Irradiance controls photodynamic efficacy and tissue heating in experimental tumours: implication for interstitial PDT of locally advanced cancer.

BACKGROUND: Currently delivered light dose (J/cm2) is the principal parameter guiding interstitial photodynamic therapy (I-PDT) of refractory locally advanced cancer. The aim of this study was to investigate the impact of light dose rate (irradiance, mW/cm2) and associated heating on tumour response and cure. METHODS: Finite-element modeling was used to compute intratumoural irradiance and dose to guide Photofrin® I-PDT in locally advanced SCCVII in C3H mice and large VX2 neck tumours in New Zealand White rabbits. Light-induced tissue heating in mice was studied with real-time magnetic resonance thermometry. RESULTS: In the mouse model, cure rates of 70-90% were obtained with I-PDT using 8.4-245 mW/cm2 and ≥45 J/cm2 in 100% of the SCCVII tumour. Increasing irradiance was associated with increase in tissue heating. I-PDT with Photofrin® resulted in significantly (p < 0.05) higher cure rate compared to light delivery alone at same irradiance and light dose. Local control and/or cures of VX2 were obtained using I-PDT with 16.5-398 mW/cm2 and ≥45 J/cm2 in 100% of the tumour. CONCLUSION: In Photofrin®-mediated I-PDT, a selected range of irradiance prompts effective photoreaction with tissue heating in the treatment of locally advanced mouse tumour. These irradiances were translated for effective local control of large VX2 tumours.

A prospective study of pain control by a 2-step irradiance schedule during topical photodynamic therapy of nonmelanoma skin cancer.

BACKGROUND: Topical photodynamic therapy (PDT) for selected nonmelanoma skin cancer using 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) has yielded high long-term complete response rates with very good cosmesis. Pain during light activation of the photosensitizer can be a serious adverse event. A 2-step irradiance protocol has previously been shown to minimize ALA-PDT pain. OBJECTIVE: To determine the irradiance-dependent pain threshold for MAL-PDT, to adapt the 2-step protocol to a light-emitting diode (LED) light source, and assess clinical response. METHODS: In this prospective study, 25 superficial basal cell carcinoma (sBCC) received an initial irradiance by laser at 40 or 50 mW/cm², or LED at 35 mW/cm² followed by an irradiance at 70 mW/cm² for a total of 75 J/cm². Pain levels were recorded for both irradiance steps. Efficacy was assessed at 6, 12, or 24 months. RESULTS: Pain was mild in the 40/70 mW/cm² laser cohort. Three instances of irradiance-limiting pain occurred at 50/70 mW/cm². Pain was minimal in the 35/70 mW/cm² LED cohort. Clinical response rates were 80% in the 50/70 mW/cm² laser cohort and 90% in the 35/70 mW/cm² LED cohort. CONCLUSION: Topical PDT can be effectively delivered to sBCC with minimal treatment-related pain by a 2-step irradiance protocol.

A retrospective review of pain control by a two-step irradiance schedule during topical ALA-photodynamic therapy of non-melanoma skin cancer.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) with topical δ-aminolevulinic acid (ALA) of non-melanoma skin cancers is often associated with treatment-limiting pain. A previous study on basal cell carcinomas (BCCs) at Roswell Park Cancer Institute evaluated a two-step irradiance scheme as a means of minimizing pain, preserving outcomes, and limiting treatment time. We used an initial low irradiance until 90% of the protoporphyrin IX was photobleached, followed by a high irradiance interval until the prescribed fluence was delivered. Success of this pilot investigation motivated integration of the protocol into routine practice. Here, we present a retrospective review of recent clinical experience in a broad patient population. STUDY DESIGN/MATERIALS AND METHODS: This was a retrospective review of an existing dermatology database. Fourteen caucasion patients-nine men and five women, ages 18-80, with a total of 51 superficial and 73 nodular BCCs, and three Bowen's disease lesions-were included. ALA was applied to each lesion for approximately 4 hours. Lesions received an initial irradiance of 30-50 mW/cm(2) for 20 J/cm(2) , followed by 150 mW/cm(2) for a total fluence of 200-300 J/cm(2) . Pain was assessed using a visual analog scale (VAS). Clinical outcome was determined at 6-12 months. RESULTS: Median VAS scores were 1.0 for both irradiances. Five of 127 lesions required pain control with 1% xylocaine. Pain was strongly influenced by lesion location but not by lesion type, number, or size. Complete responses were achieved in 84.1% of BCCs, which compares favorably with reported results for single ALA-PDT treatments. Two of three Bowen's disease lesions showed a complete response. Complete responses for nodular BCCs were 37%, which are also within the range of reported outcomes. CONCLUSIONS: A two-step irradiance protocol in ALA-PDT effectively minimizes pain, maintains excellent clinical outcomes in superficial lesions, and adds minimal treatment time.

Antimicrobial susceptibilities of Aeromonas strains isolated from clinical and environmental sources to 26 antimicrobial agents.

We determined the susceptibilities of 144 clinical and 49 environmental Aeromonas strains representing 10 different species to 26 antimicrobial agents by the agar dilution method. No single species had a predominantly nonsusceptible phenotype. A multidrug nonsusceptible pattern was observed in three (2.1%) clinical strains and two (4.0%) strains recovered from diseased fish. Common clinical strains were more resistant than the corresponding environmental isolates, suggesting that resistance mechanisms may be acquired by environmental strains from clinical strains.

Prevalence and genotypic characteristics of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae in Australia.

OBJECTIVES: To determine the prevalence of ß-lactamase-negative ampicillin-resistant (BLNAR) Haemophilus influenzae in Australia and characterize the associated amino acid substitutions in penicillin-binding protein 3. METHODS: Two hundred consecutive non-repeat clinical isolates of H. influenzae were collected and ß-lactamase-negative isolates were screened for reduced ampicillin susceptibility using an ampicillin 2 µg disc (breakpoint <17 mm) and Etest (breakpoint ≥0.25 mg/L). All screen-positive isolates had their ampicillin MICs determined by reference broth microdilution and their ftsI genes were sequenced. RESULTS: No BLNAR strains (MIC ≥4 mg/L) were found, but 5 (2.5%) low BLNAR (L-BLNAR) strains (MIC ≥2 mg/L) and 36 (18%) genetic BLNAR (gBLNAR) strains (R517H or N526K) were found. Of the gBLNAR strains, four had the R517H substitution and the remainder had N526K, while no strains had combined N526K and M377I/S385T/L389F substitutions. A number of strains with neither R517H nor N526K substitutions that did not meet the gBLNAR definition had other BLNAR-associated substitutions. CONCLUSIONS: BLNAR and L-BLNAR strains are uncommon in Australia, while gBLNAR strains are more common than previously recognized.

Photodynamic therapy (PDT) using HPPH for the treatment of precancerous lesions associated with Barrett's esophagus.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) with porfimer sodium, FDA approved to treat premalignant lesions in Barrett's esophagus, causes photosensitivity for 6-8 weeks. HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) shows minimal photosensitization of short duration and promising efficacy in preclinical studies. Here we explore toxicity and optimal drug and light dose with endoscopic HPPH-PDT. We also want to know the efficacy of one time treatment with HPPH-PDT. STUDY DESIGN/MATERIALS AND METHODS: Two nonrandomized dose escalation studies were performed (18 patients each) with biopsy-proven high grade dysplasia or early intramucosal adenocarcinoma of esophagus. HPPH doses ranged from 3 to 6 mg/m2 . At 24 or 48 hours after HPPH administration the lesions received one endoscopic exposure to 150, 175, or 200 J/cm of 665 nm light. RESULTS: Most patients experienced mild to moderate chest pain requiring symptomatic treatment only. Six patients experienced grade 3 and 4 adverse events (16.6%). Three esophageal strictures were treated with dilatation. No clear pattern of dose dependence of toxicities emerged. In the drug dose ranging study (light dose of 150 J/cm at 48 hours), 3 and 4 mg/m2 of HPPH emerged as most effective. In the light dose ranging study (3 or 4 mg/m2 HPPH, light at 24 hours), complete response rates (disappearance of high grade dysplasia and early carcinoma) of 72% were achieved at 1 year, with all patients treated with 3 mg/m2 HPPH plus 175 J/cm and 4 mg/m2 HPPH plus 150 J/cm showing complete responses at 1 year. CONCLUSIONS: HPPH-PDT for precancerous lesions in Barrett's esophagus appears to be safe and showing promising efficacy. Further clinical studies are required to establish the use of HPPH-PDT.

Monitoring photobleaching and hemodynamic responses to HPPH-mediated photodynamic therapy of head and neck cancer: a case report.

We present initial results obtained during the course of a Phase I clinical trial of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photo-dynamic therapy (PDT) in a head and neck cancer patient. We quantified blood flow, oxygenation and HPPH drug photobleaching before and after therapeutic light treatment by utilizing fast, non-invasive diffuse optical methods. Our results showed that HPPH-PDT induced significant drug photobleaching, and reduction in blood flow and oxygenation suggesting significant vascular and cellular reaction. These changes were accompanied by cross-linking of the signal transducer and activator of transcription 3 (STAT3), a molecular measure for the oxidative photoreaction. These preliminary results suggest diffuse optical spectroscopies permit non-invasive monitoring of PDT in clinical settings of head and neck cancer patients.

Irradiance, Photofrin® Dose and Initial Tumor Volume are Key Predictors of Response to Interstitial Photodynamic Therapy of Locally Advanced Cancers in Translational Models.

The objective of the present study was to develop a predictive model for Photofrin® -mediated interstitial photodynamic therapy (I-PDT) of locally advanced tumors. Our finite element method was used to simulate 630-nm intratumoral irradiance and fluence for C3H mice and New Zealand White rabbits bearing large squamous cell carcinomas. Animals were treated with light only or I-PDT using the same light settings. I-PDT was administered with Photofrin® at 5.0 or 6.6 mg kg-1 , 24 h drug-light interval. The simulated threshold fluence was fixed at 45 J cm-2 while the simulated threshold irradiance varied, intratumorally. No cures were obtained in the mice treated with a threshold irradiance of 5.4 mW cm-2 . However, 20-90% of the mice were cured when the threshold irradiances were ≥8.6 mW cm-2 . In the rabbits treated with I-PDT, 13 of the 14 VX2 tumors showed either local control or were cured when threshold irradiances were ≥15.3 mW cm-2 and fluence was 45 J cm-2 . No tumor growth delay was observed in VX2 treated with light only (n = 3). In the mouse studies, there was a high probability (92.7%) of predicting cure when the initial tumor volume was below the median (493.9 mm3 ) and I-PDT was administered with a threshold intratumoral irradiance ≥8.6 mW cm-2 .

Light delivery over extended time periods enhances the effectiveness of photodynamic therapy.

PURPOSE: The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. EXPERIMENTAL DESIGN: Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis. RESULTS: In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO(2) were observed with extended exposures, which persisted after completion of treatment. CONCLUSIONS: These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.

Cross-linking of signal transducer and activator of transcription 3--a molecular marker for the photodynamic reaction in cells and tumors.

PURPOSE: Photodynamic therapy (PDT) depends on the delivery of a photosensitizer to the target tissue that, under light exposure, produces singlet oxygen and other reactive oxygen species, which in turn cause the death of the treated cell. This study establishes a quantitative marker for the photoreaction that will predict the outcome of PDT. EXPERIMENTAL DESIGN: Cells in tissue culture, murine s.c. tumors, and endobronchial carcinomas in patients were treated with PDT, and the noncleavable cross-linking of the latent signal transducer and activator of transcription 3 (STAT3) was determined. RESULTS: Murine and human cancer cell lines reacted to PDT by an immediate covalent cross-linking of STAT3 to homodimeric and other complexes. The magnitude of this effect was strictly a function of the PDT reaction that is determined by the photosensitizer concentration and light dose. The cross-link reaction of STAT3 was proportional to the subsequent cytotoxic outcome of PDT. An equivalent photoreaction as detected in vitro occurred in tumors treated in situ with PDT. The light dose-dependent STAT3 cross-linking indicated the relative effectiveness of PDT as a function of the distance of the tissue to the treating laser light source. Absence of cross-links correlated with treatment failure. CONCLUSIONS: The data suggest that the relative amount of cross-linked STAT3 predicts the probability for beneficial outcome, whereas absence of cross-links predicts treatment failure. Determination of STAT3 cross-links after PDT might be clinically useful for early assessment of PDT response.

Generation of effective antitumor vaccines using photodynamic therapy.

Preclinical studies have shown that photodynamic therapy (PDT) of tumors augments the host antitumor immune response. However, the role of the PDT effect on tumor cells as opposed to the host tissues has not been determined. To test the contribution of the direct effects of PDT on tumor cells to the enhanced antitumor response by the host, we examined the immunogenicity of PDT-generated murine tumor cell lysates in a preclinical vaccine model. We found that the PDT-generated tumor cell lysates were potent vaccines and that PDT-generated vaccines are more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation, and unlike other traditional vaccines, PDT vaccines do not require coadministration of an adjuvant to be effective. PDT vaccines are tumor specific and appear to induce a cytotoxic T-cell response. We have demonstrated that although both UV and PDT-generated tumor cell lysates are able to induce phenotypic DC maturation, only PDT-generated lysates are able to activate DCs to express IL-12, which is critical to the development of a cellular immune response. Our results show that PDT effects on tumor cells alone are sufficient to generate an antitumor immune response, indicating that the direct tumor effects of PDT play an important role in enhancing that host antitumor immune response. These studies also suggest that in addition to the role of PDT as a therapeutic modality, PDT-generated vaccines may have clinical potential as an adjuvant therapy.

Photodynamic therapy: a means to enhanced drug delivery to tumors.

Using the photosensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a, we have determined that photodynamic therapy (PDT) can be used to facilitate the delivery of macromolecular agents. PDT regimens that use low fluences and fluence rates were the most successful. This effect was demonstrated for fluorescent microspheres with diameters ranging from 0.1 to 2 microm. Such treatment given immediately before administration of Doxil, a liposomally encapsulated formulation of doxorubicin with an average diameter of 0.1 microm, significantly enhanced its accumulation in transplanted murine Colo 26 tumors. The combination of PDT and Doxil led to a highly significant potentiation in tumor control without concomitant enhancement of systemic or local toxicity. Interestingly, concentration-effect modeling suggested that the enhanced cure rate was greater than what was predicted based on the increase in intratumor Doxil concentration. In summary, we have developed a novel PDT treatment that enhances the delivery and efficacy of macromolecule-based cancer therapies such as Doxil.

Choice of oxygen-conserving treatment regimen determines the inflammatory response and outcome of photodynamic therapy of tumors.

The rate of light delivery (fluence rate) plays a critical role in photodynamic therapy (PDT) through its control of tumor oxygenation. This study tests the hypothesis that fluence rate also influences the inflammatory responses associated with PDT. PDT regimens of two different fluences (48 and 128 J/cm(2)) were designed for the Colo 26 murine tumor that either conserved or depleted tissue oxygen during PDT using two fluence rates (14 and 112 mW/cm(2)). Tumor oxygenation, extent and regional distribution of tumor damage, and vascular damage were correlated with induction of inflammation as measured by interleukin 6, macrophage inflammatory protein 1 and 2 expression, presence of inflammatory cells, and treatment outcome. Oxygen-conserving low fluence rate PDT of 14 mW/cm(2) at a fluence of 128 J/cm(2) yielded approximately 70-80% tumor cures, whereas the same fluence at the oxygen-depleting fluence rate of 112 mW/cm(2) yielded approximately 10-15% tumor cures. Low fluence rate induced higher levels of apoptosis than high fluence rate PDT as indicated by caspase-3 activity and terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. The latter revealed PDT-protected tumor regions distant from vessels in the high fluence rate conditions, confirming regional tumor hypoxia shown by 2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl) acetamide staining. High fluence at a low fluence rate led to ablation of CD31-stained endothelium, whereas the same fluence at a high fluence rate maintained vessel endothelium. The highest levels of inflammatory cytokines and chemokines and neutrophilic infiltrates were measured with 48 J/cm(2) delivered at 14 mW/cm(2) ( approximately 10-20% cures). The optimally curative PDT regimen (128 J/cm(2) at 14 mW/cm(2)) produced minimal inflammation. Depletion of neutrophils did not significantly change the high cure rates of that regimen but abolished curability in the maximally inflammatory regimen. The data show that a strong inflammatory response can contribute substantially to local tumor control when the PDT regimen is suboptimal. Local inflammation is not a critical factor for tumor control under optimal PDT treatment conditions.

A Phase I Study of Light Dose for Photodynamic Therapy Using 2-[1-Hexyloxyethyl]-2 Devinyl Pyropheophorbide-a for the Treatment of Non-Small Cell Carcinoma In Situ or Non-Small Cell Microinvasive Bronchogenic Carcinoma: A Dose Ranging Study.

INTRODUCTION: We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL). METHODS: The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was performed at 1 and 6 months, respectively. RESULTS: The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2. CONCLUSIONS: PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies.

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

BACKGROUND: The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses. METHODS: A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response. RESULTS: Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD. CONCLUSION: HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016.

Bacteriopurpurinimides: highly stable and potent photosensitizers for photodynamic therapy.

The in situ conversion of the unstable bacteriochlorophyll a present in Rhodobacter sphaeroides produced highly stable bacteriopurpurin-18 which in a sequence of reactions was converted into a series of alkyl ether analogues of bacteriopurpurin-18-N-alkylimides with long wavelength absorption near 800 nm. The effective photosensitizers were found to localize in mitochondria but did not show any specific displacement of (3)H-PK11195, suggesting that the mitochondrial peripheral benzodiazepine receptor is not the cellular binding site for this class of compounds.

Synthesis and photosensitizing efficacy of isomerically pure bacteriopurpurinimides.

The isomerically pure 3-deacetyl-3-(1-heptyloxy)ethylbacteriopurpurin-N-hexylimides exhibiting long-wavelength absorption near 800 nm were obtained from 3-acetylbacteriopurpurin-N-hexylimide in high stereospecificity by following Corey's synthetic approach. Both heptyl ether derivatives (R- and S-isomers) showed similar in vitro photosensitizing efficacy and limited skin phototoxicity and were found to localize in mitochondria. However, in preliminary in vivo screening, compared to the S-isomer, the corresponding R-isomer produced enhanced in vivo photodynamic therapy efficacy.

Quantification of PpIX concentration in basal cell carcinoma and squamous cell carcinoma models using spatial frequency domain imaging.

5-aminolaevulinic acid photodynamic therapy (ALA-PDT) is an attractive treatment option for nonmelanoma skin tumors, especially for multiple lesions and large areas. The efficacy of ALA-PDT is highly dependent on the photosensitizer (PS) concentration present in the tumor. Thus it is desirable to quantify PS concentration and distribution, preferably noninvasively to determine potential outcome. Here we quantified protoporphyrin IX (PpIX) distribution induced by topical and intra-tumoral (it) administration of the prodrug ALA in basal and squamous cell carcinoma murine models by using spatial frequency domain imaging (SFDI). The in vivo measurements were validated by analysis of the ex vivo extraction of PpIX. The study demonstrates the feasibility of non-invasive quantification of PpIX distributions in skin tumors.

Adjuvant intraoperative photodynamic therapy in head and neck cancer.

IMPORTANCE: There is an immediate need to develop local intraoperative adjuvant treatment strategies to improve outcomes in patients with cancer who undergo head and neck surgery. OBJECTIVES: To determine the safety of photodynamic therapy with 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) in combination with surgery in patients with head and neck squamous cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Nonrandomized, single-arm, single-site, phase 1 study at a comprehensive cancer center among 16 adult patients (median age, 65 years) with biopsy-proved primary or recurrent resectable head and neck squamous cell carcinoma. INTERVENTIONS: Intravenous injection of HPPH (4.0 mg/m2), followed by activation with 665-nm laser light in the surgical bed immediately after tumor resection. MAIN OUTCOMES AND MEASURES: Adverse events and highest laser light dose. RESULTS: Fifteen patients received the full course of treatment, and 1 patient received HPPH without intraoperative laser light because of an unrelated myocardial infarction. Disease sites included larynx (7 patients), oral cavity (6 patients), skin (1 patient), ear canal (1 patient), and oropharynx (1 patient, who received HPPH only). The most frequent adverse events related to photodynamic therapy were mild to moderate edema (9 patients) and pain (3 patients). One patient developed a grade 3 fistula after salvage laryngectomy, and another patient developed a grade 3 wound infection and mandibular fracture. Phototoxicity reactions included 1 moderate photophobia and 2 mild to moderate skin burns (2 due to operating room spotlights and 1 due to the pulse oximeter). The highest laser light dose was 75 J/cm2. CONCLUSIONS AND RELEVANCE: The adjuvant use of HPPH-photodynamic therapy and surgery for head and neck squamous cell carcinoma seems safe and deserves further study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00470496.