Cancer is a global health issue, with up to 1.8 million estimated new cases in 2020 in the United States alone.¹ While survival rates have generally improved in the past few decades owing to advances in diagnosis and treatment,¹ the side effects of various treatments still plague cancer survivors, adversely affecting their quality of life.²

There has been a surge in anticancer drug research and development to produce drugs that are more efficient at targeting cancerous cells rather than host tissues. Systemic side effects such as alopecia and fatigue are well-established, but ocular side effects, particularly those pertaining to the ocular surface, are less recognized. In this article, we summarize the characteristics of various anticancer drugs and discuss the distinct ocular surface changes that are associated with them and that can affect quality of life and contact lens wear.

ANTICANCER DRUGS

Anticancer drugs typically fall into one of three broad categories:

1. Cytotoxic chemotherapy prevents cells from dividing by interfering with processes required for cellular division such as DNA synthesis.³ This results in death of cancerous cells, which usually divide at a more rapid rate compared to cells of the host tissues.
2. Hormonal agents halt the growth of cancerous cells that rely on hormones to develop and proliferate such as in breast and prostate cancers.⁴
3. Molecularly targeted therapies are designed to act more specifically on cancerous cells and on associated processes that lead to their malignancy. This group is comprised of small-molecule kinase inhibitors and monoclonal antibodies.⁵ Some also have immune-mediating actions that render cancerous cells more susceptible to the host immune system.

OCULAR SURFACE SIDE EFFECTS FROM ANTICANCER TREATMENTS

While not an exhaustive list, the following sections describe the most distinct changes of the ocular surface that have been associated with anticancer drugs.

Lacrimal Drainage Obstruction with Cytotoxic Chemotherapy 5-Fluorouracil (5-FU) is an antimetabolite that interferes with nucleic acid synthesis during DNA replication. It is used intravenously to treat breast, head, neck, and gastrointestinal cancers. Punctal and canalicular stenoses have been reported with this drug, including regimens involving 5-FU combined with other agents such as CMF (cyclophosphamide, methotrexate, and 5-FU), FEC (5-FU, epirubicin, and cyclophosphamide), and S-1 (tegafur [a prodrug of 5-FU], gimeracil, and oteracil).^6-9 An incidence rate of 4.9% to 5.8% has been reported, with symptoms usually developing within the third cycle of treatment.^9,10 Epiphora in treated patients should alert clinicians to the possibility of stenosis in the lacrimal drainage system.

Another notable drug associated with punctal stenosis is docetaxel, a mitotic inhibitor commonly used to treat breast, lung, ovarian, and prostate cancers. Research has shown that lacrimal drainage stenosis occurs at much higher incidence rates with weekly docetaxel treatment compared to with three-weekly treatment.¹¹

The proposed pathophysiological mechanism relates to the susceptibility of the lacrimal drainage apparatus’ mucosal membrane linings to direct toxicity from the accumulation of these anticancer drugs in the tear film following intravenous administration.^12,13 Cells in these tissues undergo constant cellular turnover, not unlike rapidly dividing cancerous cells. While symptoms of epiphora usually resolve after treatment has been completed, repeated punctal dilation and use of topical corticosteroids during the course of anticancer treatment may be required, with silicone intubation or surgical interventions needed for persistent or more serious cases, which may lead to permanent tear duct blockage.

Dry Eye with Hormonal Agents Tamoxifen is a hormonal agent used in estrogen-dependent breast cancer treatment to inhibit estrogen from binding to its receptor, which prevents further cellular proliferation and reduces recurrence rates following surgical resection. While tamoxifen is known to cause crystalline retinopathy, it is also associated with keratopathy in up to 10.8% of patients.¹⁴ These may be subtle findings characterized by bilateral subepithelial deposits or distinct whorl-like and linear opacities, with no-to-minimal effects on visual acuity.¹⁴ It may occur even at low doses (20mg/day), with the first corneal findings observed from six months to two years after commencing treatment.¹⁴ No action is usually required, as the corneal findings are usually reversible with drug discontinuation if the treating oncologist chooses alternative treatments as a result of more sight-reducing side effects such as retinal complications.

In contrast to the competitive binding of estrogen receptors with tamoxifen, aromatase inhibitors such as anastrozole inhibit the aromatase enzyme needed for the synthesis of estrogen; hence, these drugs are used more widely in postmenopausal women. As estrogen is putatively required for meibomian gland development,¹⁵ it comes as no surprise that aromatase inhibitors are associated with meibomian gland dysfunction (MGD) and with dry eye disease. MGD has been documented in up to 42.5% of treated patients.¹⁶ A recent study has also documented with the Ocular Surface Disease Index questionnaire a higher risk of dry eye symptoms in treated patients (35.5%) compared to healthy controls (18%).¹⁷ The amount of time for symptom onset, including blurred vision and foreign body sensation, from the commencement of treatment can range widely (13.2 ± 12.6 months).¹⁶ While discontinuation of aromatase inhibitors usually results from systemic side effects—such as arthralgias and hot flashes—rather than from ocular surface side effects,¹⁸ it is important to understand the potential ocular surface changes, which may be just as frustrating to patients. As symptoms are usually mild-to-moderate, the MGD and dry eye disease usually can be managed according to standard protocols.¹⁹

CORNEAL CHANGES WITH TARGETED THERAPIES

Epithelial growth factor receptor (EGFR), a transmembrane protein activated by tyrosine kinase activity, is found in high levels in certain types of cancer cells. EGFR is also present in ocular tissues such as corneal epithelial basal cells and is needed for proper cellular growth and migration.^20,21 Vortex keratopathy has been reported with vandetanib treatment, which is used for advanced or metastatic medullary thyroid cancer.²² This is presumably due to the impact of anti-EGFR properties on corneal epithelial cell migration.

Other nonspecific corneal changes, including persistent corneal epithelial defects and superficial punctate keratitis, have been reported with small-molecule kinase inhibitors, including gefitinib,²³ and with monoclonal antibodies, including trastuzumab.²⁴ Mild corneal findings usually require only conservative treatment such as lubricating eyedrops; however, severe cases involving corneal thinning and melting may require more involved interventions or discontinuation of treatment, as reported with erlotinib.²⁵

CORNEAL SUB-BASAL NERVE PLEXUS CHANGES WITH NEUROTOXIC CHEMOTHERAPY

In-vivo corneal confocal microscopy has revealed corneal nerve changes (Figure 1) associated with cytotoxic chemotherapy that cause peripheral neuropathy, which affects patients’ distal extremities. Researchers have found evidence of corneal nerve loss with chemotherapy treatment, including oxaliplatin in gastrointestinal tumor treatment, which forms platinum-DNA adducts, and paclitaxel, a mitotic inhibitor similar to docetaxel, in breast cancer treatment.^26,27 There have been equivocal results, however, with a longitudinal study also showing increased corneal nerve fiber length rather than loss.²⁸ The clinical significance and impact on ocular surface health is still unknown, with no specific intervention required.

CLINICAL TAKEAWAY

Anticancer drugs can be associated with distinct ocular surface changes that can affect health and quality of life. Eyecare practitioners should be cognizant of the potential side effects and appropriate interventions for comanagement with patients’ general practitioner or medical oncologist. CLS

The authors thank Professor Arun Krishnan and Professor David Goldstein (Prince of Wales Clinical School, UNSW Sydney, Australia) for their expertise in neurology and medical oncology. This work is supported by an Australian Government Research Training Program Scholarship.

REFERENCES

1. American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer Society; 2020.
2. American Cancer Society. Cancer Treatment & Survivorship Facts & Figures 2019-2021. Atlanta: American Cancer Society; 2019.
3. ldred EM. Pharmacology: A Handbook for Complementary Healthcare Professionals. Elsevier Health Sciences; 2008.
4. Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 2014 Aug;5:248-262.
5. Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008 Feb;77:311-319.
6. Brink HM, Beex LV. Punctal and canalicular stenosis associated with systemic fluorouracil therapy. Report of five cases and review of the literature. Doc Ophthalmol. 1995;90(1):1-6.
7. Esmaeli B, Golio D, Lubecki L, Ajani J. Canalicular and nasolacrimal duct blockage: an ocular side effect associated with the antineoplastic drug S-1. Am J Ophthalmol. 2005 Aug;140:325-327.
8. Stevens A, Spooner D. Lacrimal duct stenosis and other ocular toxicity associated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer. Clin Oncol (R Coll Radiol). 2001;13(6):438-440.
9. Karamitsos A, Kokkas V, Goulas A, et al. Ocular surface and tear film abnormalities in women under adjuvant chemotherapy for breast cancer with the 5-Fluorouracil, Epirubicin and Cyclophosphamide (FEC) regimen. Hippokratia. 2013 Apr;17:120-125.
10. Eiseman AS, Flanagan JC, Brooks AB, Mitchell EP, Pemberton CH. Ocular surface, ocular adnexal, and lacrimal complications associated with the use of systemic 5-fluorouracil. Ophthalmic Plast Reconstr Surg. 2003 May;19:216-224.
11. Mansur C, Pfeiffer ML, Esmaeli B. Evaluation and Management of Chemotherapy-Induced Epiphora, Punctal and Canalicular Stenosis, and Nasolacrimal Duct Obstruction. Ophthalmic Plast Reconstr Surg. 2017 Jan/Feb;33:9-12.
12. Loprinzi CL, Love RR, Garrity JA, Ames MM. Cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-induced ocular toxicity. Cancer Invest. 1990;8(5):459-465.
13. Esmaeli B, Ahmadi MA, Rivera E, et al. Docetaxel secretion in tears: association with lacrimal drainage obstruction. Arch Ophthalmol. 2002 Sep;120:1180-1182.
14. Noureddin BN, Seoud M, Bashshur Z, Salem Z, Shamseddin A, Khalil A. Ocular toxicity in low-dose tamoxifen: A prospective study. Eye (Lond). 1999 Dec;13 (Pt 6):729-733.
15. Butovich IA, Bhat N, Wojtowicz JC. Comparative Transcriptomic and Lipidomic Analyses of Human Male and Female Meibomian Glands Reveal Common Signature Genes of Meibogenesis. Int J Mol Sci. 2019 Sep;20:4539.
16. Chatziralli I, Sergentanis T, Zagouri F, et al. Ocular Surface Disease in Breast Cancer Patients Using Aromatase Inhibitors. Breast J. 2016 Sep;22:561-563.
17. Inglis H, Boyle FM, Friedlander ML, Watson SL. Dry eyes and AIs: If you don’t ask you won’t find out. Breast. 2015 Dec;24:694-698.
18. Bell SG, Dalton L, McNeish BL, et al. Aromatase inhibitor use, side effects and discontinuation rates in gynecologic oncology patients. Gynecol Oncol. 2020 Nov;159:509-514.
19. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017 Jul;15:575-628.
20. Zieske JD, Takahashi H, Hutcheon AE, Dalbone AC. Activation of epidermal growth factor receptor during corneal epithelial migration. Invest Ophthalmol Vis Sci. 2000 May;41:1346-1355.
21. Dong F, Call M, Xia Y, Kao WW. Role of EGF receptor signaling on morphogenesis of eyelid and meibomian glands. Exp Eye Res. 2017 Oct;163:58-63.
22. Ahn J, Wee WR, Lee JH, Hyon JY. Vortex keratopathy in a patient receiving vandetanib for non-small cell lung cancer. Korean J Ophthalmol. 2011 Oct;25:355-357.
23. Tullo AB, Esmaeli B, Murray PI, Bristow E, Forsythe BJ, Faulkner K. Ocular findings in patients with solid tumours treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Phase I and II clinical trials. Eye (Lond). 2005 Jul;19:729-738.
24. Orlandi A, Fasciani R, Cassano A, et al. Trastuzumab-induced corneal ulceration: successful no-drug treatment of a “blind” side effect in a case report. BMC Cancer. 2015 Dec;15:973.
25. Saint-Jean A, Sainz de la Maza M, Morral M, et al. Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: report of 5 cases. Ophthalmology. 2012 Sep;119:1798-1802.
26. Venkitaraman R, Sharma S, Soomal R, Scrase CD, Rayman G. Chemotherapy-induced peripheral neuropathy: a prospective study using methods of small fibre function and structure. J Clin Oncol. 2015;33(15_suppl):e20723-e20723.
27. Campagnolo M, Lazzarini D, Fregona I, et al. Corneal confocal microscopy in patients with oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst. 2013 Sep;18:269-271.
28. Ferdousi M, Azmi S, Petropoulos IN, et al. Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy. PLoS One. 2015 Oct;10:e0139394.