Efficient Assessment of Tumor Vascular Shutdown by Photodynamic Therapy on Orthotopic Pancreatic Cancer Using High-Speed Wide-Field Waterproof Galvanometer Scanner Photoacoustic Microscopy.

To identify the vascular alteration by photodynamic therapy (PDT), the utilization of high-resolution, high-speed, and wide-field photoacoustic microscopy (PAM) has gained enormous interest. The rapid changes in vasculature during PDT treatment and monitoring of tumor tissue activation in the orthotopic pancreatic cancer model have received limited attention in previous studies. Here, a fully two-axes waterproof galvanometer scanner-based photoacoustic microscopy (WGS-PAM) system was developed for in vivo monitoring of dynamic variations in micro blood vessels due to PDT in an orthotopic pancreatic cancer mouse model. The photosensitizer (PS), Chlorin e6 (Ce6), was utilized to activate antitumor reactions in response to the irradiation of a 660 nm light source. Microvasculatures of angiogenesis tissue were visualized on a 40 mm2 area using the WGS-PAM system at 30 min intervals for 3 h after the PDT treatment. The decline in vascular intensity was observed at 24.5% along with a 32.4% reduction of the vascular density at 3 h post-PDT by the analysis of PAM images. The anti-vascularization effect was also identified with fluorescent imaging. Moreover, Ce6-PDT increased apoptotic and necrotic markers while decreasing vascular endothelial growth factor (VEGF) expression in MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. The approach of the WGS-PAM system shows the potential to investigate PDT effects on the mechanism of angiographic dynamics with high-resolution wide-field imaging modalities.

Carrier Free O2 -Economizer for Photodynamic Therapy Against Hypoxic Tumor by Inhibiting Cell Respiration.

Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to economize O2 for enhanced PDT against hypoxic tumors. The carrier-free O2 -economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self-assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self-delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier-free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.

Assessment of choriocapillary blood flow changes in response to half-dose photodynamic therapy in chronic central serous chorioretinopathy using optical coherence tomography angiography.

BACKGROUND: Optical coherence tomography angiography (OCTA) is a newly developed imaging quantitative technique for analysis of choriocapillaris (CC) flow changes, thereby exploring the pathological mechanism of chronic central serous chorioretinopathy (CCSC) and the therapeutic effects of photodynamic therapy (PDT). In this study, we sought to quantify the blood flow changes in CC of CCSC patients receiving half-dose PDT using OCTA. METHODS: A total of 28 affected eyes and 24 unaffected eyes of 26 CCSC patients receiving half-dose PDT, and 40 eyes of 20 healthy gender- and age-matched subjects were retrospectively enrolled in this study. The proportion of total areas of flow signal voids (FSV, %) in CC level of OCTA was assessed in both eyes of the CCSC patients at baseline and repeated in multiple sections at 1-week, 1-month, 3-month and 6-month intervals after PDT. In addition, the CC patterns in response to PDT at early stage and the subsequent morphologic changes were qualitatively documented using OCTA. RESULTS: For affected eyes, FSV at 6-m follow-up was significantly lower than that at 1-m follow-up (p = 0.036). When compared to normal control eyes, FSV in affected eyes was significantly higher at 1-m, 3-m and 6-m follow-up (p < 0.05 for all), and FSV in unaffected eyes was significantly higher at baseline, 1-w, 1-m and 3-m follow-up (p < 0.05 for all). Three CC patterns of early response to PDT were identified, including signs of recovery with more even flow signals, transient appearance of worse ischemia and secondary neovascularization within CC level. CONCLUSION: Abnormal CC flow attenuation remains in completely resolved eyes of CCSC patients treated with half-dose PDT.

Assessment of the efficacy of photodynamic therapy in patients with chronic central serous chorioretinopathy.

PURPOSE: The aim of this prospective clinical study was to evaluate the anatomical and functional results of the treatment of 54 eyes with chronic form of central serous chorioretinopathy (CSC) using photodynamic therapy in a reduced (half) verteporfin (HD-PDT) dosing regimen. MATERIALS AND METHODS: Our prospective study included 54 eyes of 52 patients (40 males, 12 females) at an average age of 50.1 years (median 49.5, range 30-75 years) treated at the Ophthalmology Clinic of the First Faculty of Medicine and Military University Hospital in Prague from January 2012 to January 2018 for chronic form of CSC with a minimum disease duration of 3 months. In our study, we evaluated the improvement of the best corrected visual acuity (BCVA) and central retinal thickness (CRT) before treatment and at 1, 3, 6 and 12 months after HD-PDT. RESULTS: The mean baseline BCVA was 68.91 ± 10.5 ETDRS letters (median 71; range 35-85) and the mean baseline CRT was 385.6 ± 118.5 µm (median 367, 5 µm; range 245-1000 µm). At the end of the follow-up period, the average BCVA was 79 ± 11 ETDRS letters (median 82; range 38-93). The improvement in BCVA before and after treatment was statistically significant in all measurements (p < 0.0001). The mean CRT at the end of the follow-up period was 263.5 ± 52 µm (median 258.5 µm; range 162-404 µm). The decrease in CRT at all timepoints was statistically significant compared to baseline (p < 0.0001). In our set of patients, at the end of the follow-up period, the retinal finding was improved or stabilized in 50 eyes (92.6 %). In this study, we observed in 2 cases the development of secondary choroidal neovascularization (CNV). CONCLUSION: HD-PDT is a long-term safe and effective method of treating chronic forms of CSC. However, despite a reduced dose of verteporfin, complications may occur.

Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent / Produção, controle de qualidade, avaliação de biodistribuição e avaliação da dose preliminar de [177Lu] -tetra complexo fenil porfirina como um possível agente terapêutico

Due to interesting therapeutic properties of ¹⁷⁷Lu and tumor avidity of tetraphenyl porphyrins (TPPs), ¹⁷⁷Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. ¹⁷⁷Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu₂O₃sample with thermal neutron flux of 4 × 10¹³ n.cm^-2.s^-1. Tetraphenyl porphyrin was synthetized and labeled with ¹⁷⁷Lu. Radiochemical purity of the complex was studied using Instant thin layer chromatography (ITLC) method. Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied up to 7 d. The absorbed dose of each human organ was calculated by medical internal radiation dose (MIRD) method. A detailed comparative pharmacokinetic study was performed for ¹⁷⁷Lu cation and [¹⁷⁷Lu]-TPP. The complex was prepared with a radiochemical purity: >97±1% and specific activity: 970-1000 MBq/mmol. Biodistribution data and dosimetric results showed that all tissues receive approximately an insignificant absorbed dose due to rapid excretion of the complex through the urinary tract. [¹⁷⁷Lu]-TPP can be an interesting tumor targeting agent due to low liver uptake and very low absorbed dose of approximately 0.036 to the total body of human...

Devido às propriedades interessantes do ¹⁷⁷Lu e da avidez tumoral das tetrafenil porfirinas (TPP), desenvolveu-se a ¹⁷⁷Lu-tetrafenil porfirina como composto terapêutico potencial. ¹⁷⁷Lu de atividade específica de 2,6-3 GBq/mg foi obtido por irradiação de amostra de Lu₂O₃ com fluxo térmico de nêutrons de 4 × 10¹³ n.cm^-2.s^-1. Sintetizou-se a tetrafenil porfirina e marcou-se com ¹⁷⁷Lu. A pureza radioquímica do complexo foi estudada usando método de Cromatografia Instantânea de Camada Delgada ( ITLC). A estabilidade do complexo foi checada na formulação final e no ser humano por 48 h. A biodistribuição do composto marcado em órgãos vitais de ratos do tipo selvagem foi estudada por mais de 7 dias. A dose absorvida para cada órgão humano foi calculada pelo método da Dose Médica de Radiação Interna (MIRD). Estudo farmacocinético comparativo detalhado foi efetuado para o cátion ¹⁷⁷Lu e para o [¹⁷⁷Lu]-TPP. O complexo foi preparado com pureza radioquímica >97±1% e atividade específica de 970-1000 MBq/mmol. Os dados de biodistribuição e os resultados dosimétricos mostraram que todos os tecidos receberam uma dose absorvida aproximadamente insignificante devido à rápida excreção do complexo pelo trato urinário. O [¹⁷⁷Lu]-TPP pode ser um agente interessante de direcionamento do tumor devido à baixa captação pelo fígado e pela dose bem baixa absorvida, de, aproximadamente, 0,036 do corpo humano total...

Ranibizumab, verteporfin photodynamic therapy or observation for the treatment of myopic choroidal neovascularization: cost effectiveness in the UK.

PURPOSE: The aim of this study was to evaluate the cost effectiveness of ranibizumab compared with verteporfin photodynamic therapy (vPDT) or no treatment (observation) in patients with visual impairment due to myopic choroidal neovascularization (CNV). METHODS: A Markov model with health states defined by best-corrected visual acuity and a 3-month cycle length was developed. It had a healthcare provider (UK National Health Service and personal social services) perspective, a lifetime time horizon, and was based on 2011 prices; future costs and health outcomes were discounted at 3.5 % per annum. Baseline characteristics were based on the phase III RADIANCE (Ranibizumab and vPDT Evaluation in Myopic CNV) study, and year 1 health-state transitions were based on this and the VIP (Verteporfin in Photodynamic Therapy) study. Extensive sensitivity analyses tested the robustness of the model. RESULTS: The lifetime cost of treating myopic CNV with ranibizumab was £12,866, whereas vPDT and observation were associated with total costs of £14,421 and £8,163, respectively. Ranibizumab treatment produced higher cumulative quality-adjusted life-years (QALYs; 12.99) than vPDT (12.60) or observation (12.45). Ranibizumab treatment was therefore dominant, with greater health gains and lower overall costs than vPDT. Ranibizumab was cost effective compared with observation, with an incremental cost-effectiveness ratio of £8,778/QALY. In the probabilistic sensitivity analysis, ranibizumab had a 100 % and 88 % probability of being cost effective compared with vPDT and observation, respectively, at a willingness-to-pay threshold of £20,000/QALY. CONCLUSION: This study indicates that ranibizumab therapy is dominant over vPDT for the treatment of visual impairment due to CNV secondary to pathologic myopia in the UK healthcare setting and cost effective compared with observation.

Assessment of choroidal topographic changes by swept source optical coherence tomography after photodynamic therapy for central serous chorioretinopathy.

PURPOSE: To investigate the relationship between choroidal thickness and angiographic abnormalities in central serous chorioretinopathy (CSC) eyes by swept-source optical coherence tomography (swept-OCT), before and after half-fluence photodynamic therapy (PDT). DESIGN: Prospective interventional case series. METHODS: Consecutive patients presenting with treatment-naive active CSC underwent a complete ophthalmologic examination, including swept-OCT at study entry and at 7 days and 30 days after treatment with half-fluence PDT. The main outcome measures were changes in choroidal maps after PDT (mean ± SD) and the relationship between choroidal thickness and angiographic abnormalities. RESULTS: Of 12 patients (2 females, 10 males; mean age, 55.6 ± 14.0 years), 12 eyes were included. At study entry, mean choroidal thickness measured in the center of the fovea was significantly thicker in the study eyes as compared to the fellow eyes (420.7 ± 107.5 µm vs 349.2 ± 109.7 µm, respectively; P = 0.016). Mean choroidal thickness in the center of the fovea significantly decreased in the study eyes at both 7 days (380.2 ± 113 µm; P = 0.005) and 30 days after PDT (362.3 ± 111 µm; P = 0.002). A similar significant choroidal thinning was recorded in each early treatment of diabetic retinopathy study (ETDRS) applied to 3D swept-OCT maps. At each time point, mean choroidal thickness was significantly thicker in sectors with than in sectors without angiographic abnormalities (421 ± 102.4 µm vs 397.6 ± 96.5 µm, P = 0.002 at study entry; 381.2 ± 106.6 µm vs 364 ± 101.2 µm, P = 0.01 at day 7; 366.3 ± 103.2 µm vs 347.2 ± 99.6 µm at day 30). CONCLUSIONS: Using swept-OCT, we demonstrated that in active CSC, choroidal thickness is increased to a greater extent in areas characterized by angiographic abnormalities. This increased choroidal thickness may persist even after PDT.

[The treatment of age-related macular degeneration (AMD) in practice]. / Indications et traitement de la dégénérescence maculaire liée à l'âge (DMLA) en pratique.

AIM: The purpose of this paper is to describe and analyze the diagnosis and treatment of age-related macular degeneration (AMD) based on current guidelines. METHODS: A study was conducted on a sample of French AMD patients covered by the RSI (public health insurance for self-employed workers), who received a first reimbursement in 2008 for treatments including verteporfin (Visudyne®), pegaptanib (Macugen®) and/or ranibizumab (Lucentis®). Data were collected retrospectively from the ophthalmologist by the medical adviser. Treatments were compared with the marketing authorisation for AMD drugs and therapeutic indications. Complementary examinations were also examined based on the recommendations of the Haute Autorité de Santé (HAS). RESULTS: 184 patients were included in the sample. Lucentis® was used in 91.8% of cases. 62.0% of the patients treated with Lucentis® had subfoveal CNV. Visual acuity was good in 83.5% of cases. Fluorescein angiography (recommended by the HAS before treatment initiation) was performed in 87.5% of cases. CONCLUSION: The gap between guidelines and practice is illustrated by the case of Lucentis®, which is increasingly used for indications other than those reimbursed by health insurance. The findings indicate that the current price does not reflect sales volume estimates based on current guidelines, a problem that may be compounded by the recent extension of indications covered by health insurance.

Cost and effectiveness of therapy for wet age-related macular degeneration in routine clinical practice.

PURPOSE: Evaluation of the cost and effectiveness of therapy for patients with the wet form of age-related macular degeneration (AMD) in routine clinical practice. METHODS: A retrospective multicentre evaluation of changes in the best-corrected visual acuity in applied kinds of therapy and a comparison with the cost of individual therapeutic procedures. RESULTS: An overall total of 788 eyes of 763 patients with an average age of 73.2 ± 8.6 years was evaluated for a 1-year minimum period. In the ranibizumab and pegaptanib therapy groups, a reduction of 1.3 letters (p = 0.303) and 1.4 letters (p = 0.197) was found, respectively. In the group of photodynamic therapy (PDT) with verteporfin, a reduction of 5.2 letters was achieved (p < 0.001). Under the conditions of routine practice in the Czech Republic, the annual cost is highest (EUR 5,467.63/patient) in patients with pegaptanib therapy. The annual cost in patients with ranibizumab therapy is lower by EUR 1,220.16. The cost is nearly half (EUR 2,783.65) in the group treated with PDT with verteporfin. CONCLUSION: An initiation of AMD therapy by ranibizumab is cost-effective as compared to pegaptanib. Both ranibizumab and pegaptanib are significantly more efficient as compared to PDT with verteporfin. Therapy with ranibizumab and pegaptanib, as compared to PDT with verteporfin, prevents the loss of 1 line of vision on the ETDRS chart for EUR 1,225.98 and 2,286.18, respectively.

Cost-effectiveness analysis of ranibizumab versus verteporfin photodynamic therapy, pegaptanib sodium, and best supportive care for the treatment of age-related macular degeneration in Greece.

BACKGROUND: Age-related macular degeneration (AMD) is a progressive disease that results in loss of central vision, significant functional impairment, and a subsequent heavy socioeconomic burden. AMD treatments delay disease progression, improve patient outcomes, and reduce resource use associated with visual impairment, however, in a varying way concerning costs and effects. OBJECTIVE: The purpose of this study was to investigate the cost effectiveness of ranibizumab compared with verteporfin photodynamic therapy, pegaptanib sodium, and best supportive care for the treatment of AMD in Greece. METHODS: A 6-state Markov model was constructed according to patient visual acuity in the better-seeing eye. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of ranibizumab versus alternative AMD treatments. Resource utilization reflected the Greek health care setting and was defined by a panel of experts. All treatments were administered for a 2-year period and evaluated during a 10-year time frame from a third-party payer perspective and discounted at 3.5% per annum. RESULTS: Estimated mean 10-year direct costs of treatment in the ranibizumab arm ranged from €23,733 to €31,795 (2011 Euros), with a projected gain of 4.50 to 4.74 quality-adjusted life years (QALYs) or 2.97 to 4.47 vision years, depending on type of lesion. For predominantly classic lesions, the cost per QALY gained with ranibizumab was estimated at €6444/QALY (95% uncertainty interval [UI], €-30,403/QALY to €44,524/QALY), €15,344 (95% UI, €-11,433 to €53,554) and dominant relative to photodynamic therapy, best supportive care, and pegaptanib, respectively. Corresponding ratios for patients with minimally classic lesions were €24,580/QALY (95% UI, €-5580/QALY to €76,229/QALY) and €13,112/QALY (95% UI, €-3839/QALY to €37,527/QALY) for ranibizumab relative to best supportive care and pegaptanib, and for patients with occult lesions were estimated at €19,407/QALY (95% UI, €-1486 to €46,434) and €28,561/QALY (95% UI, €6143 to 73,431), respectively. Sensitivity analysis provided robust results in all cases. CONCLUSION: Ranibizumab can be a cost-effective option for the treatment of AMD compared with selected alternatives in the Greek health care setting.

Verteporfin photodynamic therapy for neovascular age-related macular degeneration: cohort study for the UK.

OBJECTIVES: The verteporfin photodynamic therapy (VPDT) cohort study aimed to answer five questions: (a) is VPDT in the NHS provided as in randomised trials?; (b) is 'outcome' the same in the nhs as in randomised trials?; (c) is 'outcome' the same for patients ineligible for randomised trials?; (d) is VPDT safe when provided in the NHS?; and (e) how effective and cost-effective is VPDT? DESIGN: Treatment register. SETTING: All hospitals providing VPDT in the NHS. PARTICIPANTS: All patients attending VPDT clinics. INTERVENTIONS: Infusion of verteporfin followed by infrared laser exposure is called VPDT, and is used to treat neovascular age-related macular degeneration (nAMD). The VPDT cohort study advised clinicians to follow patients every 3 months during treatment or active observation, retreating based on criteria used in the previous commercial 'TAP' (Treatment of Age-related macular degeneration with Photodynamic therapy) trials of VPDT. MAIN OUTCOME MEASURES: The primary outcome was logarithm of the minimum angle of resolution monocular best-corrected distance visual acuity (BCVA). Secondary outcomes were adverse reactions and events; morphological changes in treated nAMD (wet) lesions; and for a subset of patients, 6-monthly contrast sensitivity, generic and visual health-related quality of life (HRQoL) and resource use. Treated eyes were classified as eligible for the TAP trials (EFT), ineligible (IFT) or unclassifiable (UNC). RESULTS: Forty-seven hospitals submitted data for 8323 treated eyes in 7748 patients; 4919 eyes in 4566 patients were treated more than 1 year before the last data submission or had completed treatment. Of 4043 eyes with nAMD in 4043 patients, 1227 were classified as EFT, 1187 as IFT and 1629 as UNC. HRQoL and resource use data were available for about 2000 patients. The mean number of treatments in years 1 and 2 was 2.3 and 0.4 respectively. About 50% of eyes completed treatment within 1 year. BCVA deterioration in year 1 did not differ between eligibility groups. EFT eyes lost 11.6 letters (95% confidence interval 10.1 to 13.0 letters) compared with 9.9 letters in VPDT-treated eyes in the TAP trials. EFT eyes had poorer BCVA at baseline than IFT and UNC eyes. Adverse reactions and events were reported for 1.4% of first visits - less frequently than those reported in the TAP trials. Associations between BCVA in the best-seeing eye with HRQoL and community health and social care resource use showed that the 11-letter difference in BCVA between VPDT and sham treatment in the TAP trials corresponded to differences in utility of 0.012 and health and social service costs of £60 and £92 in years 1 and 2, respectively. VPDT provided an incremental cost per quality-adjusted life-year (QALY) of £170,000 over 2 years. CONCLUSIONS: VPDT was administered less frequently than in the TAP trials, with less than half of those treated followed up for > 1 year in routine clinical practice. Deterioration in BCVA over time in EFT eyes was similar to that in the TAP trials. The similar falls in BCVA after VPDT across the pre-defined TAP eligibility groups do not mean that the treatment is equally effective in these groups because deterioration in BCVA can be influenced by the parameters that determined group membership. Safety was no worse than in the TAP trials. The estimated cost per QALY was similar to the highest previous estimate. Although VPDT is no longer in use as monotherapy for neovascular AMD, its role as adjunctive treatment has not been fully explored. VPDT also has potential as monotherapy in the management of vascular malformations of the retina and choroid and with trials underway in neovascularisation due to myopia and polypoidal choroidopathy. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Determination of the tumor tissue optical properties during and after photodynamic therapy using inverse Monte Carlo method and double integrating sphere between 350 and 1000 nm.

Photodynamic therapy (PDT) efficacy depends on the amount of light distribution within the tissue. However, conventional PDT does not consider the laser irradiation dose during PDT. The optical properties of biological tissues (absorption coefficient µ(a), reduced scattering coefficient µ's), anisotropy factor g, refractive index, etc.) help us to recognize light propagation through the tissue. The goal of this paper is to acquire the knowledge of the light propagation within tissue during and after PDT with the optical property of PDT-performed mouse tumor tissue. The optical properties of mouse tumor tissues were evaluated using a double integrating sphere setup and the algorithm based on the inverse Monte Carlo method in the wavelength range from 350 to 1000 nm. During PDT, the µ(a) and µ's were not changed after 1 and 5 min of irradiation. After PDT, the µ's in the wavelength range from 600 to 1000 nm increased with the passage of time. For seven days after PDT, the µ's increased by 1.7 to 2.0 times, which results in the optical penetration depth decreased by 1.4 to 1.8 times. To ensure an effective procedure, the adjustment of laser parameters for the decreasing penetration depth is recommended for the re-irradiation of PDT.

A cost-effectiveness analysis of three treatments for age-related macular degeneration.

PURPOSE: The purpose of this study was to evaluate the cost effectiveness of pegaptanib sodium and ranibizumab injections compared with photodynamic therapy (PDT) with verteporfin for the treatment of choroidal neovascularization secondary to age-related macular degeneration. METHODS: The analyses were performed using outcomes data from the pivotal trials for each treatment and the medicare reimbursable costs for each treatment and associated medical procedures. A multistate transition model with 3-month cycles was created to compare incremental medical costs associated with pegaptanib or ranibizumab versus PDT for patients with starting vision of 20/40, 20/80, and 20/200 Snellen equivalent. RESULTS: Two-year medical treatment costs ranged from $3,100 to $54,100 depending on treatment and lesion type. Photodynamic therapy was less costly and more effective than pegaptanib for predominantly classic and minimally classic lesions. Ranibizumab was not only more effective but also more costly than PDT for all lesion types. CONCLUSION: Compared with PDT, pegaptanib is inferior in both cost and effectiveness, whereas ranibizumab has a greater effectiveness. Because ranibizumab does not meet 1 of the common thresholds for being considered cost effective (<$50,000 per quality-adjusted life year), there is rationale to seek other therapies that are more cost effective.

Verteporfin photodynamic therapy cohort study: report 3: cost effectiveness and lessons for future evaluations.

PURPOSE: To report (1) the costs of verteporfin photodynamic therapy (VPDT) in routine treatment of neovascular age-related macular degeneration (nAMD), (2) the relationship between health and social service costs and best-corrected visual acuity (BCVA), (3) the cost-effectiveness of VPDT versus a best supportive care (BSC) group who were assumed to have no active treatment, and (4) lessons for future cost-effectiveness analyses (CEAs). DESIGN: The CEA of VPDT versus BSC that uses health-related quality of life (HrQoL), resource use, and visual acuity data from the United Kingdom (UK) VPDT Cohort Study. PARTICIPANTS: Data on VPDT use were collected from patients attending 45 ophthalmology provider units in the UK National Health Service, 15 units collected data on self-reported use of services. METHODS: Incremental costs of VPDT versus BSC were calculated from treatment costs, change in cost associated with declining BCVA, and difference in BCVA previously attributed to VPDT. Similarly, incremental quality-adjusted life years (QALYs) were calculated from change in HRQoL associated with declining BCVA, giving an incremental cost per QALY of VPDT versus BSC over 2 years. MAIN OUTCOME MEASURES: Incremental costs (UK pounds [ pound]; United States dollars [$]); incremental QALYs; costs per QALY. RESULTS: The treatment costs of VDPT were pound 3026 ($4544) in year 1 and pound 845 ($1269) in year 2. For patients who used services, a 5-letter decrease in BCVA was associated with an increase in annual costs of approximately pound 110 ($165; 95% confidence intervals, approximately pound 48 [$72] to pound 174 [$261]). The incremental costs and QALYs for VPDT were pound 3514 ($5276) and 0.021, respectively, giving incremental costs per QALY gained of pound 170000 ($255000). CONCLUSIONS: Verteporfin photodynamic therapy is unlikely to be cost effective for patients with nAMD. This article provides realistic estimates of VPDT costs and the costs associated with declining vision. Future studies can follow this approach to assess accurately the cost effectiveness of new interventions for nAMD.

Photodynamic therapy with verteporfin in age-related macular degeneration: a systematic review of efficacy, safety, treatment modifications and pharmacoeconomic properties.

Photodynamic therapy (PDT) with verteporfin has been used less comprehensively in the treatment of exudative age-related macular degeneration (AMD), and specifically of choroidal neovascularization (CNV), since the advent of antiangiogenic therapies. Recently, there has been a renewed interest in PDT as an adjunct to these and other agents in the treatment of neovascular AMD. In light of this new development and the European Medicines Evaluation Agency's (EMEA) recent labelling decision to rescind approval for the use of PDT in occult CNV lesions, the present systematic review was undertaken to revisit the evidence supporting its clinical application. Photodynamic therapy provided the first pharmacological treatment for patients suffering from subfoveal CNV, the major cause of severe vision loss in AMD. Key clinical trials evaluating efficacy and safety have examined patients with all lesion subtypes, with the primary labelled indication (i.e. lesions containing a classic component of > or = 50% ) deriving from the results of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study. The subsequent TAP Study Group post hoc categorization of lesions as predominantly classic is open to question, however, as it appears that the overall efficacy in this group only may have reflected the especially strong response in 100% classic lesions. Based on a subgroup analysis of the Verteporfin in Photodynamic Therapy Study, the indication for PDT subsequently was expanded in some jurisdictions, including that of the EMEA, to include occult lesions with no classic component. However, the subsequent Visudyne in Occult Study found no benefit in 100% occult lesions, resulting in the EMEA rescinding its approval for this indication.

Cost-effectiveness sequential modeling of ranibizumab versus usual care in age-related macular degeneration.

AIMS: To assess effectiveness, cost, and cost-effectiveness of ranibizumab versus the current medical practices of treating age-related macular degeneration in France. METHODS: A simulation decision framework over 1 year compared ranibizumab versus the usual care using two effectiveness criteria: the "visual acuity improvement rate" (greater than 15 letters on the ETDRS scale) and the "rate of legal blindness avoided". Two decision trees included various sequences of current treatments, with or without ranibizumab. RESULTS: Ranibizumab appeared significantly more effective than the usual care (p < 0.001), providing greater treatment success rate of visual acuity improvement (48.8% versus 33.9%). The cost of the ranibizumab strategy was higher (9,123 euros over 1 year for ranibizumab versus 7,604 euros for the usual care) but the average cost-effectiveness was lower--18,721 euros/success for ranibizumab versus 22,543 euros/success for usual care (p < 0.001). Considering the "legal blindness avoided" success criterion, the ranibizumab strategy appeared significantly more effective (p < 0.001), providing greater treatment success rate for of legal blindness avoided than usual care (99.7% versus 93.1%) although it was more expensive (9,196 euros over 1 year for ranibizumab versus 5,713 euros for the usual care). CONCLUSION: Ranibizumab significantly improved the rate of visual acuity improvement and reduced the rate of legal blindness. Ranibizumab appeared significantly more cost-effective than the usual treatments in terms of visual acuity improvement.

Ranibizumab for the treatment of neovascular age-related macular degeneration: a review.

BACKGROUND: Choroidal neovascular (wet) age-related macular degeneration (ARMD) is becoming more prevalent worldwide as life expectancy continues to increase. Ranibizumab for intravitreal injection is an inhibitor of human vascular endothelial growth factor A approved by the US Food and Drug Administration for the treatment of ARMD in June 2006. The actions of ranibizumab result in reduced cell proliferation, reduced formation of new blood vessels, and minimization of vascular leakage. OBJECTIVE: This paper reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of ranibizumab, and pharmacoeconomic considerations associated with its use. METHODS: MEDLINE (1966-December 2006) and International Pharmaceutical Abstracts (1970-December 2007) were searched for original research studies (Phase I, II, III, and IIIb), abstracts, and review articles concerning ranibizumab. The search terms were choroidal neovascularization, macular degeneration, Lucentis, ranibizumab, retinal degeneration, and vascular endothelial growth factor. Preference was given to Phase IlfllI studies. Selected information from the manufacturer of ranibizumab was also included. RESULTS: The efficacy of ranibizumab has been studied in 3 large clinical trials having the same primary efficacy end point, the proportion of patients losing <15 letters from baseline at 12 months (Early Treatment of Diabetic Retinopathy Study chart). A multicenter, Phase III, randomized, double-blind, sham-controlled, 24-month clinical trial evaluated ranibizumab 0.3 and 0.5 mg in 716 patients with minimally classic or occult choroidal neovascularization (CNV) associated with ARMD. The results for the primary efficacy end point were 94.5% and 94.6% in the ranibizumab 0.3- and 0.5-mg groups, respectively, compared with 62.2% in the sham-injection group (P < 0.001, both ranibizumab groups vs sham injection); at 24 months, the corresponding proportions were 92.0%, 90.0%, and 52.9% (P < 0.001, both ranibizumab groups vs sham injection). A 2-year, Phase I/II, single-masked (masked patient and visual acuity examiner, unmasked investigator), multicenter trial evaluated the tolerability and efficacy of the combination of ranibizumab 0.5 mg and verteporfin photodynamic therapy (PDT) compared with verteporfin PDT alone in 162 patients with predominantly classic CNV. For the primary efficacy end point, the results were 90.5% for ranibizumab + PDT and 67.9% for PDT alone (P < 0.001). Receipt of ranibizumab + PDT was also associated with improved visual acuity, with 23.8% of patients gaining >15 letters from baseline, compared with 5.4% of those who received PDT alone (P = 0.003). Finally, an international Phase III, double-blind, active-controlled study compared ranibizumab 0.3 and 0.5 mg with verteporfin PDT in 423 patients with predominantly classic lesions associated with CNV secondary to ARMD. For the primary efficacy end point, the results were 35.7% for ranibizumab 0.3 mg, 40.3% for ranibizumab 0.5 mg, and 5.6% for verteporfin PDT (P < 0.001). Serious adverse ocular events, which occurred in association with < 0.1% of intravitreal injections in these trials, included retinal detachment and endophthalmitis. Less serious adverse ocular reactions occurring in < 2% of patients included intraocular inflammation and increased intraocular pressure. CONCLUSION: The findings of these 3 large clinical trials suggest that ranibizumab was effective and well tolerated in patient.

Cost-effectiveness of pegaptanib compared to photodynamic therapy with verteporfin and to standard care in the treatment of subfoveal wet age-related macular degeneration in Canada.

BACKGROUND: Age-related macular degeneration (AMD) is characterized by loss of central vision and is the leading cause of blindness among persons over the age of 50 years in Canada. The wet form of AMD has 3 subtypes-occult, minimally classic, and predominantly classic. Photodynamic therapy (PDT) with verteporfin is indicated only for the category of predominantly classic wet AMD. Currently, there are no treatments available for the other AMD subtypes. Pegaptanib sodium was the first pharmacologic therapy approved in Canada for the treatment of subfoveal wet AMD regardless of subtype. OBJECTIVE: The aim of this study was to examine the cost-effectiveness of pegaptanib versus PDT with verteporfin and versus standard care for the treatment of subfoveal wet AMD in patients aged 65 years in Canada. METHODS: A Markov model based on visual acuity in the better-seeing eye was developed. Clinical efficacy was taken from the clinical trials. Costs of treatment, comorbidities (eg, depression, fractures, need for assisted living), vision rehabilitation, visual aids, and adverse events were considered. Costs, utilities, and mortality were estimated from data from the available published literature. Costs were reported in 2004 Canadian dollars, and costs and outcomes were discounted at 3% per annum. Lifetime costs, quality-adjusted life-years (QALYs), and vision years gained (VYGs) were estimated. Sensitivity analyses were performed to determine model robustness. RESULTS: Patients who received pegaptanib experienced more QALYs gained (4.17) and VYGs (3.83) compared with patients who received PDT (3.87 and 3.01, respectively) or standard care (3.96 and 3.26). Mean total costs per patient were greater in patients who received pegaptanib compared to those who received PDT or standard care ($20,016 vs $15,345 or $7669, respectively). The incremental cost per QALY in patients receiving pegaptanib compared to those receiving PDT was $49,052 and $59,039 for patients receiving pegaptanib versus standard care. The incremental cost per VYG was $20,401 and $21,559 with pegaptanib versus PDT and standard care, respectively. Sensitivity analyses found that the model was relatively robust to changes in various model parameters. CONCLUSION: The results of this analysis suggest that in Canada, pegaptanib is a cost-effective treatment for subfoveal wet AMD in elderly patients, regardless of lesion subtype, compared to PDT with verteporfin and to standard care.