- Email: [email protected]
IIIA.4 Side-effects of targeted therapy
S6
Critical Reviews in Oncology/Hematology 60 (2006)
two schedules of trastuzumab, in patients with advanced breast cancer (ABC) that overexpresses HER-2. Eur J Cancer 2006; 4(2): 173 (abstract 429). [16] Miller K, Wang M, Gralow J, et al. First-line bevacizumab and paclitaxel in patients with locally recurrent or metastatic breast cancer: a randomized, phase III trial coordinated by the Eastern Cooperative Oncology Group (E2100). Eur J Cancer Suppl 2005; 3(2): 77−8. [17] Bianchi G, Loibl S, Zamagni C, et al. A Phase II multicentre uncontrolled trial of sorafenib (BAY 43–9006) in patients with metastatic breast cancer. Eur J Cancer 2005; 3S(2): 78. [18] Deprimo SE, Friece C, Huang J et al. Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulanting plasma levels of VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer. J Clin Oncol 2006; 24(18S): 22s.
IIIA.3 15.10–15.25 Targeted therapy in elderly cancer patients. Renal cell carcinoma P.H.M. De Mulder *. Department of Medical Oncology, Radboud University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, Netherlands Renal cell carcinoma (RCC) accounts for 3% of all malignancies in man and is the third most common urological cancer after prostate and bladder cancer. The incidence of RCC in Europe is increasing with approximately 20,000 new cases each year and an annual death rate due to metastatic disease (mRCC) of 8000. The peak incidence in the Netherlands is in the age cohort 70−80 years with 31 % of all patients (482 of 1532). According to the SEER data the 5-year survival of localized disease (T1−2) is 89%, 61% in regionally advanced disease and only 9 % in case of metastatic disease. The majority of the tumours comprise adenocarcinomas originating form the proximal tubular cells. Most adenocarcinomas are of the clear cell type and are considered the most sensitive subtype for systemic therapy. The standard and only curative treatment for local disease is surgery. In case of metastatic disease a nephrectomy should only be considered when treatment with cytokines is indicated. Until recently IFN-a and IL-2 were the only available tretament options. For elderly patients this type of treatment is considered very troublesome in view of the considerable constitutional side effects. More recently a new class of compounds, based on crucial new knowledge regarding the pathophysiology, has gained significant relevance for this disease. Especially the clear cell subtype is charcaterized by mutations in the von Hippel Lindau gene (VHL) leading to the transcription of hypoxiainducible genes resulting in a strong angiogenic signal inducing neo angiogenesis. This process can be targeted at several levels i.e the the vascular endothelial factor (VEGF), the receptor, especially the tyrosine kinase part and more upstream in the tumor cell by inhibition of the m-TOR pathway. Compounds of interest are bevacizumab, a monoclonal antibody directed against VEGF-a, and the first in this class showing a progression free survival advantage in cytokine refractory patients when compared with placebo. Furthermore sorafinib, sunitinib and temsirolimus. Sorafinib an oral compound (Raf kinase, VEGFR-2 and PGFR inhibitor), has shown a progression free survival advantage of 12 months (median PFS 12 weeks for placebo and 24 wks for sorafinib, hazard ratio 0.44, p < 0.000001) in patients refractory to cytokines or unfit to receive these. There was no age limit and a subgroup analysis revealed a similar effect for patients below the age of 65 versus above. Sunitinib (VEGFR and PGFR inhibitor) has been evaluated in first line versus IFN-a. This oral compound induced a median PFS of 11 months versus 5 for IFN (hazard ratio 0.415, p < 0.000001). In this trial the oldest treated patient was 87 but no subgroup data are available. Temsirolimus is an i.v. compound and has shown in the poor risk group a median survival advantage of 3.6 months (7.3 versus 10.9 months, p = 0.0069). The side effects for al these compounds are different but mangeable and favourable in comparison to cytokine based treatment regimens. Complete remissions are rare. Conclusion: Renal cell carcinoma is a relevant disease for the elderly patients with until recently very limited treatment options. In case of systemic disease angiogenesis inhibitors are a new option and should be considered. The M-TOR inhibitor Temsirolimus is an option for patients with poor prognostic features. Cytokines may have a very limited indication for the elderly patients with good risk features.
Abstracts IIIA.4 Side-effects of targeted therapy
15.25–15.45
F.A.L.M. Eskens *. department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam, The Netherlands Cancer is a disease that occurs most frequently in the elderly population. Apart from a small minority of patients that can be cured by surgery, chemotherapy or radiotherapy, most patients will ultimately die from metastatic disease. Conventional chemotherapy targets mechanisms that are active in normal cells and tissues as well as in cancercells, and this explains the fact that this treatment is almost without exception accompanied by, sometimes debilitating, side-effects. Hormonal therapy, that can be considered as an old and well established form of targeted therapy is much more friendly for patients which could partly be explained by the fact that predominantly cancer specific receptors are being targeted. Modern targeted therapy is rationally and structurally based, with drugs being designed and developed following the recognition and sequencing of cancer specific targets or receptors. These cancer specific targets are located either within the cellular stroma or at the surface/membrane of cancer cells. Another target that has obtained great interest is the endothelial cell, as angiogenesis has become an extreme important target for the development of a new class of specifically targeted anticancer agents. With the introduction of a wide variety of new targeted anticancer agents the spectrum of observed side-effects has impressively shifted away ot that of the conventional or classic cytotoxic anticancer agents; myelosuppression has been replaced by skin rash or hypertension, just to mention such a shift! In this presentation some of the most frequently used modern targeted anticancer agents will be discussed, and the most frequently occurring drug or class related side-effects will be highlighted. In addition, some considerations with regard to the underlying pathophysiological mechanisms as well as some suggestions for treatment of these side-effects will be discussed. 14.30–15.45
Room: Jan Toorop
Parallel session IIIB: Lung cancer in elderly patients Moderators: Cesare Gridelli & Carmela Pepe IIIB.1 14.30–14.50 Adjuvant chemotherapy in elderly patients: an analysis of National Cancer Institute of Canada Clinical Trials Group and Intergroup JBR.10 C. Pepe *, B. Hasan, T. Winton, L. Seymour, J. Pater, R. Livingston, D. Johnson, J. Rigas, K. Ding, F.A. Shepherd. Background: Adjuvant chemotherapy after resection of NSCLC has become standard of care, with several recent trials showing a significant survival benefit compared to observation alone. It is not known whether elderly patients derive the same survival advantage or whether they can tolerate platinum-based adjuvant chemotherapy. This retrospective analysis evaluated the influence of age on survival, and the deliverability and toxicity of adjuvant chemotherapy in elderly patients in NCIC CTG JBR.10. Methods: Patients aged 65 and >65 were compared for baseline characteristics and survival benefit from treatment. Chemotherapy delivery and toxicity were also compared by age group (total of 213 treated patients). Results: All randomized patients from JBR.10, including 327 young and 155 elderly patients, were compared for baseline prognostic factors by age. Only histology (adenocarcinoma: 58% young, 43% elderly; squamous carcinoma: 32% young, 49% elderly; p = 0.001) and performance status (PS 0: 53% young, 41% elderly; p = 0.01) were significantly different between the two age groups. Overall survival by age was not significantly different, though a trend favoring the young was seen in univariate (HR 0.77, CI 0.58−1.04, p = 0.084) and multivariate analyses (HR 0.75, CI 0.56−1.01, p = 0.059). Overall survival for patients >65 was significantly better with chemotherapy vs. observation (HR 0.61, CI 0.38−0.98, p = 0.04). Patients
Critical Reviews in Oncology/Hematology 60 (2006)
two schedules of trastuzumab, in patients with advanced breast cancer (ABC) that overexpresses HER-2. Eur J Cancer 2006; 4(2): 173 (abstract 429). [16] Miller K, Wang M, Gralow J, et al. First-line bevacizumab and paclitaxel in patients with locally recurrent or metastatic breast cancer: a randomized, phase III trial coordinated by the Eastern Cooperative Oncology Group (E2100). Eur J Cancer Suppl 2005; 3(2): 77−8. [17] Bianchi G, Loibl S, Zamagni C, et al. A Phase II multicentre uncontrolled trial of sorafenib (BAY 43–9006) in patients with metastatic breast cancer. Eur J Cancer 2005; 3S(2): 78. [18] Deprimo SE, Friece C, Huang J et al. Effect of treatment with sunitinib malate, a multitargeted tyrosine kinase inhibitor, on circulanting plasma levels of VEGF receptors 2 and 3, and soluble KIT in patients with metastatic breast cancer. J Clin Oncol 2006; 24(18S): 22s.
IIIA.3 15.10–15.25 Targeted therapy in elderly cancer patients. Renal cell carcinoma P.H.M. De Mulder *. Department of Medical Oncology, Radboud University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, Netherlands Renal cell carcinoma (RCC) accounts for 3% of all malignancies in man and is the third most common urological cancer after prostate and bladder cancer. The incidence of RCC in Europe is increasing with approximately 20,000 new cases each year and an annual death rate due to metastatic disease (mRCC) of 8000. The peak incidence in the Netherlands is in the age cohort 70−80 years with 31 % of all patients (482 of 1532). According to the SEER data the 5-year survival of localized disease (T1−2) is 89%, 61% in regionally advanced disease and only 9 % in case of metastatic disease. The majority of the tumours comprise adenocarcinomas originating form the proximal tubular cells. Most adenocarcinomas are of the clear cell type and are considered the most sensitive subtype for systemic therapy. The standard and only curative treatment for local disease is surgery. In case of metastatic disease a nephrectomy should only be considered when treatment with cytokines is indicated. Until recently IFN-a and IL-2 were the only available tretament options. For elderly patients this type of treatment is considered very troublesome in view of the considerable constitutional side effects. More recently a new class of compounds, based on crucial new knowledge regarding the pathophysiology, has gained significant relevance for this disease. Especially the clear cell subtype is charcaterized by mutations in the von Hippel Lindau gene (VHL) leading to the transcription of hypoxiainducible genes resulting in a strong angiogenic signal inducing neo angiogenesis. This process can be targeted at several levels i.e the the vascular endothelial factor (VEGF), the receptor, especially the tyrosine kinase part and more upstream in the tumor cell by inhibition of the m-TOR pathway. Compounds of interest are bevacizumab, a monoclonal antibody directed against VEGF-a, and the first in this class showing a progression free survival advantage in cytokine refractory patients when compared with placebo. Furthermore sorafinib, sunitinib and temsirolimus. Sorafinib an oral compound (Raf kinase, VEGFR-2 and PGFR inhibitor), has shown a progression free survival advantage of 12 months (median PFS 12 weeks for placebo and 24 wks for sorafinib, hazard ratio 0.44, p < 0.000001) in patients refractory to cytokines or unfit to receive these. There was no age limit and a subgroup analysis revealed a similar effect for patients below the age of 65 versus above. Sunitinib (VEGFR and PGFR inhibitor) has been evaluated in first line versus IFN-a. This oral compound induced a median PFS of 11 months versus 5 for IFN (hazard ratio 0.415, p < 0.000001). In this trial the oldest treated patient was 87 but no subgroup data are available. Temsirolimus is an i.v. compound and has shown in the poor risk group a median survival advantage of 3.6 months (7.3 versus 10.9 months, p = 0.0069). The side effects for al these compounds are different but mangeable and favourable in comparison to cytokine based treatment regimens. Complete remissions are rare. Conclusion: Renal cell carcinoma is a relevant disease for the elderly patients with until recently very limited treatment options. In case of systemic disease angiogenesis inhibitors are a new option and should be considered. The M-TOR inhibitor Temsirolimus is an option for patients with poor prognostic features. Cytokines may have a very limited indication for the elderly patients with good risk features.
Abstracts IIIA.4 Side-effects of targeted therapy
15.25–15.45
F.A.L.M. Eskens *. department of Medical Oncology, Erasmus MC University Medical Center, Rotterdam, The Netherlands Cancer is a disease that occurs most frequently in the elderly population. Apart from a small minority of patients that can be cured by surgery, chemotherapy or radiotherapy, most patients will ultimately die from metastatic disease. Conventional chemotherapy targets mechanisms that are active in normal cells and tissues as well as in cancercells, and this explains the fact that this treatment is almost without exception accompanied by, sometimes debilitating, side-effects. Hormonal therapy, that can be considered as an old and well established form of targeted therapy is much more friendly for patients which could partly be explained by the fact that predominantly cancer specific receptors are being targeted. Modern targeted therapy is rationally and structurally based, with drugs being designed and developed following the recognition and sequencing of cancer specific targets or receptors. These cancer specific targets are located either within the cellular stroma or at the surface/membrane of cancer cells. Another target that has obtained great interest is the endothelial cell, as angiogenesis has become an extreme important target for the development of a new class of specifically targeted anticancer agents. With the introduction of a wide variety of new targeted anticancer agents the spectrum of observed side-effects has impressively shifted away ot that of the conventional or classic cytotoxic anticancer agents; myelosuppression has been replaced by skin rash or hypertension, just to mention such a shift! In this presentation some of the most frequently used modern targeted anticancer agents will be discussed, and the most frequently occurring drug or class related side-effects will be highlighted. In addition, some considerations with regard to the underlying pathophysiological mechanisms as well as some suggestions for treatment of these side-effects will be discussed. 14.30–15.45
Room: Jan Toorop
Parallel session IIIB: Lung cancer in elderly patients Moderators: Cesare Gridelli & Carmela Pepe IIIB.1 14.30–14.50 Adjuvant chemotherapy in elderly patients: an analysis of National Cancer Institute of Canada Clinical Trials Group and Intergroup JBR.10 C. Pepe *, B. Hasan, T. Winton, L. Seymour, J. Pater, R. Livingston, D. Johnson, J. Rigas, K. Ding, F.A. Shepherd. Background: Adjuvant chemotherapy after resection of NSCLC has become standard of care, with several recent trials showing a significant survival benefit compared to observation alone. It is not known whether elderly patients derive the same survival advantage or whether they can tolerate platinum-based adjuvant chemotherapy. This retrospective analysis evaluated the influence of age on survival, and the deliverability and toxicity of adjuvant chemotherapy in elderly patients in NCIC CTG JBR.10. Methods: Patients aged 65 and >65 were compared for baseline characteristics and survival benefit from treatment. Chemotherapy delivery and toxicity were also compared by age group (total of 213 treated patients). Results: All randomized patients from JBR.10, including 327 young and 155 elderly patients, were compared for baseline prognostic factors by age. Only histology (adenocarcinoma: 58% young, 43% elderly; squamous carcinoma: 32% young, 49% elderly; p = 0.001) and performance status (PS 0: 53% young, 41% elderly; p = 0.01) were significantly different between the two age groups. Overall survival by age was not significantly different, though a trend favoring the young was seen in univariate (HR 0.77, CI 0.58−1.04, p = 0.084) and multivariate analyses (HR 0.75, CI 0.56−1.01, p = 0.059). Overall survival for patients >65 was significantly better with chemotherapy vs. observation (HR 0.61, CI 0.38−0.98, p = 0.04). Patients