- Email: [email protected]
Nivolumab-associated nausea and vomiting as an immune adverse event
European Journal of Cancer xx (2017) 1e3
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Nivolumab-associated nausea and vomiting as an immune adverse event Yiwen Shi a,*,1, Paul Lin a,b,1, Edith Y. Ho a,c, Charles J. Nock a,d a
Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106, USA Department of Medicine, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA c Division of Gastroenterology, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA d Division of Hematology and Oncology, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA b
Received 17 July 2017; accepted 19 July 2017
Dear Editor,
Immunotherapy in the form of programmed cell death protein 1 (PD-1) inhibitors such as nivolumab have been found highly effective in treatment of several malignancies, including metastatic melanoma and squamous non-small-cell lung cancer [1,2]. Although studies suggest smaller percentages of immune-related adverse events (iAEs) with the use of PD-1 inhibitors as compared with cytotoxic T-lymphocyteeassociated antigen 4 inhibitors, the increasingly wide use of these newer agents places importance on physician awareness and recognition of their side-effects [3]. Here, we report a severe case of intractable nausea and vomiting in a non-small-cell lung cancer (NSCLC) patient treated with nivolumab. We demonstrate that these symptoms could be classified as an immune-related adverse event of PD-1 inhibitors as evidenced by the esophagogastroduodenoscopy (EGD) and biopsy results. Our patient is a 75-year-old Caucasian man with a medical history of NSCLC on nivolumab, panhypopituitarism and hypothyroidism admitted for * Corresponding author. E-mail address: [email protected] (Y. Shi). 1 Yiwen Shi and Paul Lin contributed equally to this work.
hypotension and unremitting nausea and vomiting for several weeks. He had completed treatment with carboplatin/paclitaxel before initiating nivolumab 9 months before admission, completing 17 cycles. Over the last 2 months, he began to have increasingly severe and frequent daily emesis with no association with oral intake. An extensive workup including leucocyte differential, renal and liver function panels, gastricemptying study, Positron Emission Tomography and Computed Tomography (PET-CT) and Magnetic Resonance Imaging (MRI) were unremarkable. However, his EGD showed diffusely friable, erythematous, denuded mucosa of the entire stomach and oedematous duodenal mucosa (Fig. 1B). In contrast, his EGD, a year ago, showed normal mucosa (Fig. 1A). The patient was trialed on several anti-emetics and treated with intravenous (i.v.) pantoprazole for 2 weeks and ranitidine for 1 week without symptomatic improvement. A repeat EGD showed no improvement on this regimen. Histologic evaluation of the biopsy samples showed active enteritis with surface erosion, crypt dropout in the duodenum and chronic gastritis with ulceration concerning for infectious versus chemotherapy-induced aetiology (Fig. 2). Duodenal findings included small bowel mucosa with variable villous blunting, reactive mucin loss, expansion of the lamina propria with
http://dx.doi.org/10.1016/j.ejca.2017.07.029 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029
2
Y. Shi et al. / European Journal of Cancer xx (2017) 1e3
Fig. 1. EGD changes showing normal mucosa one year ago (A) compared with the diffusely friable, erythematous, and atrophic mucosa affecting the entire stomach after nivolumab treatment (B).
Fig. 2. Pathology slides showing neutrophil infiltrates surrounding gastric glands in the lamina propria and the lumen, with inflammatory cells in ulcerations and crypt abscesses.
lymphocytes and plasma cells and abundant neutrophilmediated epithelial injury, including abscess formation. Gastric findings included ulceration, neutrophilic abscesses and expansion of the lamina propria with lymphocytes and plasma cells. Pathology stains for cytomegalovirus, adenovirus, and helicobacter pylori
were negative and serum viral panels were unremarkable. We discontinued nivolumab treatment and started the patient on 125-mg i.v. Solu-Medrol. He was markedly improved by day 4 and after 1 week of SoluMedrol, was discharged on a prednisone taper starting at 100 mg (1 mg/kg) over 30e45 days. Outpatient follow-up 2 weeks later, noted no additional nausea or vomiting. Immune therapies have been associated with various iAEs that affect the skin, gastrointestinal (GI), renal and endocrine systems [2e4]. Among patients treated with PD-1 inhibitors, GI side-effects such as diarrhoea and colitis are the most common iAEs and have been reported in 6.0e16.0% of patients [3]. However, if we consider nivolumab-related adverse effects of any cause rather than those of proven immune aetiology, the incidence becomes quite high. About 59e96% of patients treated with nivolumab have reported some form of adverse effects, albeit with less frequency and severity compared with standard chemotherapy regimens [5e10]. Nausea is among the most common of treatment-related adverse events (3e17%), along with fatigue (16e33%), asthenia (10%) and pruritus (14e17%) [6e10]. Most studies on the safety profile of nivolumab treatment differentiate adverse effects by the grade of severity rather than aetiology. However, there are important distinctions between general treatmentrelated symptoms and iAEs. Although nausea and vomiting are common nivolumab-associated symptoms, they are rarely documented as signs of immunologic attack. In current literature, discussion of immunerelated GI adverse events largely focus on diarrhoea and colitis, without mention of nausea as an indicating symptom [3e5,9,11]. This is likely a combination of the rarity of using EGDs to confirm immune attack on gastric mucosa and because nausea is generally not a high-grade adverse event warranting further investigation [4,6,7]. In rare cases where nausea is documented as due to immune attack, it is usually in conjunction with
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029
Y. Shi et al. / European Journal of Cancer xx (2017) 1e3
other presenting symptoms such as diarrhoea, a common immune-associated symptom [12]. However, our patient presented with severe, intractable nausea and vomiting confirmed by EGD and biopsy to be isolated symptoms indicative of immune-mediated gastroduodenitis with ulceration. There are limited studies in which endoscopic evaluation and histology are discussed. To our knowledge, histologic discussion specifically of PD-1 inhibitoreinduced GI inflammation, aside from one case report of pembrolizumab-induced new onset collagenous colitis, is limited to a single case series by Gonzalez et al. (2017) [12]. In this study, which investigated 19 patients with PD-1 inhibitoreinduced gastroenterocolitis, diarrhoea from colitis was the most common symptom (17 of 19) [12]. Four patients developed nausea, three vomiting and four abdominal pain/cramping, usually concurrently with diarrhoea. Duodenal findings included lymphoplasmacytic lamina propria expansion with eosinophils and crypt abscesses. Common gastric findings included lamina propria expansion, intra epithelial neutrophils and gland abscesses [12]. These pathology findings were similar to our patient’s findings of lamina propria expansion, neutrophil infiltrates and abscesses [12]. In conclusion, we present a severe case of isolated intractable nausea and vomiting in an NSCLC patient treated with nivolumab. We demonstrate that nausea and vomiting can be symptoms of an immune-related adverse effect on gastric and intestinal mucosa with distinct histologic findings. It is important to recognise that while PD-1 or its ligand inhibitors are documented to have a lower risk of all-grade treatment-related symptoms (e.g. fatigue, anorexia and nausea), they have a significantly higher risk of all-grade iAEs [5]. With the increasing use of new immune checkpoint inhibitors, it is increasingly important for physicians to remain vigilant in identifying potential iAEs, particularly due to the treatment implications. Although termination of therapy may be sufficient to improve general drug-related effects, iAEs may require treatment with corticosteroids or immunosuppressants [3,4,11,13]. With optimal recognition and management, recovery rates from iAEs are generally very favourable [3,4,12]. Sources of support None. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors.
3
Financial support We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. Conflict of interest statement None declared.
Acknowledgements None.
References [1] DM P. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012 Mar 22;12(4):252e64. [2] Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33(17):1974e82. http://dx.doi.org/10.1200/JCO.2014.59.4358. [3] Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:190e209. http://dx.doi.org/10. 1016/j.ejca.2016.02.025. [4] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443e54. [5] Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis. Oncologist 2017. http://dx.doi.org/10.1634/theoncologist.20160419 [Epub ahead of print]. [6] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015 Nov 5;373(19):1803e13. http://dx.doi.org/10.1056/NEJMoa1510665. [7] Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015;372(4):311e9. http://dx.doi.org/10.1056/NEJ Moa1411087. [8] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373(17):1627e39. http://dx.doi.org/10.1056/N EJMoa1507643. [9] Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320e30. http://dx.doi.org/10.1056/NEJMoa1412082. [10] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373(2):123e35. http://dx.doi.org/10.1056/NEJMoa1504627. [11] Foller S, Oppel-Heuchel H, Fetter I, et al. Adverse events of immune checkpoint inhibitors. Urologe A 2017. http: //dx.doi.org/10.1007/s00120-017-0342-3 [Epub ahead of print]. [12] Gonzalez RS, Salaria SN, Bohannon CD, et al. PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’. Histopathology 2017;70:558e67. http: //dx.doi.org/10.1111/his.13118. [13] Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017;8:49. http: //dx.doi.org/10.3389/fphar.2017.00049.
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Nivolumab-associated nausea and vomiting as an immune adverse event Yiwen Shi a,*,1, Paul Lin a,b,1, Edith Y. Ho a,c, Charles J. Nock a,d a
Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106, USA Department of Medicine, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA c Division of Gastroenterology, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA d Division of Hematology and Oncology, Louis Stokes Veterans Affairs Medical Center, 10701 East Boulevard, Cleveland, OH 44106, USA b
Received 17 July 2017; accepted 19 July 2017
Dear Editor,
Immunotherapy in the form of programmed cell death protein 1 (PD-1) inhibitors such as nivolumab have been found highly effective in treatment of several malignancies, including metastatic melanoma and squamous non-small-cell lung cancer [1,2]. Although studies suggest smaller percentages of immune-related adverse events (iAEs) with the use of PD-1 inhibitors as compared with cytotoxic T-lymphocyteeassociated antigen 4 inhibitors, the increasingly wide use of these newer agents places importance on physician awareness and recognition of their side-effects [3]. Here, we report a severe case of intractable nausea and vomiting in a non-small-cell lung cancer (NSCLC) patient treated with nivolumab. We demonstrate that these symptoms could be classified as an immune-related adverse event of PD-1 inhibitors as evidenced by the esophagogastroduodenoscopy (EGD) and biopsy results. Our patient is a 75-year-old Caucasian man with a medical history of NSCLC on nivolumab, panhypopituitarism and hypothyroidism admitted for * Corresponding author. E-mail address: [email protected] (Y. Shi). 1 Yiwen Shi and Paul Lin contributed equally to this work.
hypotension and unremitting nausea and vomiting for several weeks. He had completed treatment with carboplatin/paclitaxel before initiating nivolumab 9 months before admission, completing 17 cycles. Over the last 2 months, he began to have increasingly severe and frequent daily emesis with no association with oral intake. An extensive workup including leucocyte differential, renal and liver function panels, gastricemptying study, Positron Emission Tomography and Computed Tomography (PET-CT) and Magnetic Resonance Imaging (MRI) were unremarkable. However, his EGD showed diffusely friable, erythematous, denuded mucosa of the entire stomach and oedematous duodenal mucosa (Fig. 1B). In contrast, his EGD, a year ago, showed normal mucosa (Fig. 1A). The patient was trialed on several anti-emetics and treated with intravenous (i.v.) pantoprazole for 2 weeks and ranitidine for 1 week without symptomatic improvement. A repeat EGD showed no improvement on this regimen. Histologic evaluation of the biopsy samples showed active enteritis with surface erosion, crypt dropout in the duodenum and chronic gastritis with ulceration concerning for infectious versus chemotherapy-induced aetiology (Fig. 2). Duodenal findings included small bowel mucosa with variable villous blunting, reactive mucin loss, expansion of the lamina propria with
http://dx.doi.org/10.1016/j.ejca.2017.07.029 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029
2
Y. Shi et al. / European Journal of Cancer xx (2017) 1e3
Fig. 1. EGD changes showing normal mucosa one year ago (A) compared with the diffusely friable, erythematous, and atrophic mucosa affecting the entire stomach after nivolumab treatment (B).
Fig. 2. Pathology slides showing neutrophil infiltrates surrounding gastric glands in the lamina propria and the lumen, with inflammatory cells in ulcerations and crypt abscesses.
lymphocytes and plasma cells and abundant neutrophilmediated epithelial injury, including abscess formation. Gastric findings included ulceration, neutrophilic abscesses and expansion of the lamina propria with lymphocytes and plasma cells. Pathology stains for cytomegalovirus, adenovirus, and helicobacter pylori
were negative and serum viral panels were unremarkable. We discontinued nivolumab treatment and started the patient on 125-mg i.v. Solu-Medrol. He was markedly improved by day 4 and after 1 week of SoluMedrol, was discharged on a prednisone taper starting at 100 mg (1 mg/kg) over 30e45 days. Outpatient follow-up 2 weeks later, noted no additional nausea or vomiting. Immune therapies have been associated with various iAEs that affect the skin, gastrointestinal (GI), renal and endocrine systems [2e4]. Among patients treated with PD-1 inhibitors, GI side-effects such as diarrhoea and colitis are the most common iAEs and have been reported in 6.0e16.0% of patients [3]. However, if we consider nivolumab-related adverse effects of any cause rather than those of proven immune aetiology, the incidence becomes quite high. About 59e96% of patients treated with nivolumab have reported some form of adverse effects, albeit with less frequency and severity compared with standard chemotherapy regimens [5e10]. Nausea is among the most common of treatment-related adverse events (3e17%), along with fatigue (16e33%), asthenia (10%) and pruritus (14e17%) [6e10]. Most studies on the safety profile of nivolumab treatment differentiate adverse effects by the grade of severity rather than aetiology. However, there are important distinctions between general treatmentrelated symptoms and iAEs. Although nausea and vomiting are common nivolumab-associated symptoms, they are rarely documented as signs of immunologic attack. In current literature, discussion of immunerelated GI adverse events largely focus on diarrhoea and colitis, without mention of nausea as an indicating symptom [3e5,9,11]. This is likely a combination of the rarity of using EGDs to confirm immune attack on gastric mucosa and because nausea is generally not a high-grade adverse event warranting further investigation [4,6,7]. In rare cases where nausea is documented as due to immune attack, it is usually in conjunction with
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029
Y. Shi et al. / European Journal of Cancer xx (2017) 1e3
other presenting symptoms such as diarrhoea, a common immune-associated symptom [12]. However, our patient presented with severe, intractable nausea and vomiting confirmed by EGD and biopsy to be isolated symptoms indicative of immune-mediated gastroduodenitis with ulceration. There are limited studies in which endoscopic evaluation and histology are discussed. To our knowledge, histologic discussion specifically of PD-1 inhibitoreinduced GI inflammation, aside from one case report of pembrolizumab-induced new onset collagenous colitis, is limited to a single case series by Gonzalez et al. (2017) [12]. In this study, which investigated 19 patients with PD-1 inhibitoreinduced gastroenterocolitis, diarrhoea from colitis was the most common symptom (17 of 19) [12]. Four patients developed nausea, three vomiting and four abdominal pain/cramping, usually concurrently with diarrhoea. Duodenal findings included lymphoplasmacytic lamina propria expansion with eosinophils and crypt abscesses. Common gastric findings included lamina propria expansion, intra epithelial neutrophils and gland abscesses [12]. These pathology findings were similar to our patient’s findings of lamina propria expansion, neutrophil infiltrates and abscesses [12]. In conclusion, we present a severe case of isolated intractable nausea and vomiting in an NSCLC patient treated with nivolumab. We demonstrate that nausea and vomiting can be symptoms of an immune-related adverse effect on gastric and intestinal mucosa with distinct histologic findings. It is important to recognise that while PD-1 or its ligand inhibitors are documented to have a lower risk of all-grade treatment-related symptoms (e.g. fatigue, anorexia and nausea), they have a significantly higher risk of all-grade iAEs [5]. With the increasing use of new immune checkpoint inhibitors, it is increasingly important for physicians to remain vigilant in identifying potential iAEs, particularly due to the treatment implications. Although termination of therapy may be sufficient to improve general drug-related effects, iAEs may require treatment with corticosteroids or immunosuppressants [3,4,11,13]. With optimal recognition and management, recovery rates from iAEs are generally very favourable [3,4,12]. Sources of support None. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors.
3
Financial support We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. Conflict of interest statement None declared.
Acknowledgements None.
References [1] DM P. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012 Mar 22;12(4):252e64. [2] Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33(17):1974e82. http://dx.doi.org/10.1200/JCO.2014.59.4358. [3] Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:190e209. http://dx.doi.org/10. 1016/j.ejca.2016.02.025. [4] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443e54. [5] Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis. Oncologist 2017. http://dx.doi.org/10.1634/theoncologist.20160419 [Epub ahead of print]. [6] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015 Nov 5;373(19):1803e13. http://dx.doi.org/10.1056/NEJMoa1510665. [7] Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015;372(4):311e9. http://dx.doi.org/10.1056/NEJ Moa1411087. [8] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373(17):1627e39. http://dx.doi.org/10.1056/N EJMoa1507643. [9] Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320e30. http://dx.doi.org/10.1056/NEJMoa1412082. [10] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373(2):123e35. http://dx.doi.org/10.1056/NEJMoa1504627. [11] Foller S, Oppel-Heuchel H, Fetter I, et al. Adverse events of immune checkpoint inhibitors. Urologe A 2017. http: //dx.doi.org/10.1007/s00120-017-0342-3 [Epub ahead of print]. [12] Gonzalez RS, Salaria SN, Bohannon CD, et al. PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’. Histopathology 2017;70:558e67. http: //dx.doi.org/10.1111/his.13118. [13] Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017;8:49. http: //dx.doi.org/10.3389/fphar.2017.00049.
Please cite this article in press as: Shi Y, et al., Nivolumab-associated nausea and vomiting as an immune adverse event, European Journal of Cancer (2017), http://dx.doi.org/10.1016/j.ejca.2017.07.029