Case Reports

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Gemcitabine is a part of National Comprehensive Cancer Network (NCCN) guidelines as salvage therapy for relapsed/refractory B-cell lymphomas, but its role in chronic lymphocytic leukemia (CLL) remains unclear. We describe a case of relapsed CLL showing complete response while on gemcitabine for another primary malignancy, suggesting a potential curative role of gemcitabine for CLL.

CASE REPORT

A 78-year-old male with relapsed CD38+ CLL with del11q on ibrutinib with partial response, presented with gross hematuria for one week. Of note, he was diagnosed with BRCA-negative Stage Ib pancreatic adenocarcinoma within the previous year, treated with surgery and adjuvant capecitabine-gemcitabine. Physical examination was unremarkable and bloodwork showed a white cell count of 32,000 cells/ mm3 with 1.5% lymphocytes, hemoglobin 9.5 g/dL, and platelets 866,000 cells/mm3. Hematuria remained persistent despite frequent bladder irrigations but resolved within a week of stopping ibrutinib. Eight months later, his white cell count is 6,600 cells/mm3, with 16% lymphocytes, hemoglobin 10.2 g/dL, platelets 519,000/m3, and CT scans show no pathological lymphadenopathy. A recent flow cytometry done for academic purposes showed no clonal B cells.

DISCUSSION

Relapsed CLL has a poor prognosis with no curative treatment. Gemcitabine is a part of NCCN guidelines for relapse/refractory B-cell lymphomas but is not included in guidelines for CLL. A study by Jamie et al in 2001 suggested the pre-clinical effectiveness of gemcitabine for relapsed/refractory CLL and phase II trials conducted in 2005 and 2012 on combination chemotherapy including gemcitabine have shown overall CLL response rates of 50-65%. The resolution of B-cell clonality and improvement in biochemical markers after treatment with gemcitabine for an alternate primary malignancy suggested that gemcitabine played a potential curative role in our patient. Further prospective studies are needed to explore this avenue for the role of gemcitabine as a salvage as well as potentially curative therapy for relapsed CLL with variable cytogenetics and treatment histories.

CONCLUSIONS

Gemcitabine is not part of NCCN guidelines for CLL currently but it is a reasonable treatment option for relapsed/refractory CLL. Further studies are needed to explore its potential curative role for relapsed CLL, and update existing guidelines.

INTRODUCTION

Fragmentation of medical services is a significant barrier in modern patient care with contributing factors including patient and system level details. The Veterans Affairs (VA) department is the largest integrated health care organization in the US. Given the complex challenges of such a system, the VA has developed resources to lessen the impact of care fragmentation, potentially widening services and diminishing traditional barriers to care. We present a patient case as an example of how VA programs are impacting current veteran oncologic care.

CASE PRESENTATION

An 86-year-old veteran with shortness of breath and fatigue was found to have macrocytic anemia. Located nearly 200 miles from the closest VA with hematology services he was referred through the National TeleOncology (NTO) service to see hematology using clinical video telehealth (CVT) technology stationed at a VA approximately 100 miles from his home. Consultation led to lab work revealing no viral, nutritional, or rheumatologic explanation. A bone marrow biopsy was completed without clear diagnosis though molecular alterations demonstrated ASXL1, TET2 and CBL mutations. Hematopathology services were sought, and the patient’s case was presented at the NTO virtual hematologic tumor board where expert VA hematopathology, radiology and medical hematology opinions were available. A diagnosis of myelodysplastic syndrome was rendered with care recommendations including the novel agent luspatercept. Given patient age and comorbidities, transportation remained a barrier. The patient was set up to receive services through home based primary care (HBPC) with weekly lab draws and medication administration. Ultimately, the patient was able to receive the first dose of luspatercept through the NTO affiliated VA with subsequent administrations to be given by HBPC. Additional visits planned using at home VA video Connect (VVC) service and CVT visits with NTO hematology at his local community based outpatient center (CBOC) located 30 miles from his home.

DISCUSSION

Located over 3 hours from the closest in-person VA hematologist, this patient was able to receive complex care thanks to a marriage of in-person and virtual services involving specialty nurses, pharmacists, and physicians from across VA. Services such as the NTO hub-spoke model, virtual tumor boards and HBPC, reveal a care framework unique to the VA.

INTRODUCTION

Fragmentation of medical services is a significant barrier in modern patient care with contributing factors including patient and system level details. The Veterans Affairs (VA) department is the largest integrated health care organization in the US. Given the complex challenges of such a system, the VA has developed resources to lessen the impact of care fragmentation, potentially widening services and diminishing traditional barriers to care. We present a patient case as an example of how VA programs are impacting current veteran oncologic care.

CASE PRESENTATION

An 86-year-old veteran with shortness of breath and fatigue was found to have macrocytic anemia. Located nearly 200 miles from the closest VA with hematology services he was referred through the National TeleOncology (NTO) service to see hematology using clinical video telehealth (CVT) technology stationed at a VA approximately 100 miles from his home. Consultation led to lab work revealing no viral, nutritional, or rheumatologic explanation. A bone marrow biopsy was completed without clear diagnosis though molecular alterations demonstrated ASXL1, TET2 and CBL mutations. Hematopathology services were sought, and the patient’s case was presented at the NTO virtual hematologic tumor board where expert VA hematopathology, radiology and medical hematology opinions were available. A diagnosis of myelodysplastic syndrome was rendered with care recommendations including the novel agent luspatercept. Given patient age and comorbidities, transportation remained a barrier. The patient was set up to receive services through home based primary care (HBPC) with weekly lab draws and medication administration. Ultimately, the patient was able to receive the first dose of luspatercept through the NTO affiliated VA with subsequent administrations to be given by HBPC. Additional visits planned using at home VA video Connect (VVC) service and CVT visits with NTO hematology at his local community based outpatient center (CBOC) located 30 miles from his home.

DISCUSSION

Located over 3 hours from the closest in-person VA hematologist, this patient was able to receive complex care thanks to a marriage of in-person and virtual services involving specialty nurses, pharmacists, and physicians from across VA. Services such as the NTO hub-spoke model, virtual tumor boards and HBPC, reveal a care framework unique to the VA.

INTRODUCTION

Fragmentation of medical services is a significant barrier in modern patient care with contributing factors including patient and system level details. The Veterans Affairs (VA) department is the largest integrated health care organization in the US. Given the complex challenges of such a system, the VA has developed resources to lessen the impact of care fragmentation, potentially widening services and diminishing traditional barriers to care. We present a patient case as an example of how VA programs are impacting current veteran oncologic care.

CASE PRESENTATION

An 86-year-old veteran with shortness of breath and fatigue was found to have macrocytic anemia. Located nearly 200 miles from the closest VA with hematology services he was referred through the National TeleOncology (NTO) service to see hematology using clinical video telehealth (CVT) technology stationed at a VA approximately 100 miles from his home. Consultation led to lab work revealing no viral, nutritional, or rheumatologic explanation. A bone marrow biopsy was completed without clear diagnosis though molecular alterations demonstrated ASXL1, TET2 and CBL mutations. Hematopathology services were sought, and the patient’s case was presented at the NTO virtual hematologic tumor board where expert VA hematopathology, radiology and medical hematology opinions were available. A diagnosis of myelodysplastic syndrome was rendered with care recommendations including the novel agent luspatercept. Given patient age and comorbidities, transportation remained a barrier. The patient was set up to receive services through home based primary care (HBPC) with weekly lab draws and medication administration. Ultimately, the patient was able to receive the first dose of luspatercept through the NTO affiliated VA with subsequent administrations to be given by HBPC. Additional visits planned using at home VA video Connect (VVC) service and CVT visits with NTO hematology at his local community based outpatient center (CBOC) located 30 miles from his home.

DISCUSSION

Located over 3 hours from the closest in-person VA hematologist, this patient was able to receive complex care thanks to a marriage of in-person and virtual services involving specialty nurses, pharmacists, and physicians from across VA. Services such as the NTO hub-spoke model, virtual tumor boards and HBPC, reveal a care framework unique to the VA.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

The development of imatinib and now newer tyrosine kinase inhibitors (TKIs) has revolutionized the overall survival of patients with CML. However, toxicity and treatment-resistance can result in premature discontinuation of therapy. Asciminib, a novel TKI, may have fewer off-target effects. It also bypasses the mechanism of resistance to first-line TKIs by binding to a different site on the BCR-ABL fusion protein. In our institution, three patients have been initiated on asciminib thus far. We present their cases, with a focus on quality of life.

CASE PRESENTATIONS

(1) A 76-year-old male with a history of diffuse vascular disease experienced off-target effects on multiple TKIs (i.e. intolerable nausea on imatinib, pleural effusion on dasatinib, complete heart block on nilotinib), so he was switched to asciminib. He has been tolerating asciminib well over five months and continues to see significant log reduction in BCR-ABL transcripts. (2) A 71-year-old male with a history of multiple complicated gastrointestinal infections never achieved major molecular remission on imatinib and was unable to tolerate dasatinib or bosutinib due to severe nausea and vomiting. He was switched to asciminib, which he has been tolerating well for one year, and has achieved complete hematologic response. (3) A 73-year-old male with a history of chronic kidney disease experienced kidney injury thought to be due to imatinib and was switched to bosutinib. His BCRABL transcripts rose on bosutinib, so patient was started on asciminib, which he has been tolerating well.

DISCUSSION

In this series of patients in their 70s with multiple underlying comorbidities, the unifying theme is that of intolerance to first-line TKIs due to toxicity (cardiac, pulmonary, gastrointestinal, and renal). Existing data suggests that asciminib results in less toxicity than other first-line TKIs, and this is evident in our patients. More importantly, the combination of efficacy and tolerability gives these patients the opportunity to proceed with life-prolonging therapy, even for those who face treatment resistance with other agents.

CONCLUSIONS

For CML patients who have failed at least two lines of treatment, whether it is due to disease progression or intolerable toxicity, asciminib is an effective alternative. Further study may result in its promotion to first-line therapy for this disease.

INTRODUCTION

Medulloblastoma (MB) is rarely seen in adulthood. Treatment guidelines are derived from studies of the pediatric population, results favoring the Packer regimen (cisplatin plus cyclophosphamide or lomustine plus vincristine). MB rarely has extraneural metastases, especially the bone marrow.

CASE PRESENTATION

A 32-year-old female with a past medical history of cerebellar MB confirmed on surgical pathology status post resection, weekly radiation and vincristine treatment presented to us in clinic to re-establish care. She was lost to follow-up 9 months after initial diagnosis and wished to continue treatment. She was started on Lomustine, Cisplatin and Vincristine after discussion with our colleagues at MSKCC, where she had received her initial treatment. After cycle three, she developed intractable bone pain and pancytopenia. Bone marrow biopsy revealed metastasis of Sonic Hedgehog Desmoplastic/nodular variant MB. PET and CT imaging confirmed metastatic disease in the bone marrow and repeat MRI brain showed abnormal nodular enhancement. CSF analysis to assess for spinal metastasis was negative. The patient was started on Temozolomide, Irinotecan and Bevacizumab with significant improvement in bone pain and radiological improvement noted on PET and CT scans. After cycle six, the patient had increased bone pain and repeat FDG-PET showed increased uptake, however, she continued to receive treatment and her pain has improved off narcotics.

DISCUSSION

We highlight a case of adult MB in the bone marrow responsive to temozolomide, irinotecan and bevacizumab. We conducted a literature search using PubMed, Medline and Web of Science between 1990 to 2022. In 2021, COG Phase 2 screening trial showed bevacizumab, temozolamide/irinotecan therapy significantly reduced the risk of death with recurrent MBs, two studies included patients up to 21 and 23 years of age. Other modalities showing some response include Vincristine plus cyclophosphamide as well as high dose carboplatin, thiotepa and etoposide alongside autologous SCT. Vismodegib has also shown varied response of 15 months in two adults with extraneural MB metastasis. Given the unique entity of adult MB and extraneural metastasis, limitations include small sample and lack of generalizability.

CONCLUSIONS

Extraneural metastasis of MB yields a poor prognosis. Future considerations include randomized trials to establish efficacy of Temozolomide, Irinotecan plus Bevacizumab in this population.

INTRODUCTION

Medulloblastoma (MB) is rarely seen in adulthood. Treatment guidelines are derived from studies of the pediatric population, results favoring the Packer regimen (cisplatin plus cyclophosphamide or lomustine plus vincristine). MB rarely has extraneural metastases, especially the bone marrow.

CASE PRESENTATION

A 32-year-old female with a past medical history of cerebellar MB confirmed on surgical pathology status post resection, weekly radiation and vincristine treatment presented to us in clinic to re-establish care. She was lost to follow-up 9 months after initial diagnosis and wished to continue treatment. She was started on Lomustine, Cisplatin and Vincristine after discussion with our colleagues at MSKCC, where she had received her initial treatment. After cycle three, she developed intractable bone pain and pancytopenia. Bone marrow biopsy revealed metastasis of Sonic Hedgehog Desmoplastic/nodular variant MB. PET and CT imaging confirmed metastatic disease in the bone marrow and repeat MRI brain showed abnormal nodular enhancement. CSF analysis to assess for spinal metastasis was negative. The patient was started on Temozolomide, Irinotecan and Bevacizumab with significant improvement in bone pain and radiological improvement noted on PET and CT scans. After cycle six, the patient had increased bone pain and repeat FDG-PET showed increased uptake, however, she continued to receive treatment and her pain has improved off narcotics.

DISCUSSION

We highlight a case of adult MB in the bone marrow responsive to temozolomide, irinotecan and bevacizumab. We conducted a literature search using PubMed, Medline and Web of Science between 1990 to 2022. In 2021, COG Phase 2 screening trial showed bevacizumab, temozolamide/irinotecan therapy significantly reduced the risk of death with recurrent MBs, two studies included patients up to 21 and 23 years of age. Other modalities showing some response include Vincristine plus cyclophosphamide as well as high dose carboplatin, thiotepa and etoposide alongside autologous SCT. Vismodegib has also shown varied response of 15 months in two adults with extraneural MB metastasis. Given the unique entity of adult MB and extraneural metastasis, limitations include small sample and lack of generalizability.

CONCLUSIONS

Extraneural metastasis of MB yields a poor prognosis. Future considerations include randomized trials to establish efficacy of Temozolomide, Irinotecan plus Bevacizumab in this population.

INTRODUCTION

Medulloblastoma (MB) is rarely seen in adulthood. Treatment guidelines are derived from studies of the pediatric population, results favoring the Packer regimen (cisplatin plus cyclophosphamide or lomustine plus vincristine). MB rarely has extraneural metastases, especially the bone marrow.

CASE PRESENTATION

A 32-year-old female with a past medical history of cerebellar MB confirmed on surgical pathology status post resection, weekly radiation and vincristine treatment presented to us in clinic to re-establish care. She was lost to follow-up 9 months after initial diagnosis and wished to continue treatment. She was started on Lomustine, Cisplatin and Vincristine after discussion with our colleagues at MSKCC, where she had received her initial treatment. After cycle three, she developed intractable bone pain and pancytopenia. Bone marrow biopsy revealed metastasis of Sonic Hedgehog Desmoplastic/nodular variant MB. PET and CT imaging confirmed metastatic disease in the bone marrow and repeat MRI brain showed abnormal nodular enhancement. CSF analysis to assess for spinal metastasis was negative. The patient was started on Temozolomide, Irinotecan and Bevacizumab with significant improvement in bone pain and radiological improvement noted on PET and CT scans. After cycle six, the patient had increased bone pain and repeat FDG-PET showed increased uptake, however, she continued to receive treatment and her pain has improved off narcotics.

DISCUSSION

We highlight a case of adult MB in the bone marrow responsive to temozolomide, irinotecan and bevacizumab. We conducted a literature search using PubMed, Medline and Web of Science between 1990 to 2022. In 2021, COG Phase 2 screening trial showed bevacizumab, temozolamide/irinotecan therapy significantly reduced the risk of death with recurrent MBs, two studies included patients up to 21 and 23 years of age. Other modalities showing some response include Vincristine plus cyclophosphamide as well as high dose carboplatin, thiotepa and etoposide alongside autologous SCT. Vismodegib has also shown varied response of 15 months in two adults with extraneural MB metastasis. Given the unique entity of adult MB and extraneural metastasis, limitations include small sample and lack of generalizability.

CONCLUSIONS

Extraneural metastasis of MB yields a poor prognosis. Future considerations include randomized trials to establish efficacy of Temozolomide, Irinotecan plus Bevacizumab in this population.

INTRODUCTION

Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome

CASE REPORT

A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.

DISCUSSION

Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.

CONCLUSIONS

A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.

INTRODUCTION

Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome

CASE REPORT

A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.

DISCUSSION

Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.

CONCLUSIONS

A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.

INTRODUCTION

Prostate cancer rarely metastasizes to the pituitary gland and the close relationship of these sellar masses to cavernous sinuses and major vessels makes management challenging. We describe a unique case of complete reversal of ptosis in metastatic prostate cancer presenting as cavernous sinus syndrome

CASE REPORT

A 76-year-old male presented with left diplopia, ptosis, and facial numbness. Examination showed left oculomotor palsy and numbness in the V1 and V2 distribution of trigeminal nerve. MRI revealed an 11 × 26 × 17 mm posterior sellar mass extending into the left cavernous sinus. Prolactin was slightly elevated, but rest of the pituitary hormones were normal. Resection of the sellar mass showed metastatic prostatic adenocarcinoma positive for NKX-3.1 and prostate-specific antigen (PSA), and Gleason score 4. PSA was elevated at 32 ng/ mL. Positron emission tomography (PET) showed lesions in the left prostatic lobe, pelvic lymph nodes, L5 spine, and right femoral head. FoundationOne testing found no actionable mutations. He was started on leuprorelin-docetaxel and received radiation for the brain and bony lesions. He is currently being maintained on leuprorelin-abiraterone and prednisone, which he is tolerating well.

DISCUSSION

Pituitary metastases (PMs) from prostate cancer are rare and are usually confined to the posterior pituitary. The close relationship of pituitary masses to the cavernous sinuses and internal carotid artery can lead to catastrophic neurovascular consequences. Imaging has limited sensitivity for differentiating non-invasive metastases from adenomas. Older age, new-onset diabetes insipidus, invasive masses, and rapidly growing lesions should raise suspicion for PMs. Intracranial prostatic metastases indicate poor prognosis with a reported median survival of 6-10 months. Timely diagnosis and management can prevent permanent neurologic damage as illustrated by our case in which ptosis and extraocular symptoms were completely resolved by surgery and radiation. Such unique cases underline the significance of suspecting metastatic disease in appropriate demographic groups and the crucial role of multidisciplinary care for oncologic patients.

CONCLUSIONS

A high index of suspicion for PMs in elderly people with new-onset sellar symptoms and early involvement of multidisciplinary teams can lead to prevention and even reversal of serious neurologic symptoms.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Leptomeningeal metastasis (LM) is an extremely rare complication of gastroesophageal (GE) cancer. Diagnosis is challenging due to frequently nonspecific clinical presentations, limited sensitivity of diagnostic testing, and potential overlap with neurologic immune-related adverse events (irAE). We describe a case of metastatic gastroesophageal cancer on immunotherapy presenting with LM masquerading as polyneuropathy.

CASE REPORT

A 74-year-old male with HER2+ GE junction cancer with peritoneal metastases diagnosed 6 months ago, on maintenance trastuzumab/pembrolizumab and with no previous history of cranial or spinal disease, presented with worsening ataxia, headache, and diplopia for one month with multiple negative outpatient MRIs. Examination showed left abducens nerve palsy, dysmetria and absent deep tendon reflexes in upper and lower extremities. CT head was unremarkable, and MRI showed non-specific mild enhancement of the right optic nerve, symmetrical lumbosacral nerve roots and cauda equina concerning for paraneoplastic versus immunotherapy-related polyneuropathy. He was started on empiric high-dose corticosteroids. PET-CT was negative for FDG-avid lesions. Cerebrospinal fluid (CSF) analysis revealed moderate pleocytosis with many large atypical cells, elevated protein (118 mg/dL) and LDH (28 IU/L). Immunohistochemistry was positive for CDX2, CA 19-9, CK7, and pankeratin, consistent with metastatic adenocarcinoma, negative for HER2 in contrast to the original tumor. He subsequently developed hydrocephalus requiring a ventriculoperitoneal shunt. He received ten fractions of whole brain irradiation before electing to pursue hospice care.

DISCUSSION

LM is an extremely rare complication of GE cancer with an incidence of <0.2% and carries a poor prognosis. Differentiation between LM and irAE in patients on immunotherapy can be challenging. Diagnosis relies mostly on CSF cytology, and lumbar puncture should not be delayed in patients with new neurologic symptoms. Treatment options are intrathecal chemotherapy, radiation and steroids. A recent phase II trial has shown promise for intrathecal trastuzumab in patients with HER2+ cancers, but options for HER2 negative disease remain mostly palliative.

CONCLUSIONS

Our case highlights the need for suspecting this rare metastatic site, as early diagnosis and genetic characterization allow for exploring more treatment options including targeted therapies which may improve overall survival and quality of life.

INTRODUCTION

Excluding skin cancer, prostate cancer is the most common malignancy affecting men in the United States, accounting for ~33% of VA cancer cases. Androgen deprivation therapy (ADT) is considered standard of care in treating advanced prostate cancer. Pituitary apoplexy is a rare and morbid adverse event associated with GnRH agonist treatment. We describe a patient with advanced prostate cancer who developed pituitary apoplexy shortly after leuprolide therapy.

CASE PRESENTATION

A 70-year-old African-American male was diagnosed with a T2aN1M1 stage IVB prostate cancer, Gleason 4+5, PSA 19.5. Four hours after his first leuprolide injection, he developed vomiting, diaphoresis, myalgia, and a severe frontal headache. Brain MRI revealed a 2.4 × 1.3 × 1.3cm pituitary mass, suspicious for an adenoma with hemorrhage. Labs noted low TSH, prolactin, LH, growth hormone, ACTH, cortisol, and testosterone, consistent with pituitary apoplexy. He was treated with steroids. Three weeks later, testosterone levels remained very low. He started abiraterone and prednisone without further leuprolide.

DISCUSSION

Prostate cancer is ubiquitous among VA patients, and ADT with GnRH agonist is vital in their care. These medications stimulate the pituitary to release LH and FSH resulting in a negative feedback loop, ultimately decreasing the levels of testosterone. Common side effects of GnRH agonists include hot flashes, diaphoresis, and sexual dysfunction. We present a patient who started leuprolide for prostate cancer. Symptoms including a severe headache led to an evaluation confirming pituitary apoplexy. Literature review reveals ~ 21 cases of pituitary apoplexy associated with GnRH agonist treatment for prostate cancer, and apoplexy can occur immediately to months later Undiagnosed pituitary adenomas are common among these patients. Treatment includes pituitary surgery or conservative management. Further prostate cancer treatment needs investigation, but we propose that GnRH modifying treatment can be withheld while testosterone levels remain low.

CONCLUSIONS

Prostate cancer is extremely common in the VA population, and treatment with leuprolide is standard. Pituitary apoplexy is a rare, but devastating complication of this treatment, and providers should be aware of the symptoms in order to intervene quickly. Further testosterone lowering treatment may be withheld if testosterone levels remain low.

INTRODUCTION

Excluding skin cancer, prostate cancer is the most common malignancy affecting men in the United States, accounting for ~33% of VA cancer cases. Androgen deprivation therapy (ADT) is considered standard of care in treating advanced prostate cancer. Pituitary apoplexy is a rare and morbid adverse event associated with GnRH agonist treatment. We describe a patient with advanced prostate cancer who developed pituitary apoplexy shortly after leuprolide therapy.

CASE PRESENTATION

A 70-year-old African-American male was diagnosed with a T2aN1M1 stage IVB prostate cancer, Gleason 4+5, PSA 19.5. Four hours after his first leuprolide injection, he developed vomiting, diaphoresis, myalgia, and a severe frontal headache. Brain MRI revealed a 2.4 × 1.3 × 1.3cm pituitary mass, suspicious for an adenoma with hemorrhage. Labs noted low TSH, prolactin, LH, growth hormone, ACTH, cortisol, and testosterone, consistent with pituitary apoplexy. He was treated with steroids. Three weeks later, testosterone levels remained very low. He started abiraterone and prednisone without further leuprolide.

DISCUSSION

Prostate cancer is ubiquitous among VA patients, and ADT with GnRH agonist is vital in their care. These medications stimulate the pituitary to release LH and FSH resulting in a negative feedback loop, ultimately decreasing the levels of testosterone. Common side effects of GnRH agonists include hot flashes, diaphoresis, and sexual dysfunction. We present a patient who started leuprolide for prostate cancer. Symptoms including a severe headache led to an evaluation confirming pituitary apoplexy. Literature review reveals ~ 21 cases of pituitary apoplexy associated with GnRH agonist treatment for prostate cancer, and apoplexy can occur immediately to months later Undiagnosed pituitary adenomas are common among these patients. Treatment includes pituitary surgery or conservative management. Further prostate cancer treatment needs investigation, but we propose that GnRH modifying treatment can be withheld while testosterone levels remain low.

CONCLUSIONS

Prostate cancer is extremely common in the VA population, and treatment with leuprolide is standard. Pituitary apoplexy is a rare, but devastating complication of this treatment, and providers should be aware of the symptoms in order to intervene quickly. Further testosterone lowering treatment may be withheld if testosterone levels remain low.

INTRODUCTION

Excluding skin cancer, prostate cancer is the most common malignancy affecting men in the United States, accounting for ~33% of VA cancer cases. Androgen deprivation therapy (ADT) is considered standard of care in treating advanced prostate cancer. Pituitary apoplexy is a rare and morbid adverse event associated with GnRH agonist treatment. We describe a patient with advanced prostate cancer who developed pituitary apoplexy shortly after leuprolide therapy.

CASE PRESENTATION

A 70-year-old African-American male was diagnosed with a T2aN1M1 stage IVB prostate cancer, Gleason 4+5, PSA 19.5. Four hours after his first leuprolide injection, he developed vomiting, diaphoresis, myalgia, and a severe frontal headache. Brain MRI revealed a 2.4 × 1.3 × 1.3cm pituitary mass, suspicious for an adenoma with hemorrhage. Labs noted low TSH, prolactin, LH, growth hormone, ACTH, cortisol, and testosterone, consistent with pituitary apoplexy. He was treated with steroids. Three weeks later, testosterone levels remained very low. He started abiraterone and prednisone without further leuprolide.

DISCUSSION

Prostate cancer is ubiquitous among VA patients, and ADT with GnRH agonist is vital in their care. These medications stimulate the pituitary to release LH and FSH resulting in a negative feedback loop, ultimately decreasing the levels of testosterone. Common side effects of GnRH agonists include hot flashes, diaphoresis, and sexual dysfunction. We present a patient who started leuprolide for prostate cancer. Symptoms including a severe headache led to an evaluation confirming pituitary apoplexy. Literature review reveals ~ 21 cases of pituitary apoplexy associated with GnRH agonist treatment for prostate cancer, and apoplexy can occur immediately to months later Undiagnosed pituitary adenomas are common among these patients. Treatment includes pituitary surgery or conservative management. Further prostate cancer treatment needs investigation, but we propose that GnRH modifying treatment can be withheld while testosterone levels remain low.

CONCLUSIONS

Prostate cancer is extremely common in the VA population, and treatment with leuprolide is standard. Pituitary apoplexy is a rare, but devastating complication of this treatment, and providers should be aware of the symptoms in order to intervene quickly. Further testosterone lowering treatment may be withheld if testosterone levels remain low.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.