Cancer Chemother Pharmacol (2014) 73:199–205 DOI 10.1007/s00280-013-2341-4
Original Article
The effect of chemotherapy with cisplatin and pemetrexed for choroidal metastasis of non‑squamous cell carcinoma Chih‑Jen Yang · Ying‑Ming Tsai · Ming‑Ju Tsai · Hsu‑Liang Chang · Ming‑Shyan Huang
Received: 26 March 2013 / Accepted: 25 October 2013 / Published online: 8 November 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Choroidal metastasis from lung cancer is very rare in the clinical setting. Treatment for lung cancer with symptomatic choroidal metastasis remains uncertain because of the rarity of such cases. Methods We performed a retrospective study on symptomatic choroidal metastasis from lung cancer at the Kaohsiung Medical University Hospital from January 2010 to August 2011. In addition, we also performed literature review of all such patients (or of cancers with choroidal metastasis) treated with systemic chemotherapy. Results In our study, a total of 226 lung cancer patients were registered during the study period, and only four had choroidal metastasis (4/226, 1.77 %). Three were female (75 %) and one was male, with a mean age of 40.74 (range
26–60) years. Three patients had marked choroidal tumor regression after treatment with pemetrexed and cisplatin. In the literature reviews, there are only 12 patients (including our patients) received systemic chemotherapy alone instead of local therapy and eight (66.7 %) demonstrated choroidal tumor regression after treatment. Conclusions Symptomatic choroidal metastasis from lung cancer is extremely rare. Our findings indicate that systemic chemotherapy with pemetrexed and cisplatin may be a good option for such patients. Further large-scale studies for the treatment of such patients are warranted. However, currently, radiotherapy is still the gold standard for such patients.
Chih-Jen Yang and Ying-Ming Tsai have contributed equally to this article.
Introduction
C.-J. Yang · Y.-M. Tsai · H.-L. Chang Department of Internal Medicine, Kaohsiung Municipal Ta‑Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan C.-J. Yang (*) · Y.-M. Tsai · M.-J. Tsai · H.-L. Chang · M.-S. Huang Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, #100, Tzyou 1st Road, Kaohsiung 807, Taiwan e-mail: [email protected] C.-J. Yang · M.-S. Huang Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan C.-J. Yang Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Keywords Choroidal metastasis · Lung cancer · Chemotherapy · Pemetrexed · Cisplatin · Adenocarcinoma
Lung cancer is the most common cause of cancer-related mortality worldwide including Taiwan. It tends to metastasize to various organs such as the brain, bone, adrenal gland, and liver [1]. Symptomatic choroidal metastasis has rarely been reported in cases of lung cancer. Patients with choroidal metastasis detected in a screening study had an exceptionally short median survival period of only 2 months [2]. The optimal treatment for lung cancer patients with symptomatic choroidal metastasis is uncertain because of the rarity of this condition [3–9]. Local treatment with external beam radiation or laser photocoagulation has been proposed to treat choroidal metastasis, because the choroid is a photosensitive organ [10–12]. However, complications such as cataract, retinopathy, glaucoma, and even blindness may occur when patients undergo radiotherapy [10, 12]. Effectiveness of
13
RLL AD 33/F 4
RLL RUL RLL AD AD AD 26/M 44/F 60/F 1 2 3
AD adenocarcinoma, CR complete remission, PR partial remission, PD progression of the disease, RUL right upper lobe, RML right middle lobe, RLL right lower lobe, PPD packs per day, EGFR epidermal growth factor receptor
Gefitinib Blurred vision decreased visual acuity
13
Wild type Never Bronchoscopic biopsy
Bilateral
Pemetrexed + Cisplatin Pemetrexed + Cisplatin Pemetrexed + Cisplatin Blurred vision metamorphopsia Blurred vision metamorphopsia Blurred vision, decreased visual acuity 1 PPD for 10 years Wild type Never Wild type Never Exon 18 point mutation Bronchoscopic biopsy Bronchoscopic biopsy Bronchoscopic biopsy
Bilateral Left Bilateral
Treatment option EGFR status Smoking status Diagnostic method for lung cancer
Unilateral or bilateral
Initial presentations of choroid metastasis
Cancer Chemother Pharmacol (2014) 73:199–205
Patient (No.) Age/Sex Cell type Lung cancer location
Table 1 All cases of symptomatic choroidal metastasis from lung cancer at the Kaohsiung Medical University Hospital from January 2010 to August 2011
200
chemotherapy or targeted therapy alone for choroidal metastasis has been limited in the literature [6, 13–16]. Therefore, we performed a retrospective study to summarize the treatment of lung cancer patients with symptomatic choroidal metastasis in a tertiary teaching hospital and performed a literature review of all lung cancer patients with choroidal metastasis who were treated with systemic chemotherapy.
Patients and methods All tissue-proven lung cancer patients who had symptomatic choroidal metastasis treated at the Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, from January 2010 to August 2011 were enrolled. The symptoms of choroidal metastasis included blurred vision, decreased visual acuity, tenderness, flashes, floaters, metamorphopsia, and scotomas. Diagnoses were made by ophthalmologists based on imaging results and clinical findings. The choices of treatment for these patients were decided by the duty physicians. We also performed a literature search of all relevant articles published in English in Pubmed up to August 2012. We carefully documented all of the patients who received systemic chemotherapy alone. Patients who underwent ocular treatment such as photodynamic therapy, local radiotherapy, enucleation, and intravitreous injections were excluded. Data were recorded on a standard data extraction form including age, gender, and the location of ocular and extraocular metastatic sites. Epidermal growth factor receptor (EGFR) mutations, chemotherapy or targeted therapy alone, response to chemotherapy in the ocular and primary site of lung cancer, and outcomes were also reviewed.
Results In total, 226 patients with newly diagnosed lung cancer were registered at the Kaohsiung Medical University Hospital during the study period. Only four (4/226, 1.77 %) patients were diagnosed with lung cancer with choroidal metastasis, and they were enrolled into this study. Their basic characteristics, clinical presentations, and treatment options are listed in Table 1. Case 1 A 26-year-old male patient had a 10 pack-year smoking history and strong lung cancer family history (both his grandfather and uncle died of lung cancer). He was diagnosed as lung adenocarcinoma based on bronchoscopic biopsy. He also had multiple metastases. An EGFR mutation test
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Fig. 1 The thickness of the fundus represented a choroidal tumor. The choroidal tumor had recovered to normal thickness after chemotherapy (Case 1, 2, 3), indicating the regression of the choroidal tumor based on the optical coherence tomography
was negative. He received chemotherapy with vinorelbine (25 mg/m2) plus cisplatin (75 mg/m2); however, he experienced blurred vision, decreased visual acuity, and metamorphopsia over left eye after the second cycle of chemotherapy. According to the ophthalmologist, there was a high probability of choroidal metastasis over both eyes based on optical coherence tomography (Fig. 1), fundoscopy (Fig. 2), and fluorescence angiography (Fig. 3). He refused radiotherapy as a local treatment to the metastasis because of concerns over side effects. He was treated with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2). The choroidal tumor showed marked regression after the second cycle of chemotherapy, although there was no significant change in the lung mass. Totally, he underwent 4 cycles of pemetrexed and cisplatin. Unfortunately, the patient developed pneumonia and sepsis 3 months after the occurrence of choroidal metastasis and died soon thereafter (Tables 2, 3). Case 2 A 44-year-old female who had never smoked presented with dry cough and blurred vision for 1 month. Lung
adenocarcinoma was diagnosed via bronchoscopic biopsy. Bedsides, multiple intrapulmonary metastatic nodules were noticed. An EGFR mutation test was negative. Due to blurred vision and metamorphopsia over left eye, we consulted an ophthalmologist and left choroidal metastasis was proved based on imaging results (Fig. 1). She refused radiotherapy due to concerns with side effects and decided to receive systemic chemotherapy alone. Therefore, she was treated with pemetrexed (500 mg/m2) plus cisplatin (75 mg/ m2). There was dramatic regression of the choroidal tumor after 2 cycles of chemotherapy, and her pulmonary tumors also had a partial response to the chemotherapy. There was no evidence of choroidal tumor recurrence after 6 months, and she was still alive after 16 months of follow-up. Case 3 A 60-year-old female visited our clinic because of chronic dry cough and dizziness. A bronchoscopic biopsy from mass over right lower lung demonstrated lung adenocarcinoma and showed an EGFR exon 18-point mutation. She also had bilateral blurred vision, and the ophthalmologist
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Fig. 2 (Case 1) Tumor regressed after chemotherapy on fundoscopy
Fig. 3 Bilateral choroid tumors were noticed by fluorescence angiography
indicated the high probability of choroidal metastasis over both eyes. She elected to receive systemic chemotherapy with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2). There was marked regression in the choroidal tumors after the first cycle of chemotherapy (Fig. 1). Unfortunately, she had a sudden onset of consciousness disturbance at home before the second cycle of chemotherapy. Acute brain stem stroke was impressed and pneumonia then developed. She died of sepsis 2 months later.
choroidal metastases were impressed according to the results of optical coherence tomography and fundoscopy. She refused to receive chemotherapy or local choroid therapy and insisted on taking gefitinib even though an EGFR mutation test was negative. Unfortunately, the response to gefitinib was poor, and her visual defect became worse. She died of cachexia, malnutrition, and a fatal nosocomial pneumonia 3 months later.
Case 4
Literature review
A 33-year-old female who had never smoked presented with multiple bone pain, poor appetite, and dry cough for 2 months. A right lower lung mass was found, and a bronchoscopic biopsy confirmed the diagnosis of lung adenocarcinoma. She complained of blurred vision, and bilateral
Including the patients in the current study, there were a total of twelve patients who had choroidal metastasis from the lung and received systemic chemotherapy. Most of them were adenocarcinoma (9/12, 75 %), and at least 58.3 % (7/12) had not only choroidal metastasis but also
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Table 2 Systemic chemotherapy or targeted therapy alone for choroidal metastasis from lung cancer in a search of the English literature Lung tumor response
Local choroid response
Outcome (since the date of choroid metastasis)
Vindesine + cisplatin + 5FU Lung cancer NA Chemotherapy SqCC NA Chemotherapy LCC Bone, liver Paclitaxel + carboplatin NSCLC Brain Docetaxel + carboplatin LCC Lung to lung Gemcitabine, carboplatin, bevacizumab
PD
NA
NA
NA PR PD SD PR
NA Regression Progression Regression Regression
NA >5 months 4 months >18 months >5 months
42/F 50/M
AD AD
Singh et al. [15]
60/F
AD
Our case 1 Our case 2
26/M 44/F
Our case 3
60/F
References
Age/sex Histology
Other metastasis site
Harino et al. [17]
53/M
NA
Harino et al. [17] Kiratli et al. [31] Hasturk et al. [18] Shields et al. [20] George et al. [16]
46/F 37/M 51/M 75/F 42/F
Ascaso et al. [19] Singh et al. [6]
SqCC
Systemic treatment
Paclitaxel + cisplatin Gemcitabine + cisplatin
NA NA
NA Regression
NA >13 months
Pemetrexed + cisplatin
PR
Regression
>11 months
AD AD
Brain, bone No distant metastasis No distant metastasis Bone Lung to lung
Pemetrexed + cisplatin Pemetrexed + cisplatin
SD PR
Regression Regression
6 months (pneumonia) >16 months
AD
Bone, brain
Pemetrexed + cisplatin
PR
Regression
3 months (Unexpected Stroke)
AD adenocarcinoma, SqCC squamous cell carcinoma, LCC large cell carcinoma, NSCLC non-small cell lung cancer, PR partial response, PD progression of the disease, SD stable disease, NA not available
Table 3 Systemic-targeted therapy alone for choroidal metastasis from lung cancer in a search of the English literature Reference
Age/sex Histology Other metasta- EGFR muta- Systemic sis site tion status treatment
Lung tumor Local choroid response response
Outcome (since the date of choroid metastasis)
Inoue et al. [14] 68/F Fujiu et al. [21] 49/F
AD AD
Lung to lung NA
NA Exon 19 mutation
Gefitinib Erlotinib
NA PR
Regression Regression
>3 months NA
Our case 4
AD
Lung to lung
Wild type
Gefitinib
PD
Progression
3 months (died of a nosocomial pneumonia, not related to gefitinib)
33/F
AD adenocarcinoma, PR partial response, PD progression of the disease, NA not available
other sites of metastasis. There was female predominance (7/12, 58.3 %), and the median age was 48.83 years (range 26–75 years). Several chemotherapy regimens were tried, including vindesine plus cisplatin plus 5-FU, pemetrexed plus cisplatin [17], gemcitabine plus cisplatin [15], paclitaxel plus carboplatin [18], paclitaxel plus cisplatin [19], docetaxel plus carboplatin [20], and gemcitabine plus carboplatin plus bevacizumab [16]. In those who received pemetrexed plus cisplatin [15] (including our patients),choroidal tumors showed a high response rate (4/4, 100 %) and two of our patients remained alive for more than 11 months. Three patients received targeted therapy [14, 21]. Of these patients, two (one had an exon 19 deletion EGFR mutation, the other was unknown) had regression of the choroidal tumors and one (our case 4) experienced disease progression and died 3 months later.
Discussion We showed the incidence of symptomatic choroidal metastasis from lung cancer in a single institute in Taiwan. We also demonstrated that systemic chemotherapy had a good response rate for choroidal metastasis from lung adenocarcinoma, indicating that chemotherapy such as pemetrexed plus cisplatin may be a treatment option for such patients. The choroid, located between the retina and sclera, a vascular and pigmented tissue layer, provides the vascular supply to the outer part of the retina. The route of metastasis to the choroid is hematogenous because of the hypervascularity. Tumor cells usually pass through the internal carotid artery to the ophthalmic artery then reaching the intraocular and orbital structures [22–24].
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Choroidal metastasis has been detected in many primary cancers, but predominantly in breast and lung cancers [23–25]. A prospective screening study for choroidal metastasis in patients with metastatic lung cancer reported an incidence rate of 7.1 %, and it is the sixth most common site for metastasis from primary lung cancer [26]. Nevertheless, choroidal metastasis is relatively rare and often asymptomatic. In Taiwan, lung and breast cancers represent more than two-thirds of primary tumor sites [25]. Choroidal metastasis from primary tumors has a significantly high impact on the quality of life and is representative of poor outcomes [2, 8, 15]. Kreusel et al. reported that 36 % of patients with lung cancer had been diagnosed before the occurrence of choroidal metastasis. The choroidal metastasis was often unilateral, solitary, and located close to or at the posterior pole in the majority of patients [2]. Bilateral choroidal metastasis has been reported in 20–40 % of choroidal metastasis [2]. In our study, three patients had bilateral choroidal metastasis, and one patient had involvement with the left eye only. The clinical presentations of choroidal metastasis include blurred vision, decreased visual acuity, tenderness, flashes, floaters, metamorphopsia, and scotomas [2, 15, 26]. Among these symptoms, blurred vision and decreased visual acuity are the most common symptoms, and they have a strong influence on daily activity. Metastatic carcinoma to the choroid can cause visual dysfunction due to the accumulation of subretinal fluid and/or tumoral involvement of the macular region [2, 23]. However, most patients with choroidal metastasis are asymptomatic. In patients with SCLC, carcinoma-associated retinopathy (CAR) syndrome should be one of the differential diagnoses of visual disturbance. CAR syndrome is a paraneoplastic syndrome and characterized by the production of an autoantibody to recovering a retinal photoreceptor protein in the retinal cone. The diagnosis of CAR often based on electroretinogram because of the presence of this antibody is difficult to detect in general hospitals [7]. The differential diagnoses of a choroidal mass include choroidal neovascularization, primary choroidal malignant melanoma, choroidal metastasis, inflammatory granulomas, and hemangioma [2, 22, 23, 26, 27]. The related diagnostic procedures include slit-lamp biomicroscopy, ophthalmoscopy, ultrasonography, fluorescein angiography, optical coherence tomography, and magnetic resonance imaging [2, 15, 17, 26, 28–31]. Typical ophthalmoscopic features include one or multiple creamy yellow choroidal lesions associated, in some advanced cases, with secondary retinal detachment. Under fluorescein angiography, these lesions are usually fluorescent in the early phases of study and then become progressively hyperfluorescent in the late phases. B-scan ultrasound shows an echogenic subretinal mass
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with diffuse, ill-defined borders. Optical coherence tomography shows retro-retinal space thickening [15, 29]. With regard to survival, Wang et al. [25] reported that the mean survival time after the diagnosis of choroidal metastasis from different cancers was 4.3 months in Taiwan. Chong et al. [30] reported that patients with choroidal metastasis from lung cancer had a 1.9- to 3.3-month survival time. Kreusel et al. [2] reported that patients with choroidal metastasis detected in a screening study of lung cancer had an exceptionally short median survival period of only 2 months. These studies showed the choroidal metastasis is a poor prognostic predictor in lung cancer patients. Treatment for choroidal metastasis is palliative because the presence of such metastasis suggests hematogenous spread of the lung cancer. The aims for treatment are to maximize the quality of life and to restore or preserve vision. There are many methods to treat choroidal metastasis locally, such as radiotherapy, laser photocoagulation, photodynamic therapy, transpupillary thermotherapy, chemotherapy, and enucleation [2, 10–12]. External beam radiation therapy is the most common choice of treatment for choroidal metastasis, because the choroid is radiosensitive. The dose of external beam radiotherapy required for the successful palliation of choroidal metastasis for most primary tumors is 30 grays in daily fractions of 3 grays. However, radiotherapy may result in permanent orbital complications such as conjunctivitis, cataracts, glaucoma, retinopathy, optic neuropathy, or even blindness [10, 12]. The use of chemotherapy alone for choroidal metastasis has recently been documented [6, 13–16]; however, no large-scale clinical trials have been performed because of the relative rarity of choroidal metastasis. The choice of drugs for each patient depends on the types of primary cancer. For non-small cell lung cancer, several kinds of targeted therapy or chemotherapy have been used, such as gefitinib [14], gemcitabine plus carboplatin, or a combination of bevacizumab, gemcitabine, and carboplatin. Kim et al. [5] reported a patient who had complete regression with a combination of intravitreal bevacizumab and oral erlotinib. Pemetrexed is a new potent inhibitor of thymidylate synthase and other folate-dependent enzymes, and is currently approved for the first- and second-line treatment of advanced stage or recurrent non-squamous, non-small cell lung cancer, especially the non-squamous subtype. Pemetrexed plus cisplatin has been shown to have better efficacy, fewer side effects, and more convenient administration than cytotoxic chemotherapy such as gemcitabine plus cisplatin in lung adenocarcinoma [32]. Singh et al. [15] demonstrated a partial response to pemetrexed plus cisplatin in the treatment of choroidal metastasis from lung cancer. In our study, pemetrexed plus cisplatin demonstrated a good response to choroidal metastatic tumors from lung adenocarcinoma (3/3, 100 %), and one of our patients
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had survived for more than 16 months (still alive). These patients also had a better quality of life because of recovery of visual acuity subjectively and objectively. To the best of our knowledge, this is the largest retrospective study to discuss the systemic treatment alone for symptomatic choroidal metastasis from lung cancer.
Conclusion Symptomatic choroidal metastasis from primary lung adenocarcinoma is rare, and the ideal treatment option has yet to be determined. Based on our retrospective study and literature search, systemic chemotherapy alone instead of local therapy resulted in regression of the choroid tumors. With regards to the chemotherapy drugs, pemetrexed plus cisplatin seemed to be the most effective drug combination. Further large-scale studies are warranted. However, currently, radiotherapy for such patients is still the gold standard. Conflicts of interest The authors declare that they have no competing.
References 1. Postmus PE, Brambilla E, Chansky K et al (2007) The IASLC lung cancer staging project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2:686–693 2. Kreusel KM, Bechrakis NE, Wiegel T et al (2008) Incidence and clinical characteristics of symptomatic choroidal metastasis from lung cancer. Acta Ophthalmol 86:515–519 3. Herrag M, Lahmiti S, Yazidi AA et al (2010) Choroidal metastasis revealing a lung adenocarcinoma. Ann Thorac Surg 89:1013–1014 4. John VJ, Jacobson MS, Grossniklaus HE (2010) Bilateral choroidal metastasis as the presenting sign of small cell lung carcinoma. J Thorac Oncol 5:1289 5. Kim SW, Kim MJ, Huh K et al (2009) Complete regression of choroidal metastasis secondary to non-small-cell lung cancer with intravitreal bevacizumab and oral erlotinib combination therapy. Ophthalmologica 223:411–413 6. Singh A, Singh P, Sahni K et al (2010) Non-small cell lung cancer presenting with choroidal metastasis as first sign and showing good response to chemotherapy alone: a case report. J Med Case Rep 4:185 7. Okuma Y, Hosomi Y, Kitamura K et al (2009) Choroidal metastasis in a patient with small cell lung cancer discovered during treatment with chemotherapy. Int J Clin Oncol 14:541–544 8. Chen CJ, McCoy AN, Brahmer J et al (2011) Emerging treatments for choroidal metastases. Surv Ophthalmol 56:511–521 9. Amer R, Pe’er J, Chowers I et al (2004) Treatment options in the management of choroidal metastases. Ophthalmologica 218:372–377 10. Rosset A, Zografos L, Coucke P et al (1998) Radiotherapy of choroidal metastases. Radiother Oncol 46:263–268 11. Mauget-Faysse M, Gambrelle J, Quaranta-El MM et al (2006) Photodynamic therapy for choroidal metastasis from lung adenocarcinoma. Acta Ophthalmol Scand 84:552–554
205 12. Wiegel T, Bottke D, Kreusel KM et al (2002) External beam radiotherapy of choroidal metastases–final results of a prospective study of the German Cancer Society (ARO 95-08). Radiother Oncol 64:13–18 13. Asteriou C, Konstantinou D, Kleontas A et al (2010) Blurred vision due to choroidal metastasis as the first manifestation of lung cancer: a case report. World J Surg Oncol 8:2 14. Inoue M, Watanabe Y, Yamane S et al (2010) Choroidal metastasis with adenocarcinoma of the lung treated with gefitinib. Eur J Ophthalmol 20:963–965 15. Singh N, Kulkarni P, Aggarwal AN et al (2012) Choroidal metastasis as a presenting manifestation of lung cancer: a report of 3 cases and systematic review of the literature. Medicine (Baltimore) 91:179–194 16. George B, Wirostko WJ, Connor TB et al (2009) Complete and durable response of choroid metastasis from non-small cell lung cancer with systemic bevacizumab and chemotherapy. J Thorac Oncol 4:661–662 17. Harino S, Miyamoto K, Okada M et al (1995) Indocyanine green videoangiographic findings in choroidal metastatic tumor. Graefes Arch Clin Exp Ophthalmol 233:339–346 18. Hasturk S, Soylu M, Zeren EH et al (2001) Basaloid large cell lung carcinoma presenting concurrently with metastatic uveal tumor. Lung Cancer 32:95–101 19. Ascaso FJ, Castillo JM, Garcia FJ et al (2009) Bilateral choroidal metastases revealing an advanced non-small cell lung cancer. Ann Thorac Surg 88:1013–1015 20. Shields JA, Perez N, Shields CL et al (2002) Simultaneous choroidal and brain metastasis as initial manifestations of lung cancer. Ophthalmic Surg Lasers 33:323–325 21. Fujiu K, Kobayashi N, Miyamoto H et al (2012) A case of choroidal metastasis of lung cancer successfully treated with erlotinib. Gan To Kagaku Ryoho 39:269–271 22. De PP (1998) Ocular manifestations of cancer. Curr Opin Ophthalmol 9:100–104 23. Freedman MI, Folk JC (1987) Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics. Arch Ophthalmol 105:1215–1219 24. Kanthan GL, Jayamohan J, Yip D et al (2007) Management of metastatic carcinoma of the uveal tract: an evidence-based analysis. Clin Experiment Ophthalmol 35:553–565 25. Wang TJ, Yang CM, Ho TC et al (2005) Metastatic choroidal tumors in Taiwan: an 11-year experience. Am J Ophthalmol 140:735–737 26. Kreusel KM, Wiegel T, Stange M et al (2002) Choroidal metastasis in disseminated lung cancer: frequency and risk factors. Am J Ophthalmol 134:445–447 27. Shields JA, Shields CL, Eagle RC et al (2004) Lung cancer presenting as vitreous hemorrhage from choroidal metastasis. Retina 24:168–170 28. Abundo RE, Orenic CJ, Anderson SF et al (1997) Choroidal metastases resulting from carcinoma of the lung. J Am Optom Assoc 68:95–108 29. Arevalo JF, Fernandez CF, Garcia RA (2005) Optical coherence tomography characteristics of choroidal metastasis. Ophthalmology 112:1612–1619 30. Chong JT, Mick A (2005) Choroidal metastasis: case reports and review of the literature. Optometry 76:293–301 31. Kiratli H, Kiratli PO, Ercan MT (1998) Scintigraphic evaluation of tumors metastatic to the choroid using technetium-99 m(V)dimercaptosuccinic acid. Jpn J Ophthalmol 42:60–65 32. Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage nonsmall-cell lung cancer. J Clin Oncol 26:3543–3551
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Original Article
The effect of chemotherapy with cisplatin and pemetrexed for choroidal metastasis of non‑squamous cell carcinoma Chih‑Jen Yang · Ying‑Ming Tsai · Ming‑Ju Tsai · Hsu‑Liang Chang · Ming‑Shyan Huang
Received: 26 March 2013 / Accepted: 25 October 2013 / Published online: 8 November 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Choroidal metastasis from lung cancer is very rare in the clinical setting. Treatment for lung cancer with symptomatic choroidal metastasis remains uncertain because of the rarity of such cases. Methods We performed a retrospective study on symptomatic choroidal metastasis from lung cancer at the Kaohsiung Medical University Hospital from January 2010 to August 2011. In addition, we also performed literature review of all such patients (or of cancers with choroidal metastasis) treated with systemic chemotherapy. Results In our study, a total of 226 lung cancer patients were registered during the study period, and only four had choroidal metastasis (4/226, 1.77 %). Three were female (75 %) and one was male, with a mean age of 40.74 (range
26–60) years. Three patients had marked choroidal tumor regression after treatment with pemetrexed and cisplatin. In the literature reviews, there are only 12 patients (including our patients) received systemic chemotherapy alone instead of local therapy and eight (66.7 %) demonstrated choroidal tumor regression after treatment. Conclusions Symptomatic choroidal metastasis from lung cancer is extremely rare. Our findings indicate that systemic chemotherapy with pemetrexed and cisplatin may be a good option for such patients. Further large-scale studies for the treatment of such patients are warranted. However, currently, radiotherapy is still the gold standard for such patients.
Chih-Jen Yang and Ying-Ming Tsai have contributed equally to this article.
Introduction
C.-J. Yang · Y.-M. Tsai · H.-L. Chang Department of Internal Medicine, Kaohsiung Municipal Ta‑Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan C.-J. Yang (*) · Y.-M. Tsai · M.-J. Tsai · H.-L. Chang · M.-S. Huang Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, #100, Tzyou 1st Road, Kaohsiung 807, Taiwan e-mail: [email protected] C.-J. Yang · M.-S. Huang Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan C.-J. Yang Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Keywords Choroidal metastasis · Lung cancer · Chemotherapy · Pemetrexed · Cisplatin · Adenocarcinoma
Lung cancer is the most common cause of cancer-related mortality worldwide including Taiwan. It tends to metastasize to various organs such as the brain, bone, adrenal gland, and liver [1]. Symptomatic choroidal metastasis has rarely been reported in cases of lung cancer. Patients with choroidal metastasis detected in a screening study had an exceptionally short median survival period of only 2 months [2]. The optimal treatment for lung cancer patients with symptomatic choroidal metastasis is uncertain because of the rarity of this condition [3–9]. Local treatment with external beam radiation or laser photocoagulation has been proposed to treat choroidal metastasis, because the choroid is a photosensitive organ [10–12]. However, complications such as cataract, retinopathy, glaucoma, and even blindness may occur when patients undergo radiotherapy [10, 12]. Effectiveness of
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RLL AD 33/F 4
RLL RUL RLL AD AD AD 26/M 44/F 60/F 1 2 3
AD adenocarcinoma, CR complete remission, PR partial remission, PD progression of the disease, RUL right upper lobe, RML right middle lobe, RLL right lower lobe, PPD packs per day, EGFR epidermal growth factor receptor
Gefitinib Blurred vision decreased visual acuity
13
Wild type Never Bronchoscopic biopsy
Bilateral
Pemetrexed + Cisplatin Pemetrexed + Cisplatin Pemetrexed + Cisplatin Blurred vision metamorphopsia Blurred vision metamorphopsia Blurred vision, decreased visual acuity 1 PPD for 10 years Wild type Never Wild type Never Exon 18 point mutation Bronchoscopic biopsy Bronchoscopic biopsy Bronchoscopic biopsy
Bilateral Left Bilateral
Treatment option EGFR status Smoking status Diagnostic method for lung cancer
Unilateral or bilateral
Initial presentations of choroid metastasis
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Patient (No.) Age/Sex Cell type Lung cancer location
Table 1 All cases of symptomatic choroidal metastasis from lung cancer at the Kaohsiung Medical University Hospital from January 2010 to August 2011
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chemotherapy or targeted therapy alone for choroidal metastasis has been limited in the literature [6, 13–16]. Therefore, we performed a retrospective study to summarize the treatment of lung cancer patients with symptomatic choroidal metastasis in a tertiary teaching hospital and performed a literature review of all lung cancer patients with choroidal metastasis who were treated with systemic chemotherapy.
Patients and methods All tissue-proven lung cancer patients who had symptomatic choroidal metastasis treated at the Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, from January 2010 to August 2011 were enrolled. The symptoms of choroidal metastasis included blurred vision, decreased visual acuity, tenderness, flashes, floaters, metamorphopsia, and scotomas. Diagnoses were made by ophthalmologists based on imaging results and clinical findings. The choices of treatment for these patients were decided by the duty physicians. We also performed a literature search of all relevant articles published in English in Pubmed up to August 2012. We carefully documented all of the patients who received systemic chemotherapy alone. Patients who underwent ocular treatment such as photodynamic therapy, local radiotherapy, enucleation, and intravitreous injections were excluded. Data were recorded on a standard data extraction form including age, gender, and the location of ocular and extraocular metastatic sites. Epidermal growth factor receptor (EGFR) mutations, chemotherapy or targeted therapy alone, response to chemotherapy in the ocular and primary site of lung cancer, and outcomes were also reviewed.
Results In total, 226 patients with newly diagnosed lung cancer were registered at the Kaohsiung Medical University Hospital during the study period. Only four (4/226, 1.77 %) patients were diagnosed with lung cancer with choroidal metastasis, and they were enrolled into this study. Their basic characteristics, clinical presentations, and treatment options are listed in Table 1. Case 1 A 26-year-old male patient had a 10 pack-year smoking history and strong lung cancer family history (both his grandfather and uncle died of lung cancer). He was diagnosed as lung adenocarcinoma based on bronchoscopic biopsy. He also had multiple metastases. An EGFR mutation test
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Fig. 1 The thickness of the fundus represented a choroidal tumor. The choroidal tumor had recovered to normal thickness after chemotherapy (Case 1, 2, 3), indicating the regression of the choroidal tumor based on the optical coherence tomography
was negative. He received chemotherapy with vinorelbine (25 mg/m2) plus cisplatin (75 mg/m2); however, he experienced blurred vision, decreased visual acuity, and metamorphopsia over left eye after the second cycle of chemotherapy. According to the ophthalmologist, there was a high probability of choroidal metastasis over both eyes based on optical coherence tomography (Fig. 1), fundoscopy (Fig. 2), and fluorescence angiography (Fig. 3). He refused radiotherapy as a local treatment to the metastasis because of concerns over side effects. He was treated with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2). The choroidal tumor showed marked regression after the second cycle of chemotherapy, although there was no significant change in the lung mass. Totally, he underwent 4 cycles of pemetrexed and cisplatin. Unfortunately, the patient developed pneumonia and sepsis 3 months after the occurrence of choroidal metastasis and died soon thereafter (Tables 2, 3). Case 2 A 44-year-old female who had never smoked presented with dry cough and blurred vision for 1 month. Lung
adenocarcinoma was diagnosed via bronchoscopic biopsy. Bedsides, multiple intrapulmonary metastatic nodules were noticed. An EGFR mutation test was negative. Due to blurred vision and metamorphopsia over left eye, we consulted an ophthalmologist and left choroidal metastasis was proved based on imaging results (Fig. 1). She refused radiotherapy due to concerns with side effects and decided to receive systemic chemotherapy alone. Therefore, she was treated with pemetrexed (500 mg/m2) plus cisplatin (75 mg/ m2). There was dramatic regression of the choroidal tumor after 2 cycles of chemotherapy, and her pulmonary tumors also had a partial response to the chemotherapy. There was no evidence of choroidal tumor recurrence after 6 months, and she was still alive after 16 months of follow-up. Case 3 A 60-year-old female visited our clinic because of chronic dry cough and dizziness. A bronchoscopic biopsy from mass over right lower lung demonstrated lung adenocarcinoma and showed an EGFR exon 18-point mutation. She also had bilateral blurred vision, and the ophthalmologist
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Fig. 2 (Case 1) Tumor regressed after chemotherapy on fundoscopy
Fig. 3 Bilateral choroid tumors were noticed by fluorescence angiography
indicated the high probability of choroidal metastasis over both eyes. She elected to receive systemic chemotherapy with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2). There was marked regression in the choroidal tumors after the first cycle of chemotherapy (Fig. 1). Unfortunately, she had a sudden onset of consciousness disturbance at home before the second cycle of chemotherapy. Acute brain stem stroke was impressed and pneumonia then developed. She died of sepsis 2 months later.
choroidal metastases were impressed according to the results of optical coherence tomography and fundoscopy. She refused to receive chemotherapy or local choroid therapy and insisted on taking gefitinib even though an EGFR mutation test was negative. Unfortunately, the response to gefitinib was poor, and her visual defect became worse. She died of cachexia, malnutrition, and a fatal nosocomial pneumonia 3 months later.
Case 4
Literature review
A 33-year-old female who had never smoked presented with multiple bone pain, poor appetite, and dry cough for 2 months. A right lower lung mass was found, and a bronchoscopic biopsy confirmed the diagnosis of lung adenocarcinoma. She complained of blurred vision, and bilateral
Including the patients in the current study, there were a total of twelve patients who had choroidal metastasis from the lung and received systemic chemotherapy. Most of them were adenocarcinoma (9/12, 75 %), and at least 58.3 % (7/12) had not only choroidal metastasis but also
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203
Table 2 Systemic chemotherapy or targeted therapy alone for choroidal metastasis from lung cancer in a search of the English literature Lung tumor response
Local choroid response
Outcome (since the date of choroid metastasis)
Vindesine + cisplatin + 5FU Lung cancer NA Chemotherapy SqCC NA Chemotherapy LCC Bone, liver Paclitaxel + carboplatin NSCLC Brain Docetaxel + carboplatin LCC Lung to lung Gemcitabine, carboplatin, bevacizumab
PD
NA
NA
NA PR PD SD PR
NA Regression Progression Regression Regression
NA >5 months 4 months >18 months >5 months
42/F 50/M
AD AD
Singh et al. [15]
60/F
AD
Our case 1 Our case 2
26/M 44/F
Our case 3
60/F
References
Age/sex Histology
Other metastasis site
Harino et al. [17]
53/M
NA
Harino et al. [17] Kiratli et al. [31] Hasturk et al. [18] Shields et al. [20] George et al. [16]
46/F 37/M 51/M 75/F 42/F
Ascaso et al. [19] Singh et al. [6]
SqCC
Systemic treatment
Paclitaxel + cisplatin Gemcitabine + cisplatin
NA NA
NA Regression
NA >13 months
Pemetrexed + cisplatin
PR
Regression
>11 months
AD AD
Brain, bone No distant metastasis No distant metastasis Bone Lung to lung
Pemetrexed + cisplatin Pemetrexed + cisplatin
SD PR
Regression Regression
6 months (pneumonia) >16 months
AD
Bone, brain
Pemetrexed + cisplatin
PR
Regression
3 months (Unexpected Stroke)
AD adenocarcinoma, SqCC squamous cell carcinoma, LCC large cell carcinoma, NSCLC non-small cell lung cancer, PR partial response, PD progression of the disease, SD stable disease, NA not available
Table 3 Systemic-targeted therapy alone for choroidal metastasis from lung cancer in a search of the English literature Reference
Age/sex Histology Other metasta- EGFR muta- Systemic sis site tion status treatment
Lung tumor Local choroid response response
Outcome (since the date of choroid metastasis)
Inoue et al. [14] 68/F Fujiu et al. [21] 49/F
AD AD
Lung to lung NA
NA Exon 19 mutation
Gefitinib Erlotinib
NA PR
Regression Regression
>3 months NA
Our case 4
AD
Lung to lung
Wild type
Gefitinib
PD
Progression
3 months (died of a nosocomial pneumonia, not related to gefitinib)
33/F
AD adenocarcinoma, PR partial response, PD progression of the disease, NA not available
other sites of metastasis. There was female predominance (7/12, 58.3 %), and the median age was 48.83 years (range 26–75 years). Several chemotherapy regimens were tried, including vindesine plus cisplatin plus 5-FU, pemetrexed plus cisplatin [17], gemcitabine plus cisplatin [15], paclitaxel plus carboplatin [18], paclitaxel plus cisplatin [19], docetaxel plus carboplatin [20], and gemcitabine plus carboplatin plus bevacizumab [16]. In those who received pemetrexed plus cisplatin [15] (including our patients),choroidal tumors showed a high response rate (4/4, 100 %) and two of our patients remained alive for more than 11 months. Three patients received targeted therapy [14, 21]. Of these patients, two (one had an exon 19 deletion EGFR mutation, the other was unknown) had regression of the choroidal tumors and one (our case 4) experienced disease progression and died 3 months later.
Discussion We showed the incidence of symptomatic choroidal metastasis from lung cancer in a single institute in Taiwan. We also demonstrated that systemic chemotherapy had a good response rate for choroidal metastasis from lung adenocarcinoma, indicating that chemotherapy such as pemetrexed plus cisplatin may be a treatment option for such patients. The choroid, located between the retina and sclera, a vascular and pigmented tissue layer, provides the vascular supply to the outer part of the retina. The route of metastasis to the choroid is hematogenous because of the hypervascularity. Tumor cells usually pass through the internal carotid artery to the ophthalmic artery then reaching the intraocular and orbital structures [22–24].
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Choroidal metastasis has been detected in many primary cancers, but predominantly in breast and lung cancers [23–25]. A prospective screening study for choroidal metastasis in patients with metastatic lung cancer reported an incidence rate of 7.1 %, and it is the sixth most common site for metastasis from primary lung cancer [26]. Nevertheless, choroidal metastasis is relatively rare and often asymptomatic. In Taiwan, lung and breast cancers represent more than two-thirds of primary tumor sites [25]. Choroidal metastasis from primary tumors has a significantly high impact on the quality of life and is representative of poor outcomes [2, 8, 15]. Kreusel et al. reported that 36 % of patients with lung cancer had been diagnosed before the occurrence of choroidal metastasis. The choroidal metastasis was often unilateral, solitary, and located close to or at the posterior pole in the majority of patients [2]. Bilateral choroidal metastasis has been reported in 20–40 % of choroidal metastasis [2]. In our study, three patients had bilateral choroidal metastasis, and one patient had involvement with the left eye only. The clinical presentations of choroidal metastasis include blurred vision, decreased visual acuity, tenderness, flashes, floaters, metamorphopsia, and scotomas [2, 15, 26]. Among these symptoms, blurred vision and decreased visual acuity are the most common symptoms, and they have a strong influence on daily activity. Metastatic carcinoma to the choroid can cause visual dysfunction due to the accumulation of subretinal fluid and/or tumoral involvement of the macular region [2, 23]. However, most patients with choroidal metastasis are asymptomatic. In patients with SCLC, carcinoma-associated retinopathy (CAR) syndrome should be one of the differential diagnoses of visual disturbance. CAR syndrome is a paraneoplastic syndrome and characterized by the production of an autoantibody to recovering a retinal photoreceptor protein in the retinal cone. The diagnosis of CAR often based on electroretinogram because of the presence of this antibody is difficult to detect in general hospitals [7]. The differential diagnoses of a choroidal mass include choroidal neovascularization, primary choroidal malignant melanoma, choroidal metastasis, inflammatory granulomas, and hemangioma [2, 22, 23, 26, 27]. The related diagnostic procedures include slit-lamp biomicroscopy, ophthalmoscopy, ultrasonography, fluorescein angiography, optical coherence tomography, and magnetic resonance imaging [2, 15, 17, 26, 28–31]. Typical ophthalmoscopic features include one or multiple creamy yellow choroidal lesions associated, in some advanced cases, with secondary retinal detachment. Under fluorescein angiography, these lesions are usually fluorescent in the early phases of study and then become progressively hyperfluorescent in the late phases. B-scan ultrasound shows an echogenic subretinal mass
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with diffuse, ill-defined borders. Optical coherence tomography shows retro-retinal space thickening [15, 29]. With regard to survival, Wang et al. [25] reported that the mean survival time after the diagnosis of choroidal metastasis from different cancers was 4.3 months in Taiwan. Chong et al. [30] reported that patients with choroidal metastasis from lung cancer had a 1.9- to 3.3-month survival time. Kreusel et al. [2] reported that patients with choroidal metastasis detected in a screening study of lung cancer had an exceptionally short median survival period of only 2 months. These studies showed the choroidal metastasis is a poor prognostic predictor in lung cancer patients. Treatment for choroidal metastasis is palliative because the presence of such metastasis suggests hematogenous spread of the lung cancer. The aims for treatment are to maximize the quality of life and to restore or preserve vision. There are many methods to treat choroidal metastasis locally, such as radiotherapy, laser photocoagulation, photodynamic therapy, transpupillary thermotherapy, chemotherapy, and enucleation [2, 10–12]. External beam radiation therapy is the most common choice of treatment for choroidal metastasis, because the choroid is radiosensitive. The dose of external beam radiotherapy required for the successful palliation of choroidal metastasis for most primary tumors is 30 grays in daily fractions of 3 grays. However, radiotherapy may result in permanent orbital complications such as conjunctivitis, cataracts, glaucoma, retinopathy, optic neuropathy, or even blindness [10, 12]. The use of chemotherapy alone for choroidal metastasis has recently been documented [6, 13–16]; however, no large-scale clinical trials have been performed because of the relative rarity of choroidal metastasis. The choice of drugs for each patient depends on the types of primary cancer. For non-small cell lung cancer, several kinds of targeted therapy or chemotherapy have been used, such as gefitinib [14], gemcitabine plus carboplatin, or a combination of bevacizumab, gemcitabine, and carboplatin. Kim et al. [5] reported a patient who had complete regression with a combination of intravitreal bevacizumab and oral erlotinib. Pemetrexed is a new potent inhibitor of thymidylate synthase and other folate-dependent enzymes, and is currently approved for the first- and second-line treatment of advanced stage or recurrent non-squamous, non-small cell lung cancer, especially the non-squamous subtype. Pemetrexed plus cisplatin has been shown to have better efficacy, fewer side effects, and more convenient administration than cytotoxic chemotherapy such as gemcitabine plus cisplatin in lung adenocarcinoma [32]. Singh et al. [15] demonstrated a partial response to pemetrexed plus cisplatin in the treatment of choroidal metastasis from lung cancer. In our study, pemetrexed plus cisplatin demonstrated a good response to choroidal metastatic tumors from lung adenocarcinoma (3/3, 100 %), and one of our patients
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had survived for more than 16 months (still alive). These patients also had a better quality of life because of recovery of visual acuity subjectively and objectively. To the best of our knowledge, this is the largest retrospective study to discuss the systemic treatment alone for symptomatic choroidal metastasis from lung cancer.
Conclusion Symptomatic choroidal metastasis from primary lung adenocarcinoma is rare, and the ideal treatment option has yet to be determined. Based on our retrospective study and literature search, systemic chemotherapy alone instead of local therapy resulted in regression of the choroid tumors. With regards to the chemotherapy drugs, pemetrexed plus cisplatin seemed to be the most effective drug combination. Further large-scale studies are warranted. However, currently, radiotherapy for such patients is still the gold standard. Conflicts of interest The authors declare that they have no competing.
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