Medical Oncology

, 31:901

Combination of intravitreal bevacizumab and systemic therapy for choroidal metastases from lung cancer: report of two cases and a systematic review of literature

Authors

  • Venkata Nagarjuna Maturu
    • Department of Pulmonary MedicinePostgraduate Institute of Medical Education and Research (PGIMER)
    • Department of Pulmonary MedicinePostgraduate Institute of Medical Education and Research (PGIMER)
  • Pooja Bansal
    • Department of OphthalmologyPostgraduate Institute of Medical Education and Research (PGIMER)
  • Bhagwant Rai Mittal
    • Department of Nuclear MedicinePostgraduate Institute of Medical Education and Research (PGIMER)
  • Nalini Gupta
    • Department of Cytology and Gynecological PathologyPostgraduate Institute of Medical Education and Research (PGIMER)
  • Digambar Behera
    • Department of Pulmonary MedicinePostgraduate Institute of Medical Education and Research (PGIMER)
  • Amod Gupta
    • Department of OphthalmologyPostgraduate Institute of Medical Education and Research (PGIMER)
Short Communication

DOI: 10.1007/s12032-014-0901-z

Cite this article as:
Maturu, V.N., Singh, N., Bansal, P. et al. Med Oncol (2014) 31: 901. doi:10.1007/s12032-014-0901-z

Abstract

Symptomatic choroidal metastasis (SCM) is an uncommon manifestation of lung cancer (LC). Treatment of SCM usually includes a combination of systemic therapy (chemotherapy and/or targeted therapy) for the primary tumor as well as local therapy (ocular radiation) for CM. Intravitreal bevacizumab (IV-Bev) is a newer modality being tried for local control of SCM. We describe here two patients with LC who presented with CM and were treated with IV-Bev. We performed a systematic literature review of previously reported patients with CM from LC who were treated with IV-Bev. Six reports (involving seven patients) in which IV-Bev was used as primary treatment modality for CM from LC were identified in the systematic literature review. A total of nine patients (seven previously reported and two index cases) were analyzed further. Along with individual case descriptions of index patients, pooled analysis of demographic profile, histology and outcomes with treatment (systemic and ocular) for the nine patients identified in this systematic review are described. A majority (n = 7) had non-small-cell lung cancer (NSCLC) histology, CM as presenting manifestation (n = 6) and unilateral ocular involvement (n = 8). IV-Bev was used in a dose of either 1.25 mg/cycle (n = 5) or 2.5 mg/cycle (n = 4) with number of cycles varying from 2 to 14 and duration between cycles varying from 2 to 8 weeks. Of the nine patients treated with IV-Bev as the primary ocular treatment modality, six (all non-squamous NSCLC) had favorable ocular response. No short-term ocular complications related to therapy were noted. We suggest that IV-Bev is a promising and safe alternative to ocular radiation for initial treatment of CM from non-squamous NSCLC. However, we recommend against using it for patients with small-cell lung cancer.

Keywords

BevacizumabChoroidMetastasisLung cancerIntravitrealNon-squamous NSCLC

Introduction

The choroid is the most common site for ocular metastases. The most common primary sites associated with ocular metastases are breast cancer in women and lung cancer (LC) in men [1, 2]. In most cases, these lesions are asymptomatic and are not evaluated by an ophthalmologist. Symptomatic choroidal metastasis (SCM) from LC is uncommon, and SCM as its presenting feature is even rarer [3]. Treatment of SCM usually includes a combination of systemic therapy (chemotherapy and/or targeted therapy) for the primary tumor as well as local therapy for choroidal deposits [4]. Till date, ocular radiation (external beam radiotherapy) has remained the cornerstone of management of SCM but has several complications including cataract, exposure keratopathy, iris neovascularization, radiation retinopathy and radiation papillopathy. Other ocular treatment modalities have therefore been tried [4, 5]. Intravitreal bevacizumab (IV-Bev) is a newer modality being tried for local control of SCM. We herein report two cases of LC presenting with SCM in whom IV-Bev was used as initial treatment. We also report results of a systematic review on the use of IV-Bev for CM from LC.

Case reports

Patient 1

A 60-year-old lady and never smoker presented to the ophthalmology outpatient department in May 2012 with sudden onset painless loss of vision (SOP-LOV) in right eye (RE). There was no significant medical history. On ocular examination, her best corrected visual acuity (BCVA) was counting fingers at 1 meter in RE and 6/12 in left eye (LE). Intraocular pressure (IOP) on Goldmann applanation tonometer (GAT) was 12 and 14 mmHg in RE and LE, respectively. Anterior segment examination was unremarkable, and there was no relative afferent papillary defect (RAPD) in either eye. Fundus examination showed a large sub-retinal choroidal mass over posterior pole (Fig. 1a). Fundus fluorescein angiography (FFA) and ultrasound (USG) B scan of RE ruled out choroidal melanoma or hemangioma. Optical coherence tomography (OCT) revealed presence of cystoid macular edema (CME) (Fig. 1c). She was diagnosed as having CM in RE and underwent whole-body fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) which revealed an FDG-avid (SUVmax 8.2) soft tissue mass in left lower lobe (LL) of lung (Fig. 1e) with FDG-avid mediastinal lymph nodes (LN) (stations 6, 7, 8) and skeletal lesions suggestive of metastatic disease. Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) from sub-carinal LN confirmed diagnosis of non-small-cell LC (NSCLC) (adenocarcinoma) (Fig. 2c, d). Molecular analysis for presence of epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene rearrangements could not be performed due to technical constraints.
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Fig. 1

Fundus photograph of right eye showing a large sub-retinal choroidal mass over posterior pole (arrow) (a). Image obtained after treatment showing decrease in volume of mass (arrow) with appearance of pigmentary changes (b). OCT images obtained before (c) and after treatment (d) showing complete resolution of cystoid macular edema with treatment. Fused 18F-FDG PET-CT axial images at baseline showing FDG-avid irregular soft tissue lesion in the left lower lobe (SUVmax 8.2) (e). Image obtained at follow-up shows decrease in the size and FDG avidity (SUVmax 3.5) of the lesion (f)

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Fig. 2

Photomicrograph of FNAC smear containing small-sized tumor cells showing focal chromatin threading suggestive of small-cell lung cancer (May–Grünwald Giemsa; ×20) (a). These tumor cells showed nuclear molding and salt-pepper like finely granular chromatin which were characteristic of SCLC (H&E; ×40) (b); photomicrograph of transbronchial needle aspiration from sub-carinal lymph node showing a cluster of large tumor cells with irregular nuclear membranes, coarse chromatin and prominent nucleoli suggestive of adenocarcinoma (May–Grünwald Giemsa; ×40) (c). These tumor cells having morphology of adenocarcinoma were both in clusters and scattered among alveolar macrophages (Pap; ×40) (d)

A final diagnosis of stage IV non-squamous NSCLC (T2N2M1b) was made and patient started on systemic chemotherapy (pemetrexed 500 mg/m2 and cisplatin 65 mg/m2 each on D1 of a 3-weekly cycle) and zoledronate (4 mg intravenous every 4 weeks). Systemic bevacizumab could not be given because of financial constraints. After the first cycle, she declined further chemotherapy and was therefore started on oral gefitinib. She was lost to follow up thereafter. Subsequently, she returned after a 4-month period in view of no improvement in vision. She was then initiated on IV-Bev, while gefitinib and zoledronate were continued. She received four cycles of IV-Bev (1.25 mg in 0.05 ml every 4 weeks). Repeat whole-body 18F-FDG PET-CT done after therapy showed decrease in size and FDG avidity of lung mass (Fig. 1f) as well as mediastinal LN and skeletal lesions. Repeat ocular examination showed improvement in BCVA to 6/18, decrease in the size of choroidal mass (Fig. 1b) and resolution of CME (Fig. 1d).

Patient 2

A 49-year-old man experienced SOP-LOV in LE 3 weeks before presentation to us. He was a never smoker with no history of environmental tobacco smoke or other occupational exposures. Ocular examination showed BCVA of 6/6 in RE and 6/18 in LE. IOP on GAT was 16 and 18 mmHg in RE and LE, respectively. Anterior segment examination was unremarkable, and there was no RAPD in either eye. Fundus examination revealed an elevated large sub-retinal dome-shaped choroidal mass measuring around 10 disk diameters (DD) just temporal to the fovea associated with two small sub-retinal masses in the periphery and inferior exudative retinal detachment in LE (Fig. 3a). RE also showed a small plaque-like sub-retinal mass along the superior vascular arcade measuring 1.5–2 DD (Fig. 3c). A possibility of bilateral CM was considered. FFA and USG B scan also supported the clinical diagnosis of CM. Whole-body 18F-FDG PET-CT scan was then performed which revealed an FDG-avid (SUVmax 3.7) 1.9 × 1.3 cm soft tissue lesion in upper lobe of right lung and FDG-avid mediastinal LN and liver lesions (Fig. 4a, c) suggestive of metastatic disease. Mild FDG uptake was also noted in posterior compartment of both eye balls. An ultrasound-guided FNAC performed from liver lesions was suggestive of a metastatic carcinoma. EBUS-TBNA confirmed diagnosis of small-cell LC (SCLC) (Fig. 2a, b).
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Fig. 3

Fundus photograph of left eye at presentation showing a large choroidal mass in temporal half of retina (arrow) with multiple small peripheral choroidal lesions (a). Images obtained after treatment showing no decrease in size of masses and appearance of a new lesion in inferior periphery of fundus (arrow) (d). OCT image of right eye showing normal foveal contour before treatment (b) and appearance of sub-retinal fluid pocket involving the fovea following treatment (e). Fundus photograph of right eye at presentation showing presence of a plaque-like sub-retinal mass (arrow) along the superior vascular arcade (c). Images obtained post-treatment show no decrease in size of mass and a shallow exudative retinal detachment over posterior pole in right eye (arrow) (f)

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Fig. 4

Fused 18F-FDG PET-CT axial images at baseline showing FDG-avid irregular soft tissue lesion in posterior segment of right upper lobe (SUVmax 3.7), mediastinal lymph nodes (a) and multiple hypodense lesions in liver (SUVmax4.1) (c). Images obtained at follow-up showing persistence of all lesions with no significant interval change in FDG uptake from baseline (b, d)

A final diagnosis of stage IV SCLC (T1aN2M1b) was made, and he was started on systemic chemotherapy (cisplatin 30 mg/m2 and irinotecan 65 mg/m2 on days 1, 8 of a 3-weekly cycle) along with IV-Bev (1.25 mg in 0.05 ml every 4 weeks) to both eyes. Repeat PET-CT performed after four cycles of chemotherapy and three sessions of IV-Bev to both eyes was suggestive of stable disease (Fig. 4b, d). However, exudative retinal detachment surrounding the choroidal lesion and encroaching the fovea developed in RE (Fig. 3f), while a new sub-retinal lesion appeared inferiorly in LE (Fig. 3d). BCVA in RE dropped from 6/6 at baseline to 6/24 and that in LE to 6/36. OCT showed the development of sub-retinal fluid pocket involving the fovea in the left eye which was not present at presentation (Fig. 3b, e). In view of progression in ocular disease, he is currently receiving external beam radiation treatment to both eyes and also has been started on second-line chemotherapy (oral topotecan 2.3 mg/m2 D1-5 q 3 weeks).

Systematic literature review

Methodology followed in and results of this systematic literature search are given in Supplementary Appendix and Supplementary Figure 1, respectively. We identified a total of six reports [3, 610] (seven patients) in addition to two index cases in which IV-Bev was used as primary treatment modality for CM from LC. Individual case descriptions are provided in Table 1, while pooled demographic characteristics as well as treatment profile of these patients are presented in Table 2. Of seven patients with NSCLC, all of whom had non-squamous NSCLC histology, six responded favorably to IV-Bev. The latter also responded to an additional two cycles of IV-Bev along with systemic bevacizumab, second-line chemotherapy and ocular radiation. There were only two patients with CM from SCLC and in both, the ocular lesions progressed despite receiving IV-Bev.
Table 1

Individual characteristics of nine cases identified in systematic literature review who received intravitreal bevacizumab for choroidal metastases from lung cancer

Author, year (no. of patients)

Age, sex, smoking status

Histology

TNM status

Choroidal metastasis as presenting manifestation

Eye involved

Dose of intravitreal bevacizumab (cycles)

Ocular outcome

First-line systemic therapy

Second-line systemic therapy

Kim 2009 (1)

57/F/NA

NSCLC (ADC)

NA

No

Left

2.5 mg every 6 weeks (three cycles)

Improved

Doc–Cis (six cycles)

Erlotinib

de la Barquera Cordero, A. S 2010 (1)

50/F/NA

NSCLC (NOS)

NA

No

Right

2.5 mg every 4–8 weeks (five cycles)

Improved

Pacl–Carb and Bev

 

D’Antonio, C 2012 (1)

34/F/NA

NSCLC (ADC)

NA

Yes

Left

1.25 mg every 2 weeks (14 cycles)

Improved

Gem–Cis (six cycles)

 

Lai, 2012 (1)

73/M/SM

NSCLC (ADC)

NA

No

Left

2.5 mg every 2 weeks (two cycles)

Improved

Vin–Cis (three cycles) followed by Erlotinib

Doc and Pem

Singh, 2012 (2)

42/F/NS

NSCLC (large cell) T1N3M1

Yes

Left

1.25 mg every 4 weeks (seven cycles)

Improved

Pacl–Cis (four cycles)

 

53/M/SM

NSCLC (ADC) T2N2M1

Yes

Right

1.25 mg every 4 weeks (three cycles)

Progression

Pem–Cis (four cycles)

Doc–Car and Bev (five cycles), IV-Bev (two more cycles) and ocular XRT

Bhattacharyya, 2013 (1)

54/M/SM

SCLC

T3N2M1

Yes

Right

2.5 mg every 4 weeks (five cycles)

Progression

Eto–Cis (six cycles)

Ocular XRT

Current series, 2013 (2)

49/M/NS

SCLC

T1N2M1

Yes

Bilateral

1.25 mg every 4 weeks (three cycles) to both eyes

Progression

Irin–Cis (four cycles)

Topotecan and ocular XRT

60/F/NS

NSCLC (ADC)

T2N2M1

Yes

Right

1.25 mg every 4 weeks (four cycles)

Improved

Pem–Cis (one cycle) followed by Gefitinib

 

ADC adenocarcinoma, Bev bevacizumab, Cis cisplatin, Carb carboplatin, Doc docetaxel, Eto etoposide, F female, Gem gemcitabine, Irin irinotecan, IV-Bev intravitreal bevacizumab, M male, NA not available, NS non-smoker, NOS not otherwise specified, NSCLC non-small-cell lung cancer, Pacl paclitaxel, Pem pemetrexed, XRT radiotherapy, SCLC small-cell lung cancer, SM smoker, Vin vinorelbine

Table 2

Pooled characteristics of nine patients with choroidal metastases from lung cancer who received intravitreal bevacizumab

Agea

52.4 (11.0) years

Males

6 (66.7 %)

Current/ex-smokersb

3 (50 %)

Histology

 Non-small-cell lung cancer

7 (77.8 %)

  Adenocarcinoma

5 (55.5 %)

  Large cell carcinoma

1 (11.1 %)

  NSCLC-NOS

1 (11.1 %)

 Small-cell lung cancer

2 (22.2 %)

Choroidal metastasis as presenting manifestation

6 (66.7 %)

Ocular involvement

 Unilateral

8 (88.9 %)

 Bilateral

1 (11.1 %)

Side involved

 

 Right eye

5 (55.5 %)

 Left eye

5 (55.5 %)

Dose of IV-Bev per cycle

 1.25 mg

5 (55.5 %)

 2.5 mg

4 (44.4 %)

Number of cycles given

4 (3–6)

Interval between the cycles (weeks)

4 (3–5)

Clinical response to IV-Bev

 Favorable response/regression

6 (66.7 %)

 Progression

3 (33.3 %)

Values expressed as percentages or median (inter quantile range) unless specified otherwise

NSCLC-NOS non-small-cell lung cancer not otherwise specified

aMean (standard deviation)

bData available for six patients only

Discussion

Symptomatic CM from LC remains a rare occurrence. The largest review on CM from LC by us previously identified only 78 patients, among whom 55 patients had SCM as the presenting manifestation [3]. As life expectancy of patients with LC especially non-squamous NSCLC is increasing with development of newer chemotherapeutic drugs (primarily pemetrexed) and targeted agents, incidence of local complications from ocular radiation therapy is also expected to rise since the latter increase with time since radiation exposure [4].

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor. Systemic bevacizumab is approved for use as first-line therapy of advanced/metastatic non-squamous NSCLC in combination with platinum-based chemotherapy doublet and subsequently as single agent for continuation maintenance therapy [11]. However, it has not been approved in SCLC as its use has not been shown to confer any survival advantage over that conferred by chemotherapy alone [12, 13]. Reasons for its lack of efficacy in SCLC patients remain unclear.

Instillation of IV-Bev is another upcoming treatment modality for SCM. Currently, its use in this indication represents an off-label use. IV-Bev has been used to treat SCM from breast cancer [14, 15], colorectal carcinoma [16, 17] as well as LC. Till date, there are only case reports of individual patients. Ours is the first systematic review on the role of IV-Bev for treatment of LC-associated CM. Results of this review indicate that IV-Bev is a promising alternative to ocular radiation for treatment of SCM from NSCLC especially for non-squamous histology. However, the preliminary experience in both patients with SCLC seems to suggest that IV-Bev is not an effective treatment of CM in SCLC, and this observation is similar to the lack of benefit seen with use of systemic bevacizumab in small cell histology. However, considering that the number of SCLC patients in which IV-Bev has been attempted so far is very small, a more definitive recommendation regarding its use in SCLC cases may not be possible at present. Another highlight of this review is that the largest experience for use of IV-Bev for SCM from LC is from our center and half of the patients identified were those treated at the authors’ institute.

As of now, several questions related to use of IV-Bev for SCM from LC remain unanswered namely (a) Do all patients with SCM need local therapy in addition to systemic therapy, (b) Optimal dose to be used, (c) Optimal interval needed between cycles, (d) Number of cycles to be given and (e) Role of maintenance IV-Bev to prevent ocular relapses. Thus, experience with a larger number of patients is needed to confirm the efficacy of IV-Bev. Potential benefits of IV-Bev over conventional ocular radiation may need to be evaluated in a head-to-head trial. However, given the rarity of this condition per se, this may not be practically feasible.

Conclusions

IV-Bev is a promising alternative to ocular radiotherapy in managing patients with SCM from non-squamous NSCLC and should be used in conjunction with systemic chemotherapy. However, we recommend against using it for patients with SCLC.

Conflict of interest

None.

Supplementary material

12032_2014_901_MOESM1_ESM.doc (24 kb)
Supplementary material 1 (DOC 24 kb)
12032_2014_901_MOESM2_ESM.jpg (1 mb)
Supplementary material 2 (JPG 1041 kb)

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© Springer Science+Business Media New York 2014