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ORIGINAL CONTRIBUTIONS

Received: May 19^th 2014

Accepted: February 27^th 2015

Subconjunctival chemotherapy in patients with acquired immunodeficiency syndrome. Experimental study of 3 clinical cases

María de los Ángeles Melgares-Ramos,^a Deyanira Carnesoltas-Lázaro,^a Yiliam Suyen Silveira-Melgares,^a Aníbal Domínguez-Odio^b

^aInstituto Nacional de Oncología y Radiobiología. Servicio de Oftalmología, Departamento de Farmacología Clínica, Vicedirección de Asistencia Médica e Investigaciones

^bDirección de Investigación y Desarrollo, LABIOFAM

La Habana, Cuba

Communication with: Maria de los Ángeles Melgares-Ramos

Telephone: (53) 5292 9134

Email: maria.melgares@infomed.sld.cu

Background: Squamous carcinoma of conjuctive (SCC) is a rare tumour with different geographic frequency. The ethiology is multifactorial, and included high exposition to UV and also systematic infections (HPV and HIV). Those tumours have low potential of malignity, but occasionally this type of cancer is capable to provoke local recidive and distant metastasis and finally the death of patients. The aim of this work was to investigate the antitumoral response, the tolerable and safe doses of cysplatin preparation in three patients with HIV with recurrent SCC by subconjuctival and topical administration after conservative surgery.

Methods: The patients were treated with cysplatin preparation. The treatment was about 3 months in 6 cycles. The patients were clinical follow since the last administration until update.

Results: The evolution was favorable. The patients preserved the eyes and their vision without SCC recidive. One patient died about 2 years after he finalized the treatment with conservative vision and without tumoral activity and the cause was HIV infection.

Conclusion: Treatment with adjuvant chemotherapy to surgery subconjunctival is effective and tolerable in the population of patients treated.

Keywords: Carcinoma, HIV, Cisplatin, Conjunctival neoplasms.

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Conjunctival squamous cell carcinoma (CSCC) is part of a spectrum of conditions that can infiltrate the corneal tissue.¹ Its worldwide incidence varies geographically from 0.02 to 3.5 per 100,000 inhabitants.² In Cuba 44 new cases are diagnosed year, constituting the second most frequent tumor of the eye and its components.^3,4

The presence of the disease has been associated with infection by the human immunodeficiency virus (HIV) and human papilloma virus (HPV),^5,6 immunosuppression from organ transplant⁷ and by exposure to ultraviolet rays (UV).⁸ The treatment of this cancer has not been well established, so multiple therapeutic modalities have been designed. Excisional surgery plus adjuvant cryotherapy treatment is the most used,⁹ followed by surgery and local chemotherapy with eye drops, or shallow or deep radiotherapy depending on the tumoral extent.¹⁰ For advanced cases, after applying some of the above measures, they are may receive radical surgical treatment (enucleation or exenteration).¹¹

This study aimed to evaluate the antitumor response of a preparation of cisplatin as an alternative treatment in patients with recurrent conjunctival squamous cell carcinoma, who had received the oncospecific treatments designed for the management of this tumor in the institution (surgery and radiotherapy).

At the time of evaluation, patients were only subject to radical surgery as enucleation or exenteration.

Clinical cases

Clinical case 1

Male patient aged 34, Caucasian, gardener by profession, enrolled in the Instituto Nacional de Oncología y Radiobiología (INOR) in 2004. At the time of registration he reported tearing and red eye.

An eye examination found the presence of a tumor in the form of honeycomb, with great vascularization, which infiltrated the cornea from approximately 12 to 3 o’clock.

HIV positivity was verified while doing preoperative studies and treatment was planned according to established INOR rules: tumor excision with oncological margin and superficial adjuvant radiotherapy; the postoperative results were favorable.

The histological diagnosis corresponded with moderately differentiated CSCC invading the conjunctiva. Treatment was completed with superficial adjuvant radiotherapy 6000 cg following up.

In July 2006, the disease recurred with rapid growth, so exenteration was proposed, the patient did not accept and did not attend the following consultations.

In September of the same year he was reassessed, the physical examination with slit lamp found an infiltrating tumor nodule with exophytic growth infiltrating the cornea and occupying three-quarters of the bulbar conjunctiva, upper and lower conjunctival sac, and anterior orbit. The visual acuity in the physical exam was 0.5, eye movements were limited, sclerosis of the lens was also detected. The fundus was normal.

Because of rejecting the radical treatment, participation was proposed in an expanded clinical study, which had been conducted only in preclinical studies.¹² The patient accepted the treatment by signing the informed consent. Prior to the start of the treatment scheme, corresponding systemic clinical studies are done, which were normal.

The treatment performed was excisional surgery on demand, and the subconjunctival administration of a preparation of neoadjuvant and adjuvant cisplatin to this surgery until completing 6 cycles, of which 3 doses were subconjunctival and the other 3 doses eye drops.

Patient follow-up was done at 24, 48 and 72 hours, and then weekly until the first month and then every two weeks until finishing the treatment regimen designed. The result was satisfactory with disease control and maintenance of sight (Figure 1).

In early 2012 a new tumor recurrence appears, for which only surgery was performed. The patient had continued persistence of the tumor, so it was decided to perform local chemotherapy treatment again with the same regimen explained above, more than five years having passed since the rescue treatment. This time it was also associated with the presence of a tumor infiltrating the skin of the dorsum of the foot, which was treated with surgery and diagnosis was squamous cell carcinoma of the skin.

In June 2013 he was again treated with a chemotherapy regime similar to the previous times. The patient maintained normal fundus and decreased vision due to post-radiogenic cataract.

Clinical case 2

Male patient aged 46, Caucasian, history of HIV, diagnosed three years before the first symptoms of eye disease. Registered in the INOR in 2008.

At the clinical examination he presented foreign body sensation and growth of a whitish lesion in bulbar conjunctiva of the left eye. He said that he had been operated on two previous occasions, without further disease control and without histological diagnosis. Biomicroscopic physical examination found a nodular tumor infiltrating the cornea at about 4 o’clock, measuring 0.5 centimeters, with neovascularization and two thick sentinel nodes. Preoperative studies were performed, all were normal, with HIV positivity confirmed.

Corneal laminectomy and excision of the tumor were performed. The diagnosis was well-differentiated CSCC. Because one tumor was recurrent, treatment with subconjunctival and topical chemotherapy was chosen, supplying the patient with relevant information to the alternative treatment and informed consent, which was accepted by him.

The patient received three courses of subconjunctival treatment with preparation of cisplatin and three courses of cisplatin eyedrops, achieving control of the disease. Monitoring was continued for three years. Treatment response was satisfactory (Figure 2). Among the observed adverse reactions were inflammation, periocular edema, and subconjunctival hemorrhage in the treated area, which responded well to antineoplastic treatment.

Two years later, in early 2013 at a later revisit, he reported vision loss. On physical examination a bilateral posterior uveitis was diagnosed, caused by infection with cytomegalovirus, due to progression of the underlying disease. However, no tumor activity was observed in the treated area.

He was referred immediately to specialized consultation, where he was treated, but had a torpid development and died three months after the diagnosis of uveitis, with control of the conjunctival carcinoma.

Clinical case 3

Male patient aged 32, caucasian, farmer by profession. Enrolled and recorded in the INOR in early 2007 because of a recurrence of an infiltrating nodular tumor in the left eye conjunctiva. Clinical examination of the patient was performed.

When performing the anamnesis patient reported having been treated before, in 2006, because of conjunctival squamous cell carcinoma diagnosis, where he was given treatment with surgery and superficial radiotherapy, and shortly afterwards there began growth and recurrence of the infiltrative conjunctival tumor.

Surgical treatment and adjuvant chemotherapy were proposed. In additional preoperative laboratory analysis, patient was diagnosed with HIV not previously declared in his history.

Samples were taken of the recurrent lesion and the pathology report corresponded to a recurrent CSCC. The patient was told the outcome and treatment steps that he should take, the informed consent was read to him which he accepted and signed, and he enrolled in the study.

Now, 72 months after being treated as proposed in our work scheme, the patient maintains a good control of the disease and is under treatment for HIV and has returned to work (Figure 3). He also preserves vision and eye structures, with no signs of tumor recurrence. This patient had complications during treatment administration, one was chemical conjunctivitis and other subconjunctival hemorrhage. No optic neuritis was observed, and no vision loss.

Discussion

Regarding SCSS different average ages of onset have been published. In the UK, 69% of the patients were over 60 years of age.¹³ In Asia it was noted that in a series of 30 patients, 70% were male, with mean age of 64.8 years (range 39-82 years), with incidence of tumor recurrence of 36.8% in 30 months after the first therapeutic intervention.¹⁴ In Zimbabwe it was found that 70% of female patients had a mean age of 35 years.¹⁵ In Africa there is a similar incidence for men and women, with a decrease in the age of onset due to HIV infection and poor control or lack of appropriate antiretroviral therapies.16 In our study all the cases occurred in male Caucasians with average age 37, similar to that reported in South Africa.

Several risk factors have been linked. Exposure to ultraviolet radiation⁶ is currently the most important in countries with low incidence of HIV infection. A preventative therapeutic strategy to prevent recurrent lesions would be to decrease viral load and provide adequate protection against the sun. In our patients we found two cases, where in addition to HIV infection, there was repeated exposure to sunlight, in the course of agricultural work, a factor that may have contributed to tumor recurrence.

Currently SCSS does not have a single established conventional treatment;¹⁷ however multiple therapeutic modalities are used including cryotherapy adjuvant to surgery and chemotherapy, with favorable local initial results although not stable over time.^18,19 The use of subconjunctival cisplatin could join these modalities.

Concomitantly with the implementation of the proposed SCSS control treatment, the patients were on systemic and combined antiretroviral regimen: Sasquinavir, Ritonavir, Stavudine (d4T) and lamivudine (3TC), 2 times a day as established.²⁰ All patients were followed clinically 24, 48 and 72 hours after treatment and for several weeks thereafter. Adverse reactions included: inflammation, periocular edema and subconjunctival hemorrhage in the treated area, which developed favorably after antineoplastic treatment. In no case were other adverse reactions observed.

The local and topical chemotherapy proposed showed tumoricidal response and medium-term disease control. Note the precocity in obtaining these results after conventional treatment failure in patients of the Institution.⁴

Conclusion

Topical chemotherapy is, today, a widespread technique among ophthalmologists in the field of oncology.

We conclude that local and topical chemotherapy with cisplatin increases the possibility of disease stabilization in this location, proving to be a noninvasive treatment, effective with significantly stable responses in HIV patients.

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