9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor s... more 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.
Due to the nature of the disease, patients often have a privileged and close relationship with th... more Due to the nature of the disease, patients often have a privileged and close relationship with their oncologist, and the oncologist also with their patients. This may in turn be detrimental to the relation between the general practitioner and the patient. Patients will not return to their general practitioner until end of life care or a consultation at the patient's home if necessary. In order to maintain a balance between the caretakers and assure appropriate involvement of the family physician, continuous communication and exchange of information are essential. This review identifies some of the problems and potential conflicts, which may arise, and discusses how the interaction could be improved.
PURPOSE Ocular melanoma is characterized by a high rate of liver metastases and is associated wit... more PURPOSE Ocular melanoma is characterized by a high rate of liver metastases and is associated with a median survival time less than 5 months. There is no standard treatment available. Treatment strategies have, without success, relied on the experience with metastatic cutaneous melanoma. The only effective treatment is chemoembolization using cisplatin and polyvinyl sponge, which has never become accepted on a large scale. The objective of the study was to establish prospectively the efficacy and toxicity of hepatic intraarterial fotemustine, a third-generation nitrosourea, in patients with liver metastases from ocular melanoma. PATIENTS AND METHODS Thirty-one patients were subjected to laparotomy to place a totally implantable catheter into the hepatic artery and received fotemustine 100 mg/m2 as a 4-hour infusion, first once a week for four times and then, after a 5-week rest period, every 3 weeks until progression or toxicity. Cox regression models were used to assess the prognos...
3047 Background: P is an oral angiogenesis inhibitor targeting VEGFR-1, -2, -3, PDGFR-α, -β, and ... more 3047 Background: P is an oral angiogenesis inhibitor targeting VEGFR-1, -2, -3, PDGFR-α, -β, and c- Kit. The optimal modality of administration in combination with chemotherapy is not yet clear. Methods: Ptsenrolled in 3 parallel arms to receive escalating doses of P with EPI. EPI administered on Day 3 (Arms A and B) or Day 1 (Arm C) q3w. P given once daily throughout the dosing cycle (Arm A), D1-8 (Arm B) or D14-21 (Arm C). Treatment was planned until progression or unacceptable toxicity to determine the optimum tolerated regimen (OTR) on the bases of dose-limiting toxicity (DLT) rate. Blood samples are drawn for PK and detection of circulating bone-marrow derived angiogenic cells. Results: 53 pts have been treated: median age=59 (range 54-64). A maximum of two prior lines of chemotherapy for advanced disease was allowed. Pts remained on therapy for a median of 4 cycles (range 1-14). DLTs shown in the Table; OTR not yet determined. Most frequent toxicities were Gr 3-4 uncomplicated neutropenia (15%), Gr ...
Despite major progress in the understanding of biological mechanisms underlying metastatic prosta... more Despite major progress in the understanding of biological mechanisms underlying metastatic prostate cancer, the treatment of men with advanced prostate cancer remains challenging. Several randomized controlled trials with promising or positive results are underway or just released. Here we discuss new treatments which might be used in clinic in the near future: hormonal treatments (Abiraterone and MDV3100), a new chemotherapy (Cabazitaxel), a cellular vaccine (Sipuleucel-T), anti-angiogenic drugs (Bevacizumab, Aflibercept), a new radioactive treatment (Alpharadin) and a new bone-protective agent (Deno-sumab).
Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors,... more Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.
Advances in cancer biology have led to the development of screening tests that allow an early dia... more Advances in cancer biology have led to the development of screening tests that allow an early diagnosis. Cancer screening is not just the matter of a single individual patient, it is a matter of public health. Screening is commonly viewed as of no harm, when in fact harms are associated with the majority of cancer screening tests. A test should only be used when the potential of benefit clearly outweighs the risks for harm. The data in the literature are not always clear cut and in a lot of cases guidelines are somewhat controversial. What is known and what is unknown about screening tests is quite different from what is believed by the public. The aim of this work is to summarize the different methods and guidelines in cancer screening to help choosing the right test at the right time for the right person.
Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) c... more Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) complex developed in an attempt to circumvent tumour resistance and which can be administered by the oral route. The fate of platinum delivered by this oral formulation administered at various doses under the 5 or 14 days schedule, has been studied to a limited extent. Total (Ptot) and ultrafilterable (PtUF) platinum were determined in 19 patients enrolled in phase I (PI) and II (PII) studies (PI, n = 14, advanced cancer; PII, n = 5, untreated small cell lung carcinoma). JM216 doses were 10 to 50 mg m-2 day-1 x 14 d (days) (dose escalation in PI) and 120 mg m-2 day-1 x 5d (fixed dose in PII), administered to fasted patients in a standardized way. Ptot and PtUF levels were determined by atomic absorption spectrometry on d1 and d14, followed over 28 days in PI; and on d1, followed over 5 days in PII. Pharmacokinetic parameters were derived by a noncompartmental approach. JM216 is rapidly ab...
To make a diagnostic of cancer in a young adult (15-30 years of age) has important physical, psyc... more To make a diagnostic of cancer in a young adult (15-30 years of age) has important physical, psychological and social implications. The most frequent cancers seen at this age are cancer of the thyroid, testicular germ cell tumours, 'melanoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, leukaemia, cerebral tumours and sarcomas. Even if the prognostic of most of these cancers is excellent, treatments are difficult and often associated with long-term side effects. A multidisciplinary approach of these patients is essential. A long-term follow-up by a general practicioner or an oncologist is indispensable.
24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or part... more 24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or partial response to the induction of intravenous chemotherapy, underwent implantation of a subcutaneous semipermanent port-and-catheter system (Port-A-Cath) for intraperitoneal chemotherapy, which consisted of carboplatin 300 mg/m2 every 4 weeks. The median survival was 27.4 months for minimal residual disease versus 8 months for bulky disease (p = 0.0054). The median progression-free interval was 15.7 months for minimal residual disease versus 1.8 months for bulky disease (p = 0.008). There were 3 complications (12.5%) related to the catheter: 1 perforation of the large bowel and 2 catheter inflow obstructions. Myelosuppression, especially a grade 3 leucopenia in 5 patients (25%) and a grade 4 thrombopenia in 3 patients (15%), was the dose-limiting toxicity. Even with maximum cytoreductive surgery and second-line intraperitoneal carboplatin-based chemotherapy, the 5-year progression-free survival (4.1%) remains very small.
Purpose To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) i... more Purpose To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. Patients and Methods Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. Results The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose o...
9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor s... more 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.
Due to the nature of the disease, patients often have a privileged and close relationship with th... more Due to the nature of the disease, patients often have a privileged and close relationship with their oncologist, and the oncologist also with their patients. This may in turn be detrimental to the relation between the general practitioner and the patient. Patients will not return to their general practitioner until end of life care or a consultation at the patient's home if necessary. In order to maintain a balance between the caretakers and assure appropriate involvement of the family physician, continuous communication and exchange of information are essential. This review identifies some of the problems and potential conflicts, which may arise, and discusses how the interaction could be improved.
PURPOSE Ocular melanoma is characterized by a high rate of liver metastases and is associated wit... more PURPOSE Ocular melanoma is characterized by a high rate of liver metastases and is associated with a median survival time less than 5 months. There is no standard treatment available. Treatment strategies have, without success, relied on the experience with metastatic cutaneous melanoma. The only effective treatment is chemoembolization using cisplatin and polyvinyl sponge, which has never become accepted on a large scale. The objective of the study was to establish prospectively the efficacy and toxicity of hepatic intraarterial fotemustine, a third-generation nitrosourea, in patients with liver metastases from ocular melanoma. PATIENTS AND METHODS Thirty-one patients were subjected to laparotomy to place a totally implantable catheter into the hepatic artery and received fotemustine 100 mg/m2 as a 4-hour infusion, first once a week for four times and then, after a 5-week rest period, every 3 weeks until progression or toxicity. Cox regression models were used to assess the prognos...
3047 Background: P is an oral angiogenesis inhibitor targeting VEGFR-1, -2, -3, PDGFR-α, -β, and ... more 3047 Background: P is an oral angiogenesis inhibitor targeting VEGFR-1, -2, -3, PDGFR-α, -β, and c- Kit. The optimal modality of administration in combination with chemotherapy is not yet clear. Methods: Ptsenrolled in 3 parallel arms to receive escalating doses of P with EPI. EPI administered on Day 3 (Arms A and B) or Day 1 (Arm C) q3w. P given once daily throughout the dosing cycle (Arm A), D1-8 (Arm B) or D14-21 (Arm C). Treatment was planned until progression or unacceptable toxicity to determine the optimum tolerated regimen (OTR) on the bases of dose-limiting toxicity (DLT) rate. Blood samples are drawn for PK and detection of circulating bone-marrow derived angiogenic cells. Results: 53 pts have been treated: median age=59 (range 54-64). A maximum of two prior lines of chemotherapy for advanced disease was allowed. Pts remained on therapy for a median of 4 cycles (range 1-14). DLTs shown in the Table; OTR not yet determined. Most frequent toxicities were Gr 3-4 uncomplicated neutropenia (15%), Gr ...
Despite major progress in the understanding of biological mechanisms underlying metastatic prosta... more Despite major progress in the understanding of biological mechanisms underlying metastatic prostate cancer, the treatment of men with advanced prostate cancer remains challenging. Several randomized controlled trials with promising or positive results are underway or just released. Here we discuss new treatments which might be used in clinic in the near future: hormonal treatments (Abiraterone and MDV3100), a new chemotherapy (Cabazitaxel), a cellular vaccine (Sipuleucel-T), anti-angiogenic drugs (Bevacizumab, Aflibercept), a new radioactive treatment (Alpharadin) and a new bone-protective agent (Deno-sumab).
Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors,... more Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.
Advances in cancer biology have led to the development of screening tests that allow an early dia... more Advances in cancer biology have led to the development of screening tests that allow an early diagnosis. Cancer screening is not just the matter of a single individual patient, it is a matter of public health. Screening is commonly viewed as of no harm, when in fact harms are associated with the majority of cancer screening tests. A test should only be used when the potential of benefit clearly outweighs the risks for harm. The data in the literature are not always clear cut and in a lot of cases guidelines are somewhat controversial. What is known and what is unknown about screening tests is quite different from what is believed by the public. The aim of this work is to summarize the different methods and guidelines in cancer screening to help choosing the right test at the right time for the right person.
Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) c... more Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) complex developed in an attempt to circumvent tumour resistance and which can be administered by the oral route. The fate of platinum delivered by this oral formulation administered at various doses under the 5 or 14 days schedule, has been studied to a limited extent. Total (Ptot) and ultrafilterable (PtUF) platinum were determined in 19 patients enrolled in phase I (PI) and II (PII) studies (PI, n = 14, advanced cancer; PII, n = 5, untreated small cell lung carcinoma). JM216 doses were 10 to 50 mg m-2 day-1 x 14 d (days) (dose escalation in PI) and 120 mg m-2 day-1 x 5d (fixed dose in PII), administered to fasted patients in a standardized way. Ptot and PtUF levels were determined by atomic absorption spectrometry on d1 and d14, followed over 28 days in PI; and on d1, followed over 5 days in PII. Pharmacokinetic parameters were derived by a noncompartmental approach. JM216 is rapidly ab...
To make a diagnostic of cancer in a young adult (15-30 years of age) has important physical, psyc... more To make a diagnostic of cancer in a young adult (15-30 years of age) has important physical, psychological and social implications. The most frequent cancers seen at this age are cancer of the thyroid, testicular germ cell tumours, 'melanoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, leukaemia, cerebral tumours and sarcomas. Even if the prognostic of most of these cancers is excellent, treatments are difficult and often associated with long-term side effects. A multidisciplinary approach of these patients is essential. A long-term follow-up by a general practicioner or an oncologist is indispensable.
24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or part... more 24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or partial response to the induction of intravenous chemotherapy, underwent implantation of a subcutaneous semipermanent port-and-catheter system (Port-A-Cath) for intraperitoneal chemotherapy, which consisted of carboplatin 300 mg/m2 every 4 weeks. The median survival was 27.4 months for minimal residual disease versus 8 months for bulky disease (p = 0.0054). The median progression-free interval was 15.7 months for minimal residual disease versus 1.8 months for bulky disease (p = 0.008). There were 3 complications (12.5%) related to the catheter: 1 perforation of the large bowel and 2 catheter inflow obstructions. Myelosuppression, especially a grade 3 leucopenia in 5 patients (25%) and a grade 4 thrombopenia in 3 patients (15%), was the dose-limiting toxicity. Even with maximum cytoreductive surgery and second-line intraperitoneal carboplatin-based chemotherapy, the 5-year progression-free survival (4.1%) remains very small.
Purpose To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) i... more Purpose To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. Patients and Methods Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. Results The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose o...
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