Hematologic Malignancies

Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.¹ Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.²

The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).³

Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.

Unicentric Castleman Disease

Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.

Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.^4,5 No association with HIV or HHV-8 has been seen.

Unicentric CD is often amenable to resection, and a complete cure can be achieved.⁶ Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.⁷ In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.

Multicentric Castleman Disease

The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).⁸

It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma⁹; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture¹⁰; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.

Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.¹¹ The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.¹² To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.¹³ The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.¹⁴

Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.¹⁵

Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.^16-20

The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.³ Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.

Pathophysiology

Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.^15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. ^23,24

In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.^25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.²⁷

Staging

The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.

Treatment

Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).

For UCD, surgery is the mainstay of treatment.^4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.

For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.³⁰ In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.^31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.^34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.³⁶ In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.³⁷

The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.²² The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.^38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.⁴⁰

Immunomodulators & Targeted Therapies

For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.⁴¹ In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.

Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.⁴² In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.⁴³

Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.^44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.^47,48

Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.^49,50

Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.⁵¹

Conculsion

There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to
patients.

Click here to read the digital edition.

Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.¹ Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.²

The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).³

Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.

Unicentric Castleman Disease

Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.

Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.^4,5 No association with HIV or HHV-8 has been seen.

Unicentric CD is often amenable to resection, and a complete cure can be achieved.⁶ Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.⁷ In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.

Multicentric Castleman Disease

The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).⁸

It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma⁹; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture¹⁰; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.

Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.¹¹ The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.¹² To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.¹³ The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.¹⁴

Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.¹⁵

Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.^16-20

The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.³ Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.

Pathophysiology

Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.^15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. ^23,24

In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.^25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.²⁷

Staging

The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.

Treatment

Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).

For UCD, surgery is the mainstay of treatment.^4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.

For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.³⁰ In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.^31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.^34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.³⁶ In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.³⁷

The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.²² The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.^38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.⁴⁰

Immunomodulators & Targeted Therapies

For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.⁴¹ In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.

Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.⁴² In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.⁴³

Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.^44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.^47,48

Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.^49,50

Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.⁵¹

Conculsion

There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to
patients.

Click here to read the digital edition.

Castleman disease (CD) is a rare nonclonal lymphoproliferative disorder, also known as angiofollicular lymph-node hyperplasia or giant node hyperplasia. It was first reported in 1954 and in 1956 described by Benjamin Castleman, MD, in a case series of localized mediastinal lymph-node hyperplasia.¹ Unicentric Castleman (UCD) disease presents as a localized disease affecting a single lymph node/lymph node chain. Multicentric Castleman disease (MCD) is a more widespread or generalized disease (Table 1). About 4,000 to 6,000 new cases of CD are diagnosed per year of which about 20% to 25% cases are MCD. The estimated incidence rate for CD has recently been calculated as 21 to 25 per million person-years, or about 6,000 new cases annually.²

The clinical presentation of CD often overlaps with autoimmune, infectious, or other malignant diseases. The diagnosis is confirmed by a biopsy of the affected lymph-node tissue. Interleukin-6 (IL-6) and a viral analog of IL-6 play major role in the pathogenesis by stimulating a widespread inflammatory response that results in systemic manifestations. It is often associated with HIV and human herpesvirus-8 (HHV-8) infections. Castleman disease is histologically characterized into the hyaline vascular variant, the plasma-cell variant, and the mixed form. The plasmablastic variety is associated with HIV and HHV-8 infections. The prognosis ranges from good in UCD (91% overall survival [OS] at 5 y) to poor in MCD (65% OS at 5 y).³

Treatment options range from local surgical excision to systemic treatments. Newer therapies include monoclonal antibodies against both IL-6 and CD20 and a few other targets in the inflammatory cascade. This article discusses the updated approach to diagnosis and management of CD.

Unicentric Castleman Disease

Unicentric CD is more common than MCD, presents as a localized lymph node or chain involvement, and is generally diagnosed in the third or fourth decade of life but has been reported in children. The presenting symptoms of UCD vary by site. It presents as nontender lymphadenopathy when confined to peripheral lymph nodes, whereas respiratory symptoms or bowel obstruction may be seen with lymphadenopathy in the chest/mediastinum, neck, or abdomen. The systemic
symptoms, such as fever, night sweats, and weight loss, are uncommon.

Dysplastic follicular dendritic cells characterize UCD. Histologically, it is usually classified as hyaline vascular disease with the follicles comprising small lymphocytes
and dendritic cells forming concentric rings with prominent vascularity.^4,5 No association with HIV or HHV-8 has been seen.

Unicentric CD is often amenable to resection, and a complete cure can be achieved.⁶ Partial resection may be attempted when complete resection is not possible. Radiation therapy is offered for unresectable disease.⁷ In patients who are not candidates for any intervention, close long-term follow-up is recommended unless patients are symptomatic, in which case systemic treatment should be considered.

Multicentric Castleman Disease

The more widespread MCD is generally diagnosed in the fifth or sixth decade of life. It is more aggressive than UCD and presents a wide spectrum of symptoms and abnormal laboratory findings (Table 2).⁸

It is histologically classified into (a) plasmablastic or HHV-8 associated: It is often seen in patients with MCD infected with HIV, which can give rise to large B-cell lymphoma, known as HHV-8 plasmablastic lymphoma⁹; (b) plasmacytic variant has marked paracortical plasmacytosis with retained nodal architecture¹⁰; and (c) mixed MCD has abundant plasma cells with features similar to those of the hyaline-vascular variant.

Most patients with HIV-associated MCD are co-infected with HHV-8. The HHV-8 infection is also present in about 50% of HIV-negative cases.¹¹ The incidence of HIVassociated MCD is increasing in the highly active antiretroviral therapy (HAART) era secondary to improved survival of patients infected with HIV.¹² To diagnose active HIV MCD, the French Agence Nationale de Recherche sur le SIDA 117 CastlemaB trial group has described criteria based on the clinical symptoms, including fever, a raised serum C-reactive protein > 20 mg/L without any other cause, and 3 of 12 additional clinical findings described as peripheral lymphadenopathy, splenomegaly, ascites, edema, pleural effusion, cough, nasal obstruction, xerostomia, rash, central neurologic symptoms, jaundice, and autoimmune hemolytic anemia.¹³ The reported 2-year survival of patients who are HIV-negative is 97% compared with HIV-positive cases at 67%.¹⁴

Idiopathic MCD is diagnosed when there is no evidence of any underlying infectious, autoimmune, and neoplastic process.¹⁵

Patients with MCD are at an increased risk of developing non-Hodgkin and Hodgkin lymphoma, Kaposi sarcoma, primary effusion lymphoma, and follicular dendritic
cell sarcoma. POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome and paraneoplastic disease, such as paraneoplastic pemphigus myasthenia gravis, may be commonly diagnosed concurrently or sequentially with MCD.^16-20

The disease course of MCD ranges from indolent to rapidly progressive, and its 5-year OS is about 65%. When associated with POEMS syndrome, the 5-year survival was estimated to be 90% with the osteosclerotic variant and 27% without osteosclerotic lesions.³ Treatment options for MCD include systemic chemotherapy, including antiviral therapy for HHV-8 positive and HAART for HIV positive and newer monoclonal antibody therapies targeting CD20 or IL-6.

Pathophysiology

Interleukin-6 plays an important role for inflammation in both UCD and MCD (Figure 1). There is dysregulation and overproduction of IL-6, which further stimulates the production of acute-phase reactants, resulting in various systemic manifestations.^15,21,22 There is increased expression of IL-1 and IL-6, upregulation of IL-6 secondary to interaction of IL-1 with nuclear factor-kappa B (NF-kappa B), thus stimulating B-cell proliferation. IL-6 binding to IL-6 receptor (IL6-R) results in downstream activation of transcription Janus kinases/signal transducers and activators of the transcription pathway. This promotes the transcription of genes encoding the acute-phase reactant proteins. Hence, interfering with IL-6 transduction by blocking downstream signals are potential therapeutic targets. The mitogen-activated protein kinase cascade, the rapidly accelerated fibrosarcoma kinases, and the overexpression of the endothelial growth factor receptor (EGFR), all contribute to disease pathogenesis by promoting increased B-cell proliferation and vascular EGFR mediated angiogenesis. ^23,24

In HHV-8–associated MCD, the virus replicates within lymph node plasmablasts, causing increased production of viral IL-6 analog, human IL-6, and other proinflammatory proteins resulting in B-cell and plasma-cell proliferation, increased vascular endothelial growth factor secretion and angiogenesis.^25,26 The HHV-8–infected plasmablasts are marked by variable expression of CD20, and therefore, anti-CD20 is also shown to be an effective treatment. The calmodulin/calcineurin nuclear factor assists in the proliferation of HHV-8, thereby making calcineurin another potential target for the antiviral proliferation.²⁷

Staging

The treatment decisions and prognosis for patients with CD is based on the clinical and histologic staging. The initial workup includes but is not limited to routine laboratory evaluation, imaging, and HIV and HHV-8 testing (Table 3). Routine tests of the levels of cytokines are not recommended. Other relevant tests for known disease associations should be obtained when relevant.

Treatment

Better understanding of the disease process in CD has helped to identify potential therapeutic targets (Figures 2 and 3).

For UCD, surgery is the mainstay of treatment.^4,28,29 In surgically unresectable cases, radiation therapy is helpful for local disease control. Alternatively, neoadjuvant
chemotherapy and rituximab are used. Corticosteroids are generally used to treat acute exacerbations and as adjuncts to chemotherapy.

For MCD, the treatment approach depends on the HIV and HHV-8 status of the patient. For patients with HHV-8 infection, both with and without HIV co-infection, antiviral agents, such as ganciclovir, foscarnet, or cidofovir, have shown in vitro activity against HHV-8 but with limited clinical success.³⁰ In patients infected with HIV, the aim of treating with HAART is to control the disease, prevent opportunistic infections, and improve tolerance to chemotherapy.^31-33 Rituximab with or without chemotherapy is the standard treatment approach. The additional chemotherapeutic agents are used depending on the presence or absence of organ failure. This approach has improved the OS in HIV-associated MCD.^34,35 Treatment with HAART does not decrease the risk of relapse in HIV MCD; therefore, the role of rituximab and antiherpesvirus agents as maintenance therapy has been explored.³⁶ In patients who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.³⁷

The cytotoxic chemotherapy with single agents, such as etoposide, vinblastine, cyclophosphamide, cladribine, chlorambucil, and liposomal doxorubicin, has been used with limited success.²² The combination chemotherapy with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or cyclophosphamide/vincristine/
prednisone (CVP) without rituximab has been shown to achieve durable remissions. Corticosteroids are usually administered as an initial adjunct to chemotherapy or for acute exacerbations. In patients with MCD, regardless of HIV status, the interferon therapy was found to achieve long-term remission.^38,39 The interferon therapy
exerts antiviral effects via downregulation of the IL-6R and inhibition of HHV-8 replication. For patients in remission, maintenance therapy with oral valganciclovir is promising.⁴⁰

Immunomodulators & Targeted Therapies

For unresectable UCD or MCD with organ failure or relapse, the use of alternativesingle-agent or combination chemotherapies with or without rituximab is recommended. Thalidomide has shown some success, probably secondary to disruption of IL-6 production.⁴¹ In cases of progression following second-line therapy, bortezomib, antiherpesvirus therapies, or IL-6–directed therapy with siltuximab or tocilizumab should be considered.

Rituximab is a monoclonal chimeric antibody that targets CD20 on B cells, thus leading to B-cell lymphodepletion via activating complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As monotherapy, it has been shown to achieve 2-year progression-free survival in 80% of patients.⁴² In patients with MCD who are HIV positive, rituximab with and without chemotherapy has shown improved overall and disease-free survival of 70% to 80% at 2 years.⁴³

Siltuximab is a chimeric human-mouse monoclonal antibody to IL-6 that has been approved for treatment of patients with MCD who are both HIV negative and HHV-8 negative.^44-46 Tocilizumab targets the IL-6R. The antibody has shown improvement in a study in HIVseronegative adults with MCD.^47,48

Bortezomib is a proteasome inhibitor that inhibits the NF-kappa B pathway, which induces the expression of numerous proinflammatory proteins, including IL-6. It is recommended for relapsed or refractory disease.^49,50

Anakinra is a recombinant IL-1R antagonist that blocks IL-1 effects and controls disease by decreasing IL-6 production.⁵¹

Conculsion

There has been significant progress in disease diagnosis and management as more information is available about the incidence, clinical presentation, and pathophysiology of CD. The understanding of the disease pathogenesis and biology has helped to discover multiple potential therapeutic targets. Successful treatment has been achieved through targeting HHV-8 replication, CD20, and IL-6 and anti– IL-6R antibodies. Although surgical resection continues to be the
standard of therapy for UCD, the management of MCD and relapsed or refractory disease continues to evolve. Exploration of various treatment strategies in different clinical presentations is warranted.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S.
Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information
for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to
patients.

Click here to read the digital edition.

Chronic lymphocytic leukemia (CLL) is a slow-growing malignancy of B lymphocytes (B cells) that tends to affect older people and men more than women. More than 17,000 new cases of CLL are reported every year. Patients with CLL do not need treatment with chemotherapy until they become symptomatic or display evidence of rapid progression of the disease. In multiple studies and a meta-analysis, early initiation of chemotherapy has failed to show benefit in managing CLL; indeed, it may increase mortality.^1,2

The combination chemotherapy fludarabine, cyclophosphamide, and rituximab (FCR) is often the initial choice for treatment. Other chemotherapy drugs used are chlorambucil, bendamustine, pentostatin or cladribine, rituximab, ofatumumab, and alemtuzumab. Although chlorambucil is a forgotten drug in the U.S., it is still used first line in elderly, fragile populations in Europe, which make up the bulk of true CLL cases.³

Various combination regimens used in CLL treatment have shown improved response rates in several randomized trials but have failed to show any survival advantage until recently. The treatment of patients with CLL has undergone a dramatic transformation and has changed the management paradigm since the FDA approved new, targeted agents. This article includes a brief discussion of these new agents and the pipeline for new agents.

Newly Approved Treatments

Obinutuzumab is a CD20-directed cytolytic antibody, which on binding to CD20, mediates B-cell lysis. Mediation may be (1) through engagement of immune effector cells; (2) by directly activating intracellular deathsignaling pathways; and/or (3) by activation of the complement. The FDA approved obinutuzumab in November 2013 for previously untreated CLL in combination with chlorambucil based on a pivotal phase 3 trial in 356 previously untreated patients with CLL (mean age, 73 years). Those who received obinutuzumab in combination with chlorambucil had significantly better median progression-free survival (PFS) than did those treated with chlorambucil alone (23 months vs 11.1 months; P < .0001). These results effectively end the use of chlorambucil as monotherapy.⁴

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Accelerated approval of ibrutinib was based on of a clinical study of participants with CLL who had received 4 previous therapies. At 26 months, estimated PFS was 75%, and the rate of overall survival (OS) was 83%.⁵ In January 2014, the RESONATE trial was stopped early because of a positive interim analysis showing statistically significant improvement in PFS as well as in OS with oral ibrutinib compared with IV ofatumumab. The RESONATE trial was a phase 3, multicenter study involving 391 patients with relapsed or refractory CLL who had received at least 1 previous therapy.⁶ At 6 months, 88% of patients treated with ibrutinib were progression free compared with 65% with ofatumumab. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% for patients in the ofatumumab group. By traditional response criteria, the overall response rate (ORR) with ibrutinib was 43% compared with 4% for ofatumumab. Ibrutinib is now approved for chemotherapy-naïve CLL patients with a 17p13.1 deletion, a genetic abnormality that generally portends a poor prognosis.

On July 23, 2014, the FDA approved an oral PI3-kinase delta (PI3K d) inhibitor called idelalisib in combination with rituximab used as a treatment for patients with high-risk CLL. In supporting data from a phase 3 study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% vs placebo and rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression free compared with 50% of patients treated with the placebo. Approval was based on a placebo-controlled study of 220 patients in which patients treated with idelalisib plus rituximab showed significantly longer PFS (10.7 months) than did those who received placebo plus rituximab (5.5 months).⁷

Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have used this medication in treatment of patients with relapsed and refractory CLL. Response rates of 47% to 38% with complete response rates of 9% and elimination of minimal residual disease (MRD) have also been reported.⁸

CLL Pipeline

Clinical trials continue to explore new agents, with the most promising being the PI3K δ and γ inhibitor duvelisib (IPI-145) and the BCL-2 inhibitor ABT-199. In
a phase 1 study exploring duvelisib in patients with relapsed or refractory CLL, the ORR was 47%.9 Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion or p53 mutation.

ABT-199 demonstrated efficacy in a phase 1b study when administered to patients with relapsed/refractory CLL in combination with rituximab.10 In 18 evaluable patients, 39% achieved complete remission (CR) or CR with incomplete blood count recovery and 39% achieved partial remissions (78% ORR). Altogether, 22% were deemed MRD-negative. In evaluable patients with 17p deletions, 81% achieved a response to ABT-199. In patients with fludarabine-refractory CLL, 78% achieved a response.

Although it is advantageous to have so many newer effective, targeted drugs for relapsed/refractory advanced CLL, in early-stage CLL when a watch and wait approach might be best, it may become a challenge for the patient as well as for the treating physician. All these drugs are expensive and carry risks. Although PFS is promising, physicians have to make a judgment call in balancing cost and toxicity.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Chronic lymphocytic leukemia (CLL) is a slow-growing malignancy of B lymphocytes (B cells) that tends to affect older people and men more than women. More than 17,000 new cases of CLL are reported every year. Patients with CLL do not need treatment with chemotherapy until they become symptomatic or display evidence of rapid progression of the disease. In multiple studies and a meta-analysis, early initiation of chemotherapy has failed to show benefit in managing CLL; indeed, it may increase mortality.^1,2

The combination chemotherapy fludarabine, cyclophosphamide, and rituximab (FCR) is often the initial choice for treatment. Other chemotherapy drugs used are chlorambucil, bendamustine, pentostatin or cladribine, rituximab, ofatumumab, and alemtuzumab. Although chlorambucil is a forgotten drug in the U.S., it is still used first line in elderly, fragile populations in Europe, which make up the bulk of true CLL cases.³

Various combination regimens used in CLL treatment have shown improved response rates in several randomized trials but have failed to show any survival advantage until recently. The treatment of patients with CLL has undergone a dramatic transformation and has changed the management paradigm since the FDA approved new, targeted agents. This article includes a brief discussion of these new agents and the pipeline for new agents.

Newly Approved Treatments

Obinutuzumab is a CD20-directed cytolytic antibody, which on binding to CD20, mediates B-cell lysis. Mediation may be (1) through engagement of immune effector cells; (2) by directly activating intracellular deathsignaling pathways; and/or (3) by activation of the complement. The FDA approved obinutuzumab in November 2013 for previously untreated CLL in combination with chlorambucil based on a pivotal phase 3 trial in 356 previously untreated patients with CLL (mean age, 73 years). Those who received obinutuzumab in combination with chlorambucil had significantly better median progression-free survival (PFS) than did those treated with chlorambucil alone (23 months vs 11.1 months; P < .0001). These results effectively end the use of chlorambucil as monotherapy.⁴

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Accelerated approval of ibrutinib was based on of a clinical study of participants with CLL who had received 4 previous therapies. At 26 months, estimated PFS was 75%, and the rate of overall survival (OS) was 83%.⁵ In January 2014, the RESONATE trial was stopped early because of a positive interim analysis showing statistically significant improvement in PFS as well as in OS with oral ibrutinib compared with IV ofatumumab. The RESONATE trial was a phase 3, multicenter study involving 391 patients with relapsed or refractory CLL who had received at least 1 previous therapy.⁶ At 6 months, 88% of patients treated with ibrutinib were progression free compared with 65% with ofatumumab. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% for patients in the ofatumumab group. By traditional response criteria, the overall response rate (ORR) with ibrutinib was 43% compared with 4% for ofatumumab. Ibrutinib is now approved for chemotherapy-naïve CLL patients with a 17p13.1 deletion, a genetic abnormality that generally portends a poor prognosis.

On July 23, 2014, the FDA approved an oral PI3-kinase delta (PI3K d) inhibitor called idelalisib in combination with rituximab used as a treatment for patients with high-risk CLL. In supporting data from a phase 3 study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% vs placebo and rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression free compared with 50% of patients treated with the placebo. Approval was based on a placebo-controlled study of 220 patients in which patients treated with idelalisib plus rituximab showed significantly longer PFS (10.7 months) than did those who received placebo plus rituximab (5.5 months).⁷

Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have used this medication in treatment of patients with relapsed and refractory CLL. Response rates of 47% to 38% with complete response rates of 9% and elimination of minimal residual disease (MRD) have also been reported.⁸

CLL Pipeline

Clinical trials continue to explore new agents, with the most promising being the PI3K δ and γ inhibitor duvelisib (IPI-145) and the BCL-2 inhibitor ABT-199. In
a phase 1 study exploring duvelisib in patients with relapsed or refractory CLL, the ORR was 47%.9 Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion or p53 mutation.

ABT-199 demonstrated efficacy in a phase 1b study when administered to patients with relapsed/refractory CLL in combination with rituximab.10 In 18 evaluable patients, 39% achieved complete remission (CR) or CR with incomplete blood count recovery and 39% achieved partial remissions (78% ORR). Altogether, 22% were deemed MRD-negative. In evaluable patients with 17p deletions, 81% achieved a response to ABT-199. In patients with fludarabine-refractory CLL, 78% achieved a response.

Although it is advantageous to have so many newer effective, targeted drugs for relapsed/refractory advanced CLL, in early-stage CLL when a watch and wait approach might be best, it may become a challenge for the patient as well as for the treating physician. All these drugs are expensive and carry risks. Although PFS is promising, physicians have to make a judgment call in balancing cost and toxicity.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Chronic lymphocytic leukemia (CLL) is a slow-growing malignancy of B lymphocytes (B cells) that tends to affect older people and men more than women. More than 17,000 new cases of CLL are reported every year. Patients with CLL do not need treatment with chemotherapy until they become symptomatic or display evidence of rapid progression of the disease. In multiple studies and a meta-analysis, early initiation of chemotherapy has failed to show benefit in managing CLL; indeed, it may increase mortality.^1,2

The combination chemotherapy fludarabine, cyclophosphamide, and rituximab (FCR) is often the initial choice for treatment. Other chemotherapy drugs used are chlorambucil, bendamustine, pentostatin or cladribine, rituximab, ofatumumab, and alemtuzumab. Although chlorambucil is a forgotten drug in the U.S., it is still used first line in elderly, fragile populations in Europe, which make up the bulk of true CLL cases.³

Various combination regimens used in CLL treatment have shown improved response rates in several randomized trials but have failed to show any survival advantage until recently. The treatment of patients with CLL has undergone a dramatic transformation and has changed the management paradigm since the FDA approved new, targeted agents. This article includes a brief discussion of these new agents and the pipeline for new agents.

Newly Approved Treatments

Obinutuzumab is a CD20-directed cytolytic antibody, which on binding to CD20, mediates B-cell lysis. Mediation may be (1) through engagement of immune effector cells; (2) by directly activating intracellular deathsignaling pathways; and/or (3) by activation of the complement. The FDA approved obinutuzumab in November 2013 for previously untreated CLL in combination with chlorambucil based on a pivotal phase 3 trial in 356 previously untreated patients with CLL (mean age, 73 years). Those who received obinutuzumab in combination with chlorambucil had significantly better median progression-free survival (PFS) than did those treated with chlorambucil alone (23 months vs 11.1 months; P < .0001). These results effectively end the use of chlorambucil as monotherapy.⁴

Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. The BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Accelerated approval of ibrutinib was based on of a clinical study of participants with CLL who had received 4 previous therapies. At 26 months, estimated PFS was 75%, and the rate of overall survival (OS) was 83%.⁵ In January 2014, the RESONATE trial was stopped early because of a positive interim analysis showing statistically significant improvement in PFS as well as in OS with oral ibrutinib compared with IV ofatumumab. The RESONATE trial was a phase 3, multicenter study involving 391 patients with relapsed or refractory CLL who had received at least 1 previous therapy.⁶ At 6 months, 88% of patients treated with ibrutinib were progression free compared with 65% with ofatumumab. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% for patients in the ofatumumab group. By traditional response criteria, the overall response rate (ORR) with ibrutinib was 43% compared with 4% for ofatumumab. Ibrutinib is now approved for chemotherapy-naïve CLL patients with a 17p13.1 deletion, a genetic abnormality that generally portends a poor prognosis.

On July 23, 2014, the FDA approved an oral PI3-kinase delta (PI3K d) inhibitor called idelalisib in combination with rituximab used as a treatment for patients with high-risk CLL. In supporting data from a phase 3 study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% vs placebo and rituximab. At 24 weeks, 90% of patients treated with idelalisib remained progression free compared with 50% of patients treated with the placebo. Approval was based on a placebo-controlled study of 220 patients in which patients treated with idelalisib plus rituximab showed significantly longer PFS (10.7 months) than did those who received placebo plus rituximab (5.5 months).⁷

Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have used this medication in treatment of patients with relapsed and refractory CLL. Response rates of 47% to 38% with complete response rates of 9% and elimination of minimal residual disease (MRD) have also been reported.⁸

CLL Pipeline

Clinical trials continue to explore new agents, with the most promising being the PI3K δ and γ inhibitor duvelisib (IPI-145) and the BCL-2 inhibitor ABT-199. In
a phase 1 study exploring duvelisib in patients with relapsed or refractory CLL, the ORR was 47%.9 Additionally, 98% of patients with refractory disease had nodal responses, which did not differ between patients with or without the 17p deletion or p53 mutation.

ABT-199 demonstrated efficacy in a phase 1b study when administered to patients with relapsed/refractory CLL in combination with rituximab.10 In 18 evaluable patients, 39% achieved complete remission (CR) or CR with incomplete blood count recovery and 39% achieved partial remissions (78% ORR). Altogether, 22% were deemed MRD-negative. In evaluable patients with 17p deletions, 81% achieved a response to ABT-199. In patients with fludarabine-refractory CLL, 78% achieved a response.

Although it is advantageous to have so many newer effective, targeted drugs for relapsed/refractory advanced CLL, in early-stage CLL when a watch and wait approach might be best, it may become a challenge for the patient as well as for the treating physician. All these drugs are expensive and carry risks. Although PFS is promising, physicians have to make a judgment call in balancing cost and toxicity.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation, t(11;14), that results in aberrant expression of cyclin D1.¹ The clinical presentation varies significantly from asymptomatic to rapidly enlarging lymph nodes, necessitating immediate treatment. Treatment approaches to newly diagnosed MCL correspondingly vary to match the clinical presentation, but they also reflect the bias of individual providers. No treatment is curative, so different treatment philosophies heavily influence management strategies. Mantle cell lymphoma was first described in the 1990s as a unique pathobiologic entity, and it is only now developing its own set of treatment principles distinct from other lymphomas.² As novel targeted therapies become available, fundamental questions regarding the best treatment approach are certain to evolve.

Traditional Intensive Treatment

The clinical challenge of treating patients with MCL centers on its propensity to relapse quickly after initial therapy. Although most patients will respond to the initial therapy, the duration of their remissions are disappointingly short. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimens can induce a complete response in the majority of patients, but they invariably relapse within 18 months of finishing therapy. Recognition of this problem led investigators to test highly intensive regimens designed to maximize the depth of remission often followed by autologous stem cell transplant. The highly intensive regimens are successful at extending remission durations to > 5 years in most cases, but at the cost of significant myelotoxicity and a nontrivial risk of death during induction therapy (Table 1).

In a subset analysis of a hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) study in MCL, it was observed that patients aged < 65 years had a better survival rate than did older patients.³ Accordingly, these regimens are largely restricted to patients aged < 65 years, which is only a minority of patients with MCL. Importantly, despite initial enthusiasm for the impressive rates of remission, most data suggest that these regimens are not curative.

Nonintensive Treatment

Until recently, patients aged > 65 years or those with significant comorbidities did not have effective treatment options that resulted in durable remissions. Most patients were treated with R-CHOP therapy, and the median survival was only 2 to 3 years.⁴ Interferon maintenance was frequently used but was largely ineffective at prolongation of remission. Treatment patterns changed quickly after the preliminary results of the randomized StiL (Study Group Indolent Lymphomas) study demonstrated that bendamustine-rituximab (BR) could induce durable remissions with less toxicity than that of R-CHOP therapy (Table 1).⁵ The superiority of BR over R-CHOP at inducing remissions in MCL was subsequently confirmed in the U.S.-led BRIGHT study; this regimen has become a popular regimen for patients aged > 65 years.⁶ Despite improved remission rate with less toxicity, however, the BR induction regimen still does not adequately address the problem of short durations of remission.

In a phase 3 study, the European MCL Network demonstrated that the use of maintenance rituximab after induction therapy prolonged both progression-free survival (PFS) as well as overall survival (when given after R-CHOP) compared with interferon maintenance.⁷ Many providers have extrapolated the benefits seen with rituximab maintenance after R-CHOP to all induction regimens, and rituximab maintenance is increasingly offered to older patients after their induction therapy. An important detail of this study is that rituximab was given indefinitely during maintenance and was not capped at 2 years, as often is done for maintenance treatment in other indolent lymphomas.

A landmark randomized study was recently published that demonstrated an advantage of substituting bortezomib for vincristine in the initial regimen.8 In a phase 3 study of 487 patients, the Vr-CAP (bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen demonstrated an improvement in median PFS over R-CHOP after 40 months of followup (24.7 months vs 14.4 months; hazard radio [HR] 0.63; P < .001) (Table 1). Of particular note, however, is that for patients who achieved a complete remission, the median duration of remission was significantly longer than that of R-CHOP (42.1 months vs 18.0 months; HR 0.63; P < .001). These data suggest that not only is Vr-CAP superior to R-CHOP as a whole, but also that some patients are particularly sensitive to bortezomib, resulting in durable remissions.

Novel Targeted Agents

Since 2006, 3 novel targeted agents have been approved for use in relapsed MCL, and many others are currently in clinical trials (Table 2). Bortezomib is approved for use in both the relapsed and upfront setting and demonstrates clear activity in MCL; however, no biomarker currently exists to help understand which patients will respond. Furthermore, most responses to single agents are partial and short-lived.⁹

Lenalidomide is an oral immunomodulatory agent that works in NHL through a variety of direct and indirect mechanisms.¹⁰ As a single agent, lenalidomide has shown activity in a number of studies and can be combined with rituximab without an apparent increase in the toxicity profile.^11-13 The EMERGE trial tested lenalidomide as a single agent at 25 mg (every 21 days out of a 28-day cycle) in patients who had previously been treated with bortezomib. In 128 patients, the overall response rate (RR) was 28% with a complete RR of 7.5%. Although these numbers are modest, long-term data from the NHL-003 trial show a subset of patients with durations of remissions nearing 4 years.¹¹ Thus, a biomarker for lenalidomide that predicts response would be of great
clinical utility.

Perhaps of even greater interest have been the clinical results seen with the use of the oral Bruton’s tyrosine kinase inhibitor, ibrutinib. In 111 patients with relapsed MCL treated with ibrutinib 560 mg, the overall RR was 68% with a complete RR of 21%.¹⁴ Most patients tolerated therapy very well, and the duration of remission was estimated at 17.5 months. This was a very impressive result with an agent that is tolerable by most patients with MCL.

Conclusions and Future Directions

Mantle cell lymphoma remains a clinical challenge to many providers due to the heterogeneity in the clinical presentation and the lack of consensus regarding the optimal management strategy. The most commonly recommended approach remains to offer highly intensive chemotherapy programs to patients aged < 65 years, but the introduction of novel active agents into the treatment paradigm is beginning to challenge the assumption that all patients need aggressive therapy.

Future research directions should include predictive biomarkers to enhance treatment decisions. Researchers also should begin to understand the toxicity profile and efficacy of the novel targeted agents when used in combination. Early, informative reports are available regarding ibrutinib when added to both rituximab and BR.^15,16 Important research questions will include the long-term effects of extended duration therapy (maintenance) paradigms as well as the introduction of novel molecular monitoring methods, such as circulating tumor DNA and circulating tumor cells, to help guide clinical decisions. In a disease with a reportedly dismal outcome, the near future holds much promise as the MCL treatment landscape evolves at a rapid pace.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation, t(11;14), that results in aberrant expression of cyclin D1.¹ The clinical presentation varies significantly from asymptomatic to rapidly enlarging lymph nodes, necessitating immediate treatment. Treatment approaches to newly diagnosed MCL correspondingly vary to match the clinical presentation, but they also reflect the bias of individual providers. No treatment is curative, so different treatment philosophies heavily influence management strategies. Mantle cell lymphoma was first described in the 1990s as a unique pathobiologic entity, and it is only now developing its own set of treatment principles distinct from other lymphomas.² As novel targeted therapies become available, fundamental questions regarding the best treatment approach are certain to evolve.

Traditional Intensive Treatment

The clinical challenge of treating patients with MCL centers on its propensity to relapse quickly after initial therapy. Although most patients will respond to the initial therapy, the duration of their remissions are disappointingly short. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimens can induce a complete response in the majority of patients, but they invariably relapse within 18 months of finishing therapy. Recognition of this problem led investigators to test highly intensive regimens designed to maximize the depth of remission often followed by autologous stem cell transplant. The highly intensive regimens are successful at extending remission durations to > 5 years in most cases, but at the cost of significant myelotoxicity and a nontrivial risk of death during induction therapy (Table 1).

In a subset analysis of a hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) study in MCL, it was observed that patients aged < 65 years had a better survival rate than did older patients.³ Accordingly, these regimens are largely restricted to patients aged < 65 years, which is only a minority of patients with MCL. Importantly, despite initial enthusiasm for the impressive rates of remission, most data suggest that these regimens are not curative.

Nonintensive Treatment

Until recently, patients aged > 65 years or those with significant comorbidities did not have effective treatment options that resulted in durable remissions. Most patients were treated with R-CHOP therapy, and the median survival was only 2 to 3 years.⁴ Interferon maintenance was frequently used but was largely ineffective at prolongation of remission. Treatment patterns changed quickly after the preliminary results of the randomized StiL (Study Group Indolent Lymphomas) study demonstrated that bendamustine-rituximab (BR) could induce durable remissions with less toxicity than that of R-CHOP therapy (Table 1).⁵ The superiority of BR over R-CHOP at inducing remissions in MCL was subsequently confirmed in the U.S.-led BRIGHT study; this regimen has become a popular regimen for patients aged > 65 years.⁶ Despite improved remission rate with less toxicity, however, the BR induction regimen still does not adequately address the problem of short durations of remission.

In a phase 3 study, the European MCL Network demonstrated that the use of maintenance rituximab after induction therapy prolonged both progression-free survival (PFS) as well as overall survival (when given after R-CHOP) compared with interferon maintenance.⁷ Many providers have extrapolated the benefits seen with rituximab maintenance after R-CHOP to all induction regimens, and rituximab maintenance is increasingly offered to older patients after their induction therapy. An important detail of this study is that rituximab was given indefinitely during maintenance and was not capped at 2 years, as often is done for maintenance treatment in other indolent lymphomas.

A landmark randomized study was recently published that demonstrated an advantage of substituting bortezomib for vincristine in the initial regimen.8 In a phase 3 study of 487 patients, the Vr-CAP (bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen demonstrated an improvement in median PFS over R-CHOP after 40 months of followup (24.7 months vs 14.4 months; hazard radio [HR] 0.63; P < .001) (Table 1). Of particular note, however, is that for patients who achieved a complete remission, the median duration of remission was significantly longer than that of R-CHOP (42.1 months vs 18.0 months; HR 0.63; P < .001). These data suggest that not only is Vr-CAP superior to R-CHOP as a whole, but also that some patients are particularly sensitive to bortezomib, resulting in durable remissions.

Novel Targeted Agents

Since 2006, 3 novel targeted agents have been approved for use in relapsed MCL, and many others are currently in clinical trials (Table 2). Bortezomib is approved for use in both the relapsed and upfront setting and demonstrates clear activity in MCL; however, no biomarker currently exists to help understand which patients will respond. Furthermore, most responses to single agents are partial and short-lived.⁹

Lenalidomide is an oral immunomodulatory agent that works in NHL through a variety of direct and indirect mechanisms.¹⁰ As a single agent, lenalidomide has shown activity in a number of studies and can be combined with rituximab without an apparent increase in the toxicity profile.^11-13 The EMERGE trial tested lenalidomide as a single agent at 25 mg (every 21 days out of a 28-day cycle) in patients who had previously been treated with bortezomib. In 128 patients, the overall response rate (RR) was 28% with a complete RR of 7.5%. Although these numbers are modest, long-term data from the NHL-003 trial show a subset of patients with durations of remissions nearing 4 years.¹¹ Thus, a biomarker for lenalidomide that predicts response would be of great
clinical utility.

Perhaps of even greater interest have been the clinical results seen with the use of the oral Bruton’s tyrosine kinase inhibitor, ibrutinib. In 111 patients with relapsed MCL treated with ibrutinib 560 mg, the overall RR was 68% with a complete RR of 21%.¹⁴ Most patients tolerated therapy very well, and the duration of remission was estimated at 17.5 months. This was a very impressive result with an agent that is tolerable by most patients with MCL.

Conclusions and Future Directions

Mantle cell lymphoma remains a clinical challenge to many providers due to the heterogeneity in the clinical presentation and the lack of consensus regarding the optimal management strategy. The most commonly recommended approach remains to offer highly intensive chemotherapy programs to patients aged < 65 years, but the introduction of novel active agents into the treatment paradigm is beginning to challenge the assumption that all patients need aggressive therapy.

Future research directions should include predictive biomarkers to enhance treatment decisions. Researchers also should begin to understand the toxicity profile and efficacy of the novel targeted agents when used in combination. Early, informative reports are available regarding ibrutinib when added to both rituximab and BR.^15,16 Important research questions will include the long-term effects of extended duration therapy (maintenance) paradigms as well as the introduction of novel molecular monitoring methods, such as circulating tumor DNA and circulating tumor cells, to help guide clinical decisions. In a disease with a reportedly dismal outcome, the near future holds much promise as the MCL treatment landscape evolves at a rapid pace.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation, t(11;14), that results in aberrant expression of cyclin D1.¹ The clinical presentation varies significantly from asymptomatic to rapidly enlarging lymph nodes, necessitating immediate treatment. Treatment approaches to newly diagnosed MCL correspondingly vary to match the clinical presentation, but they also reflect the bias of individual providers. No treatment is curative, so different treatment philosophies heavily influence management strategies. Mantle cell lymphoma was first described in the 1990s as a unique pathobiologic entity, and it is only now developing its own set of treatment principles distinct from other lymphomas.² As novel targeted therapies become available, fundamental questions regarding the best treatment approach are certain to evolve.

Traditional Intensive Treatment

The clinical challenge of treating patients with MCL centers on its propensity to relapse quickly after initial therapy. Although most patients will respond to the initial therapy, the duration of their remissions are disappointingly short. The R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimens can induce a complete response in the majority of patients, but they invariably relapse within 18 months of finishing therapy. Recognition of this problem led investigators to test highly intensive regimens designed to maximize the depth of remission often followed by autologous stem cell transplant. The highly intensive regimens are successful at extending remission durations to > 5 years in most cases, but at the cost of significant myelotoxicity and a nontrivial risk of death during induction therapy (Table 1).

In a subset analysis of a hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) study in MCL, it was observed that patients aged < 65 years had a better survival rate than did older patients.³ Accordingly, these regimens are largely restricted to patients aged < 65 years, which is only a minority of patients with MCL. Importantly, despite initial enthusiasm for the impressive rates of remission, most data suggest that these regimens are not curative.

Nonintensive Treatment

Until recently, patients aged > 65 years or those with significant comorbidities did not have effective treatment options that resulted in durable remissions. Most patients were treated with R-CHOP therapy, and the median survival was only 2 to 3 years.⁴ Interferon maintenance was frequently used but was largely ineffective at prolongation of remission. Treatment patterns changed quickly after the preliminary results of the randomized StiL (Study Group Indolent Lymphomas) study demonstrated that bendamustine-rituximab (BR) could induce durable remissions with less toxicity than that of R-CHOP therapy (Table 1).⁵ The superiority of BR over R-CHOP at inducing remissions in MCL was subsequently confirmed in the U.S.-led BRIGHT study; this regimen has become a popular regimen for patients aged > 65 years.⁶ Despite improved remission rate with less toxicity, however, the BR induction regimen still does not adequately address the problem of short durations of remission.

In a phase 3 study, the European MCL Network demonstrated that the use of maintenance rituximab after induction therapy prolonged both progression-free survival (PFS) as well as overall survival (when given after R-CHOP) compared with interferon maintenance.⁷ Many providers have extrapolated the benefits seen with rituximab maintenance after R-CHOP to all induction regimens, and rituximab maintenance is increasingly offered to older patients after their induction therapy. An important detail of this study is that rituximab was given indefinitely during maintenance and was not capped at 2 years, as often is done for maintenance treatment in other indolent lymphomas.

A landmark randomized study was recently published that demonstrated an advantage of substituting bortezomib for vincristine in the initial regimen.8 In a phase 3 study of 487 patients, the Vr-CAP (bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen demonstrated an improvement in median PFS over R-CHOP after 40 months of followup (24.7 months vs 14.4 months; hazard radio [HR] 0.63; P < .001) (Table 1). Of particular note, however, is that for patients who achieved a complete remission, the median duration of remission was significantly longer than that of R-CHOP (42.1 months vs 18.0 months; HR 0.63; P < .001). These data suggest that not only is Vr-CAP superior to R-CHOP as a whole, but also that some patients are particularly sensitive to bortezomib, resulting in durable remissions.

Novel Targeted Agents

Since 2006, 3 novel targeted agents have been approved for use in relapsed MCL, and many others are currently in clinical trials (Table 2). Bortezomib is approved for use in both the relapsed and upfront setting and demonstrates clear activity in MCL; however, no biomarker currently exists to help understand which patients will respond. Furthermore, most responses to single agents are partial and short-lived.⁹

Lenalidomide is an oral immunomodulatory agent that works in NHL through a variety of direct and indirect mechanisms.¹⁰ As a single agent, lenalidomide has shown activity in a number of studies and can be combined with rituximab without an apparent increase in the toxicity profile.^11-13 The EMERGE trial tested lenalidomide as a single agent at 25 mg (every 21 days out of a 28-day cycle) in patients who had previously been treated with bortezomib. In 128 patients, the overall response rate (RR) was 28% with a complete RR of 7.5%. Although these numbers are modest, long-term data from the NHL-003 trial show a subset of patients with durations of remissions nearing 4 years.¹¹ Thus, a biomarker for lenalidomide that predicts response would be of great
clinical utility.

Perhaps of even greater interest have been the clinical results seen with the use of the oral Bruton’s tyrosine kinase inhibitor, ibrutinib. In 111 patients with relapsed MCL treated with ibrutinib 560 mg, the overall RR was 68% with a complete RR of 21%.¹⁴ Most patients tolerated therapy very well, and the duration of remission was estimated at 17.5 months. This was a very impressive result with an agent that is tolerable by most patients with MCL.

Conclusions and Future Directions

Mantle cell lymphoma remains a clinical challenge to many providers due to the heterogeneity in the clinical presentation and the lack of consensus regarding the optimal management strategy. The most commonly recommended approach remains to offer highly intensive chemotherapy programs to patients aged < 65 years, but the introduction of novel active agents into the treatment paradigm is beginning to challenge the assumption that all patients need aggressive therapy.

Future research directions should include predictive biomarkers to enhance treatment decisions. Researchers also should begin to understand the toxicity profile and efficacy of the novel targeted agents when used in combination. Early, informative reports are available regarding ibrutinib when added to both rituximab and BR.^15,16 Important research questions will include the long-term effects of extended duration therapy (maintenance) paradigms as well as the introduction of novel molecular monitoring methods, such as circulating tumor DNA and circulating tumor cells, to help guide clinical decisions. In a disease with a reportedly dismal outcome, the near future holds much promise as the MCL treatment landscape evolves at a rapid pace.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Supplementation with calcium and vitamin D can be effective ways to prevent skeletal or teeth-related issues during treatment for bone metastasis or multiple myeloma, according to Sheetal Malhotra, MD, of the James J. Peters VAMC in the Bronx, New York.

“Data suggest that if you optimize vitamin D levels when you are giving patients bisphosphonates it can further improve response to bisphosphonate therapy,” Malhotra said. “Supplementation should be given to these patients who are on treatment with bisphosphonates unless there is some contraindication.”
 

Supplementation with calcium and vitamin D can be effective ways to prevent skeletal or teeth-related issues during treatment for bone metastasis or multiple myeloma, according to Sheetal Malhotra, MD, of the James J. Peters VAMC in the Bronx, New York.

“Data suggest that if you optimize vitamin D levels when you are giving patients bisphosphonates it can further improve response to bisphosphonate therapy,” Malhotra said. “Supplementation should be given to these patients who are on treatment with bisphosphonates unless there is some contraindication.”
 

Supplementation with calcium and vitamin D can be effective ways to prevent skeletal or teeth-related issues during treatment for bone metastasis or multiple myeloma, according to Sheetal Malhotra, MD, of the James J. Peters VAMC in the Bronx, New York.

“Data suggest that if you optimize vitamin D levels when you are giving patients bisphosphonates it can further improve response to bisphosphonate therapy,” Malhotra said. “Supplementation should be given to these patients who are on treatment with bisphosphonates unless there is some contraindication.”
 

Emerging concepts, a growing knowledge base, and new targets are changing the way mantle cell lymphoma is treated and managed, according to Mark Roschewski, MD, of the Center for Cancer Research National Cancer Institute at the National Institutes of Health.

"With more understanding of the biology about what makes this lymphoma different than others, we see changes," Roschewski said. "We have seen a lot of changes in this particular disease even in the last year. I think this bodes well for the future of how we are going to manage patients."
 

Emerging concepts, a growing knowledge base, and new targets are changing the way mantle cell lymphoma is treated and managed, according to Mark Roschewski, MD, of the Center for Cancer Research National Cancer Institute at the National Institutes of Health.

"With more understanding of the biology about what makes this lymphoma different than others, we see changes," Roschewski said. "We have seen a lot of changes in this particular disease even in the last year. I think this bodes well for the future of how we are going to manage patients."
 

Emerging concepts, a growing knowledge base, and new targets are changing the way mantle cell lymphoma is treated and managed, according to Mark Roschewski, MD, of the Center for Cancer Research National Cancer Institute at the National Institutes of Health.

"With more understanding of the biology about what makes this lymphoma different than others, we see changes," Roschewski said. "We have seen a lot of changes in this particular disease even in the last year. I think this bodes well for the future of how we are going to manage patients."
 

Bone metastasis is a relatively common complication of cancer, often developing as they advance, especially in prostate cancer and breast cancer. Bone metastasis can profoundly affect patients’ daily activities and quality of life (QOL) due to severe pain and associated major complications. Prompt palliative therapy is required for symptomatic pain relief and prevention of the devastating complications of bone metastasis.

Epidemiology

Bone is the most common and preferred site for metastatic involvement of cancer. Advanced cancers frequently develop metastases to the bone during the later phases of cancer progression. At least 100,000 patients develop bone metastases every year, although the exact number of bone metastases is not known.¹ Multiple myeloma (MM), breast cancer, and prostate cancer are responsible for up to 70% of bone metastases cases.² Gastrointestinal cancers contribute least to bone metastases: < 15% of all cases.²

Related: Effective Treatment Options for Metastatic Pancreatic Cancer

The prognosis of bone metastases is generally poor, although it partly depends on the primary site of the original cancer and on the presence of any additional metastases to visceral organs. For example, it is known that survival times are longer for patients with primary prostate or breast cancer than for patients with lung cancer primary tumors.^3,4

Prostate and breast cancers are the most common primary cancers of bone metastases. At postmortem studies, patients who died of prostate cancer or breast cancer revealed evidence of bone metastases in up to 75% of cases (Figure 1). Regardless of their survival expectancy, however, most patients with bone metastasis need immediate medical attention and active palliative therapy to prevent devastating complications related to bone metastasis, such as pathologic bone fractures and severe bone pain.

Clinical Features

Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and is caused by an abnormal accumulation of clonal plasma cells in the bone marrow. Characteristic clinical manifestations include bony destruction and related features of bone pain, anemia (80% of cases), hypocalcemia, and renal dysfunction. Pathologic fractures, renal failure, or hyperviscosity syndrome often develops. More than 20,000 new patients are diagnosed with MM and about 11,000 patients in the U.S. die of MM every year. Multiple myeloma and is twice as likely to develop in men as it is in women. A large number of MM cases are under the care of VAMCs (about 10%-12% of all MM cases).^7,8

Abnormal laboratory tests show an elevated total protein level in the blood and/or urine (Bence Jones proteinuria). Serum electrophoresis detects M-protein in about 80% to 90% of patients. Patients may also present with renal failure. The differential diagnosis includes other malignancies, such as metastatic carcinoma, lymphoma, leukemia, and monoclonal gammopathy.

Pathophysiology

Normal bone tissue is made up of 2 different types of cells: osteoblasts and osteoclasts. New bone is constantly being produced while old bone is broken down. When tumor cells invade bone, the cancer cells produce 1 of 2 distinct substances; as a result, either osteoclasts or osteoblasts are stimulated, depending on tumor type metastasized to the bone. The activated osteoclasts then dissolve the bone, weakening the bone (osteolytic phenomenon), and the osteoblasts stimulate bone formation, hardening the bone (osteoblastic or sclerotic process).

Diagnosis and Evaluation

The most important first step in evaluating bone metastasis in a patient is to take a thorough, careful medical history and perform a physical examination. The examination not only helps locate suspected sites of bone metastases, but also helps determine necessary diagnostic studies.

The radiographic appearance of bone metastasis can be classified into 4 groups: osteolytic, osteoblastic, osteoporotic, and mixed. Imaging characteristics of osteolytic lesions include the destruction/thinning of bone, whereas osteoblastic (osteosclerotic) lesions appear with excess deposition of new bones. In contrast to malignant osteolytic lesions, osteoporotic lesions look like faded bone without cortical destruction or increased density.

The main choice of imaging study for screening suspected bone metastases is usually the bone scan (Figure 3). Plain radiographs are not useful in the early detection of bone metastases, because bone lesions do not show up on plain films until 30% to 50% of the bone mineral is lost.^5,9 Although most metastatic bone lesions represent a mixture of osteoblastic and -lytic processes, metastatic lesions of lung cancer and breast cancer are predominantly osteolytic in contrast to mainly osteoblastic lesions of prostate cancer metastases.¹⁰

The osteoblastic process of bone metastases is best demonstrated on a bone scan; however, a positive bone scan does not necessarily indicate bone metastases, because it is not highly specific of metastatic disease. Several benign bone lesions (such as osteoarthritis, traumatic injury, and Paget disease) also show positive readings. Magnetic resonance imaging (MRI) is not useful in screening for bone metastases, but it is better in assessing bone metastases compared with a bone scan, because it is more sensitive, especially for spinal lesions. The reported sensitivity of MRI is 91% to 100%, whereas bone scan sensitivity is only 62% to 85%.^11,12

Even though the bone scan has been assumed to be the best imaging study for bone metastases, positron emission tomography (PET) scans can be more useful in detecting osteolytic bone metastases, as they can light up areas of increased metabolic activity. Positron emission tomography scans, however, are less sensitive for osteoblastic metastases. An additional advantage of PET scans is that they can be used for whole-body scanning/surveillance to rule out visceral involvement.

Published studies indicate that bone scans better detect sclerotic bone metastases and PET scans are superior in revealing osteolytic metastases.^13-15 Furthermore, in contrast to bone scans, PET scans can identify additional lesions in addition to bone lesion. According to recent reports, PET provides higher sensitivity and specificity in demonstrating lytic and sclerotic metastases compared with that of the bone scan.¹⁶

Breast Cancer

The role of PET for breast cancer is controversial. A study by Lonneux and colleagues found that PET is highly sensitive in confirming distant metastasis from breast cancer, whereas researchers reported a similar sensitivity but higher specificity.¹⁷ Ohta and colleagues reported that PET and bone scan had identical sensitivity (77.7%), but PET was more specific than the bone scan (97.6% vs 80.9%, respectively).¹⁴ The study conclusion by Cook and colleagues was that PET is superior to bone scan in the detection of metastatic osteolytic bone lesions from breast cancer, whereas osteoblastic metastatic bone lesions from breast cancer are less likely to be demonstrated on a PET scan.¹⁸

Houssami and Costelloe conducted a systematic review of 16 reported studies that comparatively tested the accuracy of imaging modalities for bone metastases in breast cancer.¹⁹ Sensitivity was generally similar between PET and bone scans in most studies reviewed. Four studies reported similar sensitivity but higher specificity for PET; the median specificity for PET and bone scan was 92% vs 85.5%, respectively (Figure 4).

Prostate Cancer

Prostate cancer is now established as the “classic” cancer for false-negative results on PET. Positron emission tomography does not perform well in the identification of osteoblastic skeletal metastases from prostate cancer. Yeh and colleagues reported only 18% positivity with PET.²⁰ Interestingly, however, progressive metastatic prostate cancer showed a higher yield of 77% sensitivity with PET, perhaps because active osseous disease can be better picked up by PET scans.²¹

Related: Prostate Cancer Survivorship Care

Lung Cancer

For non-small cell lung cancer, both bone scan and PET showed a similar sensitivity for bone metastases detection, but the PET scan was more specific than the bone scan. Lung cancer often metastasizes to bone: up to 36% of patients at postmortem study. Lung cancer with bone metastases has a poor prognosis with median survival time typically measured in months. Most patients with bone metastases develop complications, such as severe pain, bone fracture, hypercalcemia, and spinal cord compression. Bone-targeted therapies play a greater role in the management of lung cancer patients, aiming for delaying disease progression and preserving QOL.^22,23

Therapeutic Strategy and Management

Major morbidities associated with bone metastases include severe pain, hypercalcemia, bone fractures, spinal compression fractures, and cord or nerve root compression. This section reviews appropriate management techniques reported in the literature, particularly external beam radiation therapy.

Radiation Therapy

Pain is the most serious complication of bone metastases. Radiation therapy has been established as standard therapy and an effective pain palliation modality. Up to 80% of patients achieve partial pain relief, and > 33% of patients experience complete pain relief after radiation (Figure 5).^24,25 Although a 3,000 cGy given over a 2-week period has been commonly used, a standard dose-fraction radiation treatment regimen has not been established.

The RTOG study was a randomized clinical study comparing various radiation schedules; 1,500 cGyin 1 week; vs 2,000 cGy in 1 week; vs 2,500 cGy in 1 week; vs 3,000 cGy in 2 weeks; or 4,050 cGy in 3 weeks. The conclusion was that local radiotherapy was an effective therapy for symptomatic and palliative therapy of bone metastases. Furthermore, low-dose radiotherapy was as good as various higher dose protracted courses of radiation treatments in terms of overall response rates (ORRs).²⁴

Nearly 96% of patients eventually reported minimal pain relief to their palliative course of radiotherapy and experienced at least some pain relief within 4 weeks of radiation therapy. Complete pain relief was attained in 54% of patients regardless of the radiation dose-fraction schedules used. The median duration of complete pain response was about 12 weeks; > 70% of patients did not experience relapse of pain.²⁶

Hartsell and colleagues investigated the efficacy of 800 cGy in a single fraction compared with 3,000 cGy in 10 fractions as part of a phase 3 randomized study of symptomatic therapy for pain palliation.²⁷ The results showed 66% ORRs with similar complete and partial response rates (RRs) for both radiation groups. The complete RRs were 15% in the 800 cGy single-fraction arm vs 18% in the 3,000 cGy therapy arm, whereas partial RRs were 50% and 48% in the single vs the 3,000 cGy arms, respectively. However, there was a higher rate of retreatment for patients treated with the 800 cGy single-fraction radiotherapy. The 800 cGy single-fraction radiotherapy program seems rather popular in Canada and in European countries but is currently not widely used in the U.S.

Surgical Therapy

The surgical indications for managing bone metastases can vary, depending on disease location, surgeon’s preference, and patient’s overall disease status and related morbidities. Pain relief of fractured long bones (humerus, femur, or tibia) is crucial. The main goals of surgical intervention in these cases include the restoration of stability and functional mobility, pain control, and improving QOL. Weight-bearing bones (humerus/tibia) are especially at risk of bone fracture, and compromise of these is an indication of surgery. Postoperative external-beam radiation is recommended in most cases to eradicate residual microscopic disease or tumor progression.²⁸

Radiopharmaceutical Therapy

Bone-seeking radiopharmaceuticals are effective and have been widely used for pain palliation. The usual indications for radiopharmaceutical therapy include diffuse osteoblastic skeletal metastases demonstrated on bone scan, painful bone metastases not responding well to analgesics, and hormone-refractory metastatic prostate cancer. At present, strontium-89 (Sr-89), samarium-153 (Sm-153), phosphorus-32 (P-32), and radium 223 dichloride are radionuclides currently accepted as attractive therapeutic modalities for pain management (Table 2).

The clinical response is not immediate, and the average time to response is 1 to 2 weeks, but sometimes much longer. The main adverse reaction of systemic radiopharmaceutical therapy is myelotoxicity, such as thrombocytopenia and/or leukopenia. Occasionally, a so-called flare phenomenon of a transient pain increase may develop as well.^29,30

Systemic Pharmacotherapy

Bisphosphonates are drugs commonly used to treat bone metastases. The benefits of bisphosphonate therapy are bone pain relief, the reduction of bone destruction, and the prevention of hypercalcemia and bone fractures. Bisphosphonates are typically more effective in osteolytic metastases and easily bind to bone, inhibiting bone resorption and increasing mineralization.^31,32 Also, recent clinical studies suggest that bisphosphonates may inhibit tumor progression of bone metastases.

Related: Cancer Drugs Increase Rate of Preventable Hospital Admissions

Zoledronic acid is currently one of the most potent bisphosphonates and is effective in most types of metastatic bone lesions.³³ Denosumab, another drug, diminishes osteoclast activity, leading to decreased bone resorption and increased bone mass.^34,35 Denosumab is useful in preventing complications as a result of bone metastases from solid tumors and has been recently approved by the FDA for treatment of postmenopausal osteoporosis and the prevention of skeletal-related events (SREs) in cancer patients with bone metastases.

Adverse Effects

Zoledronate and bisphosphonates in general are not recommended for patients with kidney disease, including hypocalcaemia and severe renal impairment. A rare but well-known complication of bisphosphonate administration is osteonecrosis of the jaw, which is somewhat more common in MM, especially after dental extractions. General nonspecific adverse effects include fatigue, anemia, muscle aches, fever, and/or edema in the feet or legs. Flulike symptoms and generalized bone discomfort can also be seen shortly after the first infusion (Table 3).

Breast Cancer

Bisphosphonates have been shown to effectively prevent SREs in breast cancer patients with bone metastases.³⁶ For example, zoledronic acid is the most effective bisphosphonate and has been demonstrated to significantly delay the time to development of a first SRE, reducing the overall SRE rate by 43%.³⁷

Lung Cancer

According to Rosen and colleagues, lung cancer patients with bone metastases who received zoledronic acid (4 mg every 3 weeks) experienced a 9% reduction in SREs, a relative delay in median time to a first SRE, and a significantly reduced incidence of SREs.³⁷

Prostate Cancer

Zoledronic acid is the only bisphosphonate that proved effective in the treatment of prostate cancer patients with bone metastases. Zoledronic acid significantly reduced the risk of SREs (36%) and bone pain as well as delayed the median time to first SRE (nearly 6 months).^38,39

Multiple Myeloma

Bisphosphonates are recommended for bone metastases to prevent new bone lesions. Studies have shown pamidronate (90 mg every 4 weeks) resulted in a 41% reduction in SREs at 9 months and a 25% reduction at 21 months.^40,41 Oral clodronate, another agent, also significantly reduced SREs and pain in patients with MM.⁴²

Conclusion

Metastatic cancer with bone metastases occurs as cancer advances and spreads to the bone from the primary site of the original solid cancer. Nearly 70% of patients with prostate and breast cancers and about 30% to 40% of patients with lung cancer develop bone metastases. In addition, up to 95% of MMs involve bone. The most frequent and important symptom of bone metastasis is pain. In addition, bone metastasis causes bone fractures, hypercalcemia, and spinal cord and nerve compression. Imaging studies, such as bone scans and PET studies, are useful tools in diagnosing bone metastases.

Therapeutic management of bone metastases is expanding and rapidly evolving. For better therapy outcomes, treatment should be both individualized and coordinated among the care team, including a medical oncologist, radiation oncologist, surgeon, and radiologist. Available therapeutic modalities include radiation therapy, radiopharmaceutical therapy, surgery, and systemic pharmacotherapy (zoledronate, pamidronate, and denosumab).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Bone metastasis is a relatively common complication of cancer, often developing as they advance, especially in prostate cancer and breast cancer. Bone metastasis can profoundly affect patients’ daily activities and quality of life (QOL) due to severe pain and associated major complications. Prompt palliative therapy is required for symptomatic pain relief and prevention of the devastating complications of bone metastasis.

Epidemiology

Bone is the most common and preferred site for metastatic involvement of cancer. Advanced cancers frequently develop metastases to the bone during the later phases of cancer progression. At least 100,000 patients develop bone metastases every year, although the exact number of bone metastases is not known.¹ Multiple myeloma (MM), breast cancer, and prostate cancer are responsible for up to 70% of bone metastases cases.² Gastrointestinal cancers contribute least to bone metastases: < 15% of all cases.²

Related: Effective Treatment Options for Metastatic Pancreatic Cancer

The prognosis of bone metastases is generally poor, although it partly depends on the primary site of the original cancer and on the presence of any additional metastases to visceral organs. For example, it is known that survival times are longer for patients with primary prostate or breast cancer than for patients with lung cancer primary tumors.^3,4

Prostate and breast cancers are the most common primary cancers of bone metastases. At postmortem studies, patients who died of prostate cancer or breast cancer revealed evidence of bone metastases in up to 75% of cases (Figure 1). Regardless of their survival expectancy, however, most patients with bone metastasis need immediate medical attention and active palliative therapy to prevent devastating complications related to bone metastasis, such as pathologic bone fractures and severe bone pain.

Clinical Features

Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and is caused by an abnormal accumulation of clonal plasma cells in the bone marrow. Characteristic clinical manifestations include bony destruction and related features of bone pain, anemia (80% of cases), hypocalcemia, and renal dysfunction. Pathologic fractures, renal failure, or hyperviscosity syndrome often develops. More than 20,000 new patients are diagnosed with MM and about 11,000 patients in the U.S. die of MM every year. Multiple myeloma and is twice as likely to develop in men as it is in women. A large number of MM cases are under the care of VAMCs (about 10%-12% of all MM cases).^7,8

Abnormal laboratory tests show an elevated total protein level in the blood and/or urine (Bence Jones proteinuria). Serum electrophoresis detects M-protein in about 80% to 90% of patients. Patients may also present with renal failure. The differential diagnosis includes other malignancies, such as metastatic carcinoma, lymphoma, leukemia, and monoclonal gammopathy.

Pathophysiology

Normal bone tissue is made up of 2 different types of cells: osteoblasts and osteoclasts. New bone is constantly being produced while old bone is broken down. When tumor cells invade bone, the cancer cells produce 1 of 2 distinct substances; as a result, either osteoclasts or osteoblasts are stimulated, depending on tumor type metastasized to the bone. The activated osteoclasts then dissolve the bone, weakening the bone (osteolytic phenomenon), and the osteoblasts stimulate bone formation, hardening the bone (osteoblastic or sclerotic process).

Diagnosis and Evaluation

The most important first step in evaluating bone metastasis in a patient is to take a thorough, careful medical history and perform a physical examination. The examination not only helps locate suspected sites of bone metastases, but also helps determine necessary diagnostic studies.

The radiographic appearance of bone metastasis can be classified into 4 groups: osteolytic, osteoblastic, osteoporotic, and mixed. Imaging characteristics of osteolytic lesions include the destruction/thinning of bone, whereas osteoblastic (osteosclerotic) lesions appear with excess deposition of new bones. In contrast to malignant osteolytic lesions, osteoporotic lesions look like faded bone without cortical destruction or increased density.

The main choice of imaging study for screening suspected bone metastases is usually the bone scan (Figure 3). Plain radiographs are not useful in the early detection of bone metastases, because bone lesions do not show up on plain films until 30% to 50% of the bone mineral is lost.^5,9 Although most metastatic bone lesions represent a mixture of osteoblastic and -lytic processes, metastatic lesions of lung cancer and breast cancer are predominantly osteolytic in contrast to mainly osteoblastic lesions of prostate cancer metastases.¹⁰

The osteoblastic process of bone metastases is best demonstrated on a bone scan; however, a positive bone scan does not necessarily indicate bone metastases, because it is not highly specific of metastatic disease. Several benign bone lesions (such as osteoarthritis, traumatic injury, and Paget disease) also show positive readings. Magnetic resonance imaging (MRI) is not useful in screening for bone metastases, but it is better in assessing bone metastases compared with a bone scan, because it is more sensitive, especially for spinal lesions. The reported sensitivity of MRI is 91% to 100%, whereas bone scan sensitivity is only 62% to 85%.^11,12

Even though the bone scan has been assumed to be the best imaging study for bone metastases, positron emission tomography (PET) scans can be more useful in detecting osteolytic bone metastases, as they can light up areas of increased metabolic activity. Positron emission tomography scans, however, are less sensitive for osteoblastic metastases. An additional advantage of PET scans is that they can be used for whole-body scanning/surveillance to rule out visceral involvement.

Published studies indicate that bone scans better detect sclerotic bone metastases and PET scans are superior in revealing osteolytic metastases.^13-15 Furthermore, in contrast to bone scans, PET scans can identify additional lesions in addition to bone lesion. According to recent reports, PET provides higher sensitivity and specificity in demonstrating lytic and sclerotic metastases compared with that of the bone scan.¹⁶

Breast Cancer

The role of PET for breast cancer is controversial. A study by Lonneux and colleagues found that PET is highly sensitive in confirming distant metastasis from breast cancer, whereas researchers reported a similar sensitivity but higher specificity.¹⁷ Ohta and colleagues reported that PET and bone scan had identical sensitivity (77.7%), but PET was more specific than the bone scan (97.6% vs 80.9%, respectively).¹⁴ The study conclusion by Cook and colleagues was that PET is superior to bone scan in the detection of metastatic osteolytic bone lesions from breast cancer, whereas osteoblastic metastatic bone lesions from breast cancer are less likely to be demonstrated on a PET scan.¹⁸

Houssami and Costelloe conducted a systematic review of 16 reported studies that comparatively tested the accuracy of imaging modalities for bone metastases in breast cancer.¹⁹ Sensitivity was generally similar between PET and bone scans in most studies reviewed. Four studies reported similar sensitivity but higher specificity for PET; the median specificity for PET and bone scan was 92% vs 85.5%, respectively (Figure 4).

Prostate Cancer

Prostate cancer is now established as the “classic” cancer for false-negative results on PET. Positron emission tomography does not perform well in the identification of osteoblastic skeletal metastases from prostate cancer. Yeh and colleagues reported only 18% positivity with PET.²⁰ Interestingly, however, progressive metastatic prostate cancer showed a higher yield of 77% sensitivity with PET, perhaps because active osseous disease can be better picked up by PET scans.²¹

Related: Prostate Cancer Survivorship Care

Lung Cancer

For non-small cell lung cancer, both bone scan and PET showed a similar sensitivity for bone metastases detection, but the PET scan was more specific than the bone scan. Lung cancer often metastasizes to bone: up to 36% of patients at postmortem study. Lung cancer with bone metastases has a poor prognosis with median survival time typically measured in months. Most patients with bone metastases develop complications, such as severe pain, bone fracture, hypercalcemia, and spinal cord compression. Bone-targeted therapies play a greater role in the management of lung cancer patients, aiming for delaying disease progression and preserving QOL.^22,23

Therapeutic Strategy and Management

Major morbidities associated with bone metastases include severe pain, hypercalcemia, bone fractures, spinal compression fractures, and cord or nerve root compression. This section reviews appropriate management techniques reported in the literature, particularly external beam radiation therapy.

Radiation Therapy

Pain is the most serious complication of bone metastases. Radiation therapy has been established as standard therapy and an effective pain palliation modality. Up to 80% of patients achieve partial pain relief, and > 33% of patients experience complete pain relief after radiation (Figure 5).^24,25 Although a 3,000 cGy given over a 2-week period has been commonly used, a standard dose-fraction radiation treatment regimen has not been established.

The RTOG study was a randomized clinical study comparing various radiation schedules; 1,500 cGyin 1 week; vs 2,000 cGy in 1 week; vs 2,500 cGy in 1 week; vs 3,000 cGy in 2 weeks; or 4,050 cGy in 3 weeks. The conclusion was that local radiotherapy was an effective therapy for symptomatic and palliative therapy of bone metastases. Furthermore, low-dose radiotherapy was as good as various higher dose protracted courses of radiation treatments in terms of overall response rates (ORRs).²⁴

Nearly 96% of patients eventually reported minimal pain relief to their palliative course of radiotherapy and experienced at least some pain relief within 4 weeks of radiation therapy. Complete pain relief was attained in 54% of patients regardless of the radiation dose-fraction schedules used. The median duration of complete pain response was about 12 weeks; > 70% of patients did not experience relapse of pain.²⁶

Hartsell and colleagues investigated the efficacy of 800 cGy in a single fraction compared with 3,000 cGy in 10 fractions as part of a phase 3 randomized study of symptomatic therapy for pain palliation.²⁷ The results showed 66% ORRs with similar complete and partial response rates (RRs) for both radiation groups. The complete RRs were 15% in the 800 cGy single-fraction arm vs 18% in the 3,000 cGy therapy arm, whereas partial RRs were 50% and 48% in the single vs the 3,000 cGy arms, respectively. However, there was a higher rate of retreatment for patients treated with the 800 cGy single-fraction radiotherapy. The 800 cGy single-fraction radiotherapy program seems rather popular in Canada and in European countries but is currently not widely used in the U.S.

Surgical Therapy

The surgical indications for managing bone metastases can vary, depending on disease location, surgeon’s preference, and patient’s overall disease status and related morbidities. Pain relief of fractured long bones (humerus, femur, or tibia) is crucial. The main goals of surgical intervention in these cases include the restoration of stability and functional mobility, pain control, and improving QOL. Weight-bearing bones (humerus/tibia) are especially at risk of bone fracture, and compromise of these is an indication of surgery. Postoperative external-beam radiation is recommended in most cases to eradicate residual microscopic disease or tumor progression.²⁸

Radiopharmaceutical Therapy

Bone-seeking radiopharmaceuticals are effective and have been widely used for pain palliation. The usual indications for radiopharmaceutical therapy include diffuse osteoblastic skeletal metastases demonstrated on bone scan, painful bone metastases not responding well to analgesics, and hormone-refractory metastatic prostate cancer. At present, strontium-89 (Sr-89), samarium-153 (Sm-153), phosphorus-32 (P-32), and radium 223 dichloride are radionuclides currently accepted as attractive therapeutic modalities for pain management (Table 2).

The clinical response is not immediate, and the average time to response is 1 to 2 weeks, but sometimes much longer. The main adverse reaction of systemic radiopharmaceutical therapy is myelotoxicity, such as thrombocytopenia and/or leukopenia. Occasionally, a so-called flare phenomenon of a transient pain increase may develop as well.^29,30

Systemic Pharmacotherapy

Bisphosphonates are drugs commonly used to treat bone metastases. The benefits of bisphosphonate therapy are bone pain relief, the reduction of bone destruction, and the prevention of hypercalcemia and bone fractures. Bisphosphonates are typically more effective in osteolytic metastases and easily bind to bone, inhibiting bone resorption and increasing mineralization.^31,32 Also, recent clinical studies suggest that bisphosphonates may inhibit tumor progression of bone metastases.

Related: Cancer Drugs Increase Rate of Preventable Hospital Admissions

Zoledronic acid is currently one of the most potent bisphosphonates and is effective in most types of metastatic bone lesions.³³ Denosumab, another drug, diminishes osteoclast activity, leading to decreased bone resorption and increased bone mass.^34,35 Denosumab is useful in preventing complications as a result of bone metastases from solid tumors and has been recently approved by the FDA for treatment of postmenopausal osteoporosis and the prevention of skeletal-related events (SREs) in cancer patients with bone metastases.

Adverse Effects

Zoledronate and bisphosphonates in general are not recommended for patients with kidney disease, including hypocalcaemia and severe renal impairment. A rare but well-known complication of bisphosphonate administration is osteonecrosis of the jaw, which is somewhat more common in MM, especially after dental extractions. General nonspecific adverse effects include fatigue, anemia, muscle aches, fever, and/or edema in the feet or legs. Flulike symptoms and generalized bone discomfort can also be seen shortly after the first infusion (Table 3).

Breast Cancer

Bisphosphonates have been shown to effectively prevent SREs in breast cancer patients with bone metastases.³⁶ For example, zoledronic acid is the most effective bisphosphonate and has been demonstrated to significantly delay the time to development of a first SRE, reducing the overall SRE rate by 43%.³⁷

Lung Cancer

According to Rosen and colleagues, lung cancer patients with bone metastases who received zoledronic acid (4 mg every 3 weeks) experienced a 9% reduction in SREs, a relative delay in median time to a first SRE, and a significantly reduced incidence of SREs.³⁷

Prostate Cancer

Zoledronic acid is the only bisphosphonate that proved effective in the treatment of prostate cancer patients with bone metastases. Zoledronic acid significantly reduced the risk of SREs (36%) and bone pain as well as delayed the median time to first SRE (nearly 6 months).^38,39

Multiple Myeloma

Bisphosphonates are recommended for bone metastases to prevent new bone lesions. Studies have shown pamidronate (90 mg every 4 weeks) resulted in a 41% reduction in SREs at 9 months and a 25% reduction at 21 months.^40,41 Oral clodronate, another agent, also significantly reduced SREs and pain in patients with MM.⁴²

Conclusion

Metastatic cancer with bone metastases occurs as cancer advances and spreads to the bone from the primary site of the original solid cancer. Nearly 70% of patients with prostate and breast cancers and about 30% to 40% of patients with lung cancer develop bone metastases. In addition, up to 95% of MMs involve bone. The most frequent and important symptom of bone metastasis is pain. In addition, bone metastasis causes bone fractures, hypercalcemia, and spinal cord and nerve compression. Imaging studies, such as bone scans and PET studies, are useful tools in diagnosing bone metastases.

Therapeutic management of bone metastases is expanding and rapidly evolving. For better therapy outcomes, treatment should be both individualized and coordinated among the care team, including a medical oncologist, radiation oncologist, surgeon, and radiologist. Available therapeutic modalities include radiation therapy, radiopharmaceutical therapy, surgery, and systemic pharmacotherapy (zoledronate, pamidronate, and denosumab).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Bone metastasis is a relatively common complication of cancer, often developing as they advance, especially in prostate cancer and breast cancer. Bone metastasis can profoundly affect patients’ daily activities and quality of life (QOL) due to severe pain and associated major complications. Prompt palliative therapy is required for symptomatic pain relief and prevention of the devastating complications of bone metastasis.

Epidemiology

Bone is the most common and preferred site for metastatic involvement of cancer. Advanced cancers frequently develop metastases to the bone during the later phases of cancer progression. At least 100,000 patients develop bone metastases every year, although the exact number of bone metastases is not known.¹ Multiple myeloma (MM), breast cancer, and prostate cancer are responsible for up to 70% of bone metastases cases.² Gastrointestinal cancers contribute least to bone metastases: < 15% of all cases.²

Related: Effective Treatment Options for Metastatic Pancreatic Cancer

The prognosis of bone metastases is generally poor, although it partly depends on the primary site of the original cancer and on the presence of any additional metastases to visceral organs. For example, it is known that survival times are longer for patients with primary prostate or breast cancer than for patients with lung cancer primary tumors.^3,4

Prostate and breast cancers are the most common primary cancers of bone metastases. At postmortem studies, patients who died of prostate cancer or breast cancer revealed evidence of bone metastases in up to 75% of cases (Figure 1). Regardless of their survival expectancy, however, most patients with bone metastasis need immediate medical attention and active palliative therapy to prevent devastating complications related to bone metastasis, such as pathologic bone fractures and severe bone pain.

Clinical Features

Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and is caused by an abnormal accumulation of clonal plasma cells in the bone marrow. Characteristic clinical manifestations include bony destruction and related features of bone pain, anemia (80% of cases), hypocalcemia, and renal dysfunction. Pathologic fractures, renal failure, or hyperviscosity syndrome often develops. More than 20,000 new patients are diagnosed with MM and about 11,000 patients in the U.S. die of MM every year. Multiple myeloma and is twice as likely to develop in men as it is in women. A large number of MM cases are under the care of VAMCs (about 10%-12% of all MM cases).^7,8

Abnormal laboratory tests show an elevated total protein level in the blood and/or urine (Bence Jones proteinuria). Serum electrophoresis detects M-protein in about 80% to 90% of patients. Patients may also present with renal failure. The differential diagnosis includes other malignancies, such as metastatic carcinoma, lymphoma, leukemia, and monoclonal gammopathy.

Pathophysiology

Normal bone tissue is made up of 2 different types of cells: osteoblasts and osteoclasts. New bone is constantly being produced while old bone is broken down. When tumor cells invade bone, the cancer cells produce 1 of 2 distinct substances; as a result, either osteoclasts or osteoblasts are stimulated, depending on tumor type metastasized to the bone. The activated osteoclasts then dissolve the bone, weakening the bone (osteolytic phenomenon), and the osteoblasts stimulate bone formation, hardening the bone (osteoblastic or sclerotic process).

Diagnosis and Evaluation

The most important first step in evaluating bone metastasis in a patient is to take a thorough, careful medical history and perform a physical examination. The examination not only helps locate suspected sites of bone metastases, but also helps determine necessary diagnostic studies.

The radiographic appearance of bone metastasis can be classified into 4 groups: osteolytic, osteoblastic, osteoporotic, and mixed. Imaging characteristics of osteolytic lesions include the destruction/thinning of bone, whereas osteoblastic (osteosclerotic) lesions appear with excess deposition of new bones. In contrast to malignant osteolytic lesions, osteoporotic lesions look like faded bone without cortical destruction or increased density.

The main choice of imaging study for screening suspected bone metastases is usually the bone scan (Figure 3). Plain radiographs are not useful in the early detection of bone metastases, because bone lesions do not show up on plain films until 30% to 50% of the bone mineral is lost.^5,9 Although most metastatic bone lesions represent a mixture of osteoblastic and -lytic processes, metastatic lesions of lung cancer and breast cancer are predominantly osteolytic in contrast to mainly osteoblastic lesions of prostate cancer metastases.¹⁰

The osteoblastic process of bone metastases is best demonstrated on a bone scan; however, a positive bone scan does not necessarily indicate bone metastases, because it is not highly specific of metastatic disease. Several benign bone lesions (such as osteoarthritis, traumatic injury, and Paget disease) also show positive readings. Magnetic resonance imaging (MRI) is not useful in screening for bone metastases, but it is better in assessing bone metastases compared with a bone scan, because it is more sensitive, especially for spinal lesions. The reported sensitivity of MRI is 91% to 100%, whereas bone scan sensitivity is only 62% to 85%.^11,12

Even though the bone scan has been assumed to be the best imaging study for bone metastases, positron emission tomography (PET) scans can be more useful in detecting osteolytic bone metastases, as they can light up areas of increased metabolic activity. Positron emission tomography scans, however, are less sensitive for osteoblastic metastases. An additional advantage of PET scans is that they can be used for whole-body scanning/surveillance to rule out visceral involvement.

Published studies indicate that bone scans better detect sclerotic bone metastases and PET scans are superior in revealing osteolytic metastases.^13-15 Furthermore, in contrast to bone scans, PET scans can identify additional lesions in addition to bone lesion. According to recent reports, PET provides higher sensitivity and specificity in demonstrating lytic and sclerotic metastases compared with that of the bone scan.¹⁶

Breast Cancer

The role of PET for breast cancer is controversial. A study by Lonneux and colleagues found that PET is highly sensitive in confirming distant metastasis from breast cancer, whereas researchers reported a similar sensitivity but higher specificity.¹⁷ Ohta and colleagues reported that PET and bone scan had identical sensitivity (77.7%), but PET was more specific than the bone scan (97.6% vs 80.9%, respectively).¹⁴ The study conclusion by Cook and colleagues was that PET is superior to bone scan in the detection of metastatic osteolytic bone lesions from breast cancer, whereas osteoblastic metastatic bone lesions from breast cancer are less likely to be demonstrated on a PET scan.¹⁸

Houssami and Costelloe conducted a systematic review of 16 reported studies that comparatively tested the accuracy of imaging modalities for bone metastases in breast cancer.¹⁹ Sensitivity was generally similar between PET and bone scans in most studies reviewed. Four studies reported similar sensitivity but higher specificity for PET; the median specificity for PET and bone scan was 92% vs 85.5%, respectively (Figure 4).

Prostate Cancer

Prostate cancer is now established as the “classic” cancer for false-negative results on PET. Positron emission tomography does not perform well in the identification of osteoblastic skeletal metastases from prostate cancer. Yeh and colleagues reported only 18% positivity with PET.²⁰ Interestingly, however, progressive metastatic prostate cancer showed a higher yield of 77% sensitivity with PET, perhaps because active osseous disease can be better picked up by PET scans.²¹

Related: Prostate Cancer Survivorship Care

Lung Cancer

For non-small cell lung cancer, both bone scan and PET showed a similar sensitivity for bone metastases detection, but the PET scan was more specific than the bone scan. Lung cancer often metastasizes to bone: up to 36% of patients at postmortem study. Lung cancer with bone metastases has a poor prognosis with median survival time typically measured in months. Most patients with bone metastases develop complications, such as severe pain, bone fracture, hypercalcemia, and spinal cord compression. Bone-targeted therapies play a greater role in the management of lung cancer patients, aiming for delaying disease progression and preserving QOL.^22,23

Therapeutic Strategy and Management

Major morbidities associated with bone metastases include severe pain, hypercalcemia, bone fractures, spinal compression fractures, and cord or nerve root compression. This section reviews appropriate management techniques reported in the literature, particularly external beam radiation therapy.

Radiation Therapy

Pain is the most serious complication of bone metastases. Radiation therapy has been established as standard therapy and an effective pain palliation modality. Up to 80% of patients achieve partial pain relief, and > 33% of patients experience complete pain relief after radiation (Figure 5).^24,25 Although a 3,000 cGy given over a 2-week period has been commonly used, a standard dose-fraction radiation treatment regimen has not been established.

The RTOG study was a randomized clinical study comparing various radiation schedules; 1,500 cGyin 1 week; vs 2,000 cGy in 1 week; vs 2,500 cGy in 1 week; vs 3,000 cGy in 2 weeks; or 4,050 cGy in 3 weeks. The conclusion was that local radiotherapy was an effective therapy for symptomatic and palliative therapy of bone metastases. Furthermore, low-dose radiotherapy was as good as various higher dose protracted courses of radiation treatments in terms of overall response rates (ORRs).²⁴

Nearly 96% of patients eventually reported minimal pain relief to their palliative course of radiotherapy and experienced at least some pain relief within 4 weeks of radiation therapy. Complete pain relief was attained in 54% of patients regardless of the radiation dose-fraction schedules used. The median duration of complete pain response was about 12 weeks; > 70% of patients did not experience relapse of pain.²⁶

Hartsell and colleagues investigated the efficacy of 800 cGy in a single fraction compared with 3,000 cGy in 10 fractions as part of a phase 3 randomized study of symptomatic therapy for pain palliation.²⁷ The results showed 66% ORRs with similar complete and partial response rates (RRs) for both radiation groups. The complete RRs were 15% in the 800 cGy single-fraction arm vs 18% in the 3,000 cGy therapy arm, whereas partial RRs were 50% and 48% in the single vs the 3,000 cGy arms, respectively. However, there was a higher rate of retreatment for patients treated with the 800 cGy single-fraction radiotherapy. The 800 cGy single-fraction radiotherapy program seems rather popular in Canada and in European countries but is currently not widely used in the U.S.

Surgical Therapy

The surgical indications for managing bone metastases can vary, depending on disease location, surgeon’s preference, and patient’s overall disease status and related morbidities. Pain relief of fractured long bones (humerus, femur, or tibia) is crucial. The main goals of surgical intervention in these cases include the restoration of stability and functional mobility, pain control, and improving QOL. Weight-bearing bones (humerus/tibia) are especially at risk of bone fracture, and compromise of these is an indication of surgery. Postoperative external-beam radiation is recommended in most cases to eradicate residual microscopic disease or tumor progression.²⁸

Radiopharmaceutical Therapy

Bone-seeking radiopharmaceuticals are effective and have been widely used for pain palliation. The usual indications for radiopharmaceutical therapy include diffuse osteoblastic skeletal metastases demonstrated on bone scan, painful bone metastases not responding well to analgesics, and hormone-refractory metastatic prostate cancer. At present, strontium-89 (Sr-89), samarium-153 (Sm-153), phosphorus-32 (P-32), and radium 223 dichloride are radionuclides currently accepted as attractive therapeutic modalities for pain management (Table 2).

The clinical response is not immediate, and the average time to response is 1 to 2 weeks, but sometimes much longer. The main adverse reaction of systemic radiopharmaceutical therapy is myelotoxicity, such as thrombocytopenia and/or leukopenia. Occasionally, a so-called flare phenomenon of a transient pain increase may develop as well.^29,30

Systemic Pharmacotherapy

Bisphosphonates are drugs commonly used to treat bone metastases. The benefits of bisphosphonate therapy are bone pain relief, the reduction of bone destruction, and the prevention of hypercalcemia and bone fractures. Bisphosphonates are typically more effective in osteolytic metastases and easily bind to bone, inhibiting bone resorption and increasing mineralization.^31,32 Also, recent clinical studies suggest that bisphosphonates may inhibit tumor progression of bone metastases.

Related: Cancer Drugs Increase Rate of Preventable Hospital Admissions

Zoledronic acid is currently one of the most potent bisphosphonates and is effective in most types of metastatic bone lesions.³³ Denosumab, another drug, diminishes osteoclast activity, leading to decreased bone resorption and increased bone mass.^34,35 Denosumab is useful in preventing complications as a result of bone metastases from solid tumors and has been recently approved by the FDA for treatment of postmenopausal osteoporosis and the prevention of skeletal-related events (SREs) in cancer patients with bone metastases.

Adverse Effects

Zoledronate and bisphosphonates in general are not recommended for patients with kidney disease, including hypocalcaemia and severe renal impairment. A rare but well-known complication of bisphosphonate administration is osteonecrosis of the jaw, which is somewhat more common in MM, especially after dental extractions. General nonspecific adverse effects include fatigue, anemia, muscle aches, fever, and/or edema in the feet or legs. Flulike symptoms and generalized bone discomfort can also be seen shortly after the first infusion (Table 3).

Breast Cancer

Bisphosphonates have been shown to effectively prevent SREs in breast cancer patients with bone metastases.³⁶ For example, zoledronic acid is the most effective bisphosphonate and has been demonstrated to significantly delay the time to development of a first SRE, reducing the overall SRE rate by 43%.³⁷

Lung Cancer

According to Rosen and colleagues, lung cancer patients with bone metastases who received zoledronic acid (4 mg every 3 weeks) experienced a 9% reduction in SREs, a relative delay in median time to a first SRE, and a significantly reduced incidence of SREs.³⁷

Prostate Cancer

Zoledronic acid is the only bisphosphonate that proved effective in the treatment of prostate cancer patients with bone metastases. Zoledronic acid significantly reduced the risk of SREs (36%) and bone pain as well as delayed the median time to first SRE (nearly 6 months).^38,39

Multiple Myeloma

Bisphosphonates are recommended for bone metastases to prevent new bone lesions. Studies have shown pamidronate (90 mg every 4 weeks) resulted in a 41% reduction in SREs at 9 months and a 25% reduction at 21 months.^40,41 Oral clodronate, another agent, also significantly reduced SREs and pain in patients with MM.⁴²

Conclusion

Metastatic cancer with bone metastases occurs as cancer advances and spreads to the bone from the primary site of the original solid cancer. Nearly 70% of patients with prostate and breast cancers and about 30% to 40% of patients with lung cancer develop bone metastases. In addition, up to 95% of MMs involve bone. The most frequent and important symptom of bone metastasis is pain. In addition, bone metastasis causes bone fractures, hypercalcemia, and spinal cord and nerve compression. Imaging studies, such as bone scans and PET studies, are useful tools in diagnosing bone metastases.

Therapeutic management of bone metastases is expanding and rapidly evolving. For better therapy outcomes, treatment should be both individualized and coordinated among the care team, including a medical oncologist, radiation oncologist, surgeon, and radiologist. Available therapeutic modalities include radiation therapy, radiopharmaceutical therapy, surgery, and systemic pharmacotherapy (zoledronate, pamidronate, and denosumab).

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Christopher Flowers, MD, discusses current management strategies for newly diagnosed and relapsed patients with Hodgkin Lymphoma (HL). He also discusses emerging opportunities for the use of novel approaches to treat HL and surveillance of patients with this type of cancer.

"Stem cell transplant still remains the standard approach for patients with relapsed Hodgkin Lymphoma," Flowers said during his presentation during the 2014 AVAHO Meeting's Lymphoma Mini-Symposium. "Turning to the novel agents... there are a number of potential approaches that can be used."

Christopher Flowers, MD, discusses current management strategies for newly diagnosed and relapsed patients with Hodgkin Lymphoma (HL). He also discusses emerging opportunities for the use of novel approaches to treat HL and surveillance of patients with this type of cancer.

"Stem cell transplant still remains the standard approach for patients with relapsed Hodgkin Lymphoma," Flowers said during his presentation during the 2014 AVAHO Meeting's Lymphoma Mini-Symposium. "Turning to the novel agents... there are a number of potential approaches that can be used."

Christopher Flowers, MD, discusses current management strategies for newly diagnosed and relapsed patients with Hodgkin Lymphoma (HL). He also discusses emerging opportunities for the use of novel approaches to treat HL and surveillance of patients with this type of cancer.

"Stem cell transplant still remains the standard approach for patients with relapsed Hodgkin Lymphoma," Flowers said during his presentation during the 2014 AVAHO Meeting's Lymphoma Mini-Symposium. "Turning to the novel agents... there are a number of potential approaches that can be used."

Federal Practitioner recently talked with Dr. Adrian Weistner and Dr. Mark Roschewski of the National Institutes of Health. Both doctors will be presenting during the September 12, 2014 Lymphoma Mini-Symposium and panel discussion that kicks off this weekend’s 2014 AVAHO Meeting in Portland, Oregon.

Federal Practitioner recently talked with Dr. Adrian Weistner and Dr. Mark Roschewski of the National Institutes of Health. Both doctors will be presenting during the September 12, 2014 Lymphoma Mini-Symposium and panel discussion that kicks off this weekend’s 2014 AVAHO Meeting in Portland, Oregon.

Federal Practitioner recently talked with Dr. Adrian Weistner and Dr. Mark Roschewski of the National Institutes of Health. Both doctors will be presenting during the September 12, 2014 Lymphoma Mini-Symposium and panel discussion that kicks off this weekend’s 2014 AVAHO Meeting in Portland, Oregon.