Intralesional Bleomycin as an Adjunct Therapeutic Modality in Eyelid and Extraocular Malignancies and Tumors.

To present our recent experience with intralesional bleomycin (IBI) in nonmelanoma extraocular tumors, and present previous experience on periocular capillary hemangiomas and orbital lymphangiomas in a tertiary referral hospital. This was a retrospective descriptive study of patients with eyelid and extraocular malignancies where conventional therapies failed, or surgery was contraindicated or refused and were offered IBI as an alternate therapy. All patients were recruited from the Oculoplastics Clinic at Tygerberg Academic Hospital, Cape Town, South Africa. A solution containing 1 international unit of bleomycin per milliliter saline was injected intralesionally together with 2% lignocaine in a ratio of 4:1. The injected volume was calculated to be equivalent to the estimated volume of the lesion. A multipuncture technique with a 29-gauge needle was used. Patients requiring retreatment were injected every 4-8 weeks until satisfactory clinical endpoints were achieved. Our previous experience with IBI in extensive capillary hemangiomas and orbital lymphangiomas is reviewed. Cases are presented to illustrate that IBI induced significant regression and reduction in tumor size and marked clinical improvement of the eyelid and orbital basal cell carcinomas, Kaposi sarcoma, and mycosis fungoides. The improvements obviated the need for further surgical intervention in most cases. Based on clinical experience we propose that IBI should be considered a treatment modality in select cases of the malignant eyelid and ophthalmic vascular tumors where the conventional standard of care is not possible. IBI is a reasonable alternative or adjunct to consider in such cases.

INTRODUCTION

At times, the practicing ophthalmologist is faced with patients who present with malignant and nonmalignant eyelid and orbital tumors where standard surgical or medical therapy is not possible. For example, surgery may not be possible due to an extensive tumor or the presence of significant co-morbidities. Hence, alternate or adjunct therapies are a viable option for consideration. Such diverse cases were the impetus for our investigation into intralesional bleomycin (IBI) as a therapeutic modality in selected eyelid, periocular, and orbital tumors. Basal cell carcinomas (BCC) are common malignancies of the mid face, nose, and periocular regions with increasing frequency with advanced age. A recent literature review of topical and intralesional nonmelanoma (but nonocular) skin cancers, concluded that IBI in two small series of cases was 100% therapeutically effective.1 There is considerable literature on the use of IBI in congenital vascular and lymphatic anomalies of the head andneck and other areas of the body. IBI is used in these cases because the sclerosing effect is beneficial in causing regression.23 There is, however, a paucity or complete absence of clinical reports on the use of IBI in eyelid and periocular tumors. In this study, we assessed the efficacy of IBI in inoperable eyelid malignancies and periocular vascular tumors.

METHODS

This retrospective descriptive study evaluated three cases of eyelid and periocular BCC and one case of Kaposi sarcoma, where the recognized surgical standard of care treatment was not possible or not advisable due to the size of the tumor or patient comorbidities and underwent IBI treatment. Case reports are presented for each case. The use of IBI in other eyelid tumors is briefly described.

Informed consent was obtained from all participants by the first author. All patients were managed with respect to the ethical principles for medical research involving human subjects in accordance with the Declaration of Helsinki.

A solution containing 1 international unit (IU) of bleomycin per milliliter in saline was injected intralesionally together with 2% lignocaine usually in a ratio of 4:1 bleomycin:lignocaine. The expected volume to be injected was calculated to be equivalent to the clinically estimated volume of the lesion. This volume was not measured precisely and was estimated based on the clinician's judgment and experience. A multipuncture technique with a 29-gauge needle was used to spread the drug as homogeneously as possible throughout the tumor. Injections were administered under general anesthesia, conscious sedation or with patients fully awake depending on their age and/or preference. Posttreatment follow-ups were performed every 4–6 weeks, and tumors requiring retreatment were injected every 4–8 weeks until satisfactory clinical endpoints were achieved. Routine postinjection histology was not obtained. Clinical photographs were used to assist with comparisons between injections.

RESULTS

Basal cell carcinoma series

Case report 1

In 2010, a 92-year-old Caucasian male was referred with a recurrent right lower lid biopsy-proven BCC. The lesion was excised 5 years earlier but had recently increased in size and involved the majority of the lower lid and lid margin as well as extending to the inferior orbit as demonstrated on computed tomography scan. Due to the patient's age, fragile condition, and extent of the tumor, IBI was used along with one minor, limited tumor debulking attempt under local anesthesia. The patient had a progressive, positive response to treatment and after 8 IBIs over the duration of 12 months, the tumor was invisible and he retained a completely functional eyelid with good cosmesis. He is currently 97 without tumor recurrence to date [Figure 1a and b].

Figure 1

(a) Pretreatment basal cell carcinoma is infiltrating the right lower eyelid and anterior orbit. (b) One year after 8 intralesional bleomycin treatments with no signs of clinical recurrence

Case report 2

In 2012, an 81-year-old female Caucasian female was referred to our tertiary eye center with a right lower lid biopsy-proven BCC. On examination, the lesion was located on the medial third of the lower lid adjacent to the lacrimal apparatus. She was frail, wheelchair-bound and was reluctant to undergo surgery. IBI was offered. After each injection, there was demonstrable tumor reduction. Four treatments of IBI were required over the duration of a year. The bleomycin was successful in shrinking the tumor to the point where no tumor was visible biomicroscopically. A totally acceptable posttreatment lid anatomy was obtained without having to intervene surgically. Currently, at 84 years of age she still has no signs of recurrence [Figure 2a and b].

Figure 2

(a) Pretreatment right lower lid histologically proven basal cell carcinoma. (b) One year after 4 intralesional bleomycin treatments

Case report 3

An 80-year-old Caucasian male was referred with a biopsy-proven BCC of the right lower lid. His general health was fragile and with inoperable unstable angina he was a procedure risk even under local anesthesia or sedation. IBI was offered and administered 4 times over the course of 6 months. Total biomicroscopic tumor regression was achieved with good anatomical outcome [Figure 3a and b]. Six monthly follow-ups was maintained, and after 4 years the patient remains alive (in spite of unstable angina) and presented recently with signs of a small tumor recurrence at the temporal edge of the treated area. This was successfully re-treated with additional IBI.

Figure 3

(a) Basal cell carcinoma involving the right lower lid margin before treatment. (b) One year after 4 intralesional bleomycin treatments. No signs of tumor recurrence clinically

Kaposi sarcoma

Case report

In 2013, a 35-year-old non-Caucasian male presented with a periocular tumor, localized to the subconjunctival bulbar and fornix. This lesion was detected 3 weeks prior to the presentation. Submental lymphadenopathy was present with oral candidiasis and a single dark purple lesion on the hard palate. He had hyperpigmented pruritic papular eruptive skin lesions in keeping with the retroviral disease. He tested positive for human immunodeficiency virus (HIV), and the CD4 lymphocyte cell count was 25/mm3 confirming a diagnosis of HIV/acquired immunodeficiency syndrome. Histological examination of the periocular lesion confirmed Kaposi sarcoma with immunohistochemistry positive for human herpes virus 8. The visual acuity in the affected eye was 20/20 and external beam radiotherapy would result in unacceptable side effects to the globe. We offered IBI treatments. Four injections with monthly intervals into all four quadrants of the tumor area were administered with a complete clinical resolution of the tumor after 6 months [Figure 4a and b].

Figure 4

(a) Kaposi sarcoma infiltration of bulbar and palpebral conjunctiva before treatment. (b) Six months after 4 intralesional bleomycin treatments. Slight injection but no tumor visible biomicroscopically

Other eyelid tumors

IBI injections have also been successfully used postoperatively in three cases undergoing adjunctive chemotherapy for eyelid BCC. In these cases, the intraoperative frozen section histology confirmed clear margins, but the later paraffin sections revealed incomplete excision. These cases were reconstructed at the primary procedure based on the intraoperative frozen section evidence of complete tumor removal. We believed repeat surgery would result in inadequate cosmesis and hence a single cycle consisting of three IBI's 4–6 weeks apart was used with no evidence of tumor recurrence to date.

There was no effect in one case of massive kissing eyelid nevus. Tumor reduction was achieved in one case of T-cell lymphoma. No patients in this study, who were treated with IBI, had any known local or systemic side effects.

DISCUSSION

A landmark case report in 2008 by Léauté-Labrèze et al.4 documented the use of systemic propranolol for severe hemangiomas of infancy. We successfully used IBI for infants with periocular capillary hemangiomas which were refractory to conventional treatments.5 In infants under 1-year-old, general anesthesia was administered and a dose of 0.5 mg/kg (range 0.2–0.9 mg/kg per injection) was injected, diluted to 15 IU in 15 ml normal saline +1% lignocaine. A multipuncture technique was used, and the injection volume did not exceed the estimated volume of the tumor. Postinjection pressure was applied for 10 min, and oral analgesics were prescribed postinjection with review and retreatment every 4 weeks.5

Recently, a case series reported good outcomes of IBI for histologically and/or radiologically confirmed orbital lymphangiomas resulting in preservation of visual acuity and no recorded orbital or optic nerve side effects.6

Bleomycin is a glycopeptide first isolated and reported by Umezawa et al. from the soil fungus, Streptomyces verticillus in 1966.7 Bleomycin has antibacterial, antineoplastic, antiviral (it induces apoptosis and tumor necrosis factor), and antiangiogenic properties.7 These are principally due to its sclerosing effect on the vascular endothelium. Of all the various biochemical actions, the most important is the effect on DNA where strand scission results in free radicals release once the metal core is oxidized.8 Bleomycin is directly cytotoxic to keratinocytes and eccrine epithelium.9 Cysteine proteinase is an enzyme found in most tissues, except the skin, and lungs. It inactivates bleomycin via hydrolyzation.10 The cytotoxic effects of bleomycin are therefore magnified in the skin (and lungs) due to the absence of this enzyme, explaining some pulmonary and dermatologic side effects of the drug.9 Systemic bleomycin is approved by the United States Food and Drug Administration (FDA) approval for chemotherapeutic treatment of squamous cell carcinoma of the head and neck, cervix, penis, and skin. It has also been approved for use in the management of Hodgkin's and non-Hodgkin's lymphoma, testicular carcinoma, and malignant pleural effusions. There are currently no FDA-approved treatments using IBI, but it is used off-label most frequently for the treatment of recalcitrant warts.89

Salwa et al. reported on a series of 3 patients with periocular BCC where significant co-morbidities precluded surgical resection. Patients were successfully treated with a combination of IBI and electrochemotherapy (ECT), a technique where cells are temporarily permeabilized after exposure to a brief electric pulse thus enhancing the intracellular uptake of chemotherapeutic drugs.11

In this series, we have used IBI supplemented with lignocaine to enhance the intracellular uptake of this chemotherapeutic antibiotic. Lignocaine acts as a local anesthetic and enhances the uptake of hydrophilic chemotherapeutic agents such as bleomycin via a membrane stabilizing effect.

In our series of patients, we have observed a range of outcomes from no effect (in kissing congenital nevus) to tumor reduction (T-cell lymphoma, congenital capillary hemangiomas) and tumor ablation (BCC, orbital lymphangioma). No local or systemic side effects occurred in any of the patients. The most commonly reported side effects associated with IBI are a pain, erythema, and swelling. The pain usually lasts 72 h but is relieved with analgesia.8 Local skin necrosis, ulceration, and eschar formation may also occur at the site of injection.12 Reports of patients developing flagellate hyperpigmentation of the skin after treatment with bleomycin may be as high as 20%. The pigmentation often fades with the cessation of drug use. The above reactions may be explained by the decreased concentration of hydrolase in the skin resulting in increased levels of bleomycin.10 There are no reports of pulmonary fibrosis attributed to IBI in humans8 but in the murine model pulmonary fibrosis is well recognized.13 Concerns about side effects of the intralesional drug in children have been mitigated by reports of serum levels of bleomycin that are 100 times lower when the drug is injected intralesionally than when the same dose is administered intravenously.14

Recent guidelines on the management of BCC do not include the use of intralesional chemotherapy. Reasons for the current exclusion include a lack of adequate, well-designed randomized trials with a long-term follow-up. The result is an absence of therapeutic guidelines but widespread off-label use.12 At present, the most commonly used intralesional agents (mostly off-label) in the management of BCC are methotrexate (MTX), 5-fluorouracil (5-FU), bleomycin and interferon, with interferon-α, and 5-FU being the most widely used.9

Kirby and Miller12 reviewed 56 articles on the use of intralesional chemotherapy in nonmelanoma noneyelid skin cancers. They12 reported IBI in 11 case reports that documented a 100% clearance rate after IBI. This rate is better than that reported for conventional excision (90%) and similar to the cure rate after Mohs micrographic surgery (99%).12 High-risk histological subtypes were excluded from these case reports.12 The review did find higher cure rates of BCC with IBI compared to intralesional agents, such as MTX, 5-FU, and interferon, however, the sample size was smaller for the bleomycin group compared to the other groups.12 Good et al.9 reviewed the literature on intralesional chemotherapy in the treatment of BCC, including bleomycin. There were a number of reports on bleomycin-mediated ECT to treat BCC. As bleomycin is a hydrophilic molecule, ECT is postulated to enhance intracellular penetration of bleomycin by changing the permeability of the cell membrane. Adding local anesthetic to the mixture may also enhance penetration. In the largest series15 to date, 20 patients with BCC were treated with ECT and bleomycin with a complete cure rate of 98%. In a single case report, an 82-year-old female with multiple recurrent BCCs on her face was treated with multiple IBIs without ECT and all lesions healed without recurrence.16 Salwa et al.11 describe 3 cases with significant comorbidities precluding surgical resection where ECT with IBI was used effectively in periocular BCC's after a single treatment. This outcome concurs with earlier trials of the ECT/IBI combination in BCC elsewhere on the skin.15 Mechanisms for enhancing the efficacy of IBI include the use of local anesthetics, ECT or electroporation. Electropermeabilization is claimed to enhance intracellular delivery of hydrophilic molecules possibly necessitating only a single injection.11

Recently Chitwood et al.1 reviewed the topical and intralesional treatment of nonmelanoma skin cancer (NMSC) and evaluated the efficacy and cost-effectiveness of treatment. In comparison to other treatment modalities, IBI had a 100% aggregate clearance rate in nonocular NMSC.1 The cost of IBI was similar to intralesional 5-FU (clearance rate 98%) and MTX (clearance rate 98%), but only 16% the cost of interferon alfa-2b (clearance rate 72–79%), 14% of interferon gamma (clearance rate 14–33%) and <1% the cost of Interferon beta (with a clearance rate of 59%).1 Therefore, IBI is not only highly effective but also a cost effective treatment in cutaneous BCC. A paucity of published experience exists with intralesional chemotherapeutics on lesions of the eyes and ocular adnexa.

We believe that once an eyelid lesion is healed to the point of it being invisible to the individual, it is difficult and unethical to convince a patient to accept a posttreatment biopsy. Hence, we have not routinely performed posttreatment biopsies in this series. Currently, are evaluating posttreatment biopsy specimens for the histologic effect of IBI. Recurrence rates are vital to determine whether to institute IBI as a definitive treatment for BCC in anatomically sensitive sites such as the eyelids. Our longest follow-up is 4 years with a mean of all our cases around 2 years. Clearly, longer follow-up would warrant reporting in future publications. A larger case series will not only assist in generating long-term follow-up data but will also contribute to establishing confidence in this treatment modality. However, Léauté-Labrèze et al.4 have shown the world that the “humble” academic effort of reporting clinical cases can dramatically change global patterns of patient care.17

CONCLUSION

Based on clinical experience over 6 years, we propose that IBI be considered a treatment modality in select cases of the malignant eyelid and ophthalmic vascular tumors where the conventional standard of care is not possible.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.