Variation of Plasma Damage-Associated Molecular Patterns in Patients with Advanced Solid Tumors after Standard of Care Systemic Treatment.

BACKGROUND: Immunogenic cell death (ICD) is known for releasing damage-associated molecular patterns (DAMPs) from tumor cells. We aimed to find ICD signals by assessing the variation of plasmatic DAMPs (HMGB1, S100A8) before-after standard of care (SoC) systemic treatment in patients with advanced solid tumors. METHODS: Patients scheduled to start a new line of systemic treatment were included. Plasmatic concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. RESULTS: Fifty-two patients were included. Forty-four patients (85%) had metastases, and 8 (15%) were treated for stage III tumors. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment in the first-line setting. Thirty-six patients (69%) were treated chemotherapy (CT) alone, ten (19%) CT plus targeted therapy, two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Median plasmatic concentration of S100A8 was significantly higher before than after treatment in the whole population (3.78 vs. 2.91 ng/mL; p = 0.011) and more markedly in the subgroups of patients who experienced RECIST-assessed tumor response (5.70 vs. 2.63 ng/mL; p = 0.002). Median plasmatic concentration of HMGB1was not significantly different before and after treatment (10.23 vs. 11.85 ng/mL; p = 0.382) and did not differ depending on tumor response. Median PFS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (8.0 vs. 10.6 months; p = 0.29) after treatment. Median PFS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (12 vs. 4.7 months; p < 0.001). Median OS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (13.1 vs. 14.7 months; p = 0.46) after treatment. Median OS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (16.7 vs. 9.0 months; p < 0.001). CONCLUSIONS: Signals of ICD were not observed. S100A8 behaves as an inflammatory marker with decreased concentration after treatment, mostly in RECIST-responders. PFS and OS were significantly prolonged in those patients who experienced a decrease of S100A8 compared with those patients who experienced increase of plasma S100A8 at three months.

Streptozotocin, 1982-2022: Forty Years from the FDA's Approval to Treat Pancreatic Neuroendocrine Tumors.

In May 1982, the US Food and Drug Administration (FDA) approved the use of streptozotocin to treat pancreatic neuroendocrine tumors (panNETs). Thus, this year marks 40 years since that landmark date. This review of streptozotocin to treat panNETs is intended to commemorate this anniversary. A historical perspective of the chemical structure, pharmacokinetics, and mechanism of action of streptozotocin is followed by data from prospective and retrospective clinical studies. The last section of the review addresses the latest aspects and takes note of the prospects that lie ahead on the future horizon of the use of streptozotocin to treat panNETs, including ongoing clinical trials.

Fooled by Randomness. The Misleading Effect of Treatment Crossover in Randomized Trials of Therapies with Marginal Treatment Benefit.

Crossover can bias clinical outcomes of randomized clinical trials by increasing the risk of both type I (false positive) and type II (false negative) errors. To show how crossover can increase type I error, we provide computer simulation and review herein illustrative examples (iniparib, olaratumab) of recently reported RCTs that demonstrated false-positive treatment efficacy signals due to crossover. The ethical issues associated with crossover are also discussed.

Hospital Volume Versus Good Clinical Practice.

This letter to the editor comments on a recently published article that assessed the treatment of patients with soft tissue sarcoma in high­volume versus low­volume centers.

Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study).

INTRODUCTION: Concurrent chemotherapy and radiotherapy is recommended for the treatment of locally advanced unresectable head and neck (H&N) cancer. OBJECTIVE: The primary purpose of the Phase I part of the study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose (RD) of docetaxel with hyperfractionation radiotherapy. The primary objective of the Phase II part was to determine the response rate to the RD of treatment and, secondarily, to assess the toxicity of the schedule, time to progression, duration of response and overall survival (OS). MATERIALS AND METHODS: Patients (n=9 in Phase I; n=19 in Phase II) had unresectable H&N cancer. The starting docetaxel dose was 20 mg/m(2) plus hyperfractionated radiotherapy. Ramping of docetaxel was 5 mg/m(2) if MTD was not reached. RESULTS: MTD of docetaxel was 20 mg/m(2). Limiting toxicities were grade 4 pneumonia and grade 4 mucositis. The RD was 15 mg/m(2). Phase II initial response was 76% (CR=18%; PR=9%); updated response was 89% (CR=59%; PR=29%). The median progression-free survival was 7.8 months (95%CI: 0-22.3) and the median OS was 15.1 months (95%CI: 0-35.9). Grade 3-4 toxicities included mucositis (91%), pneumonia (27%) and fatigue (27%). There were 5 toxic deaths (2 from intestinal perforation, 3 from pneumonia). CONCLUSIONS: Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify.

A phase I clinical and pharmacokinetic study of paclitaxel and docetaxel given in combination in patients with solid tumours.

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100 mg/m(2)) as a 3-h IV infusion followed by DTX (50 mg/m(2)) as 1-h IV infusion or the alternative sequence in every other patient. The sequence was alternated in the second course in each patient treated. Cycle duration was 21 days. Twenty patients received 103 cycles of treatment through three dose levels. Febrile neutropenia and grade 4 neutropenia lasting longer than 7 days were dose-limiting and defined the toxic dose of DTX (50 mg/m(2)) and PTX (135 mg/m(2)) in patients with prior treatment and the recommended dose in patients without prior treatment. Non-hematological toxicities included asthenia, neuropathy, arthralgia/myalgia and stomatitis. Pharmacokinetics of DTX were significantly affected by the sequence. Nadir ANC was more profound when DTX was administered first (P=0.022). There were one complete response and six partial responses, giving an overall response rate of 35%. DTX (50 mg/m(2)) followed by PTX (135 mg/m(2)) can be administered safely and it is an active regimen. The pharmacokinetics of PTX are not influenced by DTX but DTX pharmacokinetics depend on the sequence of administration, which influences its haematological toxicity profile.

Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer.

PURPOSE: To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). PATIENTS AND METHODS: Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1000 [corrected] mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). RESULTS: A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). CONCLUSION: Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment.

Radiation-induced mandibular osteogenic sarcoma: report of a case and review of the literature.

The case of a 56-year-old man with osteogenic sarcoma of the mandible diagnosed 7 years after radiotherapy treatment of a laryngeal cancer is reported. Surgery was the initial treatment. The progress was poor after local and pulmonary relapse, without response to chemotherapy treatment. Radiation-induced sarcomas are uncommon tumors that are diagnosed by meeting some diagnostic criteria. The mandible is a location very sensitive to radiation effects. The authors have found in the literature 30 cases of mandibular radiation-induced osteogenic sarcomas, most of them secondary to treatment of benign lesions, none of them secondary to treatment of a laryngeal cancer, as was seen in their case.