Combined photodynamic therapy for metastatic breast cancer: possibilities and results (clinical case)

Background : Electrochemotherapy (ECT) is a new local therapy combining the administration of an intravenous chemotherapy (bleomycin) followed by the direct application of electric pulses by an electrode to the treated areas. Electric pulses transiently permeabilize the membrane of the tumor cell ( electroporation), improving intracellular diffusion of a poorly permeant chemotherapeutic agent, ithereby ncreasing its cytotoxicity and decreasing systemic toxicity. ECT can be offered to patients with cutaneous or subutaneous metastases of breast cancer who are no longer suitable for extensive surgery or radiotherapy ( e.g. due to past irradiation of the breast or chest wall). ECT 's applications are palliative. It is -, delivered with the aim of local control of the tumor, relief of symptoms associated with cutaneous recurrence -(ulceration, bleeding, pain),i and mproving patients'quality of life. The aim of this study is to demonstrate that ECT has a high efficacity and a low toxicity profile making it an interesting alternative to conventional therapies. Material and methods : our study is a retrospective study (approved by our local ethics committee) which included 8 patients between June 2013 and June 2016. The patients had histologically proven cutaneous and or subcutaneous metastases of their breast cancer, without any sign of lymphangitis. All the tumors expressed ER and /or PgR and 2 of them were HER2 positive tumors. The patients received a single or multiple courses of ECT ; the outcomes were clinical response, toxicity, local and distant recurrence. The two patients whose tumors expressed HER2, also had synchronous controlateral axillary nodal metastases. They underwent axillary dissection performed during ECT course. Among the six other patients, no other metastases than cutaneous lesions were observed. Results : The 8 included patients had already received chest wall irradiation for the treatment of their primary breast cancer. A total of 37 nodules were treated (mean : 4.5 per patient), whose mean size was 17mm (10-34mm). Six patients(75%) had a complete response after a single course of ECT. Two patients exhibited a partial response and underwent a second course of ECT at 6 months. The two patients with Her2 positive tumors received taxane-based chemotherapy and anti HER2 agents. All the patients were also given endocrine therapy. After a median follow up of 26 months (11-47 months), no patient had a local cutaneous recurrence. Overall survival rate was 75% : 2 patients died following progression of systemic disease (pulmonary and hepatic metastases). No complications due to toxicity were observed. Discussion and conclusion :In selected patients with ( cutaneous and subcutaneous metastases of breast cancer with no sign of lymphangitis), ECT offers a very good rate of clinical response and a durable control of metastases. This innovative technique has the advantage of being minimally –invasive and well –tolerated. Citation Format: Berliere M, Raguzzi E, Bernard M, Gerday A, Coyette M, Piette P, Duhoux F, Lengele B. Electrochemotherapy : A new local therapy for cutaneous metastases of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-23.

This article presents the construction of a multimodality platform that can be used for efficient destruction of brain tumor by a combination of photodynamic and sonodynamic therapy. For in vivo studies, U87 patient-derived xenograft tumors were implanted subcutaneously in SCID mice. For the first time, it has been shown that the cell-death mechanism by both treatment modalities follows two different pathways. For example, exposing the U87 cells after 24 h incubation with HPPH [3-(1′-hexyloxy)ethyl-3-devinyl-pyropheophorbide-a) by ultrasound participate in an electron-transfer process with the surrounding biological substrates to form radicals and radical ions (Type I reaction); whereas in photodynamic therapy, the tumor destruction is mainly caused by highly reactive singlet oxygen (Type II reaction). The combination of photodynamic therapy and sonodynamic therapy both in vitro and in vivo have shown an improved cell kill/tumor response, that could be attributed to an additive and/or synergetic effect(s). Our results also indicate that the delivery of the HPPH to tumors can further be enhanced by using cationic polyacrylamide nanoparticles as a delivery vehicle. Exposing the nano-formulation with ultrasound also triggered the release of photosensitizer. The combination of photodynamic therapy and sonodynamic therapy strongly affects tumor vasculature as determined by dynamic contrast enhanced imaging using HSA-Gd(III)DTPA.

To analyse the antibacterial effect of photodynamic therapy (PDT) in combination with various irrigation protocols on a multispecies biofilm in root canals exvivo. A total of 160 extracted human single-rooted teeth were divided into four groups (n=40). In group G1, root canals were instrumentedup to size 60 (control group), whereas in G2 to G4 canals were enlarged up to size 40. All root canals were inoculated with a multispecies biofilm (Enterococcus faecalis, Streptococcus oralis, Prevotella intermedia) for 5days. In G2 to G4, instrumentation up to size 60 was performed using 0.9% sodium chloride (NaCl) (G2), 1% sodium hypochlorite (NaOCl) (G3), 1% NaOCl and a final irrigation with 2% chlorhexidine (CHX) (G4), respectively. In all groups half of the specimens received adjunctive PDT using phenothiazine chloride as photosensitizer and a diode laser (wavelength 660nm). Counts of colony-forming units(CFUs) in each group were analysed separately for planktonic and dentine-adherent bacteria immediately after therapy (T1) and after 5days of further incubation (T2). Descriptive statistics and two-way analysis of variance were carried out to analyse reduction of planktonic bacteria and nonparametrictests were used to analyse dentine-adherent bacteria. CFU reduction in planktonic bacteria was significantly affected by the irrigation protocol at T1 and T2 (P<0.0001), but PDT significantly reduced CFUs only at T2 (P=0.01; anova). Irrigation using NaOCl, CHX and adjunctive PDT significantly reduced CFUs at T2 (P<0.0001; Tukey HSD) compared to the control group. In 85.6% of all samples the same categories of CFU counts in both planktonic and dentine-adherent bacteria were detected at T1 and T2. Adjunctive photodynamic therapy in combination with an irrigation protocol including NaOCl and CHX was an effective method for reduction of bacterial biofilm inside the root canals of extracted teeth.

Background: To assess the efficacy and safety of combined intravitreal triamcinolone (IVTA) and photodynamic therapy (PDT) with verteporfin in the treatment of choroidal neovascularisation (CNV) secondary to pathological myopia. Methods:...

Background:The validity of progression-free survival (PFS) as a surrogate end point for overall survival (OS) in maintenance therapy trials of metastatic breast cancer (MBC) is uncertain. We aimed to compare treatment effect sizes and the strength of associations between OS and PFS in trials of maintenance therapy for MBC. Methods: We searched for randomized trials investigating maintenance chemotherapy, endocrine therapy or immunotherapy after first-line chemotherapy in MBC and selected those reporting results for both OS and PFS. Treatment effect size differences between OS and PFS by a ratio of hazard ratios (rHRs) with 95% confidence intervals [CIs] were evaluated using random effects analysis. Surrogacy were analyzed using a weighted linear regression model, correlations were evaluated by squared correlation R2. Results: We analyzed data from 16 trials and 3,898 patients that received maintenance chemotherapy, endocrine therapy or immunotherapy for MBC. In the all trial-level analysis, treatment effect sizes were 28% greater for PFS than for OS (combined rHR, 0.72; 95% CI, 0.62 to 0.85, P &amp;lt; 0.001), and the correlation coefficient R2 between PFS and OS was 18% (95% CI, 12% to 26%). Differences were greater with PFS than OS for trials of maintenance chemotherapy compared with observation (rHR, 0.72; 95% CI, 0.59 to 0.80, P &amp;lt; 0.001), and the correlation coefficient R2between treatment effects on PFS and on OS ranged from 12% (95% CI, 8% to 16%) when all trials were considered to 40% (95%CI, 30% to 54%) after exclusion of one highly influential trial by sensitivity analysis. Differences were also great for trials of maintenance endocrine therapy vs. observation (rHR, 0.54; 95% CI, 0.44 to 0.66), and immunotherapy vs. observation (rHR, 0.85; 95% CI, 0.80 to 0.91). Conclusion: PFS was greater than OS in the treatment effect sizes, which is a valid surrogate end point for OS to assess treatment effect in MBC maintenance therapy trials. PROSPERO registry: No. CRD42017071858; Support: ChiCTR-IIR-17014036, SYS-C-201801. Citation Format: Song E, Yao H, Yu Y, Ou Q, Wang Y. Progression-free survival is a surrogate of survival in maintenance therapy for metastatic breast cancer: Randomized trial level analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-07.

Core-shell structured nanoparticles for photodynamic therapy-based cancer treatment and related imaging

Aim: To evaluate the outcomes of combined intravitreal triamcinolone (IVTA) and photodynamic therapy (PDT) with verteporfin in the treatment of subfoveal choroidal neovascularisation (CNV) caused by age related macular degeneration...

Photodynamic Therapy for Urological Malignancies: Past to Current Approaches

Photodynamic therapy (PDT) is a common cancer treatment strategy that combines the use of light, a photosensitizer, and oxygen to precisely generate reactive oxygen species (ROS). However, the efficacy of this method is limited by the shallow tissue penetration of the short-wavelength lasers involved, and combination therapy with other treatments such as photothermal therapy (PTT) or radiation therapy requires additional lasers or instruments. A new dual therapy approach using a single laser could minimize the treatment procedure. Chlorin e6 (Ce6) loaded-NaYF4:Yb,Er@NaYF4:Yb,Nd upconversion nanoparticles@mesoporous silica@mesoporous polydopamine nanoparticles (U@MSC@MP NPs) were fabricated to achieve PDT and PTT combination cancer therapy using a single 808 nm laser. The NaYF4:Yb,Er@NaYF4:Yb,Nd upconversion nanoparticles (UCNPs) were coated with mesoporous silica (MS) for Ce6-loading and coated with mesoporous polydopamine (MP) as a PTT photosensitizer. The PDT and PTT effects were measured using ROS generation detection and a thermal camera, respectively; in vitro cytotoxicity studies and in vivo antitumor efficacy analysis using tumor xenograft mouse models were performed to confirm the dual effects. The PDT-PTT UCNPs were successfully synthesized and emit photoluminescence spectra that can be absorbed by Ce6 to induce the PDT effect. Significant ROS generation was observed from U@MSC@MP NPs following 808 nm laser irradiation for 5 min, which corresponded to intracellular ROS detection in human colorectal adenocarcinoma HT-29 cells. The NPs significantly reduced HT-29 cell viability compared with PDT or PTT alone, demonstrating the potential of the designed UCNPs. Moreover, the in vivo antitumor efficacy analysis confirmed the dual effect with no signs of toxicity, supporting the safety and biocompatibility of the synthesized NPs. These findings suggest that the combination of PDT and PTT using a single laser can be achieved with UCNPs. This approach is a promising strategy for simplifying the cancer treatment procedures in clinical applications.

Photodynamic therapy (PDT) is a treatment for cancer based on the photosensitization of tumor cells by photosensitive drugs and their subsequent destruction on exposure to light of particular wavelength. The combination of drug uptake in malignant tissues and selective delivery of laser-generated light provides an effective therapy with efficient tumor citotoxicity and minimal normal tissue damage. Since immune response of the host is important in the control of tumor growth and spreading, PDT is able to increase the antitumor immunity. In our laboratory we examined the antitumor effect of combination of PDT, with photoactivated M-THPC (meta-tetrahydroxyphenylchlorin, FOSCAN, Temoporphirin), adoptive immunotherapy, with immune lymphocytes, and chemotherapy on advanced murine tumors. Mice bearing L1210 tumor were treated at day +4 with Navelbine (NVB 1mg/Kg), at day +5,+6 with PDT (0.3mg/Kg of mTHPC and 100mW/cm(2) x 200'' of exposure of laser light), and at day + 7 with immune lymphocytes(IL), collected from mice pretreated with PDT(2x10(7) cells). The results show that the combination NVB + PDT + IL demonstrates a significant synergistic antitumor effect while the chemotherapy treatment with low dose of the drug is uneffective. The same positive results were obtained with the combination of Cisplatin (CDDP 0.5mg/Kg), PDT and IL, while the CDDP treatment alone is completely uneffective. In conclusion, these results suggest that it is possible to completely cure animals bearing advanced tumors, with a combined therapy, PDT + adoptive immunotherapy + low dose chemotherapy.

Photodynamic therapy (PDT), a non-invasive and highly selective method for cancer treatment, has gained increasing attention due to its unique ability to activate a photosensitizer with near-infrared laser irradiation, generating reactive oxygen species (ROS) and inducing cytotoxic effects on tumors. However, PDT faces challenges such as the shallow penetration depth of the laser impacting treatment efficacy and the variability in ROS yield depending on various factors. Recent advancements in nanotechnology have paved the way for solutions, showing promising results in addressing these limitations. Therefore, there is rising interest in utilizing PDT in combination with other therapeutic modalities to enhance its anti-tumor efficacy. This review aims to compile relevant basic experiments and clinical studies on the principles, mechanisms, and various combination therapies of PDT, including with photothermal therapy, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. The findings from these studies consistently confirm that photodynamic combination therapy achieves a higher therapeutic index with lower side effects compared to the use of these modalities individually. The demonstrated synergistic effects and enhanced therapeutic outcomes in various studies underscore the need for additional research and development in this direction.

Combination of different therapeutic strategies to treat cancer has attracted tremendous attention in recent years. Herein, the authors develop polydopamine (PDA) nanoparticles with polyethylene glycol (PEG) modification as a multifunctional nanocarrier for coloading photosensitizer chlorine6 (Ce6) and curcumin (Cur) for combined photodynamic therapy (PDT) and radiotherapy (RT) of cancer. PEGylated PDA nanoparticles (PDA‐PEG) exhibit well water soluble and biocompatible in different physiological solutions and cause no obvious toxicity to cancer cells. In this nanoparticle, the loaded Ce6 can trigger the generation of single oxygen under near‐infrared laser irradiation for PDT, while the loaded Cur can act as an excellent radiosensitizer under X‐ray irradiation for enhanced external RT. As demonstrated by in vitro and in vivo therapeutic efficiency, combined PDT and RT based on PDA‐PEG/Cur/Ce6 nanoparticles exhibits significant inhibition the growth of cancer cells, revealing perfect performance in cancer treatment. Therefore, the study not only presents a polymer‐based theranostic platform for cancer treatment but also demonstrates the potential applications of combined RT and PDT for the future clinic cancer therapy.

Rationale: A robust index for gene expression related to activity of estrogen (ESR1) and progesterone (PGR) receptors could predict sensitivity to endocrine therapy in metastatic breast cancer. Methods: Transcripts correlated with ESR1 and PGR expression in 389 hormone receptor-positive breast cancer samples (Affymetrix U133A microarrays) were ranked for reliability according to their pre-analytical (intratumoral heterogeneity, biopsy type) and analytical reproducibility. Eighteen target and ten reference genes were selected and summarized as the SETER/PR index. The SETER/PR index was evaluated in a different set of 140 biopsies from distant metastases of hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, and in additional pre-analytical and analytical sample cohorts. Thereafter, SETER/PR was translated to a customized format for application to formalin-fixed and paraffin-embedded (FFPE) sections. Results: Higher SETER/PR in a metastasis was associated with longer progression-free survival (PFS, 9 vs. 2 months) and overall survival (OS, 50 vs. 19 months) following endocrine therapy in the cohort with metastatic breast cancer (MBC) and relapsed disease (n=79), so a cut point was defined in that cohort. SETER/PR was also significantly associated with PFS after adjusting for PR status of the metastasis, presence of visceral metastases, number of previous relapse events, and clinical history of previous sensitivity to endocrine therapy (HR 0.485, 95%CI 0.265 – 0.889, p = 0.019). Technically, SETER/PR was highly reproducible under different pre-analytical and analytical conditions, including host organ contamination. The translated SETER/PR assay used a single 10 µm FFPE tissue section, did not require RNA purification, and represented the microarray results from matched fresh samples with excellent agreement (correlation = 0.980, n = 31). Conclusion: The SETER/PR index is a new biomarker to predict PFS and OS for patients with HR+/HER2- MBC who receive endocrine therapy. The assay is applicable to FFPE tissue sections from small biopsies of metastases. Additional independent (blinded) validation studies will be necessary to confirm these results.Rationale: A robust index for gene expression related to activity of estrogen (ESR1) and progesterone (PGR) receptors could predict sensitivity to endocrine therapy in metastatic breast cancer. Methods: Transcripts correlated with ESR1 and PGR expression in 389 hormone receptor-positive breast cancer samples (Affymetrix U133A microarrays) were ranked for reliability according to their pre-analytical (intratumoral heterogeneity, biopsy type) and analytical reproducibility. Eighteen target and ten reference genes were selected and summarized as the SETER/PR index. The SETER/PR index was evaluated in a different set of 140 biopsies from distant metastases of hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, and in additional pre-analytical and analytical sample cohorts. Thereafter, SETER/PR was translated to a customized format for application to formalin-fixed and paraffin-embedded (FFPE) sections. Results: Higher SETER/PR in a metastasis was associated with longer progression-free survival (PFS, 9 vs. 2 months) and overall survival (OS, 50 vs. 19 months) following endocrine therapy in the cohort with metastatic breast cancer (MBC) and relapsed disease (n=79), so a cut point was defined in that cohort. SETER/PR was also significantly associated with PFS after adjusting for PR status of the metastasis, presence of visceral metastases, number of previous relapse events, and clinical history of previous sensitivity to endocrine therapy (HR 0.485, 95%CI 0.265 – 0.889, p = 0.019). Technically, SETER/PR was highly reproducible under different pre-analytical and analytical conditions, including host organ contamination. The translated SETER/PR assay used a single 10 µm FFPE tissue section, did not require RNA purification, and represented the microarray results from matched fresh samples with excellent agreement (correlation = 0.980, n = 31). Conclusion: The SETER/PR index is a new biomarker to predict PFS and OS for patients with HR+/HER2- MBC who receive endocrine therapy. The assay is applicable to FFPE tissue sections from small biopsies of metastases. Additional independent (blinded) validation studies will be necessary to confirm these results. Citation Format: Sinn BV, Tsai T-H, Lau R, Fu C, Gould R, Murthy R, King TA, Hatzis C, Kwiatkowski DN, Valero V, Symmans WF. SETER/PR - A robust 18-gene predictor of sensitivity to endocrine therapy in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-23.

Comparison of the efficacy of indocyanine green-mediated photodynamic therapy and nystatin therapy in treatment of denture stomatitis.

Background: Endocrine therapy (ET) is the preferred 1st line therapy in ER+ HER2- metastatic breast cancer (MBC) patients, but not all benefit from such strategy for which predictive biomarkers are lacking. Prior studies showed that circulating tumor cells (CTC) count is the strongest prognostic factor beyond PS in that population. The STIC CTC trial (NCT01710605) assessed whether CTC count could drive the choice between frontline ET or chemotherapy (CT, with or without ET maintenance). Methods: For this multicenter phase 3 non-inferiority trial, main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to ET or CT, informed consent. Patients were randomized 1:1 between clinically-driven choice (single agent ET if clinicallow, CT if clinicalhigh, as decided by physician based on clinical factors, blinded to CTC results) or a CTC-driven choice [ET if CTClow (&amp;lt;5 CTCs/7.5mL), CT if CTChigh (≥5 CTCs/7.5mL)]. The primary objective was treatment efficacy ([PFS hazard ratio (HR)], non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is &amp;lt;1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: In this trial, 778 patients were randomized between both strategies. Of all patients, 71.0%, 26.6% and 2.4% were considered as endocrine-sensitive, with secondary or with primary endocrine resistance, respectively. In both arms (clinically- and CTC-driven), prognostic evaluation by physician/CTCs and allocated treatments were as follows: (i) clinicallow/CTClow 46.5% and 48.6% of patients, all treated with ET. (ii) clinicalhigh/CTChigh 14.0% and 13.0%, all treated with CT. (iii) clinicallow/CTChigh 26.1% and 24.2%, treated with ET or CT respectively. (iv) clinicalhigh/CTClow 13.4% and 14.0%, treated with CT or ET respectively. CTC-driven strategy met the primary endpoint, yielding a non-inferior PFS (median: 17 months; 95%CI [15.4-20.3] vs 18 months 95%CI[13.9-23.3]). In the 2 discordant subgroups, preplanned analyses showed the following results: in the clinicallow/CTChigh subgroup, patients treated with CT had a significantly longer PFS than those treated with ET (15.6 months, 95%CI [12.2-22.7] vs 10.5 months, 95%CI [7.3-15.4], log rank p=0.002). In the clinicalhigh/CTClow subgroup, patients treated with CT had a non-significant PFS advantage over patients treated with ET. Pooling these two subgroups of patients (N=292) with discordant treatment recommendations (depending on clinician or CTC count standpoint), an exploratory analysis showed that patients treated with CT frontline had significantly longer PFS (HR=0.66; 95%CI [0.51-0.85]) and OS (HR=0.65; 95%CI [0.43-0.98]); 2-year OS were 82.9% versus 74.7% in patients treated with CT (±maintenance ET) or ET, respectively. Conclusion: This trial demonstrates the utility of CTC count to select 1st line therapy in ER+ HER2- MBC patients, especially in those for whom single agent ET is the recommended therapy based on clinical factors. With this modern prognostic biomarker, the STIC CTC trial is the first one to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT followed by maintenance ET than from frontline ET, challenging current standards. Funding: French Ministry of Health (PSTIC 2011); Menarini SB; Institut Curie. Citation Format: Francois-Clement Bidard, William Jacot, Sylvain Dureau, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Goncalves, Sylvain Ladoire, Herve Naman, Florence Dalenc, Joseph Gligorov, Marc Espie, Christelle Levy, Jean-Marc Ferrero, Delphine Loirat, Paul Cottu, Veronique Dieras, Marie-Emmanuelle Legrier, Frederique Berger, Catherine Alix-Panabieres, Jean-Yves Pierga. Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT140.