Head & Neck/Thyroid Cancers

Plasma cell neoplasms involving tissues other than the bone marrow are known as extramedullary plasmacytoma (EMP).¹ EMPs mostly involve the head and neck region.² Solitary EMP involving only the thyroid gland is very rare.^3,4 Because of the limited knowledge about this condition and its rarity, its management can be challenging and is often extrapolated from plasma cell myeloma.^5,6 In general, surgery or radiation are considered as front-line therapy.^3,5 EMPs usually respond well to radiotherapy with almost complete remission. No definite guidelines outlining the treatment of radio-resistant EMP of the thyroid have yet been published. Data supporting the use of chemotherapy is particularly limited.^4,7,8

Here, we describe the case of a 53-year-old woman with a long history of thyroiditis who presented with rapidly worsening symptomatic thyroid enlargement. She was diagnosed with EMP of the thyroid gland that was not amenable to surgery and was refractory to radiotherapy but responded to adjuvant chemotherapy with bortezomib. This report highlights 2 unique aspects of this condition: it focuses on a rare case of EMP and, as far as we know, it reports for the first time on EMP that was resistant to radiotherapy. It also highlights the need for guidelines for the treatment of EMPs.
 

Case presentation and summary

A 53-year-old woman presented to the emergency department with complaints of difficulty swallowing, hoarseness, and neck pain during the previous 1 month. She had a known history of Hashimoto’s thyroiditis, and an ultrasound scan of her neck 6 years previously had demonstrated diffuse thyromegaly without discrete nodules. On presentation, the patient’s vitals were stable, and a neck examination revealed a firm and enlarged thyroid without any cervical adenopathy. Laboratory investigations revealed a normal complete blood count and comprehensive metabolic panel. She had an elevated thyroid-stimulating hormone level of 13.40 mIU/L (reference range, 0.47-4.68 mIU/L) and normal thyroxine level of 4.5 pmol/L (reference range, 4.5-12.0 pmol/L). A computerized tomography (CT) scan of the neck revealed an enlarged thyroid gland (right lobe length, 10.3 cm; isthmus, 2 cm; left lobe, 8 cm) with a focal area of increased echogenicity in the midpole of the left lobe measuring 9.5 mm × 5.5 mm. The patient was discharged to home with pain medications, and urgent follow-up with an otolaryngologist was arranged. A flexible laryngoscopy was done in the otolaryngology clinic, which revealed retropharyngeal bulging that correlated with the thyromegaly evident on the CT scan.

Because of the patient’s significant symptoms, we decided to proceed with surgery with a clinical diagnosis of likely thyroiditis. A left subtotal thyroidectomy with extension to the superior mediastinum was performed, but a right thyroidectomy could not be done safely. On gross examination, a well-capsulated left lobe with a tan-white, lobulated, soft cut surface was seen. Microscopic examination revealed replacement of thyroid parenchyma with sheets of mature-appearing plasma cells with eccentric round nuclei, abundant eosinophilic cytoplasm without atypia, and few scattered thyroid follicles with lymphoepithelial lesions (Figure 1A). Immunohistochemistry confirmed plasma cells with expression of CD138 (Figure 1B).

Discussion

Plasma cells are well-differentiated B-lymphocytes that secrete antibodies and provide protective immunity to the human body.⁹ Plasma cell neoplasms are clonal proliferation of plasma cells, producing monoclonal immunoglobulins. They are of the following different types: plasma cell myeloma, monoclonal gammopathy of unknown significance, immunoglobulin deposition disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, and plasmacytomas, which are divided into 2 types – solitary plasmacytoma of the bone, and extramedullary plasmacytoma (EMP).¹⁰ EMP is a rare condition and encompasses 3% to 5% of all plasma cell neoplasms, depending on the study.^1,2,5 It is more common in men than in women (2.6:1, respectively), with equal incidence among black and white patients. Median age at diagnosis is 62 years, and it is more common among those aged 40 to 70 years.^2,11 The most common sites of occurrence are the respiratory tract, the mouth, and the pharynx, but other sites such as the eyes, brain, skin, and lymph nodes may also be involved.²

EMP involving the thyroid gland is a very rare occurrence, but plasma cell myeloma has been shown to secondarily involve the thyroid.⁴ Similar to our report, EMP of the thyroid in the setting of thyroiditis has been reported by other authors.^3,4 The incidence of EMP occurring in the thyroid varies according to different authors. Wiltshaw found 7 cases involving the thyroid out of 272 cases of EMP.¹ Galieni and colleagues reported only 1 case that involved the thyroid out of 46 described cases of EMP.¹²

El- Siemińska and colleagues showed that levels of interleukin (IL)-6 are elevated in thyroiditis.¹³ IL-6 promotes monoclonal as well as polyclonal proliferation of plasma cells. Kovalchuk and colleagues showed an increase in EMP in IL-6 transgenic mice, suggesting a pathophysiologic explanation.¹⁴

The diagnostic requirements of EMP include the following: histology showing monoclonal plasma cell infiltration in tissue; bone marrow biopsy with normal plasma cell aspirate and biopsy (plasma cells, <5%); no lytic lesions on skeletal survey; no anemia, renal impairment, or hypercalcemia; and absent or low serum M protein.¹²

Our case fulfilled those criteria.

The treatment options for EMP include surgery, radiotherapy, or a combined approach including both. Usually, EMPs are very sensitive to radiotherapy, and complete remission can be achieved by radiotherapy alone in 80% to 100% of cases.^6,11,15 Surgery is considered if the tumor is diffuse or is causing symptoms secondary to pressure on surrounding structures. A combined approach is recommended in cases with incomplete surgical margin or lymph node involvement.^5,6

There is limited evidence about and experience with the use of chemotherapy in the treatment of EMP. It has been recommended that chemotherapy be considered in patients with refractory or relapsed disease using the same regimen used in plasma cell myeloma.⁵ Katodritou and colleagues have reported using bortezomib and dexamethasone without surgery in a solitary gastric plasmacytoma to avoid the toxicity of gastrointestinal irradiation.⁷ Wei and colleagues treated a patient with EMP in the pancreas with bortezomib and achieved a near-complete remission.⁸ To our knowledge, there is no documented literature about the treatment of EMP of the thyroid with chemotherapy. In our patient, despite the treatment with surgery and radiation, there was persistent uptake on the PET scan, so we treated her with bortezomib and dexamethasone. Because there is an 11% to 30% risk of progression to multiple myeloma, long-term follow-up is recommended in EMP.¹¹

Conclusions

Solitary EMP of the thyroid gland is a rare condition. Plasma cell myeloma must be ruled out to make a diagnosis. Data on the incidence of EMP and its clinicopathological features are sparse, and literature describing proper guidelines on treatment is limited. It can be treated with radiotherapy, surgery, or a combined approach. There is limited data on the role of chemotherapy; our case adds to the available literature on using myeloma-based therapy in refractory disease and, to our knowledge, is the only case report using this in the literature on cases of EMP of the thyroid. Regular follow-up, even after the disease is in remission, is necessary because of the high risk of progression to plasma cell myeloma.

Plasma cell neoplasms involving tissues other than the bone marrow are known as extramedullary plasmacytoma (EMP).¹ EMPs mostly involve the head and neck region.² Solitary EMP involving only the thyroid gland is very rare.^3,4 Because of the limited knowledge about this condition and its rarity, its management can be challenging and is often extrapolated from plasma cell myeloma.^5,6 In general, surgery or radiation are considered as front-line therapy.^3,5 EMPs usually respond well to radiotherapy with almost complete remission. No definite guidelines outlining the treatment of radio-resistant EMP of the thyroid have yet been published. Data supporting the use of chemotherapy is particularly limited.^4,7,8

Here, we describe the case of a 53-year-old woman with a long history of thyroiditis who presented with rapidly worsening symptomatic thyroid enlargement. She was diagnosed with EMP of the thyroid gland that was not amenable to surgery and was refractory to radiotherapy but responded to adjuvant chemotherapy with bortezomib. This report highlights 2 unique aspects of this condition: it focuses on a rare case of EMP and, as far as we know, it reports for the first time on EMP that was resistant to radiotherapy. It also highlights the need for guidelines for the treatment of EMPs.
 

Case presentation and summary

A 53-year-old woman presented to the emergency department with complaints of difficulty swallowing, hoarseness, and neck pain during the previous 1 month. She had a known history of Hashimoto’s thyroiditis, and an ultrasound scan of her neck 6 years previously had demonstrated diffuse thyromegaly without discrete nodules. On presentation, the patient’s vitals were stable, and a neck examination revealed a firm and enlarged thyroid without any cervical adenopathy. Laboratory investigations revealed a normal complete blood count and comprehensive metabolic panel. She had an elevated thyroid-stimulating hormone level of 13.40 mIU/L (reference range, 0.47-4.68 mIU/L) and normal thyroxine level of 4.5 pmol/L (reference range, 4.5-12.0 pmol/L). A computerized tomography (CT) scan of the neck revealed an enlarged thyroid gland (right lobe length, 10.3 cm; isthmus, 2 cm; left lobe, 8 cm) with a focal area of increased echogenicity in the midpole of the left lobe measuring 9.5 mm × 5.5 mm. The patient was discharged to home with pain medications, and urgent follow-up with an otolaryngologist was arranged. A flexible laryngoscopy was done in the otolaryngology clinic, which revealed retropharyngeal bulging that correlated with the thyromegaly evident on the CT scan.

Because of the patient’s significant symptoms, we decided to proceed with surgery with a clinical diagnosis of likely thyroiditis. A left subtotal thyroidectomy with extension to the superior mediastinum was performed, but a right thyroidectomy could not be done safely. On gross examination, a well-capsulated left lobe with a tan-white, lobulated, soft cut surface was seen. Microscopic examination revealed replacement of thyroid parenchyma with sheets of mature-appearing plasma cells with eccentric round nuclei, abundant eosinophilic cytoplasm without atypia, and few scattered thyroid follicles with lymphoepithelial lesions (Figure 1A). Immunohistochemistry confirmed plasma cells with expression of CD138 (Figure 1B).

Discussion

Plasma cells are well-differentiated B-lymphocytes that secrete antibodies and provide protective immunity to the human body.⁹ Plasma cell neoplasms are clonal proliferation of plasma cells, producing monoclonal immunoglobulins. They are of the following different types: plasma cell myeloma, monoclonal gammopathy of unknown significance, immunoglobulin deposition disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, and plasmacytomas, which are divided into 2 types – solitary plasmacytoma of the bone, and extramedullary plasmacytoma (EMP).¹⁰ EMP is a rare condition and encompasses 3% to 5% of all plasma cell neoplasms, depending on the study.^1,2,5 It is more common in men than in women (2.6:1, respectively), with equal incidence among black and white patients. Median age at diagnosis is 62 years, and it is more common among those aged 40 to 70 years.^2,11 The most common sites of occurrence are the respiratory tract, the mouth, and the pharynx, but other sites such as the eyes, brain, skin, and lymph nodes may also be involved.²

EMP involving the thyroid gland is a very rare occurrence, but plasma cell myeloma has been shown to secondarily involve the thyroid.⁴ Similar to our report, EMP of the thyroid in the setting of thyroiditis has been reported by other authors.^3,4 The incidence of EMP occurring in the thyroid varies according to different authors. Wiltshaw found 7 cases involving the thyroid out of 272 cases of EMP.¹ Galieni and colleagues reported only 1 case that involved the thyroid out of 46 described cases of EMP.¹²

El- Siemińska and colleagues showed that levels of interleukin (IL)-6 are elevated in thyroiditis.¹³ IL-6 promotes monoclonal as well as polyclonal proliferation of plasma cells. Kovalchuk and colleagues showed an increase in EMP in IL-6 transgenic mice, suggesting a pathophysiologic explanation.¹⁴

The diagnostic requirements of EMP include the following: histology showing monoclonal plasma cell infiltration in tissue; bone marrow biopsy with normal plasma cell aspirate and biopsy (plasma cells, <5%); no lytic lesions on skeletal survey; no anemia, renal impairment, or hypercalcemia; and absent or low serum M protein.¹²

Our case fulfilled those criteria.

The treatment options for EMP include surgery, radiotherapy, or a combined approach including both. Usually, EMPs are very sensitive to radiotherapy, and complete remission can be achieved by radiotherapy alone in 80% to 100% of cases.^6,11,15 Surgery is considered if the tumor is diffuse or is causing symptoms secondary to pressure on surrounding structures. A combined approach is recommended in cases with incomplete surgical margin or lymph node involvement.^5,6

There is limited evidence about and experience with the use of chemotherapy in the treatment of EMP. It has been recommended that chemotherapy be considered in patients with refractory or relapsed disease using the same regimen used in plasma cell myeloma.⁵ Katodritou and colleagues have reported using bortezomib and dexamethasone without surgery in a solitary gastric plasmacytoma to avoid the toxicity of gastrointestinal irradiation.⁷ Wei and colleagues treated a patient with EMP in the pancreas with bortezomib and achieved a near-complete remission.⁸ To our knowledge, there is no documented literature about the treatment of EMP of the thyroid with chemotherapy. In our patient, despite the treatment with surgery and radiation, there was persistent uptake on the PET scan, so we treated her with bortezomib and dexamethasone. Because there is an 11% to 30% risk of progression to multiple myeloma, long-term follow-up is recommended in EMP.¹¹

Conclusions

Solitary EMP of the thyroid gland is a rare condition. Plasma cell myeloma must be ruled out to make a diagnosis. Data on the incidence of EMP and its clinicopathological features are sparse, and literature describing proper guidelines on treatment is limited. It can be treated with radiotherapy, surgery, or a combined approach. There is limited data on the role of chemotherapy; our case adds to the available literature on using myeloma-based therapy in refractory disease and, to our knowledge, is the only case report using this in the literature on cases of EMP of the thyroid. Regular follow-up, even after the disease is in remission, is necessary because of the high risk of progression to plasma cell myeloma.

Plasma cell neoplasms involving tissues other than the bone marrow are known as extramedullary plasmacytoma (EMP).¹ EMPs mostly involve the head and neck region.² Solitary EMP involving only the thyroid gland is very rare.^3,4 Because of the limited knowledge about this condition and its rarity, its management can be challenging and is often extrapolated from plasma cell myeloma.^5,6 In general, surgery or radiation are considered as front-line therapy.^3,5 EMPs usually respond well to radiotherapy with almost complete remission. No definite guidelines outlining the treatment of radio-resistant EMP of the thyroid have yet been published. Data supporting the use of chemotherapy is particularly limited.^4,7,8

Here, we describe the case of a 53-year-old woman with a long history of thyroiditis who presented with rapidly worsening symptomatic thyroid enlargement. She was diagnosed with EMP of the thyroid gland that was not amenable to surgery and was refractory to radiotherapy but responded to adjuvant chemotherapy with bortezomib. This report highlights 2 unique aspects of this condition: it focuses on a rare case of EMP and, as far as we know, it reports for the first time on EMP that was resistant to radiotherapy. It also highlights the need for guidelines for the treatment of EMPs.
 

Case presentation and summary

A 53-year-old woman presented to the emergency department with complaints of difficulty swallowing, hoarseness, and neck pain during the previous 1 month. She had a known history of Hashimoto’s thyroiditis, and an ultrasound scan of her neck 6 years previously had demonstrated diffuse thyromegaly without discrete nodules. On presentation, the patient’s vitals were stable, and a neck examination revealed a firm and enlarged thyroid without any cervical adenopathy. Laboratory investigations revealed a normal complete blood count and comprehensive metabolic panel. She had an elevated thyroid-stimulating hormone level of 13.40 mIU/L (reference range, 0.47-4.68 mIU/L) and normal thyroxine level of 4.5 pmol/L (reference range, 4.5-12.0 pmol/L). A computerized tomography (CT) scan of the neck revealed an enlarged thyroid gland (right lobe length, 10.3 cm; isthmus, 2 cm; left lobe, 8 cm) with a focal area of increased echogenicity in the midpole of the left lobe measuring 9.5 mm × 5.5 mm. The patient was discharged to home with pain medications, and urgent follow-up with an otolaryngologist was arranged. A flexible laryngoscopy was done in the otolaryngology clinic, which revealed retropharyngeal bulging that correlated with the thyromegaly evident on the CT scan.

Because of the patient’s significant symptoms, we decided to proceed with surgery with a clinical diagnosis of likely thyroiditis. A left subtotal thyroidectomy with extension to the superior mediastinum was performed, but a right thyroidectomy could not be done safely. On gross examination, a well-capsulated left lobe with a tan-white, lobulated, soft cut surface was seen. Microscopic examination revealed replacement of thyroid parenchyma with sheets of mature-appearing plasma cells with eccentric round nuclei, abundant eosinophilic cytoplasm without atypia, and few scattered thyroid follicles with lymphoepithelial lesions (Figure 1A). Immunohistochemistry confirmed plasma cells with expression of CD138 (Figure 1B).

Discussion

Plasma cells are well-differentiated B-lymphocytes that secrete antibodies and provide protective immunity to the human body.⁹ Plasma cell neoplasms are clonal proliferation of plasma cells, producing monoclonal immunoglobulins. They are of the following different types: plasma cell myeloma, monoclonal gammopathy of unknown significance, immunoglobulin deposition disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, and plasmacytomas, which are divided into 2 types – solitary plasmacytoma of the bone, and extramedullary plasmacytoma (EMP).¹⁰ EMP is a rare condition and encompasses 3% to 5% of all plasma cell neoplasms, depending on the study.^1,2,5 It is more common in men than in women (2.6:1, respectively), with equal incidence among black and white patients. Median age at diagnosis is 62 years, and it is more common among those aged 40 to 70 years.^2,11 The most common sites of occurrence are the respiratory tract, the mouth, and the pharynx, but other sites such as the eyes, brain, skin, and lymph nodes may also be involved.²

EMP involving the thyroid gland is a very rare occurrence, but plasma cell myeloma has been shown to secondarily involve the thyroid.⁴ Similar to our report, EMP of the thyroid in the setting of thyroiditis has been reported by other authors.^3,4 The incidence of EMP occurring in the thyroid varies according to different authors. Wiltshaw found 7 cases involving the thyroid out of 272 cases of EMP.¹ Galieni and colleagues reported only 1 case that involved the thyroid out of 46 described cases of EMP.¹²

El- Siemińska and colleagues showed that levels of interleukin (IL)-6 are elevated in thyroiditis.¹³ IL-6 promotes monoclonal as well as polyclonal proliferation of plasma cells. Kovalchuk and colleagues showed an increase in EMP in IL-6 transgenic mice, suggesting a pathophysiologic explanation.¹⁴

The diagnostic requirements of EMP include the following: histology showing monoclonal plasma cell infiltration in tissue; bone marrow biopsy with normal plasma cell aspirate and biopsy (plasma cells, <5%); no lytic lesions on skeletal survey; no anemia, renal impairment, or hypercalcemia; and absent or low serum M protein.¹²

Our case fulfilled those criteria.

The treatment options for EMP include surgery, radiotherapy, or a combined approach including both. Usually, EMPs are very sensitive to radiotherapy, and complete remission can be achieved by radiotherapy alone in 80% to 100% of cases.^6,11,15 Surgery is considered if the tumor is diffuse or is causing symptoms secondary to pressure on surrounding structures. A combined approach is recommended in cases with incomplete surgical margin or lymph node involvement.^5,6

There is limited evidence about and experience with the use of chemotherapy in the treatment of EMP. It has been recommended that chemotherapy be considered in patients with refractory or relapsed disease using the same regimen used in plasma cell myeloma.⁵ Katodritou and colleagues have reported using bortezomib and dexamethasone without surgery in a solitary gastric plasmacytoma to avoid the toxicity of gastrointestinal irradiation.⁷ Wei and colleagues treated a patient with EMP in the pancreas with bortezomib and achieved a near-complete remission.⁸ To our knowledge, there is no documented literature about the treatment of EMP of the thyroid with chemotherapy. In our patient, despite the treatment with surgery and radiation, there was persistent uptake on the PET scan, so we treated her with bortezomib and dexamethasone. Because there is an 11% to 30% risk of progression to multiple myeloma, long-term follow-up is recommended in EMP.¹¹

Conclusions

Solitary EMP of the thyroid gland is a rare condition. Plasma cell myeloma must be ruled out to make a diagnosis. Data on the incidence of EMP and its clinicopathological features are sparse, and literature describing proper guidelines on treatment is limited. It can be treated with radiotherapy, surgery, or a combined approach. There is limited data on the role of chemotherapy; our case adds to the available literature on using myeloma-based therapy in refractory disease and, to our knowledge, is the only case report using this in the literature on cases of EMP of the thyroid. Regular follow-up, even after the disease is in remission, is necessary because of the high risk of progression to plasma cell myeloma.

Salivary ductal adenocarcinomas make up about 9% of malignant salivary gland tumors and occur mostly in men older than 50 years, with a peak incidence in the sixth and seventh decades. It is the most aggressive of salivary gland tumors and is histologically similar to high-grade, invasive ductal carcinoma of the breast. In all, 65% of patients will die of the disease, and most will experience skin ulceration and nerve palsy.¹ With such an aggressive clinical picture, the temptation for many oncologists and patients is to use aggressive cytotoxic chemotherapies. Considering the lack of large trials exploring treatment options in this less-common subtype of salivary gland carcinoma, practice guidelines also recommend the use of aggressive chemotherapies. Unlike other types of malignant cancers of the salivary glands, 70% to 90% of ductal adenocarcinomas express the androgen receptor (AR) by immunohistochemistry.² There are reported cases of androgen deprivation therapy (ADT) as a successful treatment for salivary ductal adenocarcinomas that express the AR (Table).In 2003, Locati and colleagues reported the case of a man with salivary ductal adenocarcinomas who had a complete response with ADT.³ In 2016, the same group of authors published a retrospective analysis of 17 patients with recurrent or metastatic AR-positive salivary gland cancers who were treated with ADT and reported a 64.7% overall response rate among the patients.⁴ A 10-patient case series in the Netherlands demonstrated a 50% response rate to ADT plus bicalutamide, including a palliative effect in the form of pain relief.⁵ A retrospective analysis by Price and colleagues of 5 patients with AR-positive metastatic salivary duct adenocarcinoma showed a 60% response rate to a combination of leuprolide and bicalutamide.⁶

Case presentation and summary

A 91-year-old man was diagnosed with salivary ductal adenocarcinoma of the left parotid gland in September 2013 and underwent left parotidectomy and lymph node dissection, which revealed AJCC stage IVA (pT2 pN3 M0) disease. The following year, in December 2014, he had an enlarging left neck mass that was pathologically confirmed to be recurrent disease, and he underwent left level V neck dissection in February 2015. Five months after surgery, in July 2015, he presented with left neck fullness and new skin nodules, and the results of a biopsy confirmed recurrent disease. Given his relatively asymptomatic state and advanced age, the oncology care team decided to follow the patient without any pharmacologic therapy.

The patient felt relatively well for 11 months but slowly developed increasing pain in the left neck in June 2016. The skin nodules also began to spread inferiorly from his left neck to his upper chest with the development of open sores that wept serous fluid with scab formation (Figure 1). He and his wife lived independently and managed all their own instrumental activities of daily living (IADL). Eventually, the pain in his neck became so severe that it began to interfere with his ability to drive. He declined radiation therapy because of side effects and transportation issues, but he desired something to alleviate the burden of the disease. During a multidisciplinary cancer conference, the staff pathologist and oncologist discussed AR immunohistochemistry to assist with management. In June 2016, the patient’s tumor was found to have AR immunostaining (nuclear pattern) in 100% of cells, and he was treated with combined androgen blockade, consisting of monthly 3.6 mg goserelin injections and daily bicalutamide 50 mg orally.

Discussion

The oncology care team clearly defined the goal of care for this patient as palliative and conveyed as such to the patient. The team considered the risks and side effects of cytotoxic chemotherapy agents to be contrary to the patient’s stated primary goal of independence. We selected the combined androgen blockade because it has a low toxicity rate and thus met the primary goals of therapy.

The European Organization for Research and Treatment of Cancer is presently conducting a trial in which cytotoxic chemotherapy is being compared with ADT in AR-positive salivary duct tumors. Findings from a recent prospective, phase-2 trial conducted in Japan suggested that combined AR blockade has similar efficacy and less toxicity than conventional cytotoxic chemotherapy for recurrent and/or metastatic and unresectable locally advanced AR-positive salivary gland carcinoma.⁷ As more data become available from other studies, it is possible that practice guidelines will be revised to recommend this treatment approach for these cancers.

Salivary ductal adenocarcinomas make up about 9% of malignant salivary gland tumors and occur mostly in men older than 50 years, with a peak incidence in the sixth and seventh decades. It is the most aggressive of salivary gland tumors and is histologically similar to high-grade, invasive ductal carcinoma of the breast. In all, 65% of patients will die of the disease, and most will experience skin ulceration and nerve palsy.¹ With such an aggressive clinical picture, the temptation for many oncologists and patients is to use aggressive cytotoxic chemotherapies. Considering the lack of large trials exploring treatment options in this less-common subtype of salivary gland carcinoma, practice guidelines also recommend the use of aggressive chemotherapies. Unlike other types of malignant cancers of the salivary glands, 70% to 90% of ductal adenocarcinomas express the androgen receptor (AR) by immunohistochemistry.² There are reported cases of androgen deprivation therapy (ADT) as a successful treatment for salivary ductal adenocarcinomas that express the AR (Table).In 2003, Locati and colleagues reported the case of a man with salivary ductal adenocarcinomas who had a complete response with ADT.³ In 2016, the same group of authors published a retrospective analysis of 17 patients with recurrent or metastatic AR-positive salivary gland cancers who were treated with ADT and reported a 64.7% overall response rate among the patients.⁴ A 10-patient case series in the Netherlands demonstrated a 50% response rate to ADT plus bicalutamide, including a palliative effect in the form of pain relief.⁵ A retrospective analysis by Price and colleagues of 5 patients with AR-positive metastatic salivary duct adenocarcinoma showed a 60% response rate to a combination of leuprolide and bicalutamide.⁶

Case presentation and summary

A 91-year-old man was diagnosed with salivary ductal adenocarcinoma of the left parotid gland in September 2013 and underwent left parotidectomy and lymph node dissection, which revealed AJCC stage IVA (pT2 pN3 M0) disease. The following year, in December 2014, he had an enlarging left neck mass that was pathologically confirmed to be recurrent disease, and he underwent left level V neck dissection in February 2015. Five months after surgery, in July 2015, he presented with left neck fullness and new skin nodules, and the results of a biopsy confirmed recurrent disease. Given his relatively asymptomatic state and advanced age, the oncology care team decided to follow the patient without any pharmacologic therapy.

The patient felt relatively well for 11 months but slowly developed increasing pain in the left neck in June 2016. The skin nodules also began to spread inferiorly from his left neck to his upper chest with the development of open sores that wept serous fluid with scab formation (Figure 1). He and his wife lived independently and managed all their own instrumental activities of daily living (IADL). Eventually, the pain in his neck became so severe that it began to interfere with his ability to drive. He declined radiation therapy because of side effects and transportation issues, but he desired something to alleviate the burden of the disease. During a multidisciplinary cancer conference, the staff pathologist and oncologist discussed AR immunohistochemistry to assist with management. In June 2016, the patient’s tumor was found to have AR immunostaining (nuclear pattern) in 100% of cells, and he was treated with combined androgen blockade, consisting of monthly 3.6 mg goserelin injections and daily bicalutamide 50 mg orally.

Discussion

The oncology care team clearly defined the goal of care for this patient as palliative and conveyed as such to the patient. The team considered the risks and side effects of cytotoxic chemotherapy agents to be contrary to the patient’s stated primary goal of independence. We selected the combined androgen blockade because it has a low toxicity rate and thus met the primary goals of therapy.

The European Organization for Research and Treatment of Cancer is presently conducting a trial in which cytotoxic chemotherapy is being compared with ADT in AR-positive salivary duct tumors. Findings from a recent prospective, phase-2 trial conducted in Japan suggested that combined AR blockade has similar efficacy and less toxicity than conventional cytotoxic chemotherapy for recurrent and/or metastatic and unresectable locally advanced AR-positive salivary gland carcinoma.⁷ As more data become available from other studies, it is possible that practice guidelines will be revised to recommend this treatment approach for these cancers.

Salivary ductal adenocarcinomas make up about 9% of malignant salivary gland tumors and occur mostly in men older than 50 years, with a peak incidence in the sixth and seventh decades. It is the most aggressive of salivary gland tumors and is histologically similar to high-grade, invasive ductal carcinoma of the breast. In all, 65% of patients will die of the disease, and most will experience skin ulceration and nerve palsy.¹ With such an aggressive clinical picture, the temptation for many oncologists and patients is to use aggressive cytotoxic chemotherapies. Considering the lack of large trials exploring treatment options in this less-common subtype of salivary gland carcinoma, practice guidelines also recommend the use of aggressive chemotherapies. Unlike other types of malignant cancers of the salivary glands, 70% to 90% of ductal adenocarcinomas express the androgen receptor (AR) by immunohistochemistry.² There are reported cases of androgen deprivation therapy (ADT) as a successful treatment for salivary ductal adenocarcinomas that express the AR (Table).In 2003, Locati and colleagues reported the case of a man with salivary ductal adenocarcinomas who had a complete response with ADT.³ In 2016, the same group of authors published a retrospective analysis of 17 patients with recurrent or metastatic AR-positive salivary gland cancers who were treated with ADT and reported a 64.7% overall response rate among the patients.⁴ A 10-patient case series in the Netherlands demonstrated a 50% response rate to ADT plus bicalutamide, including a palliative effect in the form of pain relief.⁵ A retrospective analysis by Price and colleagues of 5 patients with AR-positive metastatic salivary duct adenocarcinoma showed a 60% response rate to a combination of leuprolide and bicalutamide.⁶

Case presentation and summary

A 91-year-old man was diagnosed with salivary ductal adenocarcinoma of the left parotid gland in September 2013 and underwent left parotidectomy and lymph node dissection, which revealed AJCC stage IVA (pT2 pN3 M0) disease. The following year, in December 2014, he had an enlarging left neck mass that was pathologically confirmed to be recurrent disease, and he underwent left level V neck dissection in February 2015. Five months after surgery, in July 2015, he presented with left neck fullness and new skin nodules, and the results of a biopsy confirmed recurrent disease. Given his relatively asymptomatic state and advanced age, the oncology care team decided to follow the patient without any pharmacologic therapy.

The patient felt relatively well for 11 months but slowly developed increasing pain in the left neck in June 2016. The skin nodules also began to spread inferiorly from his left neck to his upper chest with the development of open sores that wept serous fluid with scab formation (Figure 1). He and his wife lived independently and managed all their own instrumental activities of daily living (IADL). Eventually, the pain in his neck became so severe that it began to interfere with his ability to drive. He declined radiation therapy because of side effects and transportation issues, but he desired something to alleviate the burden of the disease. During a multidisciplinary cancer conference, the staff pathologist and oncologist discussed AR immunohistochemistry to assist with management. In June 2016, the patient’s tumor was found to have AR immunostaining (nuclear pattern) in 100% of cells, and he was treated with combined androgen blockade, consisting of monthly 3.6 mg goserelin injections and daily bicalutamide 50 mg orally.

Discussion

The oncology care team clearly defined the goal of care for this patient as palliative and conveyed as such to the patient. The team considered the risks and side effects of cytotoxic chemotherapy agents to be contrary to the patient’s stated primary goal of independence. We selected the combined androgen blockade because it has a low toxicity rate and thus met the primary goals of therapy.

The European Organization for Research and Treatment of Cancer is presently conducting a trial in which cytotoxic chemotherapy is being compared with ADT in AR-positive salivary duct tumors. Findings from a recent prospective, phase-2 trial conducted in Japan suggested that combined AR blockade has similar efficacy and less toxicity than conventional cytotoxic chemotherapy for recurrent and/or metastatic and unresectable locally advanced AR-positive salivary gland carcinoma.⁷ As more data become available from other studies, it is possible that practice guidelines will be revised to recommend this treatment approach for these cancers.

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

Patients with Barrett high-grade dysplasia or esophageal adenocarcinoma who are positive for human papillomavirus (HPV) infection have significantly better outcomes than patients with the same diseases who are negative for HPV, investigators report.

Among patients with Barrett high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), mean disease-free survival (DFS) was 40.3 months for HPV-positive patients, compared with 24.1 months for HPV-negative patients (P = .003). Mean overall survival was also significantly better in HPV-positive patients, at 43.7 months versus 29.8 months (P =.009) respectively, reported Shanmugarajah Rajendra, MD, from Bankstown-Lincombe Hospital in Sydney and colleagues.

“If these findings of a favorable prognosis of HPV-positive HGD and EAC are confirmed in larger cohorts with more advanced disease, it presents an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival,” they wrote in JAMA Network Open.

The findings support those of earlier studies suggesting that HPV infection is associated with better prognosis among patients with other cancers of the head and neck. For example, a retrospective analysis of data from two clinical trials reported in 2014 found that, 2 years after a diagnosis of recurrent oropharyngeal cancer, 54.6% of HPV-positive patients were alive, compared with 27.6% of HPV-negative patients (P less than .001).

To determine whether there was a similar association between HPV infection and better prognosis of Barrett HGD or EAC, Dr. Rajendra and associates conducted a retrospective case-control study of 142 patients with HGD or EAC treated at secondary or tertiary referral centers in Australia. The patients, all of whom were white, included 126 men. The mean age was 66 years, and in all, 37 patients were positive for HPV.

As noted before, both DFS and overall survival were significantly better for HPV-infected patients, with mean differences of 16.2 months and 13.9 months, respectively. HPV-positive patients also had lower rates of progression or recurrence (24.3% vs. 58.1%; P less than .001), distant metastases (8.1% vs. 27.6%; P = .02), and death from EAC (13.5% vs. 36.2%; P = .02).

In multivariate analysis, superior DFS was associated with HPV positivity, (hazard ratio, 0.39; P = .02), biologically active virus (HR, 0.36; P = .02), E6 and E7 messenger RNA (HR, 0.36; P = .04), and with high p16 expression (HR, 0.49; P = .02).

The study was supported by the South Western Sydney Clinical School; the University of New South Wales, Sydney; and the Oesophageal Cancer Research Fund. Dr. Rajendra reported grants from the University of New South Wales and the Oesophageal Cancer Research Fund during the conduct of the study. No other disclosures were reported.

SOURCE: Rajendra S et al. JAMA Network Open. 2018 Aug 3. doi:10.1001/jamanetworkopen.2018.1054.

Patients with Barrett high-grade dysplasia or esophageal adenocarcinoma who are positive for human papillomavirus (HPV) infection have significantly better outcomes than patients with the same diseases who are negative for HPV, investigators report.

Among patients with Barrett high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), mean disease-free survival (DFS) was 40.3 months for HPV-positive patients, compared with 24.1 months for HPV-negative patients (P = .003). Mean overall survival was also significantly better in HPV-positive patients, at 43.7 months versus 29.8 months (P =.009) respectively, reported Shanmugarajah Rajendra, MD, from Bankstown-Lincombe Hospital in Sydney and colleagues.

“If these findings of a favorable prognosis of HPV-positive HGD and EAC are confirmed in larger cohorts with more advanced disease, it presents an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival,” they wrote in JAMA Network Open.

The findings support those of earlier studies suggesting that HPV infection is associated with better prognosis among patients with other cancers of the head and neck. For example, a retrospective analysis of data from two clinical trials reported in 2014 found that, 2 years after a diagnosis of recurrent oropharyngeal cancer, 54.6% of HPV-positive patients were alive, compared with 27.6% of HPV-negative patients (P less than .001).

To determine whether there was a similar association between HPV infection and better prognosis of Barrett HGD or EAC, Dr. Rajendra and associates conducted a retrospective case-control study of 142 patients with HGD or EAC treated at secondary or tertiary referral centers in Australia. The patients, all of whom were white, included 126 men. The mean age was 66 years, and in all, 37 patients were positive for HPV.

As noted before, both DFS and overall survival were significantly better for HPV-infected patients, with mean differences of 16.2 months and 13.9 months, respectively. HPV-positive patients also had lower rates of progression or recurrence (24.3% vs. 58.1%; P less than .001), distant metastases (8.1% vs. 27.6%; P = .02), and death from EAC (13.5% vs. 36.2%; P = .02).

In multivariate analysis, superior DFS was associated with HPV positivity, (hazard ratio, 0.39; P = .02), biologically active virus (HR, 0.36; P = .02), E6 and E7 messenger RNA (HR, 0.36; P = .04), and with high p16 expression (HR, 0.49; P = .02).

The study was supported by the South Western Sydney Clinical School; the University of New South Wales, Sydney; and the Oesophageal Cancer Research Fund. Dr. Rajendra reported grants from the University of New South Wales and the Oesophageal Cancer Research Fund during the conduct of the study. No other disclosures were reported.

SOURCE: Rajendra S et al. JAMA Network Open. 2018 Aug 3. doi:10.1001/jamanetworkopen.2018.1054.

Patients with Barrett high-grade dysplasia or esophageal adenocarcinoma who are positive for human papillomavirus (HPV) infection have significantly better outcomes than patients with the same diseases who are negative for HPV, investigators report.

Among patients with Barrett high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), mean disease-free survival (DFS) was 40.3 months for HPV-positive patients, compared with 24.1 months for HPV-negative patients (P = .003). Mean overall survival was also significantly better in HPV-positive patients, at 43.7 months versus 29.8 months (P =.009) respectively, reported Shanmugarajah Rajendra, MD, from Bankstown-Lincombe Hospital in Sydney and colleagues.

“If these findings of a favorable prognosis of HPV-positive HGD and EAC are confirmed in larger cohorts with more advanced disease, it presents an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival,” they wrote in JAMA Network Open.

The findings support those of earlier studies suggesting that HPV infection is associated with better prognosis among patients with other cancers of the head and neck. For example, a retrospective analysis of data from two clinical trials reported in 2014 found that, 2 years after a diagnosis of recurrent oropharyngeal cancer, 54.6% of HPV-positive patients were alive, compared with 27.6% of HPV-negative patients (P less than .001).

To determine whether there was a similar association between HPV infection and better prognosis of Barrett HGD or EAC, Dr. Rajendra and associates conducted a retrospective case-control study of 142 patients with HGD or EAC treated at secondary or tertiary referral centers in Australia. The patients, all of whom were white, included 126 men. The mean age was 66 years, and in all, 37 patients were positive for HPV.

As noted before, both DFS and overall survival were significantly better for HPV-infected patients, with mean differences of 16.2 months and 13.9 months, respectively. HPV-positive patients also had lower rates of progression or recurrence (24.3% vs. 58.1%; P less than .001), distant metastases (8.1% vs. 27.6%; P = .02), and death from EAC (13.5% vs. 36.2%; P = .02).

In multivariate analysis, superior DFS was associated with HPV positivity, (hazard ratio, 0.39; P = .02), biologically active virus (HR, 0.36; P = .02), E6 and E7 messenger RNA (HR, 0.36; P = .04), and with high p16 expression (HR, 0.49; P = .02).

The study was supported by the South Western Sydney Clinical School; the University of New South Wales, Sydney; and the Oesophageal Cancer Research Fund. Dr. Rajendra reported grants from the University of New South Wales and the Oesophageal Cancer Research Fund during the conduct of the study. No other disclosures were reported.

SOURCE: Rajendra S et al. JAMA Network Open. 2018 Aug 3. doi:10.1001/jamanetworkopen.2018.1054.

In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?

No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).

They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.

The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.

In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?

No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).

They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.

The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.

In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?

No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).

They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.

The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.

Head and neck cancer is among the most prevalent cancers in developing countries.¹ Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.¹ Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.² The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.² We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.

Case presentation and summary

A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m²). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.

The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).

Discussion

Head and neck cancer is one of the most common cancers in developing countries.¹ Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.² These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).³

Head and neck cancer is among the most prevalent cancers in developing countries.¹ Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.¹ Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.² The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.² We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.

Case presentation and summary

A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m²). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.

The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).

Discussion

Head and neck cancer is one of the most common cancers in developing countries.¹ Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.² These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).³

Head and neck cancer is among the most prevalent cancers in developing countries.¹ Most of the patients in developing countries present in locally advanced stages, and radical radiation therapy with concurrent chemotherapy is the standard treatment.¹ Radiation therapy is associated with radiation dermatitis, which causes severe symptoms in the patient and can lead to disruption of treatment, diminished rates of disease control rates, and impaired patient quality of life.² The management of advanced radiation dermatitis is difficult and can cause consequential late morbidity to patients.² We report here the rare case of a patient with locally advanced tonsil carcinoma who developed grade 3 radiation dermatitis while receiving radical chemoradiation. The patient’s radiation dermatitis was effectively managed with the use of a silver-containing antimicrobial dressing that yielded remarkable results, so the patient was able to resume and complete radiation therapy.

Case presentation and summary

A 48-year-old man was diagnosed with squamous cell carcinoma of the right tonsil, with bilateral neck nodes (Stage T4a N2c M0; The American Joint Committee on Cancer staging manual, 7th edition). In view of the locally advanced status of his disease, the patient was scheduled for radical radiation therapy at 70 Gy in 35 fractions over 7 weeks along with weekly chemotherapy (cisplatin 40 mg/m²). During the course of radiation therapy, the patient was monitored twice a week, and symptomatic care was done for radiation-therapy–induced toxicities.

The patient presented with grade 3 radiation dermatitis after receiving 58 Gy in 29 fractions over 5 weeks (grade 0, no change; grades 3 and 4, severe change). The radiation dermatitis involved the anterior and bilateral neck with moist desquamation of the skin (Figure 1).

Discussion

Head and neck cancer is one of the most common cancers in developing countries.¹ Most patients present with locally advanced disease, so chemoradiation is the standard treatment in these patents. Radiation therapy is associated with acute and chronic toxicities. The common radiation therapy toxicities are directed at skin and mucosa, which leads to radiation dermatitis and radiation mucositis, respectively.² These toxicities are graded as per the Radiation Therapy Oncology Group (RTOG) criteria (Table 2).³

The American Cancer Society reports that 1.6 million people are diagnosed with cancer each year, of whom 78% are aged 55 years or older. The 5-year survival rate for cancer is 68%.¹ Almost 15.5 million living Americans have been diagnosed with cancer.² Many patients with cancer have difficulty walking and with activities of daily living. Patients with primary brain tumors or tumors metastatic to the brain may present with focal weakness or cognitive deficits similar to patients with stroke. Patients with tumors metastatic to the spine may have the same deficits as a patient with a traumatic spinal cord injury. Patients with metastasis to bone may have pathologic fractures of the hip or long bones. Patients may develop peripheral neuropathy associated with a paraneoplastic syndrome, chemotherapy, or critical illness neuropathy. Lehmann and colleagues evaluated 805 patients admitted to hospitals affiliated with the University of Washington Medical School with a diagnosis of cancer and found that 15% had difficulty walking and 20% had difficulty with activities of daily living.³

Many patients with cancer can benefit from inpatient rehabilitation.^4,5 Study findings have shown that patients with impairments in function related to cancer are often not referred for rehabilitation. Among the reasons mentioned for that are that oncologists are more focused on treating the patients’ cancer than on their functional deficits and that specialists in rehabilitation medicine do not want to be involved with patients with complex medical problems. Rehabilitation facilities may not want to incur the costs associated with caring for patients with cancer.⁶

The present paper looks at the outcomes of 61 consecutive patients with cancer who were admitted to an inpatient rehabilitation facility (IRF) and received radiation therapy concurrent with rehabilitation. It compares the outcomes of the cancer patients with the outcomes of patients without cancer who were admitted with stroke or spinal cord injury, conditions more commonly treated at an IRF.
 

Methods

We reviewed electronic medical records of all patients with cancer admitted to the IRF from 2008 through 2013 who received radiation therapy while at the facility. We also reviewed the data of all patients without cancer admitted with a diagnosis of stroke in 2013 and all patients admitted with a diagnosis of traumatic spinal cord injury in 2012 and 2013. No patients were excluded from stroke and traumatic spinal cord injury groups.

We recorded the sex, age, diagnostic group, Functional Independence Measure (FIM) admission score, FIM discharge score, length of stay (LoS) in the IRF, place of discharge of each patient (eg, home, acute care, or subacute care), and calculated the FIM efficiency score (change in FIM/LoS) for each patient. The FIM is an instrument that has 18 items measuring mobility, participation in activities of daily living, ability to communicate, and cognitive function.⁷ Each item is scored from 1 to 7, with 1 denoting that the patient cannot perform the task and 7 that the activity can be performed independently. The minimum score is 18 (complete dependence), and the maximum score is 126 (independent function). Thirteen items compose the motor FIM score: eating, grooming, bathing, dressing upper body, dressing lower body, toileting, bladder management, management of bowel, transfer to bed or wheelchair, transfer to toilet, tub transfer, walking (or wheelchair use), and climbing stairs. Five items – comprehension, expression, social interaction, problem solving, and memory – compose the cognitive FIM score.

We used a 1-way analysis of variance to evaluate differences between age and cancer type, age and diagnostic group, admission FIM score and cancer type, discharge FIM score and cancer type, change in FIM and cancer type, LoS and cancer type, and LoS and diagnostic group. The Pearson chi-square test was used to test the goodness of fit between the place of disposition and diagnostic group. The paired t test was used to evaluate the improvement in FIM of the patients who were in the cancer groups. The Tukey Simultaneous Tests for Differences of Means was used to compare the FIM efficiency scores of the groups. A 2-sample t test was used to evaluate the factors associated with the need for transfer from the IRF to the acute medical service.

Results

The demographic characteristics of the patients in the study and the admission and discharge FIM scores are reported in Table 1. There were initially 62 cancer patients in the radiation group, which was further divided into 4 subgroups based on the site of the primary tumor or metastasis. In all, 23 had a primary malignant brain tumor and received radiation and temozolomide. Sixteen patients had malignancies metastatic to the brain, 15 patients had tumors metastatic to the spine, and 7 had tumors metastatic to the long bones. One patient had laryngeal cancer and was excluded from the study because we did not think that we could do an analysis of a group with only 1 patient. The final number of patients in the cancer group was therefore 61. There were 69 patients in the stroke group and 23 in the spinal cord injury group.

We report improvement in total FIM, motor FIM, and cognitive FIM scores and were able to identify all 18 of the items of the FIM score on 60 of the 61 patients in the cancer group. Improvement in total FIM of the 61 patients in the cancer groups was significant at P P P = .05. Just over 75% of the patients in the cancer group had sufficient enough improvement in their level of function that they were able to return to their homes (Table 1). The average FIM score at the time of discharge was 83.08. This was not significantly different than the level of function of patients discharged after stroke (87.52) or traumatic spinal cord injury (89.13).

The patients with primary brain tumors were younger than the patients with cancer metastatic to the brain (P = .013). The patients with a primary brain tumor had lower admission FIM scores than patients with tumors metastatic to the brain (P = .027). The patients with a primary brain tumor had a greater increase in FIM score than patients with metastasis to the brain (P = .043; Table 2). There was not a significant difference between these 2 groups in FIM score at discharge or in the likelihood of discharge to home (Table 1). The FIM efficiency score was 1.12 for the patients in the primary brain tumor group and .80 in those with metastasis to the brain. This difference was not significant P = .96.

Discussion

Radiation therapy is considered a service that is provided to people who come for treatment as an outpatient. Caregivers may have difficulty transporting patients to radiation if the patient has deficits in mobility. This may be particularly true if the patient is heavy, the caregivers are frail, or perhaps if they live in rural settings where there is no wheelchair-accessible public transportation. There are many factors that help determine whether a patient with functional deficits can be discharged to his or her home. These include sex, age, marital status, family and/or community support, income, and insurance.⁸ The FIM is an instrument that indicates how much help a patient needs with mobility and self-care skills. It also correlates with the amount of time that caregivers must spend helping a patient.⁹ Study findings have shown that the FIM score is an important determinant of whether a patient can be discharged to home. The total FIM score is as useful as an analysis of the components of the FIM score in predicting whether a patient can return to the community.^10,11 Reistetter and colleagues found a total FIM score of 78 to be the score that best separates patients who are likely to be able to go home and patients who are likely to need long-term care.¹¹ Bottemiller and colleagues¹⁰ reported that 37% of patients with total discharge FIM scores of less than 40 were discharged to home. They reported that 62% of patients with FIM scores between 40 and 79 were discharged to home, and 88% of patients with scores of 80 or above were discharged to home.¹⁰ The goal in bringing patients to the IRF was to accept and treat patients with reasonable community support and potential to achieve a functional level compatible with discharge to the community. Most patients in each of the cancer groups were able to reach an FIM score of 78 to 80 and to be discharged to home.

Most of the patients in the cancer groups had underlying problems that are not considered curable. The primary goal was to enable the patients to have some time at home with their families before requiring readmission to a hospital or hospice care. Reasonable LoS and rate of progress are now expected or required by third-party payors and hospital administrators. Physicians at the Mayo Clinic have indicated that a rehabilitation service should aim for an FIM efficiency score of at least .6 points per day.¹⁰ The FIM efficiency of patients in each of the 4 cancer subgroups in this study was higher than this level.

J. Herbert Dietz, Jr was an early advocate of the need to provide comprehensive rehabilitation services for patients with cancer. He first described his work in 1969.¹² Since that time, there have been many papers that have documented the benefits of IRF for patients with cancer. O’Toole and Golden have shown outcomes of a large series of patients from an IRF. They reported that at the time of admission, 14% of patients could ambulate, but at discharge, 80% could ambulate without hands-on assistance. They reported significant improvements in continence, FIM score, and score on the Karnofsky Performance Scale.¹³ Marciniak,¹⁴ Hunter,¹⁵ Shin,¹⁶ and Cole,¹⁷ and their respective colleagues have all shown that patients with many different types of cancer benefit from rehabilitation at the IRF level. Gallegos-Kearin and colleagues⁴ reported on the care of 115,570 patients admitted to IRF with cancer from 2002 to 2014. Patients had significant improvement in function, with more than 70% of patients discharged to home.⁴ Ng and colleagues studied a group of 200 patients who received IRF care and found there was significant improvement in function. Ninety-four percent of patients rated their stay as either extremely good or very good.⁵

Metastasis to the spine is a common problem. It is found in 30% of cancer patients at autopsy. The most common sources of metastasis to the spine are breast, lung, prostate, kidney, and thyroid.¹⁸ Multiple myeloma and lymphoma may also involve the spine. Several authors have shown that these patients benefit from inpatient rehabilitation. Mckinley and colleagues¹⁹ have noted that patients with metastasis to the spine make significant improvement with care at an IRF. Compared with patients with a traumatic spinal cord injury, the cancer patients had shorter LoS, smaller improvement in FIM, equal FIM efficiency (FIM gain/LoS), and equal success in making enough progress to be discharged to home.¹⁹ Eriks and colleagues showed that patients at an IRF in Amsterdam made significant improvement in function as measured by the Barthel’s Index.²⁰ Tang .,²¹ and Parsch²² and their respective colleagues, Murray,²³ and New²⁴ and colleagues have published findings confirming that patients with spinal cord injury caused by metastasis to the spine make significant progress with inpatient rehabilitation programs. The present study adds to the literature by showing that patients with metastasis to the spine who are receiving radiation can make progress and be discharged to the community.

There are 24,000 new cases of primary malignant brain tumors in the United States each year.²⁵ The incidence of metastatic cancer to the brain has been estimated to be 100,000 cases per year in the United States. The most common cancer sources are lung, breast, melanoma, kidney, and colon.^26,27 The first study of patients admitted to an IRF for treatment of brain tumors was published in 1998 by Huang and colleagues²⁸ who compared the outcomes of 63 patients with brain tumors with the outcomes of 63 patients with stroke. They reported that the patients with the brain tumors made significant improvement in function. There was not a significant difference between the 2 groups of patients in improvement in function, FIM efficiency, or success in discharging the patients to home.²⁸ Greenberg²⁹ and Bartolo³⁰ and their respective colleagues compared the outcomes of patients admitted with brain tumors and patients with stroke and found that improvement in function and discharge to home was similar in the 2 groups. In 2000, Huang and his same colleagues³¹ compared a group of patients with brain tumors to a group of patients with traumatic brain injury. They found significant improvement in the function of the patients with brain tumors. Patients in the traumatic brain injury group made more progress but had longer LoS. FIM efficiency was not significantly different between the groups.³¹

Three papers have reported outcomes of patients who received radiation concurrent with inpatient rehabilitation. Tang and colleagues³² reported 63 patients, of whom 48% percent received radiation concurrent with rehabilitation. The patients who received radiation made significant gains in function, and more than 70% were discharged to home. There was no difference in the outcomes of the patients in the radiation and nonradiation groups.³² Marciniak³³ and O’Dell³⁴ and their colleagues also reported that patients with brain tumors that required radiation therapy can benefit from inpatient rehabilitation. The present paper is the fourth (with the largest patient group) to show that patients with primary and metastatic tumors to the brain can benefit from a program that provides radiation concurrent with inpatient rehabilitation. We have shown that patients can achieve functional levels and rates of discharge to home that are not significantly different from those of the most commonly admitted group of patients to IRF – patients with stroke.

In the present study, 18% of all of the cancer patients were transferred to medical services and/or acute hospital care (Table 1). This is consistent with a paper by Asher and colleagues³⁵ who reported that 17.4% of patients at an IRF with a diagnosis of cancer required transfer back to medical service, and that low admission motor FIM score correlated with the likelihood of transfer back to medical service. In the present paper, the total admission FIM score was not related to the likelihood of return to medical service, although a lack of improvement in the FIM score did correlate with transfer to medical service.

All of the papers we reviewed found that appropriately selected patients with cancer make significant improvement in function with treatment at an IRF. Tang and colleagues have also shown that for patients with malignant brain tumors and metastasis to the spine, improvement in function correlates with increased survival.³² Our paper confirms that patients with primary malignant brain tumors, malignant tumors metastatic to the brain or spine, and tumors metastatic to long bones may benefit from rehabilitation concurrent with radiation. Rehabilitation units are traditionally associated with treating patients with stroke and spinal cord injury. The patients in our study had cancer and were receiving radiation therapy. They had significant improvement in function and FIM efficiency scores that are not below the threshold set as expected for care at an IRF. Most patients in our study achieved a functional level consistent with what is needed to go home.

There is a prospective payment or reimbursement system for rehabilitation units.³⁶ The payments are based on the admitting diagnosis, the admission FIM score, the age of the patient, and comorbidities. There are 4 tiers for comorbidities with no additional payments for patients in tier 0 but with additional payments for patients with conditions that qualify for tiers 1 through 3. The highest payments are for patients in tier 1. Examples of conditions that can increase payment include morbid obesity, congestive heart failure, vocal cord paralysis, and the need for hemodialysis. There is no increased payment for provision of radiation therapy. There are no reports on the feasibility, in terms of finances, of providing radiation on an IRF. We asked the finance office of the Albany Medical Center to comment on the cost to the hospital of providing radiation therapy to patients on the rehabilitation unit. The hospital’s finance department reviewed available data and reported that the variable cost of providing radiation therapy is about 6.5% of the revenue collected from third-party payors for caring for patients who receive that service (personal communication from the finance office of Albany Medical Center to George Forrest, 2015). Our findings suggest that the Centers for Medicare & Medicaid Services should make an adjustment to the payment system to support the cost of providing radiation to patients at an IRF. Even under the current payment system, for a hospital that has the equipment and personnel to provide radiation treatments, the variable cost of 6.5% of revenue should not be an absolute barrier to providing this service.
 

Limitations

This study reports on the experience of only 1 facility. The number of patients in the radiation group is greater than the number of patients in any previous report of people receiving radiation at an IRF, but the statistician does not think it is large enough to allow statistical analysis of covariates such as age, sex, and comorbid conditions. In addition, we did not investigate all of the factors that influence the type of care patients are offered and their LoS, such as hospital policy, insurance coverage, income, and family structure.

Conclusions

Acute care medical units are now challenged to both reduce LoS and reduce the number of patients who are readmitted to the hospital. Rehabilitation units are challenged to maintain census, as government and private payors are shifting patients from acute rehabilitation units to subacute rehabilitation units. We found that patients with cancer who need radiation are a population of patients who are seen by payors as needing to be in a facility with excellent nursing, therapy, and comprehensive physician services. A comprehensive cancer care program within a rehabilitation unit can be a great benefit to the acute care services, the IRF, and, most importantly, patients and their families.

The American Cancer Society reports that 1.6 million people are diagnosed with cancer each year, of whom 78% are aged 55 years or older. The 5-year survival rate for cancer is 68%.¹ Almost 15.5 million living Americans have been diagnosed with cancer.² Many patients with cancer have difficulty walking and with activities of daily living. Patients with primary brain tumors or tumors metastatic to the brain may present with focal weakness or cognitive deficits similar to patients with stroke. Patients with tumors metastatic to the spine may have the same deficits as a patient with a traumatic spinal cord injury. Patients with metastasis to bone may have pathologic fractures of the hip or long bones. Patients may develop peripheral neuropathy associated with a paraneoplastic syndrome, chemotherapy, or critical illness neuropathy. Lehmann and colleagues evaluated 805 patients admitted to hospitals affiliated with the University of Washington Medical School with a diagnosis of cancer and found that 15% had difficulty walking and 20% had difficulty with activities of daily living.³

Many patients with cancer can benefit from inpatient rehabilitation.^4,5 Study findings have shown that patients with impairments in function related to cancer are often not referred for rehabilitation. Among the reasons mentioned for that are that oncologists are more focused on treating the patients’ cancer than on their functional deficits and that specialists in rehabilitation medicine do not want to be involved with patients with complex medical problems. Rehabilitation facilities may not want to incur the costs associated with caring for patients with cancer.⁶

The present paper looks at the outcomes of 61 consecutive patients with cancer who were admitted to an inpatient rehabilitation facility (IRF) and received radiation therapy concurrent with rehabilitation. It compares the outcomes of the cancer patients with the outcomes of patients without cancer who were admitted with stroke or spinal cord injury, conditions more commonly treated at an IRF.
 

Methods

We reviewed electronic medical records of all patients with cancer admitted to the IRF from 2008 through 2013 who received radiation therapy while at the facility. We also reviewed the data of all patients without cancer admitted with a diagnosis of stroke in 2013 and all patients admitted with a diagnosis of traumatic spinal cord injury in 2012 and 2013. No patients were excluded from stroke and traumatic spinal cord injury groups.

We recorded the sex, age, diagnostic group, Functional Independence Measure (FIM) admission score, FIM discharge score, length of stay (LoS) in the IRF, place of discharge of each patient (eg, home, acute care, or subacute care), and calculated the FIM efficiency score (change in FIM/LoS) for each patient. The FIM is an instrument that has 18 items measuring mobility, participation in activities of daily living, ability to communicate, and cognitive function.⁷ Each item is scored from 1 to 7, with 1 denoting that the patient cannot perform the task and 7 that the activity can be performed independently. The minimum score is 18 (complete dependence), and the maximum score is 126 (independent function). Thirteen items compose the motor FIM score: eating, grooming, bathing, dressing upper body, dressing lower body, toileting, bladder management, management of bowel, transfer to bed or wheelchair, transfer to toilet, tub transfer, walking (or wheelchair use), and climbing stairs. Five items – comprehension, expression, social interaction, problem solving, and memory – compose the cognitive FIM score.

We used a 1-way analysis of variance to evaluate differences between age and cancer type, age and diagnostic group, admission FIM score and cancer type, discharge FIM score and cancer type, change in FIM and cancer type, LoS and cancer type, and LoS and diagnostic group. The Pearson chi-square test was used to test the goodness of fit between the place of disposition and diagnostic group. The paired t test was used to evaluate the improvement in FIM of the patients who were in the cancer groups. The Tukey Simultaneous Tests for Differences of Means was used to compare the FIM efficiency scores of the groups. A 2-sample t test was used to evaluate the factors associated with the need for transfer from the IRF to the acute medical service.

Results

The demographic characteristics of the patients in the study and the admission and discharge FIM scores are reported in Table 1. There were initially 62 cancer patients in the radiation group, which was further divided into 4 subgroups based on the site of the primary tumor or metastasis. In all, 23 had a primary malignant brain tumor and received radiation and temozolomide. Sixteen patients had malignancies metastatic to the brain, 15 patients had tumors metastatic to the spine, and 7 had tumors metastatic to the long bones. One patient had laryngeal cancer and was excluded from the study because we did not think that we could do an analysis of a group with only 1 patient. The final number of patients in the cancer group was therefore 61. There were 69 patients in the stroke group and 23 in the spinal cord injury group.

We report improvement in total FIM, motor FIM, and cognitive FIM scores and were able to identify all 18 of the items of the FIM score on 60 of the 61 patients in the cancer group. Improvement in total FIM of the 61 patients in the cancer groups was significant at P P P = .05. Just over 75% of the patients in the cancer group had sufficient enough improvement in their level of function that they were able to return to their homes (Table 1). The average FIM score at the time of discharge was 83.08. This was not significantly different than the level of function of patients discharged after stroke (87.52) or traumatic spinal cord injury (89.13).

The patients with primary brain tumors were younger than the patients with cancer metastatic to the brain (P = .013). The patients with a primary brain tumor had lower admission FIM scores than patients with tumors metastatic to the brain (P = .027). The patients with a primary brain tumor had a greater increase in FIM score than patients with metastasis to the brain (P = .043; Table 2). There was not a significant difference between these 2 groups in FIM score at discharge or in the likelihood of discharge to home (Table 1). The FIM efficiency score was 1.12 for the patients in the primary brain tumor group and .80 in those with metastasis to the brain. This difference was not significant P = .96.

Discussion

Radiation therapy is considered a service that is provided to people who come for treatment as an outpatient. Caregivers may have difficulty transporting patients to radiation if the patient has deficits in mobility. This may be particularly true if the patient is heavy, the caregivers are frail, or perhaps if they live in rural settings where there is no wheelchair-accessible public transportation. There are many factors that help determine whether a patient with functional deficits can be discharged to his or her home. These include sex, age, marital status, family and/or community support, income, and insurance.⁸ The FIM is an instrument that indicates how much help a patient needs with mobility and self-care skills. It also correlates with the amount of time that caregivers must spend helping a patient.⁹ Study findings have shown that the FIM score is an important determinant of whether a patient can be discharged to home. The total FIM score is as useful as an analysis of the components of the FIM score in predicting whether a patient can return to the community.^10,11 Reistetter and colleagues found a total FIM score of 78 to be the score that best separates patients who are likely to be able to go home and patients who are likely to need long-term care.¹¹ Bottemiller and colleagues¹⁰ reported that 37% of patients with total discharge FIM scores of less than 40 were discharged to home. They reported that 62% of patients with FIM scores between 40 and 79 were discharged to home, and 88% of patients with scores of 80 or above were discharged to home.¹⁰ The goal in bringing patients to the IRF was to accept and treat patients with reasonable community support and potential to achieve a functional level compatible with discharge to the community. Most patients in each of the cancer groups were able to reach an FIM score of 78 to 80 and to be discharged to home.

Most of the patients in the cancer groups had underlying problems that are not considered curable. The primary goal was to enable the patients to have some time at home with their families before requiring readmission to a hospital or hospice care. Reasonable LoS and rate of progress are now expected or required by third-party payors and hospital administrators. Physicians at the Mayo Clinic have indicated that a rehabilitation service should aim for an FIM efficiency score of at least .6 points per day.¹⁰ The FIM efficiency of patients in each of the 4 cancer subgroups in this study was higher than this level.

J. Herbert Dietz, Jr was an early advocate of the need to provide comprehensive rehabilitation services for patients with cancer. He first described his work in 1969.¹² Since that time, there have been many papers that have documented the benefits of IRF for patients with cancer. O’Toole and Golden have shown outcomes of a large series of patients from an IRF. They reported that at the time of admission, 14% of patients could ambulate, but at discharge, 80% could ambulate without hands-on assistance. They reported significant improvements in continence, FIM score, and score on the Karnofsky Performance Scale.¹³ Marciniak,¹⁴ Hunter,¹⁵ Shin,¹⁶ and Cole,¹⁷ and their respective colleagues have all shown that patients with many different types of cancer benefit from rehabilitation at the IRF level. Gallegos-Kearin and colleagues⁴ reported on the care of 115,570 patients admitted to IRF with cancer from 2002 to 2014. Patients had significant improvement in function, with more than 70% of patients discharged to home.⁴ Ng and colleagues studied a group of 200 patients who received IRF care and found there was significant improvement in function. Ninety-four percent of patients rated their stay as either extremely good or very good.⁵

Metastasis to the spine is a common problem. It is found in 30% of cancer patients at autopsy. The most common sources of metastasis to the spine are breast, lung, prostate, kidney, and thyroid.¹⁸ Multiple myeloma and lymphoma may also involve the spine. Several authors have shown that these patients benefit from inpatient rehabilitation. Mckinley and colleagues¹⁹ have noted that patients with metastasis to the spine make significant improvement with care at an IRF. Compared with patients with a traumatic spinal cord injury, the cancer patients had shorter LoS, smaller improvement in FIM, equal FIM efficiency (FIM gain/LoS), and equal success in making enough progress to be discharged to home.¹⁹ Eriks and colleagues showed that patients at an IRF in Amsterdam made significant improvement in function as measured by the Barthel’s Index.²⁰ Tang .,²¹ and Parsch²² and their respective colleagues, Murray,²³ and New²⁴ and colleagues have published findings confirming that patients with spinal cord injury caused by metastasis to the spine make significant progress with inpatient rehabilitation programs. The present study adds to the literature by showing that patients with metastasis to the spine who are receiving radiation can make progress and be discharged to the community.

There are 24,000 new cases of primary malignant brain tumors in the United States each year.²⁵ The incidence of metastatic cancer to the brain has been estimated to be 100,000 cases per year in the United States. The most common cancer sources are lung, breast, melanoma, kidney, and colon.^26,27 The first study of patients admitted to an IRF for treatment of brain tumors was published in 1998 by Huang and colleagues²⁸ who compared the outcomes of 63 patients with brain tumors with the outcomes of 63 patients with stroke. They reported that the patients with the brain tumors made significant improvement in function. There was not a significant difference between the 2 groups of patients in improvement in function, FIM efficiency, or success in discharging the patients to home.²⁸ Greenberg²⁹ and Bartolo³⁰ and their respective colleagues compared the outcomes of patients admitted with brain tumors and patients with stroke and found that improvement in function and discharge to home was similar in the 2 groups. In 2000, Huang and his same colleagues³¹ compared a group of patients with brain tumors to a group of patients with traumatic brain injury. They found significant improvement in the function of the patients with brain tumors. Patients in the traumatic brain injury group made more progress but had longer LoS. FIM efficiency was not significantly different between the groups.³¹

Three papers have reported outcomes of patients who received radiation concurrent with inpatient rehabilitation. Tang and colleagues³² reported 63 patients, of whom 48% percent received radiation concurrent with rehabilitation. The patients who received radiation made significant gains in function, and more than 70% were discharged to home. There was no difference in the outcomes of the patients in the radiation and nonradiation groups.³² Marciniak³³ and O’Dell³⁴ and their colleagues also reported that patients with brain tumors that required radiation therapy can benefit from inpatient rehabilitation. The present paper is the fourth (with the largest patient group) to show that patients with primary and metastatic tumors to the brain can benefit from a program that provides radiation concurrent with inpatient rehabilitation. We have shown that patients can achieve functional levels and rates of discharge to home that are not significantly different from those of the most commonly admitted group of patients to IRF – patients with stroke.

In the present study, 18% of all of the cancer patients were transferred to medical services and/or acute hospital care (Table 1). This is consistent with a paper by Asher and colleagues³⁵ who reported that 17.4% of patients at an IRF with a diagnosis of cancer required transfer back to medical service, and that low admission motor FIM score correlated with the likelihood of transfer back to medical service. In the present paper, the total admission FIM score was not related to the likelihood of return to medical service, although a lack of improvement in the FIM score did correlate with transfer to medical service.

All of the papers we reviewed found that appropriately selected patients with cancer make significant improvement in function with treatment at an IRF. Tang and colleagues have also shown that for patients with malignant brain tumors and metastasis to the spine, improvement in function correlates with increased survival.³² Our paper confirms that patients with primary malignant brain tumors, malignant tumors metastatic to the brain or spine, and tumors metastatic to long bones may benefit from rehabilitation concurrent with radiation. Rehabilitation units are traditionally associated with treating patients with stroke and spinal cord injury. The patients in our study had cancer and were receiving radiation therapy. They had significant improvement in function and FIM efficiency scores that are not below the threshold set as expected for care at an IRF. Most patients in our study achieved a functional level consistent with what is needed to go home.

There is a prospective payment or reimbursement system for rehabilitation units.³⁶ The payments are based on the admitting diagnosis, the admission FIM score, the age of the patient, and comorbidities. There are 4 tiers for comorbidities with no additional payments for patients in tier 0 but with additional payments for patients with conditions that qualify for tiers 1 through 3. The highest payments are for patients in tier 1. Examples of conditions that can increase payment include morbid obesity, congestive heart failure, vocal cord paralysis, and the need for hemodialysis. There is no increased payment for provision of radiation therapy. There are no reports on the feasibility, in terms of finances, of providing radiation on an IRF. We asked the finance office of the Albany Medical Center to comment on the cost to the hospital of providing radiation therapy to patients on the rehabilitation unit. The hospital’s finance department reviewed available data and reported that the variable cost of providing radiation therapy is about 6.5% of the revenue collected from third-party payors for caring for patients who receive that service (personal communication from the finance office of Albany Medical Center to George Forrest, 2015). Our findings suggest that the Centers for Medicare & Medicaid Services should make an adjustment to the payment system to support the cost of providing radiation to patients at an IRF. Even under the current payment system, for a hospital that has the equipment and personnel to provide radiation treatments, the variable cost of 6.5% of revenue should not be an absolute barrier to providing this service.
 

Limitations

This study reports on the experience of only 1 facility. The number of patients in the radiation group is greater than the number of patients in any previous report of people receiving radiation at an IRF, but the statistician does not think it is large enough to allow statistical analysis of covariates such as age, sex, and comorbid conditions. In addition, we did not investigate all of the factors that influence the type of care patients are offered and their LoS, such as hospital policy, insurance coverage, income, and family structure.

Conclusions

Acute care medical units are now challenged to both reduce LoS and reduce the number of patients who are readmitted to the hospital. Rehabilitation units are challenged to maintain census, as government and private payors are shifting patients from acute rehabilitation units to subacute rehabilitation units. We found that patients with cancer who need radiation are a population of patients who are seen by payors as needing to be in a facility with excellent nursing, therapy, and comprehensive physician services. A comprehensive cancer care program within a rehabilitation unit can be a great benefit to the acute care services, the IRF, and, most importantly, patients and their families.

The American Cancer Society reports that 1.6 million people are diagnosed with cancer each year, of whom 78% are aged 55 years or older. The 5-year survival rate for cancer is 68%.¹ Almost 15.5 million living Americans have been diagnosed with cancer.² Many patients with cancer have difficulty walking and with activities of daily living. Patients with primary brain tumors or tumors metastatic to the brain may present with focal weakness or cognitive deficits similar to patients with stroke. Patients with tumors metastatic to the spine may have the same deficits as a patient with a traumatic spinal cord injury. Patients with metastasis to bone may have pathologic fractures of the hip or long bones. Patients may develop peripheral neuropathy associated with a paraneoplastic syndrome, chemotherapy, or critical illness neuropathy. Lehmann and colleagues evaluated 805 patients admitted to hospitals affiliated with the University of Washington Medical School with a diagnosis of cancer and found that 15% had difficulty walking and 20% had difficulty with activities of daily living.³

Many patients with cancer can benefit from inpatient rehabilitation.^4,5 Study findings have shown that patients with impairments in function related to cancer are often not referred for rehabilitation. Among the reasons mentioned for that are that oncologists are more focused on treating the patients’ cancer than on their functional deficits and that specialists in rehabilitation medicine do not want to be involved with patients with complex medical problems. Rehabilitation facilities may not want to incur the costs associated with caring for patients with cancer.⁶

The present paper looks at the outcomes of 61 consecutive patients with cancer who were admitted to an inpatient rehabilitation facility (IRF) and received radiation therapy concurrent with rehabilitation. It compares the outcomes of the cancer patients with the outcomes of patients without cancer who were admitted with stroke or spinal cord injury, conditions more commonly treated at an IRF.
 

Methods

We reviewed electronic medical records of all patients with cancer admitted to the IRF from 2008 through 2013 who received radiation therapy while at the facility. We also reviewed the data of all patients without cancer admitted with a diagnosis of stroke in 2013 and all patients admitted with a diagnosis of traumatic spinal cord injury in 2012 and 2013. No patients were excluded from stroke and traumatic spinal cord injury groups.

We recorded the sex, age, diagnostic group, Functional Independence Measure (FIM) admission score, FIM discharge score, length of stay (LoS) in the IRF, place of discharge of each patient (eg, home, acute care, or subacute care), and calculated the FIM efficiency score (change in FIM/LoS) for each patient. The FIM is an instrument that has 18 items measuring mobility, participation in activities of daily living, ability to communicate, and cognitive function.⁷ Each item is scored from 1 to 7, with 1 denoting that the patient cannot perform the task and 7 that the activity can be performed independently. The minimum score is 18 (complete dependence), and the maximum score is 126 (independent function). Thirteen items compose the motor FIM score: eating, grooming, bathing, dressing upper body, dressing lower body, toileting, bladder management, management of bowel, transfer to bed or wheelchair, transfer to toilet, tub transfer, walking (or wheelchair use), and climbing stairs. Five items – comprehension, expression, social interaction, problem solving, and memory – compose the cognitive FIM score.

We used a 1-way analysis of variance to evaluate differences between age and cancer type, age and diagnostic group, admission FIM score and cancer type, discharge FIM score and cancer type, change in FIM and cancer type, LoS and cancer type, and LoS and diagnostic group. The Pearson chi-square test was used to test the goodness of fit between the place of disposition and diagnostic group. The paired t test was used to evaluate the improvement in FIM of the patients who were in the cancer groups. The Tukey Simultaneous Tests for Differences of Means was used to compare the FIM efficiency scores of the groups. A 2-sample t test was used to evaluate the factors associated with the need for transfer from the IRF to the acute medical service.

Results

The demographic characteristics of the patients in the study and the admission and discharge FIM scores are reported in Table 1. There were initially 62 cancer patients in the radiation group, which was further divided into 4 subgroups based on the site of the primary tumor or metastasis. In all, 23 had a primary malignant brain tumor and received radiation and temozolomide. Sixteen patients had malignancies metastatic to the brain, 15 patients had tumors metastatic to the spine, and 7 had tumors metastatic to the long bones. One patient had laryngeal cancer and was excluded from the study because we did not think that we could do an analysis of a group with only 1 patient. The final number of patients in the cancer group was therefore 61. There were 69 patients in the stroke group and 23 in the spinal cord injury group.

We report improvement in total FIM, motor FIM, and cognitive FIM scores and were able to identify all 18 of the items of the FIM score on 60 of the 61 patients in the cancer group. Improvement in total FIM of the 61 patients in the cancer groups was significant at P P P = .05. Just over 75% of the patients in the cancer group had sufficient enough improvement in their level of function that they were able to return to their homes (Table 1). The average FIM score at the time of discharge was 83.08. This was not significantly different than the level of function of patients discharged after stroke (87.52) or traumatic spinal cord injury (89.13).

The patients with primary brain tumors were younger than the patients with cancer metastatic to the brain (P = .013). The patients with a primary brain tumor had lower admission FIM scores than patients with tumors metastatic to the brain (P = .027). The patients with a primary brain tumor had a greater increase in FIM score than patients with metastasis to the brain (P = .043; Table 2). There was not a significant difference between these 2 groups in FIM score at discharge or in the likelihood of discharge to home (Table 1). The FIM efficiency score was 1.12 for the patients in the primary brain tumor group and .80 in those with metastasis to the brain. This difference was not significant P = .96.

Discussion

Radiation therapy is considered a service that is provided to people who come for treatment as an outpatient. Caregivers may have difficulty transporting patients to radiation if the patient has deficits in mobility. This may be particularly true if the patient is heavy, the caregivers are frail, or perhaps if they live in rural settings where there is no wheelchair-accessible public transportation. There are many factors that help determine whether a patient with functional deficits can be discharged to his or her home. These include sex, age, marital status, family and/or community support, income, and insurance.⁸ The FIM is an instrument that indicates how much help a patient needs with mobility and self-care skills. It also correlates with the amount of time that caregivers must spend helping a patient.⁹ Study findings have shown that the FIM score is an important determinant of whether a patient can be discharged to home. The total FIM score is as useful as an analysis of the components of the FIM score in predicting whether a patient can return to the community.^10,11 Reistetter and colleagues found a total FIM score of 78 to be the score that best separates patients who are likely to be able to go home and patients who are likely to need long-term care.¹¹ Bottemiller and colleagues¹⁰ reported that 37% of patients with total discharge FIM scores of less than 40 were discharged to home. They reported that 62% of patients with FIM scores between 40 and 79 were discharged to home, and 88% of patients with scores of 80 or above were discharged to home.¹⁰ The goal in bringing patients to the IRF was to accept and treat patients with reasonable community support and potential to achieve a functional level compatible with discharge to the community. Most patients in each of the cancer groups were able to reach an FIM score of 78 to 80 and to be discharged to home.

Most of the patients in the cancer groups had underlying problems that are not considered curable. The primary goal was to enable the patients to have some time at home with their families before requiring readmission to a hospital or hospice care. Reasonable LoS and rate of progress are now expected or required by third-party payors and hospital administrators. Physicians at the Mayo Clinic have indicated that a rehabilitation service should aim for an FIM efficiency score of at least .6 points per day.¹⁰ The FIM efficiency of patients in each of the 4 cancer subgroups in this study was higher than this level.

J. Herbert Dietz, Jr was an early advocate of the need to provide comprehensive rehabilitation services for patients with cancer. He first described his work in 1969.¹² Since that time, there have been many papers that have documented the benefits of IRF for patients with cancer. O’Toole and Golden have shown outcomes of a large series of patients from an IRF. They reported that at the time of admission, 14% of patients could ambulate, but at discharge, 80% could ambulate without hands-on assistance. They reported significant improvements in continence, FIM score, and score on the Karnofsky Performance Scale.¹³ Marciniak,¹⁴ Hunter,¹⁵ Shin,¹⁶ and Cole,¹⁷ and their respective colleagues have all shown that patients with many different types of cancer benefit from rehabilitation at the IRF level. Gallegos-Kearin and colleagues⁴ reported on the care of 115,570 patients admitted to IRF with cancer from 2002 to 2014. Patients had significant improvement in function, with more than 70% of patients discharged to home.⁴ Ng and colleagues studied a group of 200 patients who received IRF care and found there was significant improvement in function. Ninety-four percent of patients rated their stay as either extremely good or very good.⁵

Metastasis to the spine is a common problem. It is found in 30% of cancer patients at autopsy. The most common sources of metastasis to the spine are breast, lung, prostate, kidney, and thyroid.¹⁸ Multiple myeloma and lymphoma may also involve the spine. Several authors have shown that these patients benefit from inpatient rehabilitation. Mckinley and colleagues¹⁹ have noted that patients with metastasis to the spine make significant improvement with care at an IRF. Compared with patients with a traumatic spinal cord injury, the cancer patients had shorter LoS, smaller improvement in FIM, equal FIM efficiency (FIM gain/LoS), and equal success in making enough progress to be discharged to home.¹⁹ Eriks and colleagues showed that patients at an IRF in Amsterdam made significant improvement in function as measured by the Barthel’s Index.²⁰ Tang .,²¹ and Parsch²² and their respective colleagues, Murray,²³ and New²⁴ and colleagues have published findings confirming that patients with spinal cord injury caused by metastasis to the spine make significant progress with inpatient rehabilitation programs. The present study adds to the literature by showing that patients with metastasis to the spine who are receiving radiation can make progress and be discharged to the community.

There are 24,000 new cases of primary malignant brain tumors in the United States each year.²⁵ The incidence of metastatic cancer to the brain has been estimated to be 100,000 cases per year in the United States. The most common cancer sources are lung, breast, melanoma, kidney, and colon.^26,27 The first study of patients admitted to an IRF for treatment of brain tumors was published in 1998 by Huang and colleagues²⁸ who compared the outcomes of 63 patients with brain tumors with the outcomes of 63 patients with stroke. They reported that the patients with the brain tumors made significant improvement in function. There was not a significant difference between the 2 groups of patients in improvement in function, FIM efficiency, or success in discharging the patients to home.²⁸ Greenberg²⁹ and Bartolo³⁰ and their respective colleagues compared the outcomes of patients admitted with brain tumors and patients with stroke and found that improvement in function and discharge to home was similar in the 2 groups. In 2000, Huang and his same colleagues³¹ compared a group of patients with brain tumors to a group of patients with traumatic brain injury. They found significant improvement in the function of the patients with brain tumors. Patients in the traumatic brain injury group made more progress but had longer LoS. FIM efficiency was not significantly different between the groups.³¹

Three papers have reported outcomes of patients who received radiation concurrent with inpatient rehabilitation. Tang and colleagues³² reported 63 patients, of whom 48% percent received radiation concurrent with rehabilitation. The patients who received radiation made significant gains in function, and more than 70% were discharged to home. There was no difference in the outcomes of the patients in the radiation and nonradiation groups.³² Marciniak³³ and O’Dell³⁴ and their colleagues also reported that patients with brain tumors that required radiation therapy can benefit from inpatient rehabilitation. The present paper is the fourth (with the largest patient group) to show that patients with primary and metastatic tumors to the brain can benefit from a program that provides radiation concurrent with inpatient rehabilitation. We have shown that patients can achieve functional levels and rates of discharge to home that are not significantly different from those of the most commonly admitted group of patients to IRF – patients with stroke.

In the present study, 18% of all of the cancer patients were transferred to medical services and/or acute hospital care (Table 1). This is consistent with a paper by Asher and colleagues³⁵ who reported that 17.4% of patients at an IRF with a diagnosis of cancer required transfer back to medical service, and that low admission motor FIM score correlated with the likelihood of transfer back to medical service. In the present paper, the total admission FIM score was not related to the likelihood of return to medical service, although a lack of improvement in the FIM score did correlate with transfer to medical service.

All of the papers we reviewed found that appropriately selected patients with cancer make significant improvement in function with treatment at an IRF. Tang and colleagues have also shown that for patients with malignant brain tumors and metastasis to the spine, improvement in function correlates with increased survival.³² Our paper confirms that patients with primary malignant brain tumors, malignant tumors metastatic to the brain or spine, and tumors metastatic to long bones may benefit from rehabilitation concurrent with radiation. Rehabilitation units are traditionally associated with treating patients with stroke and spinal cord injury. The patients in our study had cancer and were receiving radiation therapy. They had significant improvement in function and FIM efficiency scores that are not below the threshold set as expected for care at an IRF. Most patients in our study achieved a functional level consistent with what is needed to go home.

There is a prospective payment or reimbursement system for rehabilitation units.³⁶ The payments are based on the admitting diagnosis, the admission FIM score, the age of the patient, and comorbidities. There are 4 tiers for comorbidities with no additional payments for patients in tier 0 but with additional payments for patients with conditions that qualify for tiers 1 through 3. The highest payments are for patients in tier 1. Examples of conditions that can increase payment include morbid obesity, congestive heart failure, vocal cord paralysis, and the need for hemodialysis. There is no increased payment for provision of radiation therapy. There are no reports on the feasibility, in terms of finances, of providing radiation on an IRF. We asked the finance office of the Albany Medical Center to comment on the cost to the hospital of providing radiation therapy to patients on the rehabilitation unit. The hospital’s finance department reviewed available data and reported that the variable cost of providing radiation therapy is about 6.5% of the revenue collected from third-party payors for caring for patients who receive that service (personal communication from the finance office of Albany Medical Center to George Forrest, 2015). Our findings suggest that the Centers for Medicare & Medicaid Services should make an adjustment to the payment system to support the cost of providing radiation to patients at an IRF. Even under the current payment system, for a hospital that has the equipment and personnel to provide radiation treatments, the variable cost of 6.5% of revenue should not be an absolute barrier to providing this service.
 

Limitations

This study reports on the experience of only 1 facility. The number of patients in the radiation group is greater than the number of patients in any previous report of people receiving radiation at an IRF, but the statistician does not think it is large enough to allow statistical analysis of covariates such as age, sex, and comorbid conditions. In addition, we did not investigate all of the factors that influence the type of care patients are offered and their LoS, such as hospital policy, insurance coverage, income, and family structure.

Conclusions

Acute care medical units are now challenged to both reduce LoS and reduce the number of patients who are readmitted to the hospital. Rehabilitation units are challenged to maintain census, as government and private payors are shifting patients from acute rehabilitation units to subacute rehabilitation units. We found that patients with cancer who need radiation are a population of patients who are seen by payors as needing to be in a facility with excellent nursing, therapy, and comprehensive physician services. A comprehensive cancer care program within a rehabilitation unit can be a great benefit to the acute care services, the IRF, and, most importantly, patients and their families.