OTHR-15. PATIENTS WITH LIMITED STAGE SMALL CELL LUNG CANCER THAT RECUR WITH ISOLATED BRAIN METASTASES HAVE PROLONGED SURVIVAL

Abstract INTRODUCTION: Small cell lung cancer (SCLC) frequently metastasizes to the brain. In patients with limited-stage disease (disease confined to one radiation portal), the incidence of brain metastasis after 3 years is 50–60%. We reviewed patients with SCLC and hypothesized that isolated brain recurrence has a unique natural history. METHODS: 471 adult SCLC patients seen at University Hospitals Case Medical Center from 1998 to 2014 were screened. Patients were separated by those with isolated brain metastases and those with other patterns of metastasis. Demographic data including age, race, sex, smoking history and clinical data such as TNM classification, stage, treatment, and time to relapse and death were collected. Median overall survival (mOS) and progression free survival (mPFS) were compared using log-rank tests and Kaplan-Meier plots were constructed. In a separate cohort of metastatic SCLC we examined differences in next generation sequencing (NGS) of targeted exomes between primary and metastatic sites including the brain. RESULTS: 281 extensive-stage patients and 40 limited-stage patients were included. 12% (30/281) of the extensive-stage patients and 25% (10/40) of limited-stage patients had isolated brain metastases. Patients with limited-stage disease who developed isolated brain metastases had significantly improved mOS as compared to those who developed other sites of metastasis (OS = 38.7 months vs. 20.2 months, p=0.033). Furthermore, mPFS for limited-stage patients with isolated brain metastases was improved compared to other patterns of metastases (PFS = 17.9 months vs. 10.1 months, p = 0.03). NGS demonstrated that NOTCH1 mutations were infrequent in biopsies from all metastatic sites but were common in primary lung tumors. CONCLUSION: In our single center review, patients with limited-stage SCLC who recurred only in the brain had improved survival as compared to those who had other patterns of metastases. Our initial work demonstrates differences in oncogenic gene mutations between the metastatic and primary tumors.

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New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.5.1940 ◽

1998 ◽

Vol 16 (5) ◽

pp. 1940-1947 ◽

Cited By ~ 46

Author(s):

V Westeel ◽

N Murray ◽

K Gelmon ◽

A Shah ◽

F Sheehan ◽

...

Keyword(s):

Lung Cancer ◽

Elderly Patients ◽

Small Cell Lung Cancer ◽

Median Survival ◽

Phase Ii Study ◽

Small Cell ◽

Small Cell Lung ◽

Limited Stage ◽

Stage Disease ◽

Extensive Stage

PURPOSE A regimen of cisplatin, doxorubicin, vincristine, and etoposide (PAVE) was designed for patients with small-cell lung cancer (SCLC) who were older than 65 years, with the following objectives compared with standard chemotherapy regimens: maintain efficacy, diminish toxicity, enhance compliance, and improve chemotherapy administration convenience at an acceptable cost. PATIENTS AND METHODS The PAVE regimen consisted of cisplatin 30 mg/m2 intravenously (i.v.) day 1; doxorubicin 40 mg/m2 i.v. day 1; vincristine 1.0 mg/m2 i.v. day 1; and etoposide 100 mg/m2 i.v. day 1 and orally days 3 and 5. Cycles were repeated every 3 weeks for four cycles. Patients with limited-stage disease and selected patients with extensive-stage disease received thoracic irradiation delivered concurrently with etoposide-cisplatin (EP) at the time of the second chemotherapy cycle. RESULTS Sixty-six eligible patients were treated, which included 25 patients with limited-stage disease and 41 patients with extensive-stage disease. Median survival was 70 weeks and 5-year survival was 25% for limited-stage disease. Median survival was 46 weeks for extensive-stage disease. Only one treatment-related death occurred and severe toxicity was infrequent. The median delivered dose-intensity was according to protocol and the mean delivered total dose was 80% of intended. CONCLUSION The treatment outcome achieved with PAVE in a phase II study of elderly patients compared favorably with published results of standard regimens in patient populations with better prognostic factors. Because the PAVE regimen can be delivered with good compliance, has acceptable toxicity, and is associated with logistic advantages compared with standard regimens, this protocol is suitable for further investigative trials in elderly patients with SCLC.

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Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.12.3464 ◽

1997 ◽

Vol 15 (12) ◽

pp. 3464-3470 ◽

Cited By ~ 58

Author(s):

J D Hainsworth ◽

J R Gray ◽

S L Stroup ◽

L A Kalman ◽

J E Patten ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Median Survival ◽

Cell Lung Cancer ◽

Dose Regimen ◽

Small Cell ◽

Small Cell Lung ◽

Limited Stage ◽

Stage Disease ◽

Extensive Stage

PURPOSE In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.

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Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes

Current Oncology ◽

10.3390/curroncol28010036 ◽

2021 ◽

Vol 28 (1) ◽

pp. 317-331

Author(s):

Sarah Sharman Moser ◽

Jair Bar ◽

Inna Kan ◽

Keren Ofek ◽

Raanan Cohen ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Small Cell Lung Cancer ◽

Real World ◽

Treatment Patterns ◽

Small Cell ◽

Multivariable Model ◽

Small Cell Lung ◽

Limited Stage ◽

Extensive Stage

In this observational study, we assessed treatment patterns and prognostic factors in patients with small cell lung cancer (SCLC) in a large state-mandated healthcare organization in Israel. Methods: All incident cases with histologically confirmed SCLC who initiated systemic anti-cancer treatment between 2011 and 2017 were identified. Treatment patterns and overall survival (OS) were evaluated for each line of therapy. Results: A total of 235 patients were identified (61% male, median age 64 years, 95% ever smokers, 64% had extensive stage). The first-line treatment was platinum–etoposide regimen for 98.7% of the cohort. The second and third-line regimen were given to 43% and 12% of patients, respectively. Mean OS for extensive and limited stage patients was 9.1 and 23.5 months respectively. In a multivariable model, increased risk for mortality was observed among patients with an ECOG performance status (PS) of 2 compared to a PS of 0–1 for the extensive stage patients (Hazard ratio (HR) = 1.63, 95% confidence ratios (CI): 1.00–2.65); and for males compared to females for the limited stage patients (HR = 2.17; 95% CI: 1.12–4.20). Regarding all 2nd line patients in a multivariable model incorporating relevant confounding factors, demonstrated a significantly better outcome with platinum–based regimens compared to topotecan. Median survival after initiation of 2nd line in platinum-sensitive patients was longer (p = 0.056) for those re-challenged with platinum–based regimen (n = 7): 6.8mo (6.1-not reported (NR)), compared with those switched to a different treatment (n = 27): 4.5 mo (2.6–6.6) for extensive stage patients, and a non-significant difference was also observed for limited stage patients. Conclusion: To our knowledge, this is one of the largest real-world studies of SCLC patients. OS for SCLC patients was similar to that reported in clinical trials. PS for extensive stage patients and sex for limited stage patients were significant correlates of prognosis. Re-challenge of the platinum–based doublet was associated with longer OS compared to switching treatment in extensive stage patients.

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Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.6.1042 ◽

1990 ◽

Vol 8 (6) ◽

pp. 1042-1049 ◽

Cited By ~ 42

Author(s):

M P Dearing ◽

S M Steinberg ◽

R Phelps ◽

M J Anderson ◽

J L Mulshine ◽

...

Keyword(s):

Lung Cancer ◽

Prognostic Factors ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cox Proportional Hazards ◽

Small Cell ◽

Small Cell Lung ◽

Limited Stage ◽

The Impact

In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.

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Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer

Cancers ◽

10.3390/cancers13030506 ◽

2021 ◽

Vol 13 (3) ◽

pp. 506

Author(s):

Selina K. Wong ◽

Wade T. Iams

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Limited Stage ◽

Extensive Stage

After being stagnant for decades, there has finally been a paradigm shift in the treatment of small-cell lung cancer (SCLC) with the emergence and application of immune checkpoint inhibitors (ICIs). Multiple trials of first-line ICI-chemotherapy combinations have demonstrated survival benefit compared to chemotherapy alone in patients with extensive-stage SCLC, establishing this as the new standard of care. ICIs are now being applied in the potentially curative limited-stage setting, actively being investigated as concurrent treatment with chemoradiation and as adjuvant treatment following completion of chemoradiation. This review highlights the evidence behind the practice-changing addition of ICIs in the first-line setting of extensive-stage SCLC, the potentially practice-changing immunotherapy trials that are currently underway in the limited-stage setting, and alternate immunotherapeutic strategies being studied in the treatment of SCLC.

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Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.6601 ◽

2016 ◽

Vol 34 (31) ◽

pp. 3740-3748 ◽

Cited By ~ 190

Author(s):

Martin Reck ◽

Alexander Luft ◽

Aleksandra Szczesna ◽

Libor Havel ◽

Sang-We Kim ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Small Cell Lung Cancer ◽

Small Cell ◽

Phase Iii ◽

Newly Diagnosed ◽

Small Cell Lung ◽

Stage Disease ◽

Extensive Stage ◽

Study Therapy

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.

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Role of Prophylactic Cranial Irradiation in Extensive-Stage Small Cell Lung Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2021.7105 ◽

2021 ◽

Vol 19 (12) ◽

pp. 1465-1469

Author(s):

Nathan Y. Yu ◽

Terence T. Sio ◽

Vinicius Ernani ◽

Panayiotis Savvides ◽

Steven E. Schild

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Cranial Irradiation ◽

Prophylactic Cranial Irradiation ◽

Small Cell ◽

Developing Brain ◽

Small Cell Lung ◽

Extensive Stage

Patients with small cell lung cancer (SCLC) are at significant risk of developing brain metastases during their disease course. Prophylactic cranial irradiation (PCI) has been incorporated into SCLC treatment guidelines to diminish the risk of developing brain metastases. In 2007, a randomized trial suggested that PCI decreases the incidence of brain metastases and prolongs overall survival (OS) in patients with extensive-stage SCLC (ES-SCLC) who have responded to initial therapy. However, this study did not include modern central nervous system imaging with CT or MRI prior to randomization. A more recent Japanese trial with MRI staging and surveillance demonstrated that PCI diminished the incidence of brain metastases but did not improve survival. This review examines the largest clinical studies, controversies, and future directions of PCI in patients with ES-SCLC.

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Use of Immunotherapy in Extensive-Stage Small Cell Lung Cancer

Oncology ◽

10.1159/000508516 ◽

2020 ◽

Vol 98 (11) ◽

pp. 749-754 ◽

Cited By ~ 1

Author(s):

Venu Madhav Konala ◽

Bhaskar Reddy Madhira ◽

Sara Ashraf ◽

Stephen Graziano

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Initial Response ◽

The United States ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Stage Disease ◽

Extensive Stage

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60–80%, the prognosis is poor, with overall survival of 10–12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6–12% in chemorefractory disease and 15–37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.

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