other reported side-effects were probably not related to the treatment itself. After a successful treatment, the fibrovascular net is replaced by a mound of fibrous tissue clearly identified on OCT. The visual impact of this tissue located between the RPE and the neurosensory retina has never been evaluated.

effect from the multiple pulses is not additive. This makes it virtually impossible to perforate the choroid or get a white burn. The micropulse could offer a higher level of control and target specificity over the final laser–tissue interaction.

13.6Variations

Ideally, a selective approach should include maximum direct effect to the CNV (i.e., complete closure) and minimal damage to the physiological surrounding tissue (i.e., absence of nonperfusion). The treatment applied in the clinical trials has been modified in order to increase efficacy and selectivity.

13.6.1Laser Photocoagulation: Different Wavelengths

The availability of various monochromatic wavelengths permits the selection of the wavelength adapted to the target tissue in order to enhance therapeutic efficiency. High transparency of the media and minimal dispersion are essential conditions for retinal photocoagulation. Yellow wavelengths (e.g., krypton yellow or organic dye laser) penetrate well through the yellow nuclear sclerotic lens of the elderly with minimal scattering through unclear ocular media. Its transmission by xanthophyll (located in the inner and outer layers) allows treatment close to the fovea. A visible burn is obtained with less power and less collateral damage than when produced by the blue– green (rarely used nowadays) or green laser wavelengths. Conversely, hemoglobin has a high absorption of blue, green, and yellow wavelengths, but poor for red, in particular oxyhemoglobin. Krypton laser is not so readily absorbed by the inner layer of the retina, but more strongly by the RPE and the inner choroid. Therefore, the choice of a wavelength to achieve coagulative occlusion of neovascular formation in the choroid is based on all the previous considerations. Laser micropulse, instead of the continuous delivery instruments, gives rise to a final laser–tissue interaction by gradually increasing the power. The thermal

13.6.2 Photodynamic Therapy

Based on the principles of photodynamic mechanisms, there are distinct strategies to enhance selectivity, including modification of the route of administration, the timing of laser exposure, and a reduction of fluence and/or irradiance. Use of lower doses of both photosensitizer and light might modulate the tissue damage. The chemical composition of the dye and the affinity for different tissues play an important role in the treatment strategy. Hydrophilic molecules (i.e., lutetium texaphyrin) diffuse easily into the interstitial space, while lipophilic compounds (i.e. tin ethyl etiopurpurin) are confined longer in the intravascular space. Furthermore, the bolus administration of the photosensitizer increases selectivity and concentration in the choroidal neovascular tissue. According to the treatment regimen in the trials, a new session of PDT can be applied 12 weeks (±2) after the last treatment. In general, it is considered that if a well-documented vision loss occurs during the follow-up, or if the angiograms detect a significant increase in the size of the CNV, the requirement of a new treatment before the third month should be considered. However, this approach remains controversial [2].

Other photosensitizers. Among the several major classes of photosensitizers, the tetrapyrroles, phthalocyanines, benzophenoxazines, and xanthenes have been used for ocular applications. Photofrin, a firstgeneration photosensitizer dye, was approved in different countries for the treatment of cancer. Because of the slow, 3- to 6-week elimination and limited ocular penetration of photofrin, its use was abandoned in ophthalmology. Phthalocyanine, a second-generation photosensitizer, could not be used in ophthalmology either owing to its significant secondary systemic effects. Tin ethyl etiopurpurin (SnET2, Purlytin) was promising in phase II with a stabilization or improvement of visual acuity in 64% of the patients enrolled in the study. After completion of the enrollment of 900 patients in a

phase III trial, it was determined that the drug did not achieve the desired results in the treatment of CNV secondary to AMD. Lutetium texaphyrin (Lu-Tex) circulates in the bloodstream and adheres to both HDL and LDL. Experimental studies suggested its effectiveness in the treatment of neovascular nets secondary to AMD. An unexpected synergistic effect was observed when administered in conjunction with antiangiogenic drugs.

Reduced fluence. Clinical trials have provided solid information about the range of safe and effective dosages, such as phase I/II trials and the Verteporfin Treatment of Subfoveal Minimally Classic CNV in Age-related Macular Degeneration (VIM) Study [6]. Selectivity to avoid damage to the physiological choroid was attempted by bolus administration, used in PDT tumor therapy, which achieves an optimal and selective biodistribution of the sensitizer together with a reduced light dose. An occlusive effect on the choriocapillaris from which the CNV originates was evident at 50 J/cm2 with early perfusion disturbances, but not at the level of the retinal circulation. A progressive recovery of the choriocapillaris on indocyanine green angiography occurred with further follow-up at all levels of energy. Bolus infusion and reduced light dose were subsequently suggested to improve selectivity with complete angiographic closure of the CNV and absence of a significant effect on the choroid [8]. Changing treatment parameters appeared not to have a relevant effect on short-term safety.

The postulated benefits of “selective” verteporfin therapy is a lower CNV recurrence rate, improved durability of treatment effect and inhibition of the verteporfin PDT-induced angiogenic response and eventually better functional outcomes. Selecting optimal parameters allows differentiation between the intended effects on the pathological neovasculature and the unwanted effects on the physiological choroid in the early or late indocyanine green angiography phases, or alternatively immediately and during further follow-up.

13.6.3 Combination Treatments

Increased selectivity with decreased effect on the surrounding choroid should be the aim of combination strategies with less angiogenic and inflammatory side

effects in order to improve the visual results and/or decrease the number of treatment sessions. These attempts have been the major concern while awaiting the results of anti-VEGF monotherapy. Otherwise, combination therapy of verteporfin PDT with antiVEGF agents seems to have a biological rationale. Their actions complement each other and may be synergistic. PDT causes photothrombosis and occlusion of new vessels, while anti-VEGF agents inhibit vasopermeability and angiogenesis.

Combining verteporfin therapy with steroids has been attempted for a long time [9], but without convincing results or with major adverse events. Other combined treatments were tested.

Two phase II studies were implemented within the framework of SUMMIT, both combining PDT with verteporfin and ranibizumab 0.5 mg versus ranibizumab 0.5 mg monotherapy. The European arm (MONT BLANC – 255 patients) applies standard fluence PDT, whereas the US arm (DENALI – 321 patients) is also including standard (SF) and reduced fluence (RF) PDT.

At 12 months, MONT BLANC showed that combining verteporfin PDT at standard fluence with ranibizumab 0.5 mg can obtain similar visual acuity improvements (+2.5 letters) to those of a ranibizumab monotherapy regimen (+4.4 letters) with three Lucentis loading doses followed by injections on a monthly basis as needed. However, monthly Lucentis injections continue to provide the best clinical outcomes, especially in the treatment of minimally classic lesions. A combination showed a trend toward reducing ranibizumab re-treatments (4.8 injections) with no new safety signals identified.

At 12 months, in DENALI, a combination of verteporfin PDT with ranibizumab 0.5 mg, with three ranibizumab loading doses followed by additional injections on a monthly basis as needed, can improve visual acuity 5.3 (SF) and 4.4 (RF) letters (combination) vs. 8.1 letters (ranibizumab alone). The VA gain of combination therapy was inferior to therapy with monthly ranibizumab 0.5-mg injections. Combination therapy reduced the number of injections required, with mean numbers of ranibizumab re-treatments of 2.2 (SF) and 2.8 (RF) for combination and 7.6 for ranibizumab. Reduced fluence did not provide a clinical benefit over standard fluence in the verteporfin PDT combination arms.