LR and distant failure rates were calculated. Progression-free and overall survivals (OS) were determined by the Kaplan-Meier method.

Results

Three hundred thirty-six patients were identified with a diagnosis of SCLC and 215 patients had ES-SCLC. Nineteen (9%) patients were identified as receiving ≥30Gy consolidative TRT. Of this subgroup, the median age was 60 years (range 47 years to 82 years) and the median follow-up was 13 months (range 8 months to 32 months). Consolidative TRT was 40Gy/15 fractions (n = 16), 45Gy/30 fractions delivered twice daily (n = 2) and 36Gy/12 fractions (n = 1). Chemotherapy was sequential (n = 11) or concurrent (n = 8) with consolidative TRT. The incidence of LR failure was 26% and 39% at 1 and 2 years, respectively. The incidence of distant failure was 58% and 74% at 1 and 2 years, respectively. The median OS was 14 months. The 1-year and 2-year OS was 58% and 14%, respectively. No patients experienced clinical pneumonitis requiring treatment.

Conclusions

Consolidative TRT controlled LR disease in most patients with minimal acute toxicity, though distant failure remained a significant problem.     

The Role of Integrated 18F-FDG PET-CT as a Staging Tool for Limited-Stage Small Cell Lung Cancer: A Retrospective Study

Background: The aim of this study was to evaluate whether positron emission tomography-computed tomography (PET-CT) could be used as part of the staging work-up in patients with limited-stage disease (LD) small cell lung cancer (SCLC). Patients and Methods: Between January 2002 and December 2007, a total of 73 patients with presumed LD on CT, who underwent a PET-CT scan, were included in this study. Results: Conventional work-up revealed distant metastases in 12 patients. Out of 61 patients diagnosed as LD SCLC, PET-CT found unexpected distant metastases in 15 (24.6%) patients (LD/extensive-stage disease (ED)) of whom 13 (21.3%) were upstaged as a consequence. In 10 (76.9%) of the 13 upstaged patients, treatment was changed. The median survival of LD/LD SCLC patients who underwent concurrent chemoradiotherapy and chemotherapy only was 21.9 and 17.5 months, respectively. The median survival of LD/ED and ED/ED SCLC patients who received chemotherapy only was 17.4 and 14.1 months, respectively. The median survival of LD/LD SCLC patients who received concurrent chemoradiotherapy was superior to that of LD/ ED and ED/ED patients who received chemotherapy only (p = 0.037 and 0.004, respectively). Conclusion: The addition of PET-CT seems to allow more accurate staging and may thus protect a percentage of SCLC patients from potentially futile and toxic radiotherapy.     

Routine use of approximately 60 Gy once-daily thoracic irradiation for patients with limited-stage small-cell lung cancer

PURPOSE: To review the outcome of patients with limited-stage small-cell lung cancer receiving daily thoracic irradiation (RT) to approximately 60 Gy. METHODS AND MATERIALS: The records of patients treated with RT for limited-stage small-cell lung cancer between 1991 and 1999 at Duke University were retrospectively reviewed. Sixty-five patients were identified who had received continuous course once-daily 1.8-2 Gy fractions to approximately 60 Gy (range 58-66). All patients received chemotherapy (CHT); 32 received concurrent RT/CHT and 33 sequential CHT and then RT. Prophylactic cranial RT was administered to 17 patients. The time from diagnosis to local failure, tumor progression, and death was assessed using actuarial methods. The median follow-up for all patients was 16.7 months and for surviving patients was 29.6 months. The median age was 64 years (range 36-83), and the median Karnofsky performance status was 80 (range 50-100). RESULTS: The 3-year actuarial rate of local failure, progression-free survival, and overall survival was 40%, 25%, and 23%, respectively. One case of acute Grade 3 esophagitis developed. Ten late complications occurred: four pulmonary, two esophageal, two infectious, one leukemia, and one retinal toxicity with prophylactic cranial RT. Six were mild and resolved with treatment. CONCLUSION:CHT plus approximately 60 Gy of once-daily RT for limited-stage small-cell lung cancer was generally well tolerated. The survival rates were less than have been reported using 45 Gy in 1.5-Gy twice-daily fractions (2-year overall survival rate 47% compared with 30% in this study), but may be comparable because fewer than one-half our patients received concurrent CHT/RT and only 26% received prophylactic cranial RT. The relatively low rate of normal tissue morbidity in our patients supports the use of conventional once-daily fractionation to > or = 60 Gy. A randomized trial would be required to compare the outcomes after maximally tolerated dose twice-daily RT vs. maximally tolerated dose daily RT.     

Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer.

The regimen of cisplatin, vincristine, doxorubicin, and etoposide (CODE) was designed to double the dose intensity of these drugs in comparison with a standard regimen (alternating cyclophosphamide, doxorubicin, and vincristine [CAV] and etoposide-cisplatin [EP]) for extensive-stage small-cell lung cancer (SCLC). The dose intensity was increased by more frequent treatments rather than by increasing the dose size. The structure of this outpatient protocol includes weekly administration of chemotherapy, alternation of myelosuppressive and nonmyelosuppressive treatments, supportive corticosteroids, gastroprotective agents, and prophylactic antibiotics. Although the duration of chemotherapy was brief (9 to 12 weeks), the total cumulative doses of drugs delivered were similar to the standard regimen. Patients with no residual disease outside the chest after chemotherapy received thoracic irradiation, and patients with complete responses (CRs) received prophylactic cranial irradiation. Eligible extensive-stage SCLC patients were ambulatory, younger than 66 years of age, and free of brain metastasis. Forty-eight extensive-stage SCLC patients were treated. Forty-five (94%) responded to chemotherapy, with 19 (40%) attaining CR. After consolidative thoracic irradiation, the CR rate was 56%. The median time to progression was 43 weeks, and the median survival was 61 weeks. The 2-year survival rate was 30%. The most common site of first relapse was brain (38%). Although two patients (4%) died of toxicity, overall toxicity was acceptable for an outpatient regimen. We conclude that the CODE regimen reliably produces palliative remissions for selected extensive-stage SCLC patients, and it may be associated with durable remissions for some patients. The results of this pilot study are sufficiently promising to justify a phase III trial of CODE versus standard (alternating CAV and EP) chemotherapy.     

Pilot study of concurrent etoposide and cisplatin plus accelerated hyperfractionated thoracic radiotherapy followed by irinotecan and cisplatin for limited-stage small cell lung cancer: Japan Clinical Oncology Group 9903.

PURPOSE: Irinotecan and cisplatin (IP) significantly improved survival compared with etoposide and cisplatin (EP), in patients with extensive-stage small cell lung cancer (SCLC) in a previous Japan Clinical Oncology Group (JCOG) randomized trial. JCOG9903 was conducted to evaluate the safety of sequentially given IP following concurrent EP plus twice-daily thoracic irradiation (TRT) for the treatment of limited-stage SCLC (LSCLC). EXPERIMENTAL DESIGN: Between October 1999 and July 2000, 31 patients were accrued from 10 institutions. Thirty patients were assessable for toxicity, response, and survival. Treatment consisted of etoposide 100 mg/m(2) on days 1 to 3, cisplatin 80 mg/m(2) on day 1, and concurrent twice-daily TRT of 45 Gy beginning on day 2. The IP regimen started on day 29 and consisted of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1, with three 28-day cycles. RESULTS: There were no treatment-related deaths. The response rate was 97% (complete response, 37%; partial response, 60%). Median overall survival was 20.2 months; 1-, 2-, and 3-year survival rates were 76%, 41%, and 38%, respectively. Of the 24 patients who started the IP regimen, 22 received two or more cycles. Hematologic toxicities of grade 3 or 4 included neutropenia (67%), anemia (50%), and thrombocytopenia (4%). Nonhematologic toxicities of grade 3 or 4 included diarrhea (8%), vomiting (8%), and febrile neutropenia (8%). Of the 20 patients with recurrence, none had local recurrence alone and only two had both local and distant metastasis as the initial sites of disease progression. CONCLUSIONS: IP following concurrent EP plus twice-daily TRT is safe with acceptable toxicities. A randomized phase III trial comparing EP with IP following EP plus concurrent TRT for LSCLC is ongoing (JCOG0202).     

局限期小细胞肺癌三维适形放疗及同步化疗的临床研究

目的 观察三维适形放疗(3DCRT)同步化疗对局限期小细胞肺癌(LSCLC)的疗效及毒副反应.方法 93例LSCLC患者随机分为3DCRT组(46例)和常规组(47例),均先顺铂+足叶乙甙或卡铂+足叶乙甙方案化疗1周期,再同步放化疗,然后继续化疗,共4-6周期.达完全缓解者给予脑预防照射30 Gy分10次.常规组按常规设野,3DCRT组只包括原发灶、转移淋巴结及邻近一站淋巴引流区.放疗2 Gy/次,5次/周,共60～64 Gy.结果 3DCRT组和常规组随访率分别为100%和100%,随访时间满1、2、3年者分别为36和34、16和14、7和8例.3DCRT组和常规组完全缓解率分别为52%和47%,有效率分别为89%和85%(χ~2=0.34,P=0.759).3DCRT组和常规组1、2,3年生存率分别为78%和72%、35%和30%、15%和17%(χ~2=0.18,P=0.92),中位生存期分别为23.2和22.8个月.三维适形放疗组1+2级早期放射性肺和食管反应、1+2、3级晚期放射性肺损伤均轻于常规放疗组,两组均无3、4级早期肺和食管反应,以及4级晚期肺损伤;1+2、3、4级急性骨髓抑制两组相似.结论 3DCRT同步化疗用于LSCLC治疗可获得满意的近、远期疗效,毒副反应小,有较高的临床可行性.     

Ⅳ期寡转移NSCLC同期放化疗后巩固化疗前瞻性Ⅱ期临床研究

目的 研究寡转移NSCLC行胸内病灶根治性同期放化疗后巩固化疗的疗效和不良反应。方法 2008—2013年间转移灶≤5个的NSCLC患者66例入组。放疗采用IGRT, 常规分割或大分割。同期及巩固化疗均以铂类为基础两药联合方案。治疗结束后评价患者近期疗效、不良反应和生存率。结果 64例完成治疗。胸内病灶PTV中位BED为72 Gy, 中位化疗周期数4个。胸内病灶客观缓解率为70%。随访率为97%。1、2、3年OS分别为72%、53%、31%, 中位OS时间25个月;1、2、3年PFS分别为56%、26%、7%, 中位PFS时间14个月。2+3级急性放射性肺炎、放射性食管炎发生率分别为11%和17%, 3+4级白细胞、血红蛋白、血小板计数减少率分别为39%、11%、16%。结论 寡转移NSCLC胸内病灶根治性放疗联合同期化疗及巩固化疗, 可获得较好近期疗效和长期生存, 不良反应可耐受。     

Phase II study of irinotecan plus cisplatin induction followed by concurrent twice-daily thoracic irradiation with etoposide plus cisplatin chemotherapy for limited-disease small-cell lung cancer.

PURPOSE: Irinotecan plus cisplatin (IP) chemotherapy demonstrated a promising outcome with a high complete response (CR) rate in chemotherapy-na?ve patients with extensive small-cell lung cancer (SCLC). We evaluated the efficacy of induction IP chemotherapy followed by concurrent etoposide plus cisplatin (EP) chemotherapy with twice-daily thoracic radiotherapy (TDTRT) in limited-disease SCLC (LD-SCLC). PATIENTS AND METHODS: Between November 2001 and May 2003, 35 chemotherapy-na?ve patients with LD-SCLC were enrolled. Thirty-three patients (94%) were male, and 29 (83%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median age was 63 years. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m2 and irinotecan 80 mg/m2 intravenously (i.v.) on days 1 and 8 followed by two 21-day cycles of cisplatin 60 mg/m2 i.v. on days 43 and 64, and etoposide 100 mg/m2 i.v. on days 43 to 45 and 64 to 66, with concurrent TDTRT of total 45 Gy beginning on day 43. RESULTS: All 35 patients were assessable for response. The objective response rate was 97% (CR, 3; partial response [PR], 31) after induction chemotherapy and 100% (CR, 15; PR, 20) after concurrent chemoradiotherapy (CCRT). After a median follow-up of 26.5 months, the median survival was 25.0 months (95% CI, 19.0 to 30.9) with 1- and 2-year overall survival rates of 85.7% and 53.9%, respectively. Median progression-free survival (PFS) was 12.9 months with a 1- and 2-year PFS of 58.5% and 36.1%, respectively. The most common toxicities were grade 3 or 4 neutropenia in 68% of patients during induction chemotherapy and 100% during CCRT. Febrile neutropenia occurred in 20% of patients during induction chemotherapy and 60% during CCRT. CONCLUSION: IP induction chemotherapy followed by concurrent TDTRT with EP chemotherapy showed a promising activity with favorable 1- and 2-year survival rates. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.     

From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with early-stage nonsmall cell lung cancer

BACKGROUND: The authors' single-institution experience in patients with early-stage (I and II) nonsmall cell lung cancer (NSCLC) who were treated between 1980 and 1998 with either conventionally fractionated (CF) radiation therapy (RT), or hyperfractionated (HFX) RT, or HFX RT with concurrent paclitaxel/carboplatin (HFX RT-Pac/C) was reviewed. METHODS: Seventy-eight patients received 60 grays (Gy) in 30 daily fractions (CF), 116 patients received 69.6 Gy (1.2 Gy twice daily), and 56 patients received 67.6 Gy (1.3 Gy twice daily) with concurrent, low-dose, daily C (25 mg/m2) and Pac (10 mg/m2). Biologically equivalent doses for the 3 groups were 72 Gy, 78 Gy, and 76 Gy, respectively, for acute effects (alpha/beta = 10 Gy) and 120 Gy, 111 Gy, and 111 Gy, respectively, for late effects (alpha/beta = 2 Gy). RESULTS: For all 250 patients, the overall median survival was 27 months, the cause-specific survival was 27 months, the local progression-free survival was 32 months, and distant metastasis-free survival was not achieved; and the respective 5-year survival rates were 27%, 32%, 45%, and 68%. CF achieved significantly inferior survival than either HFX RT alone or HFX RT-Pac/C (P = .0332 and P = .0013, respectively), and no difference was observed between the 2 HFX RT regimens (P = .1934). Only acute hematologic high-grade toxicity (grade >or=3) was more frequent with HFX RT-Pac/C than with either RT alone, whereas other toxicities were similar between the 3 treatment groups. CONCLUSIONS: HFX RT with or without concurrent chemotherapy may be better than CF in patients with early-stage NSCLC. The role of chemotherapy deserves further investigation, because the group that received chemotherapy in the current study had a higher incidence of acute high-grade hematologic toxicity.     

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

IntruductionRadiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC.MethodsPatients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment.ResultsThirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1).ConclusionsConcurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.     

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Fran?ais de Pneumo-Cancérologie NPC 95-01 Study.

PURPOSE: We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. RESULTS: Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.     

Late consolidative radiation therapy in the treatment of limited-stage small cell lung cancer.

Two hundred twenty-three patients were enrolled on this randomized Phase III trial testing the value of late consolidative involved-field radiation therapy in the treatment of limited-stage small cell lung cancer (SCLC). Patients were treated with induction chemotherapy consisting of alternating cycles of procarbazine, vincristine, lomustine, and cyclophosphamide (POCC) and etoposide, doxorubicin, and methotrexate (VAM) for 6 to 9 months. Responding patients were then randomized at 6 or 9 months to chemotherapy alone or to involved-field radiation therapy. All partial and complete responders received prophylactic cranial irradiation. Of the 180 eligible and evaluable patients, 80 (44%) achieved a complete response and 39 (22%) achieved a partial response (overall rate of response, 66%). Actuarial median survival time was 11.6 months, with 16% of patients surviving 2 years and 11% surviving 5 years. Forty-eight patients were randomized to chemotherapy alone (24 patients) versus chemotherapy plus involved-field radiation therapy (24 patients). There were no significant differences in time to progression or survival between those patients receiving or not receiving involved-field radiation therapy. The thorax was the site of first relapse in 58% of patients randomized to chemotherapy alone versus 29% in patients randomized to chemotherapy plus involved-field radiation therapy (P equals 0.042). The major acute toxicity was reversible myelosuppression, and the major late toxicity was chronic central nervous system dysfunction. The authors conclude that the addition of late consolidative radiation therapy to induction chemotherapy in the treatment of limited-stage SCLC is well tolerated and improves local control, but does not improve time to progression or rates of survival.