Microsurgical Resection Combined With Photodynamic Therapy for Recurrent Glioblastoma

Background:

For recurrent glioblastoma (WHO grade IV), no standard therapy has been established, and the median overall survival after recurrence is 24-44 weeks.

Tumor-targeted photodynamic therapy (PDT) uses a photosensitizer that preferentially accumulates in tumor tissue; activation with 630-nm laser light generates reactive oxygen species that selectively kill residual tumor cells while sparing normal brain.

Design:

Prospective, single-arm, open-label, single-center study (Sun Yat-sen University Cancer Center, Guangzhou, China). Planned sample size: 10 participants.

Treatment:

Dexamethasone 10 mg intravenously once daily for 3 days before surgery. Two days before surgery, patients enter a darkened room and undergo a photosensitizer skin test (scratch test or intradermal test, 0.01 mg/mL). Patients with a negative skin test receive hematoporphyrin injection (Hiporfin, hematoporphyrin derivative, Chongqing Maile Biopharmaceutical Co., Ltd.; 5 mL: 25 mg) at 5 mg/kg diluted in 250 mL normal saline by light-protected intravenous infusion. Forty-eight hours after infusion, standard craniotomy with microsurgical resection of the recurrent tumor is performed, and the resection cavity is irradiated with a 630-nm semiconductor laser (output power 1 W; power density 120-150 mW/cm2; fluence 150-200 J/cm2; approximately 10-20 minutes) using a cylindrical diffuser or flat-cut fiber selected according to the cavity shape. After phototherapy, the wound is closed routinely. Postoperatively, patients remain in a darkened room with whole-body skin protection for 72 hours and avoid direct outdoor sunlight until 30 days after surgery.

Follow-up:

Contrast-enhanced brain MRI at day 3, day 7 (+/-1), day 30 (+/-2), day 90 (+/-2), day 180 (+/-2), day 270 (+/-2), and day 360 (+/-1); thereafter every 2 months (efficacy) and monthly (survival). Neurological examination, Karnofsky/ECOG performance status, EORTC QLQ-C30 quality-of-life assessment, and laboratory safety tests are performed at scheduled visits.

Analysis:

Efficacy and safety analyses will be performed on the per-protocol set. All statistical tests will be two-sided with P <= 0.05 considered significant. Adverse events will be graded according to NCI CTCAE version 5.0 and coded with MedDRA.

Inclusion criteria

• Age 18-65 years, any sex
• KPS score >= 70 and ECOG performance status 0-2
• Patient and family members willing and able to provide written informed consent
• Histopathologically confirmed glioblastoma (WHO grade IV) that has progressed or recurred after standard radiotherapy and chemotherapy, based on radiological evidence of measurable disease
• More than 3 months since completion of brain radiotherapy
• Hospitalized for recurrence/progression with a sizable lesion causing related symptoms and/or mass effect, for which gross-total or subtotal resection is considered feasible at reoperation
• No concomitant malignancy, severe autoimmune disease or congenital immunodeficiency, severe active infection, cranial nerve disorder, or psychiatric disease
• Life expectancy greater than 12 weeks
• Cardiac function: essentially normal electrocardiogram, stable hemodynamics, left ventricular ejection fraction > 55%
• White blood cell count > 3.5 x 10^9/L, platelet count > 100 x 10^9/L, absolute neutrophil count > 1.5 x 10^9/L, hemoglobin > 90 g/L
• ALT and AST < 2.5 x upper limit of normal (< 5 x ULN if hepatic impairment mainly due to tumor infiltration), total bilirubin < 1.5 x ULN, serum creatinine < 1 x ULN
• INR or prothrombin time < 1.5 x ULN and APTT < 1.5 x ULN (for patients on anticoagulation, PT/PTT within the expected therapeutic range)
• Negative for HIV antibody, Treponema pallidum antibody, HBsAg, HCV antibody, and EBV-DNA
• Female subjects must use effective contraception throughout the study, with negative serum or urine pregnancy test at screening and during the study
• Able to attend regular follow-up visits at the study institution throughout the trial
• Expected benefit of participation judged to outweigh the risks by the investigators

Exclusion criteria

• KPS score < 70
• Prior or concurrent malignancy at other sites, unless disease-free for >= 3 years
• Pregnant or lactating women
• History of allergy to photosensitizers or hematoporphyrin
• Porphyria or soy allergy
• Contraindications to surgery
• Other uncontrolled active infection
• Treatment with any investigational drug within 30 days before study entry
• Psychiatric disease or other conditions (e.g., uncontrolled cardiac or pulmonary disease, diabetes) precluding compliance with study treatment and monitoring
• Severe renal or hepatic impairment (bilirubin > 1.5 x ULN, alkaline phosphatase and AST > 2.5 x ULN, creatinine clearance < 30 mL/min)
• Prior allogeneic tissue or organ transplantation
• Poor compliance or inability to follow skin photosensitivity precautions
• HIV-positive or AIDS-related disease
• Contraindications to magnetic resonance imaging
• Follow-up impossible for psychological, family, social, or geographical reasons
• Lack of legal capacity (deprived of liberty or under guardianship)
• Refusal to participate or to provide consent
• Any other condition judged unsuitable for enrollment by the investigator