The Journal of Community and Supportive Oncology

Cabozantinib in metastatic prostate cancer^1,2

Researchers tested cabozantinib, a tyrosine-kinase inhibitor (TKI) against MET and vascular endothelial growth factor receptor 2 (VEGF), in a large phase 2 randomized discontinuation trial in 9 tumor types. A subset of 171 patients with castrateresistant prostate cancer (CRPC) was reported in this study. Patients were treated on open label for 12 weeks, and then if stable, were randomized to receive the active drug or placebo. The trial was suspended early by the study oversight committee because: a) Cabozantinib was too toxic for the study to continue. b) The prostate-specific antigen (PSA) level fell in most of the treated patients. c) In the initial 121 patients, there was an unexpected improvement in bone scans and decrease in pain in the lead-in stage of the study. d) Unexpected rapid soft tissue progression. Bone scans improved in 78% of patients, and in 12% there was complete remission. After further analysis, the following were true except for: a) Cabozantinib interfered with technetium-99, and thus, the responses were not real, but rather an artifact. b) The PSA did not correlate with improvement in bone pain. c) Markers of bone formation and resorption showed improvement, and there was no correlation with prior bisphosphonate therapy. d) Bone scan improvement correlated with improvement in soft tissue disease. 

Key points

The results in patients with prostate cancer were so striking – 72% of patients had regression in soft tissue lesions, and 68% of evaluable patients had improvement on bone scan, including complete resolution in 12% – that the subset analysis was published as a rapid communication.1,2 Because of very high response rates (5% at 12 weeks) and symptomatic improvement in the initial 122 patients who were enrolled, random assignment was discontinued. Bone markers improved in concert with the radiologic and clinical improvement. Answers c, a

Cabozantinib in metastatic prostate cancer^1,2

Researchers tested cabozantinib, a tyrosine-kinase inhibitor (TKI) against MET and vascular endothelial growth factor receptor 2 (VEGF), in a large phase 2 randomized discontinuation trial in 9 tumor types. A subset of 171 patients with castrateresistant prostate cancer (CRPC) was reported in this study. Patients were treated on open label for 12 weeks, and then if stable, were randomized to receive the active drug or placebo. The trial was suspended early by the study oversight committee because: a) Cabozantinib was too toxic for the study to continue. b) The prostate-specific antigen (PSA) level fell in most of the treated patients. c) In the initial 121 patients, there was an unexpected improvement in bone scans and decrease in pain in the lead-in stage of the study. d) Unexpected rapid soft tissue progression. Bone scans improved in 78% of patients, and in 12% there was complete remission. After further analysis, the following were true except for: a) Cabozantinib interfered with technetium-99, and thus, the responses were not real, but rather an artifact. b) The PSA did not correlate with improvement in bone pain. c) Markers of bone formation and resorption showed improvement, and there was no correlation with prior bisphosphonate therapy. d) Bone scan improvement correlated with improvement in soft tissue disease. 

Key points

The results in patients with prostate cancer were so striking – 72% of patients had regression in soft tissue lesions, and 68% of evaluable patients had improvement on bone scan, including complete resolution in 12% – that the subset analysis was published as a rapid communication.1,2 Because of very high response rates (5% at 12 weeks) and symptomatic improvement in the initial 122 patients who were enrolled, random assignment was discontinued. Bone markers improved in concert with the radiologic and clinical improvement. Answers c, a

Cabozantinib in metastatic prostate cancer^1,2

Researchers tested cabozantinib, a tyrosine-kinase inhibitor (TKI) against MET and vascular endothelial growth factor receptor 2 (VEGF), in a large phase 2 randomized discontinuation trial in 9 tumor types. A subset of 171 patients with castrateresistant prostate cancer (CRPC) was reported in this study. Patients were treated on open label for 12 weeks, and then if stable, were randomized to receive the active drug or placebo. The trial was suspended early by the study oversight committee because: a) Cabozantinib was too toxic for the study to continue. b) The prostate-specific antigen (PSA) level fell in most of the treated patients. c) In the initial 121 patients, there was an unexpected improvement in bone scans and decrease in pain in the lead-in stage of the study. d) Unexpected rapid soft tissue progression. Bone scans improved in 78% of patients, and in 12% there was complete remission. After further analysis, the following were true except for: a) Cabozantinib interfered with technetium-99, and thus, the responses were not real, but rather an artifact. b) The PSA did not correlate with improvement in bone pain. c) Markers of bone formation and resorption showed improvement, and there was no correlation with prior bisphosphonate therapy. d) Bone scan improvement correlated with improvement in soft tissue disease. 

Key points

The results in patients with prostate cancer were so striking – 72% of patients had regression in soft tissue lesions, and 68% of evaluable patients had improvement on bone scan, including complete resolution in 12% – that the subset analysis was published as a rapid communication.1,2 Because of very high response rates (5% at 12 weeks) and symptomatic improvement in the initial 122 patients who were enrolled, random assignment was discontinued. Bone markers improved in concert with the radiologic and clinical improvement. Answers c, a

Background

Levamisole is a pharmaceutical with anthelminthic and immunomodulatory properties that received approval from the Food and Drug Administration in 1991 as part of adjuvant chemotherapy regimens for colorectal cancer. The addition of levamisole to 5-flouroruacil (5-FU) was first evaluated by the North Central Cancer Treatment Group in a 3-arm clinical trial that found that 5-FUlevamisole for 12 months was superior to either surgery alone or surgery followed by levamisole alone (recurrence rate was reduced by 40% and the death rate by 33% in Dukes’ C colon cancer).1 A subsequent trial intergroup trial randomized patients with Dukes’ B2 and C colon cancer to surgery alone or 1 year of adjuvant levamisole or 5FUlevamisole and confirmed the efficacy of 5FUlevamisole with respect to disease free survival and overall survival.2 As a result, adjuvant chemotherapy became the standard for stage III colon cancer as reported by an National Cancer Institute consensus development panel.3 Subsequently, primarily because of toxicity reasons, leucovorin replaced levamisole in most adjuvant chemotheraoy regimens for stage III colorectal cancer. Clinical toxicity of levamisole was noted as early as 1976 when several cases of leukopenia and agranulocytosis were reported. Recurrence with re-exposure was well described and agranulocytosis spontaneously reversed upon discontinuation of therapy. Vasculitis secondary to levamisole treatment was first reported in 1978, presenting primarily as leukocytoclastic vasculitis, cutaneous necrotising vasculitis and thrombotic vasculopathy without vasculitis. These findings typically, but not invariably, involve the ear lobes. In the early 1990s, levamisole became unavailable for human use in the United States due to toxicity concerns. Various neurological side effects were described with levamisole therapy, the most concerning complication being multifocal inflammatory leukoencephalopathy. Recently, several persons have developed a novel syndrome characterized by necrotic noses and ears, leg ulcers, agranulocytosis, thrombovasculopathy, and positive antineutrophil cytoplasmic antibodies (ANCAs) as a result of the drug cocaine being adulterated with levamisole. We describe the drug below.

Background

Levamisole is a pharmaceutical with anthelminthic and immunomodulatory properties that received approval from the Food and Drug Administration in 1991 as part of adjuvant chemotherapy regimens for colorectal cancer. The addition of levamisole to 5-flouroruacil (5-FU) was first evaluated by the North Central Cancer Treatment Group in a 3-arm clinical trial that found that 5-FUlevamisole for 12 months was superior to either surgery alone or surgery followed by levamisole alone (recurrence rate was reduced by 40% and the death rate by 33% in Dukes’ C colon cancer).1 A subsequent trial intergroup trial randomized patients with Dukes’ B2 and C colon cancer to surgery alone or 1 year of adjuvant levamisole or 5FUlevamisole and confirmed the efficacy of 5FUlevamisole with respect to disease free survival and overall survival.2 As a result, adjuvant chemotherapy became the standard for stage III colon cancer as reported by an National Cancer Institute consensus development panel.3 Subsequently, primarily because of toxicity reasons, leucovorin replaced levamisole in most adjuvant chemotheraoy regimens for stage III colorectal cancer. Clinical toxicity of levamisole was noted as early as 1976 when several cases of leukopenia and agranulocytosis were reported. Recurrence with re-exposure was well described and agranulocytosis spontaneously reversed upon discontinuation of therapy. Vasculitis secondary to levamisole treatment was first reported in 1978, presenting primarily as leukocytoclastic vasculitis, cutaneous necrotising vasculitis and thrombotic vasculopathy without vasculitis. These findings typically, but not invariably, involve the ear lobes. In the early 1990s, levamisole became unavailable for human use in the United States due to toxicity concerns. Various neurological side effects were described with levamisole therapy, the most concerning complication being multifocal inflammatory leukoencephalopathy. Recently, several persons have developed a novel syndrome characterized by necrotic noses and ears, leg ulcers, agranulocytosis, thrombovasculopathy, and positive antineutrophil cytoplasmic antibodies (ANCAs) as a result of the drug cocaine being adulterated with levamisole. We describe the drug below.

Background

Levamisole is a pharmaceutical with anthelminthic and immunomodulatory properties that received approval from the Food and Drug Administration in 1991 as part of adjuvant chemotherapy regimens for colorectal cancer. The addition of levamisole to 5-flouroruacil (5-FU) was first evaluated by the North Central Cancer Treatment Group in a 3-arm clinical trial that found that 5-FUlevamisole for 12 months was superior to either surgery alone or surgery followed by levamisole alone (recurrence rate was reduced by 40% and the death rate by 33% in Dukes’ C colon cancer).1 A subsequent trial intergroup trial randomized patients with Dukes’ B2 and C colon cancer to surgery alone or 1 year of adjuvant levamisole or 5FUlevamisole and confirmed the efficacy of 5FUlevamisole with respect to disease free survival and overall survival.2 As a result, adjuvant chemotherapy became the standard for stage III colon cancer as reported by an National Cancer Institute consensus development panel.3 Subsequently, primarily because of toxicity reasons, leucovorin replaced levamisole in most adjuvant chemotheraoy regimens for stage III colorectal cancer. Clinical toxicity of levamisole was noted as early as 1976 when several cases of leukopenia and agranulocytosis were reported. Recurrence with re-exposure was well described and agranulocytosis spontaneously reversed upon discontinuation of therapy. Vasculitis secondary to levamisole treatment was first reported in 1978, presenting primarily as leukocytoclastic vasculitis, cutaneous necrotising vasculitis and thrombotic vasculopathy without vasculitis. These findings typically, but not invariably, involve the ear lobes. In the early 1990s, levamisole became unavailable for human use in the United States due to toxicity concerns. Various neurological side effects were described with levamisole therapy, the most concerning complication being multifocal inflammatory leukoencephalopathy. Recently, several persons have developed a novel syndrome characterized by necrotic noses and ears, leg ulcers, agranulocytosis, thrombovasculopathy, and positive antineutrophil cytoplasmic antibodies (ANCAs) as a result of the drug cocaine being adulterated with levamisole. We describe the drug below.

Metastatic melanoma is a highly challenging cancer to treat. Like other solid tumors, it is a very heterogeneous disease both clinically and biologically. Consequently, the first decision point in its management is to assess the severity of an individual patient’s disease. This can be done based on the patient’s symptoms and how they have evolved over the preceding 1-2 months, performance status, the extent of disease as determined by physical examination, and staging workup, which should include either computed tomography scans of the body or a positron emission tomography/CT study as well as a brain magnetic resonance imaging scan. Patients with brain metastases as a subset (which is sizable – 20%-25% have brain metastases) require special attention because they may not respond to systemic therapies and will thus have to be managed with brain-targeted treatment options. Tumor testing for BRAF mutations is necessary in all patients with metastatic melanoma because the BRAF inhibitors (vemurafenib or dabrafenib) are a preferred choice of targeted therapy for this subset of patients, which constitutes about 50% of all melanoma patients. Immunotherapy plays an important role in nearly all patients with metastatic melanoma including those who have progressed after anti-BRAF therapy. Chemotherapy still has a significant (yet diminishing) role for patients who are no longer suitable for immunotherapy.

Metastatic melanoma is a highly challenging cancer to treat. Like other solid tumors, it is a very heterogeneous disease both clinically and biologically. Consequently, the first decision point in its management is to assess the severity of an individual patient’s disease. This can be done based on the patient’s symptoms and how they have evolved over the preceding 1-2 months, performance status, the extent of disease as determined by physical examination, and staging workup, which should include either computed tomography scans of the body or a positron emission tomography/CT study as well as a brain magnetic resonance imaging scan. Patients with brain metastases as a subset (which is sizable – 20%-25% have brain metastases) require special attention because they may not respond to systemic therapies and will thus have to be managed with brain-targeted treatment options. Tumor testing for BRAF mutations is necessary in all patients with metastatic melanoma because the BRAF inhibitors (vemurafenib or dabrafenib) are a preferred choice of targeted therapy for this subset of patients, which constitutes about 50% of all melanoma patients. Immunotherapy plays an important role in nearly all patients with metastatic melanoma including those who have progressed after anti-BRAF therapy. Chemotherapy still has a significant (yet diminishing) role for patients who are no longer suitable for immunotherapy.

Metastatic melanoma is a highly challenging cancer to treat. Like other solid tumors, it is a very heterogeneous disease both clinically and biologically. Consequently, the first decision point in its management is to assess the severity of an individual patient’s disease. This can be done based on the patient’s symptoms and how they have evolved over the preceding 1-2 months, performance status, the extent of disease as determined by physical examination, and staging workup, which should include either computed tomography scans of the body or a positron emission tomography/CT study as well as a brain magnetic resonance imaging scan. Patients with brain metastases as a subset (which is sizable – 20%-25% have brain metastases) require special attention because they may not respond to systemic therapies and will thus have to be managed with brain-targeted treatment options. Tumor testing for BRAF mutations is necessary in all patients with metastatic melanoma because the BRAF inhibitors (vemurafenib or dabrafenib) are a preferred choice of targeted therapy for this subset of patients, which constitutes about 50% of all melanoma patients. Immunotherapy plays an important role in nearly all patients with metastatic melanoma including those who have progressed after anti-BRAF therapy. Chemotherapy still has a significant (yet diminishing) role for patients who are no longer suitable for immunotherapy.

Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now  beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.

*Click on the link to the left for a PDF of the full article.

Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now  beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.

*Click on the link to the left for a PDF of the full article.

Although the concept of using immunotherapy to target an immune response against tumors is not new, this treatment modality is only now  beginning to realize its full potential. Here, we take a look at the role of immunotherapy in cancer and some of the most exciting areas of clinical development.

*Click on the link to the left for a PDF of the full article.

Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.

*Click on the link to the left for a PDF of the full article.

Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.

*Click on the link to the left for a PDF of the full article.

Ipilimumab is an anticytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody that attenuates negative signaling from CTLA-4 and potentiates T-cell activation and proliferation. Two phase 3 randomized trials in advanced melanoma demonstrated a significant improvement in overall survival, the first of which led to regulatory approval in the United States and Europe for treatment of unresectable or metastatic melanoma. Ipilimumab administration is associated with immune-related adverse events (irAEs). Gastrointestinal (GI) irAEs are among the most common and although they are typically mild to moderate in severity, if they are left unrecognized or untreated, they can become life-threatening. These toxicities can be managed effectively in almost all patients by using established guidelines that stress vigilance and the use of corticosteroids and other immunosuppressive agents when necessary. The goal of this review is to educate physicians on the recognition and challenges associated with management of GI irAEs.

*Click on the link to the left for a PDF of the full article.

Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.

Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.

Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.

Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.


*To read the full article, click on the PDF icon at the top of this introduction.

Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.

Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.

Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.

Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.


*To read the full article, click on the PDF icon at the top of this introduction.

Objective To identify prognostic factors for overall survival (OS) and relapse-free survival (RFS) for patients with uterine serous carcinoma.

Methods From January 1, 2000 to January 1, 2010, 44 patients with uterine serous carcinoma were analyzed to determine prognostic and predictive factors for OS and RFS using the Kaplan-Meier product-limit method and log-rank tests.

Results Median follow-up was 4.1 years, median OS was 4.2 years, 2-year OS was 83% and decreased to 48% at 5 years. Two-year RFS was 82% and decreased to 75% at 5 years. Age, stage, tumor size, tumor not arising from a polyp, parametrial involvement, lymphovascular invasion, and no adjuvant treatment were prognostic factors associated with shorter OS. Higher stage and parametrial involvement were prognostic factors associated with shorter RFS. Combined adjuvant chemotherapy and radiation therapy was significantly associated with longer OS rates.

Conclusions Adjuvant chemotherapy and radiation therapy as well as tumors arising from a polyp are associated with increased overall survival in patients with uterine serous carcinoma. Early-stage disease is associated with increased relapse-free and overall survival. Adjuvant chemotherapy with a platinum and paclitaxol-based regimen and radiation therapy should be attempted in patients with uterine serous carcinoma.


*To read the full article, click on the PDF icon at the top of this introduction.