Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photo... more Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas. Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts. Results: Biodistribution studies sho...
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Osteosa... more Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Osteosarcoma is the most commonly diagnosed primary malignant bone tumor occurring in children and adolescents. Despite multimodal treatment the final outcome has not improved impressively during the last decades and side-effects of treatment could be severe. There is an urgent need for novel therapeutic approaches. Blocking mTOR signaling appeared a promising treatment option. However, in patients at best partial responses were seen during mTOR-targeted monotherapies. We hypothesized that the addition of other drugs may improve the therapeutic efficacy of mTOR-inhibitors. In this study, we examined the effects of the mTOR-inhibitor temsirolimus on the growth of human osteosarcoma xenografts in vivo, with and without chemotherapy (cisplatin) or a VEGF-inhibitor (bevacizumab). Methods: BALB/c nude mice were s.c. implanted with human osteosarcoma xenografts (OS-33 or OS-1; from PPTP) and treated with temsirolimus (1 mg/kg, every 3 days), cisplatin (3.5 mg/kg, every 21 days), bevacizumab (5 mg/kg, twice weekly), temsirolimus + cisplatin (TC) or temsirolimus + bevacizumab (TB) for 4 weeks (n=8-10 mice per group). Tumor growth was monitored by caliper measurements twice weekly. Relative tumor volumes (RTV) were used to compare tumor growth in the groups. Reductions in tumor volumes were expressed as percentage reduction compared to tumors in control mice at the end of the experiment. Results: Temsirolimus monotherapy significantly inhibited growth of OS-1 (24%, p=0.025) and OS-33 (60%, p=0.01) tumors as compared to controls. TC treatment resulted in significantly enhanced tumor growth inhibition compared to each monotherapy in mice with OS-1 tumors (cisplatin: 16%, p=0.13; TC: 49%, p<0.01) and with OS-33 tumors (cisplatin: 61%, p=0.01; TC: 85%, p<0.01). This effect was synergistic in OS-1 tumors, because these tumors were resistant to cisplatin monotherapy. Also in TB treated mice, significantly better anti-tumor responses were observed compared to the monotherapies in both OS-1 (bevacizumab: 35%, p<0.01; TB: 57%, p<0.01) and OS-33 models (bevacizumab: 70%, p=0.01; TB: 91%, p<0.01). All therapies were tolerated well. Conclusion: Temsirolimus is effective as a single agent in OS-1 and OS-33 osteosarcoma models, but the combination with cisplatin or bevacizumab induced a superior anti-tumor response compared to all monotherapies. These data indicate that temsirolimus, combined with cisplatin or bevacizumab, should be further explored in the treatment of osteosarcoma patients.We are currently analyzing the effect of these treatments on tumor proliferation and vascularization by IHC, and are exploring the possible use of 18F-FDG- and 18F-FLT-PET scans for the in vivo monitoring of therapy response. This research was supported by Pfizer. Citation Format: Emmy DG Fleuren, Yvonne MH Versleijen-Jonkers, Melissa HS Roeffen, Gerben M. Franssen, Peter J. Houghton, Wim JG Oyen, Otto C. Boerman, Winette TA van der Graaf. Temsirolimus is effective as a single agent and in combination with cisplatin or bevacizumab in preclinical osteosarcoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2761. doi:10.1158/1538-7445.AM2013-2761
Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinica... more Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-Deoxy-3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients.
To gain greater insight into the biological mechanisms occurring shortly after discontinuation of... more To gain greater insight into the biological mechanisms occurring shortly after discontinuation of VEGFR TKIs treatment because of progressive disease (PD). Sixteen patients with PD during treatment with sorafenib or sunitinib were randomized to either directly stop the VEGFR TKI or to continue for another two weeks. At baseline (i.e. at the moment of PD) and after two weeks FDG-PET/CT, functional-MRI and blood biomarkers of disease were evaluated. A statistically significant difference in median change from baseline to two weeks later in K(trans) and LDH levels was observed between patients who directly stopped versus those who continued treatment (1.6 s(-1) versus -1.1s(-1), p=0.03; -73.0 U/L versus 52.0 U/L, p=0.008; respectively). There were no further differences between groups. Two weeks after discontinuation of VEGFR TKIs in mRCC because of PD, a rise in K(trans) accompanied by a decrease in LDH indicates an increase in tumor vascularization. This implies that at the moment of...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2015
Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is ... more Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is not routinely available for this growing population. The Breast Cancer E-Health (BREATH) trial is a Web-based self-management intervention to support the psychological adjustment of women after primary treatment, by reducing distress and improving empowerment. This multicenter, randomized, controlled, parallel-group trial evaluated whether care as usual (CAU) plus BREATH is superior to CAU alone. BREATH is delivered in sixteen fully automated weekly modules covering early survivorship issues. Two to 4 months post-treatment, BCSs were randomly assigned to receive CAU + BREATH (n = 70) or CAU alone (n = 80) using a stratified block design (ratio 1:1). Primary outcomes were distress (Symptom Checklist-90) and empowerment (Cancer Empowerment Questionnaire), assessed before random assignment (baseline, T0) and after 4 (T1), 6 (T2), and 10 months (T3) of follow-up. Statistical (analysis of cov...
To report the results of accelerated radiotherapy with concomitant weekly cisplatin in head and n... more To report the results of accelerated radiotherapy with concomitant weekly cisplatin in head and neck cancer. One-hundred-and-six patients received concomitant cisplatin 40 mg/m(2) weekly with accelerated radiotherapy up to a dose of 68 Gy over 5.5 weeks. Ninety-nine percent of the patients received planned radiotherapy and 90% received ≥ 5 cycles of cisplatin. Moist desquamation of skin developed in 45% and confluent mucositis in 82%. Feeding tubes were required in 79% of the patients, and after 12 months in 4%. One patient developed nephrotoxicity. Three-year loco-regional control, disease-free survival and overall survival (OS) were 72%, 54% and 61%, respectively. HPV status was positive on PCR and p16in 11 of 50 tested oropharyngeal carcinoma (OPC) patients. Three-years OS was 81% and 66% in HPV-positive versus HPV-negative OPC patients (ns). Concomitant weekly cisplatin 40 mg/m(2) with accelerated radiotherapy was well tolerated and treatment compliance was high. This article i...
According to surveys, many patients with advanced cancer wish to receive survival information. Th... more According to surveys, many patients with advanced cancer wish to receive survival information. This study investigated information preferences by offering patients a decision aid (DA) with information on expected survival for two treatment options: supportive care with or without second-line palliative chemotherapy. Predictors of accepting survival information were explored. Eligible patients in this multicentre prospective study were offered second-line chemotherapy for advanced breast or colorectal cancer. A nurse presented a DA on second-line treatment and asked patients whether they desired information on (i) adverse events, (ii) tumour response and (iii) survival. Data on 50 clinical and psychosocial patient characteristics were collected from inclusion forms and patient questionnaires. Seventy-seven patients received a DA; median age 62 years (range 32-80), 61% female, 77% colorectal cancer. Fifty-seven patients (74%; 95% CI 64-84) desired survival information. Four psychosocial characteristics (e.g. deliberative decision style) independently predicted information desire. However, the use of these characteristics to predict information desire hardly outperformed a simple prediction rule. Many patients desired information on expected survival when deciding about second-line treatment. However, our exploratory analysis indicated that patients desiring this information could not be identified based on their clinical or psychosocial characteristics. These findings can help encourage candid discussions about expected survival. Health professionals should be careful not to make implicit assumptions of information desire based on patient characteristics, but to explicitly ask patients if survival information is desired, and act accordingly.
To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and... more To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy.
To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specif... more To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response.
Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy wit... more Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy with imatinib. Surgery is performed to remove metastatic lesions to induce long-term remission or even curation. In other patients, surgery is performed to remove (focal) progressive or symptomatic lesions. The impact and long-term results of surgery after systemic therapy have not been clearly defined. Between September 2001 and May 2010, all patients with metastatic GIST who underwent surgery for metastatic GIST after systemic therapy (that is, imatinib and sunitinib) at four Dutch specialized institutions were included. Primary end-points were progression-free survival (PFS) and overall survival (OS). All 55 patients underwent surgery after treatment with systemic therapy. At the last follow-up, tumor recurrence or progression was noted after surgery in 48% of the patients who responded on systemic therapy, and in 85% of the patients who were treated while having progressive disease. Med...
Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photo... more Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas. Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts. Results: Biodistribution studies sho...
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Osteosa... more Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Osteosarcoma is the most commonly diagnosed primary malignant bone tumor occurring in children and adolescents. Despite multimodal treatment the final outcome has not improved impressively during the last decades and side-effects of treatment could be severe. There is an urgent need for novel therapeutic approaches. Blocking mTOR signaling appeared a promising treatment option. However, in patients at best partial responses were seen during mTOR-targeted monotherapies. We hypothesized that the addition of other drugs may improve the therapeutic efficacy of mTOR-inhibitors. In this study, we examined the effects of the mTOR-inhibitor temsirolimus on the growth of human osteosarcoma xenografts in vivo, with and without chemotherapy (cisplatin) or a VEGF-inhibitor (bevacizumab). Methods: BALB/c nude mice were s.c. implanted with human osteosarcoma xenografts (OS-33 or OS-1; from PPTP) and treated with temsirolimus (1 mg/kg, every 3 days), cisplatin (3.5 mg/kg, every 21 days), bevacizumab (5 mg/kg, twice weekly), temsirolimus + cisplatin (TC) or temsirolimus + bevacizumab (TB) for 4 weeks (n=8-10 mice per group). Tumor growth was monitored by caliper measurements twice weekly. Relative tumor volumes (RTV) were used to compare tumor growth in the groups. Reductions in tumor volumes were expressed as percentage reduction compared to tumors in control mice at the end of the experiment. Results: Temsirolimus monotherapy significantly inhibited growth of OS-1 (24%, p=0.025) and OS-33 (60%, p=0.01) tumors as compared to controls. TC treatment resulted in significantly enhanced tumor growth inhibition compared to each monotherapy in mice with OS-1 tumors (cisplatin: 16%, p=0.13; TC: 49%, p<0.01) and with OS-33 tumors (cisplatin: 61%, p=0.01; TC: 85%, p<0.01). This effect was synergistic in OS-1 tumors, because these tumors were resistant to cisplatin monotherapy. Also in TB treated mice, significantly better anti-tumor responses were observed compared to the monotherapies in both OS-1 (bevacizumab: 35%, p<0.01; TB: 57%, p<0.01) and OS-33 models (bevacizumab: 70%, p=0.01; TB: 91%, p<0.01). All therapies were tolerated well. Conclusion: Temsirolimus is effective as a single agent in OS-1 and OS-33 osteosarcoma models, but the combination with cisplatin or bevacizumab induced a superior anti-tumor response compared to all monotherapies. These data indicate that temsirolimus, combined with cisplatin or bevacizumab, should be further explored in the treatment of osteosarcoma patients.We are currently analyzing the effect of these treatments on tumor proliferation and vascularization by IHC, and are exploring the possible use of 18F-FDG- and 18F-FLT-PET scans for the in vivo monitoring of therapy response. This research was supported by Pfizer. Citation Format: Emmy DG Fleuren, Yvonne MH Versleijen-Jonkers, Melissa HS Roeffen, Gerben M. Franssen, Peter J. Houghton, Wim JG Oyen, Otto C. Boerman, Winette TA van der Graaf. Temsirolimus is effective as a single agent and in combination with cisplatin or bevacizumab in preclinical osteosarcoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2761. doi:10.1158/1538-7445.AM2013-2761
Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinica... more Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-Deoxy-3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients.
To gain greater insight into the biological mechanisms occurring shortly after discontinuation of... more To gain greater insight into the biological mechanisms occurring shortly after discontinuation of VEGFR TKIs treatment because of progressive disease (PD). Sixteen patients with PD during treatment with sorafenib or sunitinib were randomized to either directly stop the VEGFR TKI or to continue for another two weeks. At baseline (i.e. at the moment of PD) and after two weeks FDG-PET/CT, functional-MRI and blood biomarkers of disease were evaluated. A statistically significant difference in median change from baseline to two weeks later in K(trans) and LDH levels was observed between patients who directly stopped versus those who continued treatment (1.6 s(-1) versus -1.1s(-1), p=0.03; -73.0 U/L versus 52.0 U/L, p=0.008; respectively). There were no further differences between groups. Two weeks after discontinuation of VEGFR TKIs in mRCC because of PD, a rise in K(trans) accompanied by a decrease in LDH indicates an increase in tumor vascularization. This implies that at the moment of...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 13, 2015
Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is ... more Early breast cancer survivors (BCSs) report high unmet care needs, and easily accessible care is not routinely available for this growing population. The Breast Cancer E-Health (BREATH) trial is a Web-based self-management intervention to support the psychological adjustment of women after primary treatment, by reducing distress and improving empowerment. This multicenter, randomized, controlled, parallel-group trial evaluated whether care as usual (CAU) plus BREATH is superior to CAU alone. BREATH is delivered in sixteen fully automated weekly modules covering early survivorship issues. Two to 4 months post-treatment, BCSs were randomly assigned to receive CAU + BREATH (n = 70) or CAU alone (n = 80) using a stratified block design (ratio 1:1). Primary outcomes were distress (Symptom Checklist-90) and empowerment (Cancer Empowerment Questionnaire), assessed before random assignment (baseline, T0) and after 4 (T1), 6 (T2), and 10 months (T3) of follow-up. Statistical (analysis of cov...
To report the results of accelerated radiotherapy with concomitant weekly cisplatin in head and n... more To report the results of accelerated radiotherapy with concomitant weekly cisplatin in head and neck cancer. One-hundred-and-six patients received concomitant cisplatin 40 mg/m(2) weekly with accelerated radiotherapy up to a dose of 68 Gy over 5.5 weeks. Ninety-nine percent of the patients received planned radiotherapy and 90% received ≥ 5 cycles of cisplatin. Moist desquamation of skin developed in 45% and confluent mucositis in 82%. Feeding tubes were required in 79% of the patients, and after 12 months in 4%. One patient developed nephrotoxicity. Three-year loco-regional control, disease-free survival and overall survival (OS) were 72%, 54% and 61%, respectively. HPV status was positive on PCR and p16in 11 of 50 tested oropharyngeal carcinoma (OPC) patients. Three-years OS was 81% and 66% in HPV-positive versus HPV-negative OPC patients (ns). Concomitant weekly cisplatin 40 mg/m(2) with accelerated radiotherapy was well tolerated and treatment compliance was high. This article i...
According to surveys, many patients with advanced cancer wish to receive survival information. Th... more According to surveys, many patients with advanced cancer wish to receive survival information. This study investigated information preferences by offering patients a decision aid (DA) with information on expected survival for two treatment options: supportive care with or without second-line palliative chemotherapy. Predictors of accepting survival information were explored. Eligible patients in this multicentre prospective study were offered second-line chemotherapy for advanced breast or colorectal cancer. A nurse presented a DA on second-line treatment and asked patients whether they desired information on (i) adverse events, (ii) tumour response and (iii) survival. Data on 50 clinical and psychosocial patient characteristics were collected from inclusion forms and patient questionnaires. Seventy-seven patients received a DA; median age 62 years (range 32-80), 61% female, 77% colorectal cancer. Fifty-seven patients (74%; 95% CI 64-84) desired survival information. Four psychosocial characteristics (e.g. deliberative decision style) independently predicted information desire. However, the use of these characteristics to predict information desire hardly outperformed a simple prediction rule. Many patients desired information on expected survival when deciding about second-line treatment. However, our exploratory analysis indicated that patients desiring this information could not be identified based on their clinical or psychosocial characteristics. These findings can help encourage candid discussions about expected survival. Health professionals should be careful not to make implicit assumptions of information desire based on patient characteristics, but to explicitly ask patients if survival information is desired, and act accordingly.
To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and... more To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy.
To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specif... more To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response.
Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy wit... more Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy with imatinib. Surgery is performed to remove metastatic lesions to induce long-term remission or even curation. In other patients, surgery is performed to remove (focal) progressive or symptomatic lesions. The impact and long-term results of surgery after systemic therapy have not been clearly defined. Between September 2001 and May 2010, all patients with metastatic GIST who underwent surgery for metastatic GIST after systemic therapy (that is, imatinib and sunitinib) at four Dutch specialized institutions were included. Primary end-points were progression-free survival (PFS) and overall survival (OS). All 55 patients underwent surgery after treatment with systemic therapy. At the last follow-up, tumor recurrence or progression was noted after surgery in 48% of the patients who responded on systemic therapy, and in 85% of the patients who were treated while having progressive disease. Med...
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Papers by Winette Van Der Graaf