original articles
Annals of Oncology
Annals of Oncology 25: 505–511, 2014 doi:10.1093/annonc/mdt535 Published online 23 December 2013
A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer B. Besse1*, R. S. Heist2, V. A. Papadmitrakopoulou3, D. R. Camidge4, J. T. Beck5, P. Schmid6, C. Mulatero7, N. Miller8, S. Dimitrijevic8, S. Urva9, I. Pylvaenaeinen8, K. Petrovic8 & B. E. Johnson10
Received 23 April 2013; revised 18 October 2013; accepted 29 October 2013
Background: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC). Patients and methods: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response. Results: Patients received everolimus 2.5 or 5 mg/day without G-CSF (n = 10; cohort A), 20 or 30 mg/week without G-CSF (n = 18; cohort B), or 2.5 or 5 mg/day with G-CSF (n = 12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively). Conclusions: Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC. Key words: cisplatin, etoposide, everolimus, phase I, small-cell lung cancer
introduction Etoposide and cisplatin (EP) chemotherapy is a current standard of care for treating small-cell lung cancer (SCLC) [1, 2]. For patients with extensive-stage SCLC, who account for the majority of cases, EP provides an 8.1–10.9-month median survival and a 2-year survival rate of 10% incidence previously observed with EP [3, 5–7]. With prophylactic G-CSF, the only feasible everolimus dose given with standard-dose EP was 2.5 mg/day. After the protocol amendment and considering the previously observed toxicity, the daily schedule was favored for further enrollment. Therefore, no feasible weekly everolimus dose given with EP was identified. The everolimus doses chosen for this study were based on previous data showing everolimus monotherapy to be pharmacodynamically active and tolerable at doses of 5 and 10 mg/day and 20–70 mg/week [15, 16]. Based on partially overlapping everolimus and EP toxicity profiles and lack of historical data on the proposed combination, both daily and weekly everolimus dosing was evaluated, with starting doses of 5 mg/day and 20 mg/week. In the present study, an adaptive Bayesian model instead of the traditional ‘3 + 3’ design typically used in dosefinding studies was used [18, 19]. Advantages of this design include a flexible dose-escalation scheme using DLT data from all doses at each decision point, the ability to evaluate the DLT rate at any time, and flexibility in the number of patients enrolled at each dose. The adaptive Bayesian model permitted rapid response to the observed myelosuppression and subsequent protocol modification to mandate prophylactic G-CSF. The observed myelosuppression was not unexpected, as it is common in EP-treated patients. Although the grade 3/4 neutropenia rate among non-G-CSF patients in the present study was within the range observed in randomized studies of EP (28%– 68%), grade 3/4 thrombocytopenia, anemia, and febrile neutropenia rates were higher than in previous EP studies [3–7]. This suggests an additive myelosuppressive effect when everolimus is combined with EP. Theoretically, adding everolimus to EP could increase infection risk because of the immunosuppressive activity of both everolimus and chemotherapy. However, no evidence of increased infection unrelated to neutropenia was observed, and all severe infections were reported in the non-GCSF population. Interestingly, pneumonitis, an AE associated with mTOR inhibitors, was not observed in this study. Although almost 50% of patients experienced stomatitis, another AE associated with mTOR inhibitors, no patient experienced stomatitis as a DLT, and grade 3/4 stomatitis was reported in only one patient. Everolimus pharmacokinetics were comparable when administered alone and with EP and consistent with those previously observed with everolimus monotherapy [15, 16]. PR occurred in ∼50% of patients across all everolimus dose levels and schedules. However, the present study included only 40 patients, and 9 (23%) did not have their best overall response assessed because they discontinued treatment before postbaseline tumor assessment (n = 4), or because they did not meet criteria for CR, PR, or stable or progressive disease (n = 5). It appears that everolimus plus EP did not substantially improve tumor response compared with EP alone, which, in randomized trials, is 46%–63%
doi:10.1093/annonc/mdt535 |
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 23, 2015
Table 3. Grade 3/4 adverse events occurring in ≥20% of patients on any everolimus schedule during the core treatment phase (safety population)
Total (N = 12)
21 (53) 11 (28) 11 (28) 9 (23) 6 (15) 2 (5)
Total (N = 40)
discussion
original articles
Annals of Oncology
Table 4. Best overall tumor response in the core treatment phase and progression-free survival (full analysis set)
Best overall response, n (%) CR PR SD PD Unknownb Objective response rate, n (%) [95% CI] Disease control rate, n (%) [95% CI]
Non-G-CSF population Daily everolimusa (N = 10)
Weekly everolimusa (N = 18)
G-CSF population Daily everolimusa (N = 12)
0 4 (40.0) 2 (20.0) 0 4 (40.0) 4 (40.0) [12.2–73.8] 6 (60.0) [26.2–87.8]
0 11 (61.1) 3 (16.7) 2 (11.1) 2 (11.1) 11 (61.1) [35.7–82.7] 14 (77.8) [52.4–93.6]
0 7 (58.3) 0 2 (16.7) 3 (25.0) 7 (58.3) [27.7–84.8] 7 (58.3) [27.7–84.8]
[3–7], suggesting the identified feasible dose level of everolimus in combination with EP may be suboptimal. In an exploratory analysis, median PFS of the seven patients who received the feasible everolimus dose level was 8.1 months, or 3–4 months longer than the median survival typically observed with EP in extensive-stage SCLC [20]. This prolongation of PFS may reflect the highly selected patient population, which may have better prognostic factors, or may be due to the maintenance phase of everolimus. The latter hypothesis appears to be refuted by results of a phase II study in which everolimus monotherapy displayed only modest clinical activity in relapsed/refractory SCLC (objective response rate, 3%; median time to progression, 1.3 months) [21]. To date, no molecular predictors of response to mTOR inhibitors have been identified, precluding selection of patients who might benefit from everolimus. In conclusion, everolimus 2.5 mg/day plus G-CSF was identified as the feasible everolimus dose given with standard-dose EP in patients with treatment-naive extensive-stage SCLC. Based on the modest clinical activity observed with everolimus monotherapy in relapsed/refractory SCLC and the hematologic and infectious complications observed with everolimus plus EP, everolimus is unlikely to be further investigated in an unselected SCLC population.
acknowledgements We thank Melanie Leiby, PhD (ApotheCom, Yardley, PA, USA), for her medical editorial assistance with this manuscript.
funding This study was supported by Novartis Pharmaceuticals. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.
| Besse et al.
disclosure VAP has had a consultant/advisory role with Genentech. DRC has had a consultant/advisory role with Novartis. SU is employed by and has stock ownership in Novartis Pharmaceuticals Corporation. IP and KP are employed by and have stock ownership in Novartis Pharma AG. NM is a former employee of Novartis Pharma AG who still has stock ownership in Novartis. SD is a former legal representative for Novartis Pharma AG. BEJ has served as a consultant to AstraZeneca, Genentech, Sanofi, Millennium, and Transgenomics. BB has received research grants from Novartis Pharmaceuticals. VAP has received research funding from Novartis, Merck, AstraZeneca, Bristol-Myers-Squibb, and Astellas. All of the other authors declare no conflict of interest.
references 1. Fruh M, De RD, Popat S et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi99–vi105. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: small cell lung cancer, version 1.2014. http://www.nccn.org/ professionals/physician_gls/pdf/sclc.pdf (30 August 2013, date last accessed). 3. Lara PN, Jr, Natale R, Crowley J et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009; 27: 2530–2535. 4. Lee SM, James LE, Qian W et al. Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer. Thorax 2009; 64: 75–80. 5. Zatloukal P, Cardenal F, Szczesna A et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 2010; 21: 1810–1816. 6. Spigel DR, Townley PM, Waterhouse DM et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensivestage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011; 29: 2215–2222.
Volume 25 | No. 2 | February 2014
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 23, 2015
Objective response rate defined as the percentage of patients with either a complete or a partial response. Disease control rate defined as the percentage of patients with either a complete or a partial response or with stable disease. a All patients received etoposide and cisplatin in addition to everolimus. b Reasons for unknown best overall response were discontinuation before postbaseline tumor assessment (n = 4) and did not meet criteria for CR, PR, stable disease, or disease progression, despite postbaseline tumor assessment (n = 5). CI, confidence interval; CR, complete response; G-CSF, granulocyte colony-stimulating factor; PD, progressive disease; PR, partial response; SD, stable disease.
original articles
Annals of Oncology
14. Tsurutani J, West KA, Sayyah J et al. Inhibition of the phosphatidylinositol 3kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res 2005; 65: 8423–8432. 15. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1603–1610. 16. O’Donnell A, Faivre S, Burris HA, III et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1588–1595. 17. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. 18. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008; 27: 2420–2439. 19. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with lateonset toxicities. Biometrics 2000; 56: 1177–1182. 20. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005; 366: 1385–1396. 21. Tarhini A, Kotsakis A, Gooding W et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 2010; 16: 5900–5907.
Annals of Oncology 25: 511–518, 2014 doi:10.1093/annonc/mdt544 Published online 9 January 2014
Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer K. Hemminki1,2*, X. Li2, A. Försti1,2, J. Sundquist2,3 & K. Sundquist2,3 1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; 2Center for Primary Health Care Research, Lund University, Malmö, Sweden; 3Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA
Received 18 September 2013; revised 30 October 2013; accepted 30 October 2013
Background: Systemic amyloidoses include immunoglobulin light chain (AL) amyloidosis, serum amyloid (AA)-related amyloidosis and senile systemic amyloidosis (SSA). AL amyloidosis is associated with myeloma, and we showed recently that transthyretin-related hereditary amyloidosis was related to non-Hodgkin lymphoma (NHL). In SSA, amyloids constitute wild-type transthyretin. We wanted to analyze cancer risks in amyloidosis, particularly in SSA. Patients and methods: Nonhereditary amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 1997 through 2010. Their cancer risk was assessed based on the Swedish Cancer Registry using standardized incidence ratio (SIR) between amyloidosis patients and the remaining population. To gain information about amyloidosis subtypes, we used the Swedish Prescribed Drug Register from years 2005 through 2010 to find out the specific medication prescribed. Results: Among 1400 identified amyloidosis patients, cancer risk was increased for myeloma, NHL and squamous cell skin cancer. Myeloma and skin cancers were diagnosed 7–8 years earlier than in the population, whereas NHL was diagnosed in elderly patients. The SIR was 204 for myeloma in patients who received AL amyloidosis medication, and it was 17.22 in patients receiving rheumatoid arthritis medication, suggesting AA amyloidosis. In remaining patients, including
*Correspondence to: Prof. Kari Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany. Tel: +49-6221421800; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 23, 2015
7. Fink TH, Huber RM, Heigener DF et al. Topotecan/cisplatin compared with cisplatin/etoposide as first-line treatment for patients with extensive disease smallcell lung cancer: final results of a randomized phase III trial. J Thorac Oncol 2012; 7: 1432–1439. 8. Jiang L, Yang KH, Guan QL et al. Cisplatin plus etoposide versus other platinbased regimens for patients with extensive small-cell lung cancer: a systematic review and meta-analysis of randomised, controlled trials. Int Med J 2012; 42: 1297–1309. 9. Marinov M, Ziogas A, Pardo OE et al. AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001. Clin Cancer Res 2009; 15: 1277–1287. 10. Schmid K, Bago-Horvath Z, Berger W et al. Dual inhibition of EGFR and mTOR pathways in small cell lung cancer. Br J Cancer 2010; 103: 622–628. 11. Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 1996; 56: 3895–3897. 12. Moore SM, Rintoul RC, Walker TR et al. The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorageindependent proliferation via a protein kinase B and p70s6k-dependent pathway. Cancer Res 1998; 58: 5239–5247. 13. Krystal GW, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy. Mol Cancer Ther 2002; 1: 913–922.
Annals of Oncology
Annals of Oncology 25: 505–511, 2014 doi:10.1093/annonc/mdt535 Published online 23 December 2013
A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer B. Besse1*, R. S. Heist2, V. A. Papadmitrakopoulou3, D. R. Camidge4, J. T. Beck5, P. Schmid6, C. Mulatero7, N. Miller8, S. Dimitrijevic8, S. Urva9, I. Pylvaenaeinen8, K. Petrovic8 & B. E. Johnson10
Received 23 April 2013; revised 18 October 2013; accepted 29 October 2013
Background: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC). Patients and methods: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response. Results: Patients received everolimus 2.5 or 5 mg/day without G-CSF (n = 10; cohort A), 20 or 30 mg/week without G-CSF (n = 18; cohort B), or 2.5 or 5 mg/day with G-CSF (n = 12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively). Conclusions: Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC. Key words: cisplatin, etoposide, everolimus, phase I, small-cell lung cancer
introduction Etoposide and cisplatin (EP) chemotherapy is a current standard of care for treating small-cell lung cancer (SCLC) [1, 2]. For patients with extensive-stage SCLC, who account for the majority of cases, EP provides an 8.1–10.9-month median survival and a 2-year survival rate of 10% incidence previously observed with EP [3, 5–7]. With prophylactic G-CSF, the only feasible everolimus dose given with standard-dose EP was 2.5 mg/day. After the protocol amendment and considering the previously observed toxicity, the daily schedule was favored for further enrollment. Therefore, no feasible weekly everolimus dose given with EP was identified. The everolimus doses chosen for this study were based on previous data showing everolimus monotherapy to be pharmacodynamically active and tolerable at doses of 5 and 10 mg/day and 20–70 mg/week [15, 16]. Based on partially overlapping everolimus and EP toxicity profiles and lack of historical data on the proposed combination, both daily and weekly everolimus dosing was evaluated, with starting doses of 5 mg/day and 20 mg/week. In the present study, an adaptive Bayesian model instead of the traditional ‘3 + 3’ design typically used in dosefinding studies was used [18, 19]. Advantages of this design include a flexible dose-escalation scheme using DLT data from all doses at each decision point, the ability to evaluate the DLT rate at any time, and flexibility in the number of patients enrolled at each dose. The adaptive Bayesian model permitted rapid response to the observed myelosuppression and subsequent protocol modification to mandate prophylactic G-CSF. The observed myelosuppression was not unexpected, as it is common in EP-treated patients. Although the grade 3/4 neutropenia rate among non-G-CSF patients in the present study was within the range observed in randomized studies of EP (28%– 68%), grade 3/4 thrombocytopenia, anemia, and febrile neutropenia rates were higher than in previous EP studies [3–7]. This suggests an additive myelosuppressive effect when everolimus is combined with EP. Theoretically, adding everolimus to EP could increase infection risk because of the immunosuppressive activity of both everolimus and chemotherapy. However, no evidence of increased infection unrelated to neutropenia was observed, and all severe infections were reported in the non-GCSF population. Interestingly, pneumonitis, an AE associated with mTOR inhibitors, was not observed in this study. Although almost 50% of patients experienced stomatitis, another AE associated with mTOR inhibitors, no patient experienced stomatitis as a DLT, and grade 3/4 stomatitis was reported in only one patient. Everolimus pharmacokinetics were comparable when administered alone and with EP and consistent with those previously observed with everolimus monotherapy [15, 16]. PR occurred in ∼50% of patients across all everolimus dose levels and schedules. However, the present study included only 40 patients, and 9 (23%) did not have their best overall response assessed because they discontinued treatment before postbaseline tumor assessment (n = 4), or because they did not meet criteria for CR, PR, or stable or progressive disease (n = 5). It appears that everolimus plus EP did not substantially improve tumor response compared with EP alone, which, in randomized trials, is 46%–63%
doi:10.1093/annonc/mdt535 |
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 23, 2015
Table 3. Grade 3/4 adverse events occurring in ≥20% of patients on any everolimus schedule during the core treatment phase (safety population)
Total (N = 12)
21 (53) 11 (28) 11 (28) 9 (23) 6 (15) 2 (5)
Total (N = 40)
discussion
original articles
Annals of Oncology
Table 4. Best overall tumor response in the core treatment phase and progression-free survival (full analysis set)
Best overall response, n (%) CR PR SD PD Unknownb Objective response rate, n (%) [95% CI] Disease control rate, n (%) [95% CI]
Non-G-CSF population Daily everolimusa (N = 10)
Weekly everolimusa (N = 18)
G-CSF population Daily everolimusa (N = 12)
0 4 (40.0) 2 (20.0) 0 4 (40.0) 4 (40.0) [12.2–73.8] 6 (60.0) [26.2–87.8]
0 11 (61.1) 3 (16.7) 2 (11.1) 2 (11.1) 11 (61.1) [35.7–82.7] 14 (77.8) [52.4–93.6]
0 7 (58.3) 0 2 (16.7) 3 (25.0) 7 (58.3) [27.7–84.8] 7 (58.3) [27.7–84.8]
[3–7], suggesting the identified feasible dose level of everolimus in combination with EP may be suboptimal. In an exploratory analysis, median PFS of the seven patients who received the feasible everolimus dose level was 8.1 months, or 3–4 months longer than the median survival typically observed with EP in extensive-stage SCLC [20]. This prolongation of PFS may reflect the highly selected patient population, which may have better prognostic factors, or may be due to the maintenance phase of everolimus. The latter hypothesis appears to be refuted by results of a phase II study in which everolimus monotherapy displayed only modest clinical activity in relapsed/refractory SCLC (objective response rate, 3%; median time to progression, 1.3 months) [21]. To date, no molecular predictors of response to mTOR inhibitors have been identified, precluding selection of patients who might benefit from everolimus. In conclusion, everolimus 2.5 mg/day plus G-CSF was identified as the feasible everolimus dose given with standard-dose EP in patients with treatment-naive extensive-stage SCLC. Based on the modest clinical activity observed with everolimus monotherapy in relapsed/refractory SCLC and the hematologic and infectious complications observed with everolimus plus EP, everolimus is unlikely to be further investigated in an unselected SCLC population.
acknowledgements We thank Melanie Leiby, PhD (ApotheCom, Yardley, PA, USA), for her medical editorial assistance with this manuscript.
funding This study was supported by Novartis Pharmaceuticals. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.
| Besse et al.
disclosure VAP has had a consultant/advisory role with Genentech. DRC has had a consultant/advisory role with Novartis. SU is employed by and has stock ownership in Novartis Pharmaceuticals Corporation. IP and KP are employed by and have stock ownership in Novartis Pharma AG. NM is a former employee of Novartis Pharma AG who still has stock ownership in Novartis. SD is a former legal representative for Novartis Pharma AG. BEJ has served as a consultant to AstraZeneca, Genentech, Sanofi, Millennium, and Transgenomics. BB has received research grants from Novartis Pharmaceuticals. VAP has received research funding from Novartis, Merck, AstraZeneca, Bristol-Myers-Squibb, and Astellas. All of the other authors declare no conflict of interest.
references 1. Fruh M, De RD, Popat S et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi99–vi105. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: small cell lung cancer, version 1.2014. http://www.nccn.org/ professionals/physician_gls/pdf/sclc.pdf (30 August 2013, date last accessed). 3. Lara PN, Jr, Natale R, Crowley J et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 2009; 27: 2530–2535. 4. Lee SM, James LE, Qian W et al. Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer. Thorax 2009; 64: 75–80. 5. Zatloukal P, Cardenal F, Szczesna A et al. A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 2010; 21: 1810–1816. 6. Spigel DR, Townley PM, Waterhouse DM et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensivestage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011; 29: 2215–2222.
Volume 25 | No. 2 | February 2014
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 23, 2015
Objective response rate defined as the percentage of patients with either a complete or a partial response. Disease control rate defined as the percentage of patients with either a complete or a partial response or with stable disease. a All patients received etoposide and cisplatin in addition to everolimus. b Reasons for unknown best overall response were discontinuation before postbaseline tumor assessment (n = 4) and did not meet criteria for CR, PR, stable disease, or disease progression, despite postbaseline tumor assessment (n = 5). CI, confidence interval; CR, complete response; G-CSF, granulocyte colony-stimulating factor; PD, progressive disease; PR, partial response; SD, stable disease.
original articles
Annals of Oncology
14. Tsurutani J, West KA, Sayyah J et al. Inhibition of the phosphatidylinositol 3kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res 2005; 65: 8423–8432. 15. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1603–1610. 16. O’Donnell A, Faivre S, Burris HA, III et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1588–1595. 17. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. 18. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med 2008; 27: 2420–2439. 19. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with lateonset toxicities. Biometrics 2000; 56: 1177–1182. 20. Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005; 366: 1385–1396. 21. Tarhini A, Kotsakis A, Gooding W et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res 2010; 16: 5900–5907.
Annals of Oncology 25: 511–518, 2014 doi:10.1093/annonc/mdt544 Published online 9 January 2014
Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer K. Hemminki1,2*, X. Li2, A. Försti1,2, J. Sundquist2,3 & K. Sundquist2,3 1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; 2Center for Primary Health Care Research, Lund University, Malmö, Sweden; 3Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA
Received 18 September 2013; revised 30 October 2013; accepted 30 October 2013
Background: Systemic amyloidoses include immunoglobulin light chain (AL) amyloidosis, serum amyloid (AA)-related amyloidosis and senile systemic amyloidosis (SSA). AL amyloidosis is associated with myeloma, and we showed recently that transthyretin-related hereditary amyloidosis was related to non-Hodgkin lymphoma (NHL). In SSA, amyloids constitute wild-type transthyretin. We wanted to analyze cancer risks in amyloidosis, particularly in SSA. Patients and methods: Nonhereditary amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 1997 through 2010. Their cancer risk was assessed based on the Swedish Cancer Registry using standardized incidence ratio (SIR) between amyloidosis patients and the remaining population. To gain information about amyloidosis subtypes, we used the Swedish Prescribed Drug Register from years 2005 through 2010 to find out the specific medication prescribed. Results: Among 1400 identified amyloidosis patients, cancer risk was increased for myeloma, NHL and squamous cell skin cancer. Myeloma and skin cancers were diagnosed 7–8 years earlier than in the population, whereas NHL was diagnosed in elderly patients. The SIR was 204 for myeloma in patients who received AL amyloidosis medication, and it was 17.22 in patients receiving rheumatoid arthritis medication, suggesting AA amyloidosis. In remaining patients, including
*Correspondence to: Prof. Kari Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany. Tel: +49-6221421800; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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