Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery will be eligible. Two hun-dred forty patients will be randomly assigned (1:1) to either standard aRCT with cisplatin (standard arm) or aRCT with cisplatin + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months) (interventional arm). Endpoints are event-free and overall survival. Recruitment started in August 2018 and is ongoing.

Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients.

PURPOSE: Lung cancer accounts for one in five cancer deaths. Broad screening strategies for high-risk populations are unavailable, and the validation of biomarkers for early cancer detection remains a prime interest. Therefore, we investigated the value of circulating U2 small nuclear RNA fragments (RNU2-1f) as a biomarker for diagnosis, prognosis estimation and treatment monitoring in a large lung cancer cohort. METHODS: We determined RNU2-1f abundance in sera of patients with treatment-naive lung cancer (n = 211, 25.6 % early stage), chronic lung disease (n = 56) and healthy controls (n = 58) by reverse transcription quantitative PCR. Initial levels and changes after one chemotherapy cycle were correlated with treatment outcomes in patient subsets. RESULTS: Relative serum RNU2-1f expression levels (REL) were elevated in lung cancer patients compared with patients with chronic lung disease and healthy controls (p < 0.0001). The area under the receiver operating characteristic curve for the complete data set (lung cancer vs. healthy) was 0.91 (95 % CI 0.87-0.95). By applying a REL of -4.505 as diagnostic cutoff (Youden's criterion), sensitivity and specificity reached 0.86 and 0.81, respectively. To determine the generalization error, in a subsampling study, sensitivity and specificity were estimated as 0.82 and 0.77 for the application to future, independent samples. High initial RNU2-1f REL were associated with shorter median survival in stage IIIB/IV disease (RNU2-1fhigh = 228 days/RNU2-1flow = 484 days; p = 0.009, log-rank test, HR1.43 95 % CI 1.23-1.66). Multivariate analysis confirmed RNU2-1f as an independent prognostic factor. Patients with subsequent RNU2-1f reduction had a trend toward better treatment outcome. CONCLUSIONS: Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring.

Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).

PURPOSE: Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction. PATIENTS AND METHODS: Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS). RESULTS: After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment. CONCLUSION: The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.

First salvage treatment in patients with advanced germ cell cancer after cisplatin-based chemotherapy: analysis of a registry of the German Testicular Cancer Study Group (GTCSG).

PURPOSE: We analyzed prognostic categories at first relapse according to the International Prognostic Factors Study Group (IPFSG) criteria as well as the efficacy of salvage treatment. METHODS: 143 patients with relapsed or refractory germ cell cancer undergoing first salvage treatment with conventional-dose (CD-CX, n = 48) or high-dose chemotherapy with autologous stem cell support (HD-CX, n = 95) contributed by nine centers were retrospectively analyzed. RESULTS: Prognostic subgroups according to IPFSG criteria were: very low risk 13/143, low risk 36/143, intermediate risk 66/143, high risk 22/143, and very high risk 6/143 patients. The IPFSG categories significantly correlated with overall survival (OS) (p = 0.025) after 1st salvage treatment. After a median follow-up of 19 months, 55 % of all patients had relapsed and 33 % had died. For the entire cohort, progression-free survival (PFS) rate after 2 years was 43 %, and OS rate after 5 years was 52 %. Compared to the HD-CX group, vital carcinoma was found more often in secondarily resected lesions following CD-CX (22/29 vs. 22/45; p = 0.021). Second relapse rate was higher with 75 versus 44 %, resulting in a shorter median PFS with 8 versus 42 months (p < 0.001), but this did not translate into different OS (p = 0.931). At subsequent relapses, 26/36 patients received HD-CX as ≥2nd-salvage treatment. CONCLUSION: This analysis confirms the prognostic value of the IPFSG prognostic score. HD-CX seemed superior to CD-CX as first salvage treatment with respect to PFS in this retrospective analysis.

Phase-I study of sagopilone in combination with cisplatin in chemotherapy-naive patients with metastasised small-cell lung cancer.

BACKGROUND: Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients. METHODS: Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics. RESULTS: Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD. CONCLUSIONS: Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.

10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)-a multicenter phase-II trial (CISTAXOL).

BACKGROUND: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. PATIENTS AND METHODS: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50 mg/m(2) day 1+8) and paclitaxel (175 mg/m(2)d1) qd 22. Concurrent CTx/RTx followed: 45 Gy (1.5 Gy bid) with cisplatin 50 mg/m(2) day 2+9 and etoposide 100 mg/m(2) d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20 Gy; 2 Gy qd) followed. Here we report 10-year-LTS for this cohort. RESULTS: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. CONCLUSIONS: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).