Preventive treatment of canalicular stenosis induced by antimitotics : Role of the Autostable bicanaliculus Intubation Set II.

Pierre BIGE, MD ––– Marseille (France)

The incidence of cancer continues to increase, and particularly so for breast cancer which is the most common cancer that affects women. The number of cases diagnosed rises by about 2 % per year (13), with about 27,000 new cases detected every year in France. Although breast cancers diagnosis rates have been rising in every country, the mortality rate is falling as a result of improved care and more effective therapies, such as better chemotherapeutic protocols (12).

The drugs used induce a high degree of morbidity, one example of which is canalicular stenosis. In coming years, one might reasonably expect to see an increase in this pathology.

The difficulty associated with the surgical treatment of canalicular stenosis, together with the low success rates, has prompted us to consider how to prevent this iatrogenic stenosis.

ANTIMITOTICS

The literature (1-4) identifies essentially three antimitot-ics responsible for canalicular stenosis. These are Do-cetaxel (4-9), 5-Fluorouracil (14-24) and Paclitaxel.

These three products are given as intravenous injec-tions in compliance with a very specific protocol and often in combination with other drugs.

Epiphora due to canalicular fibrosis has been described as a known adverse effect of chemotherapeutic proto-cols involving 5-Fluorouracil, Docetaxel and their de-rivatives for more than thirty years (17, 19).

Their toxicity is expressed as a result of their high con-centration in tears.

1. Paclitaxel (Taxol?)

Paclitaxel is a new antimicrotubule agent; it stimulates the assembly of tubulin dimers into microtubules and stabilises the microtubules by preventing their polymeri-sation.

This stability inhibits the normal dynamic reorganisation of the microtubule network, a phenomenon that is es-sential for the vital functions of the cells during the inter-phase and for mitosis.

It is used to treat ovarian and breast cancers, advanced non small-cell lung cancer and certain cases of Ka-posi’s sarcoma associated with AIDS.

2. Fluorouracil (Adrucil?, 5-FU?)

5-Fluorouracil is a pyrimidine base that is used as an antineoplastic. The drug causes metabolic disruption of the biosynthesis of DNA and RNA as a result of the re-placement of the hydrogen atom on the pyrimidine nu-cleus by a fluorine atom whose volume is similar but whose reactivity is different. 5-FU is transformed into an active metabolite which is incorporated into the biosyn-thesis of the nucleic acids and disrupts this process.

5-FU is used in breast and digestive tract cancers.

In common with all the antimitotics, its toxicity relates to its presence in the tears at high concentrations, compa-rable to those found in the plasma. With regards to 5-FU, the stenosis appear to be due to the direct antimi-totic action of the product on the epithelial cells (24).

Fezza, in a retrospective study, described all the cases of canalicular and punctal stenosis in patients who de-veloped epiphora after chemotherapy that included 5-FU, where their treatment required surgery (1).

3. Docetaxel (Taxotere?)

Docetaxel is an alkaloid derived from yew needles, and belongs to the taxane class of drugs. It inhibits cell divi-sion by “freezing” the cell’s internal skeleton, comprised of microtubules. These microtubules assemble and dis-assemble during the cell division cycle. Docetaxel facili-tates their assembly, and then blocks their disassembly, thereby preventing cell multiplication and resulting in their death.

Docetaxel is primarily used to treat breast cancers where the cancer has spread to the ganglions or where there is metastasis, as well as in certain lung cancers, hormone-resistant prostate cancers, stomach cancers and cancers of the upper airways.

Bita Esmaeli has shown that Docetaxel is secreted into tears (10), and that its presence appears to cause cana-licular and punctal stenosis due to its direct effect on the canalicular mucosa (4-9).

PREVENTIVE TREATMENT

In a recent prospective study, Esmaeli studied the ef-fect of Docetaxel as a function of chemotherapeutic protocol. For patients given weekly injections, 64 % experienced epiphora, whereas this figure dropped to 39 % when the product was administered every three weeks (25).

For the weekly Docetaxel patients with epiphora, treat-ment with steroidal and antibiotic eye drops resolved the tearing in half of the cases. Surgery was recom-mended for the other half, but only two thirds could be treated (BCSI (bicanalicular silicone intubation), DCR), since one third refused the procedure or were contrain-dicated due to their general condition.

For the patients with epiphora treated with Docetaxel every three weeks, the eye-drop therapy resolved the epiphora in 82% of cases, with surgery performed on the remaining 18 %.

This study confirms that canalicular stenosis is more frequent and more severe in patients given weekly compared with three-weekly treatment (25,8,9).

The first signs of epiphora emerged 12 to 16 weeks on average after the start of the weekly treatments (8).

Esmaeli recommends, for all patients, a systematic monthly examination by an ophthalmologist.

In response to the onset of epiphora, an eye-drop treat-ment based on Dexamethasone and Tobramycin should be administered four times a day, combined with probing and systematic irrigation of the lacrimal drain-age apparatus during each monthly check. The combi-nation of probing and irrigating the lacrimal drainage apparatus improves the results compared with instilling eye drops only (11).

If the symptoms persist, the surgical options are dis-cussed with the patient - bicanalicular silicon intubation or DCR.

This study reveals the difficulties associated with treat-ing these patients, which requires close collaboration between oncologist and ophthalmologist. When suc-cessful, this collaboration sets up early and monthly follow-up of the patients, as well as offering them effec-tive therapy.

As mentioned previously, preventive treatment using eye drops avoids canalicular stenosis in only 32% of patients who develop epiphora (25 ).

Since, as a general rule, the surgical treatment of cana-licular stenosis is complex with only average results (to our knowledge), we consider that it is essential to im-prove the preventive treatment available.

Currently, as described above, the prevention of steno-sis involves monthly irrigation and probing and the instil-lation of antibiotic steroidal eye drops. Surgery involving bicanicular silicone intubation as a preventive treatment cannot be proposed to patients whose general and psy-chological condition is weak.

Accordingly, we consider that it is appropriate to pro-pose the use of the Autostable Bicanaliculus Intubation Set II as a preventive treatment for stenosis under these conditions.

ROLE OF THE AUTOSTABLE BICANALICULUS INTUBATION SET II

The Autostable Bicanaliculus Intubation Set first ap-peared about 3 years ago. This intubation set is inserted into the lachrymal duct and acts in a similar way to BCSI devices, but does not require the intubation of the na-solachrymal duct.

The Autostable Bicanaliculus Intubation Set II (figure 1) retains most of the features of the first version:

a silicon tube, 30 mm long (for the standard version) and 0.64 mm in diameter, at each end is an anchor that maintains the position of the device.

Each anchor consists of two flexible winglets which fold up during insertion via the lachrymal meatus and unfold after passing the junction of the canaliculi and the lach-rymal sac, ensuring that the silicone tube is maintained in position (figures 2 and 3).

This new version is characterised by a new fitting fea-ture, consisting of two metal guides that are inserted in each of the two ends. These two guides facilitate the insertion process by making it easier to introduce the silicone tube during fitting, as well as overcoming any problems associated with canalicular narrowing.

Since it can be fitted in the practitioner’s consulting room after administering anaesthetic eye drops, this strictly canalicular intubation appears to satisfy the needs of patients undergoing chemotherapy.

The results obtained should be the same as with BCSI, but without a visit to the operating theatre.

We have used the Autostable Bicanaliculus Intubation Set II to treat three patients presenting with epiphora after one or more sessions of chemotherapy.

The population consisted of two women and one man, aged from 50 to 65.

The technique used was the same in all cases.

After dilating the superior and inferior meatus, probing was performed to obtain contact with the bone to elimi-nate a canalicular stenosis. The insertion of the silicone tube began with the assistance of a guide via the supe-rior meatus, then via the inferior meatus. At the end of the insertion process, the correct positioning of the intu-bation was checked by ensuring that the mark was lo-cated between the two meatuses and by checking that the intubation offered good mobility each time the eye was blinked (figure 4).

Treatment with steroidal antibiotic eye drops was pre-scribed for ten days after fitting the device, followed by administration of a simple disinfectant for as long as the intubation was left in place.

The patients were followed up after one week and then every month. In the absence of any previous experience with this form of treatment, the intubation was main-tained for several weeks after the end of the chemother-apy.

For all the patients, the epiphora was resolved and no complication was observed.

The results obtained require confirmation by a more ex-tensive prospective study.

Pending this study, it would seem to be viable to pro-pose, as a preventive treatment to patients presenting with epiphora, the fitting of an autostable probe as a re-placement for monthly probing and irrigation of the lacri-mal drainage apparatus combined with a steroidal antibi-otic eye drop. Indeed, for the entire duration of the che-motherapy, the Autostable Bicanaliculus Intubation Set II will cause less trauma than the repeated monthly prob-ings, with results that will probably offer an improvement on the 32 % satisfactory result rate obtained with the study mentioned above.

CONCLUSION

We must offer our patients the best treatment with the fewest side effects: “first, do no harm”.

When these treatments are vital, it is important that we prevent the iatrogenic effects.

While epiphora is, of course, a minor issue when com-pared with the seriousness of the cancer, once the can-cer has been treated there is no justification for not hav-ing dealt with the lachrymation that is known to have an adverse impact on the patient’s quality of life.

Moreover, in the current climate of administrative and legal pressures, in addition to the pressures of simply achieving results, we must improve the therapies of-fered by validating and utilising new products.

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