Changing equipoise in the landscape of radiation for oligometastatic lung cancer.

There is growing interest in exploring use of local therapies in the management of oligometastatic non-small cell lung cancer (NSCLC) to provide durable local and distant disease control. Prospective phase II studies have incorporated local therapy (predominantly stereotactic ablative radiotherapy or SABR) to both primary and metastatic sites. For patients who received these treatments, median progression-free survival (PFS) and overall survival (OS) exceeded that of historical controls treated with systemic therapy alone (9.7-23.5 and 13.5-41.2 months, respectively). Additionally, three trials randomized oligometastatic NSCLC patients to standard of care systemic therapy regimens vs. local consolidative therapy (LCT) plus standard of care systemic therapy (or observation) and all demonstrated a significant improvement in PFS, with two showing OS benefits to date. Notably, a majority of these trials selected patients with at least stable disease after completion of systemic therapy for local therapy and defined the oligometastatic state as one with no more than five metastatic sites spread across three organs. For patients with oligometastatic NSCLC, there are many important factors that should drive use and timing of local therapy, including metastatic presentation sequence (synchronous vs. metachronous), extent of disease (number and distribution of sites), and quality of life goals. The referenced clinical trials accrued patients prior to the approval of immunotherapy for metastatic NSCLC, so the benefits of any local therapy in this setting remain uncertain. To ultimately clarify the role of local therapy in oligometastatic NSCLC in the era of improving systemic therapy efficacy (i.e., immunotherapy and targeted therapy combinations with cytotoxics), we recommend enrollment in in phase III studies with OS endpoints (i.e., NRG LU 002 and SARON) whenever possible. These and other important issues associated with local therapy for oligometastatic NSCLC are reviewed in this paper.

Financial Toxicity and Cancer Therapy: A Primer for Radiation Oncologists.

The diagnosis and treatment of cancer places patients at risk for serious financial consequences, which are detrimental to overall health and well-being. The concept of financial toxicity (FT) describes monetary and health implications related to the financial burden of receiving care. To investigate this important area, the authors first explore aspects of the modern American health care insurance system that relate to cancer care. Then they summarize relevant literature across multiple domains of FT that include monetary, functional, and patient-reported measures. The authors conclude by making simple recommendations to begin addressing FT in clinical practice.

Prostate brachytherapy procedural training: incorporation of related procedures in resident training and competency assessment.

PURPOSE: Inadequate procedural training is of increasing concern in resident training, especially in prostate brachytherapy (PB). Transperineal rectal spacer placement (TRSP) requires many of the same proficiencies as PB. This work describes the assessment of teaching techniques focusing on developing critical competencies for PB using related clinical procedures (TRSP). MATERIAL AND METHODS: For PB and TRSP, key competencies were identified: 9 for PB and 7 for TRSP; 4 are shared between PB and TRSP. "Comfort level" with these procedures was assessed prior to and following participation in TRSP. RESULTS: 8 of 12 trainees at our institution participated in TRSP procedures. 2 of these trainees had prior experience with PB or related procedures and were excluded. Trainees self-reported "comfort levels" between 0 and 3 for four competency domains. Initial median comfort (MC) level for competency domains relevant to PB included: patient positioning (median 1, range 0-2), transrectal ultrasound imaging (median 1, range 0-1), fiducial placement (median 1, range 0-1), and hydrodissection (median 0, range 0-1). Median number of TRSP procedures performed by assessed trainees during the analysis period was 4 (range 1-6). Following TRSP procedure training, MC level increased: 2 points for patient positioning (median 3, range 1-3; p < 0.01), 1.5 points for transrectal ultrasound imaging (median 2.5, range 1.3, p < 0.001); 1 point for fiducial placement (median score 2, range 1-3; p < 0.001); and 1.5 points for hydrodissection (median score 2, range 1-3; p < 0.001). CONCLUSIONS: Increasing trainee involvement in related procedures to develop core competencies may help facilitate increased comfort with common skills critical to the independent performance of PB.

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer.

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH-, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH- decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H2O2)-mediated mechanism. In this study, we demonstrate that P-AscH- radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH-, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH- in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH- during the radiotherapy "beam on." Specifically, treatment with P-AscH- increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, P = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH--treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, P < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH- in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH- efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.

Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer.

Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.

Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

Impact of SOD-Mimetic Manganoporphyrins on Spin Trapping of Superoxide and Related Artifacts.

The superoxide dismutase (SOD)-mimetic effectiveness of [meso-tetrakis (R)porphyrinato]manganese with R = 1,3-di-N-ethylimidazolium-2-yl (Mn-TDEIP), 1,3-di-N-methylimidazolium-2-yl (Mn-TDMIP), 1,3-di-N-propylimidazolium-2-yl (Mn-TDPIP), N-ethyl-2-pyridyl (Mn-T2EPyP), 4-sulphonatophenyl (Mn-TSP), 1-methyl-4-pyridyl (Mn-T4PyP), 4-carboxyphenyl (Mn-TBAP), and ß-octabromomeso-tetrakis(4-carboxyphenyl porphyrinato)manganese (MnBr8TBAP) was compared with Cu, Zn SOD. Superoxide generated by reaction of xanthine oxidase with hypoxanthine was trapped with 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO), forming BMPO-OOH, which was monitored by electron paramagnetic resonance. Manganoporphyrins with redox potentials ranging from -0.190 to 0.346 V relative to the standard hydrogen electrode were selected for this study. With 0.1 µM manganoporphyrins and 20 mM BMPO, the effectiveness of the manganoporphyrins in inhibiting formation of BMPO-OOH increases in the order Mn-TSP < Mn-TBAP < MnBr8TBAP < Mn-T4PyP < Mn-T2EPyP < Mn-TDEIP ~ Mn-TDMIP ~ Mn-TDPIP ~ Cu, Zn SOD. However, at higher concentrations of manganoporphyrin and BMPO, a BMPO-OH signal was observed. The formation of BMPO-OH was not inhibited by catalase or dimethylsulfoxide, which demonstrated that it was not produced from hydroxyl radical. The artifactual formation of BMPO-OH is attributed to oxidation of the water adduct of BMPO by the manganoporphyrins or decomposition of BMPO-OOH. Although spin trapping is an effective method for evaluating SOD-mimetic efficacy, caution must be exercised to ensure that artifact signals are not interpreted improperly.