UVEAL METASTASIS FROM NONSMALL CELL LUNG CARCINOMA WITH DRAMATIC RESPONSE TO ERLOTINIB Anthony B. Daniels, MD, MSc,*† Matt L. Miller,‡ Amy Kotecha, MD,§ David H. Abramson, MD*
Purpose: To report the case of a never-smoker patient whose initial presentation of metastatic nonsmall cell lung carcinoma was with uveal metastasis, which had a dramatic response to targeted biologic therapy with erlotinib (Tarceva) after failing conventional chemotherapy. Methods: Case report. A 43-year-old man with uveal metastasis from nonsmall cell lung adenocarcinoma. Results: After failing conventional chemotherapy with carboplatin and taxol, with continued documented rapid growth of the uveal metastasis, treatment was initiated with the targeted biologic agent, erlotinib, which is a protein tyrosine kinase inhibitor of the epidermal growth factor receptor(EGFR). Within 3 days of starting erlotinib, shrinkage of the choroidal lesion was noted, and over the course of the next 3 months, the tumor completely and durably disappeared, with vision improving from hand motion to 20/25. The patient is still alive and well after 3 years, on continued daily oral erlotinib treatment. Conclusion: Erlotinib is a well-tolerated newly available Food and Drug Administration– approved oral targeted biologic agent, which may be beneficial in some patients with uveal metastasis from nonsmall cell lung carcinoma, in which an underlying epidermal growth factor receptor mutation is suspected. RETINAL CASES & BRIEF REPORTS 4:390–393, 2010
developing in 2.3% to 9.2% of all carcinomas.1 Between 9% and 23% of these arise from lung carcinomas, making it the second most common primary site after breast.1,2 It has been reported that as many as one third of patients who present with uveal metastases have no known history of cancer at the time of presentation, and of those with known cancer, up to one third have been reported to have uveal tumors as the first clinical sign of metastasis.3 Of those with no previous cancer diagnosis, lung carcinoma is the most likely source (35%), but no primary site is found in 51% of cases.3 While external beam radiation therapy has been the most common treatment for visionthreatening uveal metastases,2 recent advances in systemic therapies (chemotherapy, targeted biologics, and hormones) might allow for concurrent treatment of uveal and other systemic metastases. Herein, we report a dramatic example of choroidal metastasis responding to systemic therapy with a targeted biologic agent.
From the Departments of *Surgery and †Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; ‡NEC Labs America, Princeton, New Jersey; and §Capital Vision, Arlington, Virginia.
T
he most common ocular malignancy in adults is metastasis from carcinoma, with uveal metastases
There was no external or commercial funding for this work. Dr. D. H. Abramson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors has any commercial or proprietary conflicts to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinalcases.com). Reprint requests: David H. Abramson, MD, Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 70 East 66th Street, New York, NY 10065; e-mail: [email protected]
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Case Report A 43-year-old white never-smoker male patient without known malignancy presented with sudden decreased vision in his left eye (hand motion only, with afferent pupillary defect). His only other symptoms at the time were back pain, and a cough being treated with antibiotics. Central serous chorioretinopathy was suspected. On follow-up examination (1 month later), it was thought that this might represent a mass, and he was referred to us for consultation (Figure 1A). At the time of his presentation to our clinic, a large elevated amelanotic choroidal lesion was found to underlie the entire macula, with overlying retinal pigment epithelial mottling (Figure 1B). A systemic evaluation followed, revealing nonsmall cell lung adenocarcinoma with metastases to choroid, brain, and bone, confirmed by biopsy of the primary lung lesion. At this point, the tumor had a height of 3.39 mm by ultrasound, without any overlying retinal detachment noted on B-scan ultrasonography (Figure 1C). He started chemotherapy with carboplatin and taxol; yet his uveal tumor progressed (Figure 1, B–D, see Video, Supplemental Digital Content 1, http://links.lww.com/ICB/A1). Fundoscopically, the tumor obscured the entire macula and continued to further extend below the inferotemporal arcade and encircle the optic nerve completely over the course of the next 2 weeks, despite continued treatment. Subsequently, erlotinib (Tarceva) was added to the regimen. Within 3 days, fundoscopic examination revealed complete collapse and disappearance of the central tumor encompassing the fovea (Figure 2A), with improved visual acuity and less metamorphopsia. Within 3 weeks, ultrasound revealed a tumor height of only 0.5 mm. Over the course of the next 3 months on erlotinib in conjunction with carboplatin and taxol, the choroidal tumor completely disappeared,
Fig. 1. Fundus photographs showing initial progression of the tumor. A. Initial presentation on Day 1. B. Extent of the tumor on day 49, just before the initiation of of chemotherapy with carboplatin and taxol. C. B-scan ultrasound image showing a solid choroidal mass on Day 49. Tumor height was 3.39 mm at this time. No overlying retinal detachment was seen. D. Progressive growth of the tumor seen on Day 64, despite approximately 2 weeks of treatment with carboplatin and taxol (photograph taken the day before adding erlotinib).
giving way to flat chorioretinal atrophy with central retinal pigment epithelial changes and hyperpigmentation and a peau d’orange appearance, with regression and disappearance of the tumefaction noted at the optic nerve (Figure 2, B–D, see Video, Supplemental Digital Content 1, http://links.lww.com/ICB/A1). Ultrasound and optical coherence tomography imaging confirmed that the lesion was now completely flat, with a return of the normal foveal contour (Figure 2D). Vision was dramatically improved to 20/25. In addition to these readily observable results on fundoscopy, the primary lung tumor regressed, the bony lesions became asymptomatic, and the patient feels and looks well. His only side effect was a rash on his feet lasting a week.
Discussion As has been reported in one third of patients with uveal metastases,3 this represented our patient’s first manifestation of cancer, and his initial symptom of blurred vision is the most common presenting complaint.1,2 This case vividly demonstrates the rapidity with which metastases can grow, both within the choroid and elsewhere, and the speed with which vision can be lost. Conversely, this provided the rare opportunity to visually document chemotherapy failure and subsequent response of a tumor to a newly available effective targeted biologic agent. It must be noted that in our case, erlotinib was not administered
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Fig. 2. Fundus photographs showing regression of the tumor after addition of erlotinib. A. Day 3 of erlotinib. Regression of the tumor within 3 days of adding erlotinib to the regimen (Day 67). B. Day 24 of erlotinib. Continued regression of the tumor after another 3 weeks of erlotinib/carboplatin/taxol (Day 88). C. Day 93 of erlotinib. Complete durable disappearance of the choroidal metastasis after 3 months of treatment with erlotinib combination therapy (Day 157). D. Ultrasound image demonstrating complete absence of the choroidal mass after treatment with erlotinib. Insets: Optical coherence tomography image and retinal thickness map showing flat macula with return of normal foveal contour.
as monotherapy but was rather added to a conventional chemotherapy regimen that was previously failing to control tumor growth. It is possible that the continued administration of the conventional chemotherapy played a role in the tumor control that was achieved once erlotinib was added, although the tumor clearly grew at first when only chemotherapy was given. Erlotinib is a small molecule inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR). Many nonsmall cell lung carcinomas (NSCLCs) express EGFR and many harbor EGFR mutations or gene amplifications4,5; these mutations are more common in NSCLC patients who are female, are Asian, have adenocarcinoma, or are never-smokers.5 In NSCLCs
containing these genetic alterations in such patients, tumor growth becomes almost completely dependent on the EGFR signaling pathway, and therefore, disruption of this pathway leads to tumor regression, as seen in our patient. Similar targeting of a particular tyrosine kinase on which tumor growth has become dependent has been described in other cancers as well, and this dependence on a single pathway for tumor growth has sometimes been termed ‘‘oncogene addiction.’’6,7 Erlotinib is currently approved for the treatment of NSCLC that has failed at least one previous chemotherapy regimen and as first-line treatment for advanced pancreatic cancer in conjunction with gemcitibine.8
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ERLOTINIB FOR UVEAL METASTASES
In a randomized, placebo-controlled, double-blind clinical trial of 731 patients with NSCLC who failed first-line chemotherapy, there was a 9-fold increased response rate, increased disease-free survival, and 43% increased overall survival in patients treated with erlotinib, as compared with placebo among all patient groups.4 Multivariate analysis demonstrated that never having smoked, adenocarcinoma, and expression of EGFR were associated with responsiveness to erlotinib.5 Ocular toxicities (conjunctivitis, keratoconjunctivitis sicca) occurred in 28% of patients receiving erlotinib compared with 9% receiving placebo; however, there was no significant difference in Grades 3 to 4 toxicity (interfering with activities of daily living or resulting in blindness) compared with placebo, occurring in ,1% patients in both groups.4 Key words: cancer, choroid, epidermal growth factor receptor, erlotinib, neoplasm metastasis, nonsmall cell lung carcinoma, Tarceva, protein kinase inhibitors, uveal neoplasms.
References 1. Kanthan GL, Jayamohan J, Yip D, Conway RM. Management of metastatic carcinoma of the uveal tract: an evidence-based analysis. Clin Exp Ophthalmol 2007;35: 553–565. 2. Volpe NJ, Albert DM. Metastases to the uvea." In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia, PA: W.B. Saunders Company; 2000: 5073–5084. 3. Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases. Ophthalmology 1997; 104:1265–1276. 4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Eng J Med 2005;353:123–132. 5. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Eng J Med 2005;353:133–144. 6. Savage DG, Antman KH. Imatinib mesylate: a new oral targeted therapy. N Engl J Med 2002;346:683–693. 7. Daniels AB, Abramson DH. c-KIT in uveal melanoma: big fish or red herring? Arch Ophthalmol 2009;127:695–697. 8. Iyer R, Bharthuar A. A review of erlotinib—an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. Expert Opin Pharmacother 2010;11:311–320.
Purpose: To report the case of a never-smoker patient whose initial presentation of metastatic nonsmall cell lung carcinoma was with uveal metastasis, which had a dramatic response to targeted biologic therapy with erlotinib (Tarceva) after failing conventional chemotherapy. Methods: Case report. A 43-year-old man with uveal metastasis from nonsmall cell lung adenocarcinoma. Results: After failing conventional chemotherapy with carboplatin and taxol, with continued documented rapid growth of the uveal metastasis, treatment was initiated with the targeted biologic agent, erlotinib, which is a protein tyrosine kinase inhibitor of the epidermal growth factor receptor(EGFR). Within 3 days of starting erlotinib, shrinkage of the choroidal lesion was noted, and over the course of the next 3 months, the tumor completely and durably disappeared, with vision improving from hand motion to 20/25. The patient is still alive and well after 3 years, on continued daily oral erlotinib treatment. Conclusion: Erlotinib is a well-tolerated newly available Food and Drug Administration– approved oral targeted biologic agent, which may be beneficial in some patients with uveal metastasis from nonsmall cell lung carcinoma, in which an underlying epidermal growth factor receptor mutation is suspected. RETINAL CASES & BRIEF REPORTS 4:390–393, 2010
developing in 2.3% to 9.2% of all carcinomas.1 Between 9% and 23% of these arise from lung carcinomas, making it the second most common primary site after breast.1,2 It has been reported that as many as one third of patients who present with uveal metastases have no known history of cancer at the time of presentation, and of those with known cancer, up to one third have been reported to have uveal tumors as the first clinical sign of metastasis.3 Of those with no previous cancer diagnosis, lung carcinoma is the most likely source (35%), but no primary site is found in 51% of cases.3 While external beam radiation therapy has been the most common treatment for visionthreatening uveal metastases,2 recent advances in systemic therapies (chemotherapy, targeted biologics, and hormones) might allow for concurrent treatment of uveal and other systemic metastases. Herein, we report a dramatic example of choroidal metastasis responding to systemic therapy with a targeted biologic agent.
From the Departments of *Surgery and †Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; ‡NEC Labs America, Princeton, New Jersey; and §Capital Vision, Arlington, Virginia.
T
he most common ocular malignancy in adults is metastasis from carcinoma, with uveal metastases
There was no external or commercial funding for this work. Dr. D. H. Abramson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors has any commercial or proprietary conflicts to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinalcases.com). Reprint requests: David H. Abramson, MD, Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 70 East 66th Street, New York, NY 10065; e-mail: [email protected]
390
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ERLOTINIB FOR UVEAL METASTASES
Case Report A 43-year-old white never-smoker male patient without known malignancy presented with sudden decreased vision in his left eye (hand motion only, with afferent pupillary defect). His only other symptoms at the time were back pain, and a cough being treated with antibiotics. Central serous chorioretinopathy was suspected. On follow-up examination (1 month later), it was thought that this might represent a mass, and he was referred to us for consultation (Figure 1A). At the time of his presentation to our clinic, a large elevated amelanotic choroidal lesion was found to underlie the entire macula, with overlying retinal pigment epithelial mottling (Figure 1B). A systemic evaluation followed, revealing nonsmall cell lung adenocarcinoma with metastases to choroid, brain, and bone, confirmed by biopsy of the primary lung lesion. At this point, the tumor had a height of 3.39 mm by ultrasound, without any overlying retinal detachment noted on B-scan ultrasonography (Figure 1C). He started chemotherapy with carboplatin and taxol; yet his uveal tumor progressed (Figure 1, B–D, see Video, Supplemental Digital Content 1, http://links.lww.com/ICB/A1). Fundoscopically, the tumor obscured the entire macula and continued to further extend below the inferotemporal arcade and encircle the optic nerve completely over the course of the next 2 weeks, despite continued treatment. Subsequently, erlotinib (Tarceva) was added to the regimen. Within 3 days, fundoscopic examination revealed complete collapse and disappearance of the central tumor encompassing the fovea (Figure 2A), with improved visual acuity and less metamorphopsia. Within 3 weeks, ultrasound revealed a tumor height of only 0.5 mm. Over the course of the next 3 months on erlotinib in conjunction with carboplatin and taxol, the choroidal tumor completely disappeared,
Fig. 1. Fundus photographs showing initial progression of the tumor. A. Initial presentation on Day 1. B. Extent of the tumor on day 49, just before the initiation of of chemotherapy with carboplatin and taxol. C. B-scan ultrasound image showing a solid choroidal mass on Day 49. Tumor height was 3.39 mm at this time. No overlying retinal detachment was seen. D. Progressive growth of the tumor seen on Day 64, despite approximately 2 weeks of treatment with carboplatin and taxol (photograph taken the day before adding erlotinib).
giving way to flat chorioretinal atrophy with central retinal pigment epithelial changes and hyperpigmentation and a peau d’orange appearance, with regression and disappearance of the tumefaction noted at the optic nerve (Figure 2, B–D, see Video, Supplemental Digital Content 1, http://links.lww.com/ICB/A1). Ultrasound and optical coherence tomography imaging confirmed that the lesion was now completely flat, with a return of the normal foveal contour (Figure 2D). Vision was dramatically improved to 20/25. In addition to these readily observable results on fundoscopy, the primary lung tumor regressed, the bony lesions became asymptomatic, and the patient feels and looks well. His only side effect was a rash on his feet lasting a week.
Discussion As has been reported in one third of patients with uveal metastases,3 this represented our patient’s first manifestation of cancer, and his initial symptom of blurred vision is the most common presenting complaint.1,2 This case vividly demonstrates the rapidity with which metastases can grow, both within the choroid and elsewhere, and the speed with which vision can be lost. Conversely, this provided the rare opportunity to visually document chemotherapy failure and subsequent response of a tumor to a newly available effective targeted biologic agent. It must be noted that in our case, erlotinib was not administered
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RETINAL CASES & BRIEF REPORTS´ 2010 VOLUME 4 NUMBER 4
Fig. 2. Fundus photographs showing regression of the tumor after addition of erlotinib. A. Day 3 of erlotinib. Regression of the tumor within 3 days of adding erlotinib to the regimen (Day 67). B. Day 24 of erlotinib. Continued regression of the tumor after another 3 weeks of erlotinib/carboplatin/taxol (Day 88). C. Day 93 of erlotinib. Complete durable disappearance of the choroidal metastasis after 3 months of treatment with erlotinib combination therapy (Day 157). D. Ultrasound image demonstrating complete absence of the choroidal mass after treatment with erlotinib. Insets: Optical coherence tomography image and retinal thickness map showing flat macula with return of normal foveal contour.
as monotherapy but was rather added to a conventional chemotherapy regimen that was previously failing to control tumor growth. It is possible that the continued administration of the conventional chemotherapy played a role in the tumor control that was achieved once erlotinib was added, although the tumor clearly grew at first when only chemotherapy was given. Erlotinib is a small molecule inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR). Many nonsmall cell lung carcinomas (NSCLCs) express EGFR and many harbor EGFR mutations or gene amplifications4,5; these mutations are more common in NSCLC patients who are female, are Asian, have adenocarcinoma, or are never-smokers.5 In NSCLCs
containing these genetic alterations in such patients, tumor growth becomes almost completely dependent on the EGFR signaling pathway, and therefore, disruption of this pathway leads to tumor regression, as seen in our patient. Similar targeting of a particular tyrosine kinase on which tumor growth has become dependent has been described in other cancers as well, and this dependence on a single pathway for tumor growth has sometimes been termed ‘‘oncogene addiction.’’6,7 Erlotinib is currently approved for the treatment of NSCLC that has failed at least one previous chemotherapy regimen and as first-line treatment for advanced pancreatic cancer in conjunction with gemcitibine.8
393
ERLOTINIB FOR UVEAL METASTASES
In a randomized, placebo-controlled, double-blind clinical trial of 731 patients with NSCLC who failed first-line chemotherapy, there was a 9-fold increased response rate, increased disease-free survival, and 43% increased overall survival in patients treated with erlotinib, as compared with placebo among all patient groups.4 Multivariate analysis demonstrated that never having smoked, adenocarcinoma, and expression of EGFR were associated with responsiveness to erlotinib.5 Ocular toxicities (conjunctivitis, keratoconjunctivitis sicca) occurred in 28% of patients receiving erlotinib compared with 9% receiving placebo; however, there was no significant difference in Grades 3 to 4 toxicity (interfering with activities of daily living or resulting in blindness) compared with placebo, occurring in ,1% patients in both groups.4 Key words: cancer, choroid, epidermal growth factor receptor, erlotinib, neoplasm metastasis, nonsmall cell lung carcinoma, Tarceva, protein kinase inhibitors, uveal neoplasms.
References 1. Kanthan GL, Jayamohan J, Yip D, Conway RM. Management of metastatic carcinoma of the uveal tract: an evidence-based analysis. Clin Exp Ophthalmol 2007;35: 553–565. 2. Volpe NJ, Albert DM. Metastases to the uvea." In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia, PA: W.B. Saunders Company; 2000: 5073–5084. 3. Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with uveal metastases. Ophthalmology 1997; 104:1265–1276. 4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Eng J Med 2005;353:123–132. 5. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Eng J Med 2005;353:133–144. 6. Savage DG, Antman KH. Imatinib mesylate: a new oral targeted therapy. N Engl J Med 2002;346:683–693. 7. Daniels AB, Abramson DH. c-KIT in uveal melanoma: big fish or red herring? Arch Ophthalmol 2009;127:695–697. 8. Iyer R, Bharthuar A. A review of erlotinib—an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. Expert Opin Pharmacother 2010;11:311–320.
