Rodrigo Hepp

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.

Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma

Background: Pemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However, there are no established predictors of clinical benefit. Pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, but the main target is thymidylate synthase (TS). After cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-&ggr;-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expressions are associated with clinical outcome after pemetrexed-based chemotherapy. Methods: Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79 of 84) or single-agent pemetrexed (5 of 84) as first-line treatment, were retrospectively analyzed. FPGS and TS protein expressions were semiquantitatively assessed by using the Hybrid (H)-scoring system (range, 0–300). H-scores were correlated with radiological response according to modified Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS) and overall survival (OS). Results: Median H-score of the entire cohort was 230 for FPGS (range, 100–300), and 210 for TS (range, 100–300). High FPGS protein expression was significantly associated with longer PFS (pCOX = 0.0337), better objective tumor response (partial response versus stable disease + progressive disease; pKW = 0.003), and improved disease-control rate (partial response + stable disease versus progressive disease; pKW = 0.0208), but not with OS. In addition, high TS protein expression was associated with progressive disease under pemetrexed-based therapy (p = 0.0383), and shorter OS (pCOX = 0.0071), but no association with PFS was observed. Conclusion: FPGS and TS expressions were associated with clinical response and outcome to pemetrexed-based first-line chemotherapy in MPM. Prospective evaluation of FPGS and TS expressions and their prognostic/predictive power in MPM patients is warranted.

βV-tubulin expression is associated with outcome following taxane-based chemotherapy in non-small cell lung cancer

Background:Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both βIII- and βV-tubulins are expressed by cancer cells and may lead to resistance against TBAs.Methods:Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of βIII- and βV-tubulin was morphometrically quantified.Results:Median pre-treatment H-score for βIII-tubulin was 110 (range: 0–290), and 160 for βV-tubulin (range: 0–290). Low βIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high βV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high βV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy.Conclusion:Expression of βV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of βIII-tubulin. Prospective evaluation of βIII/βV-tubulin expression in NSCLC is warranted.

Salvage high-dose-rate brachytherapy for prostate cancer persistence after brachytherapy: repeated use of a polyethylene glycol hydrogel spacer

Purpose The aim of this study is to determine if a repeated hydrogel injection in a previously irradiated patient prior to salvage high-dose-rate brachytherapy (HDR-BT) is feasible. Material and methods A 61-year-old man with an organ confined (cT1c cN0 cM0, Gleason score 3 + 3 = 6, initial prostate-specific antigen [PSA] 7.9 ng/ml) prostate cancer was previously treated with HDR-BT (3 fractions of 11.5 Gy every 2nd week) after hydrogel injection to reduce the rectal dose. Ten months after, an isolated local persistence was seen on a PSMA PET-CT. Nadir PSA was 2.0 ng/ml, 3 months after treatment and was 3.95 ng/ml by the re-treatment. Salvage therapy consisted of HDR-BT (3 fractions of 9 Gy every 2nd week) with a simultaneous integrated boost to the residual region. Again, a hydrogel injection (10 ml) was applied to reduce the rectal dose prior to the treatment. Results Both hydrogel injection and salvage HDR-BT could be applied without any significant complications or toxicity. A good PSA response was observed with a nadir of 0.42 ng/ml, twelve months after salvage therapy. Acute toxicity (max grade II) resolved within 2 days after treatment. Conclusions The use of a hydrogel prior to salvage HDR-BT in a patient previously treated with HDR-BT is feasible and could help reduce the rectal exposure in the salvage setting.

Chemotherapy in stage III non-small cell lung cancer

It has recently become clear that stage III non-small cell lung cancer (NSCLC) can be treated with curative intent either by concurrent chemoradiation or combined modality approaches including surgery in wellselected patient populations [1–3]. Nevertheless, the relapse pattern of stage III NSCLC generally indicates that systemic relapse still accounts for about 40% of the first failures following initial curatively intended therapy [4]. Therefore, systemic drug treatment − similar to that in stage II and stage IV disease – will also have to remain an integrated part of the management for these patient groups [5,6]. Cisplatinbased chemotherapy combinations have proven to be systemically effective on micro-metastatic disease of stage III patients in the adjuvant setting following local treatment with surgery [7,8]. Currently, there is no clear evidence for carboplatin-based protocols or nonplatinum-containing regimens in contrast to cisplatinbased regimens in these stages [6,9–11]. Even in stage IV, cisplatin-based combinations with newer drugs lead to increased response rates and a clear trend for increased overall survival when directly compared to carboplatin-based combinations [12]. However, it should be noted that combination chemotherapy only exerts a systemic risk reduction-effect on relapses outside the brain and cannot adequately protect the central nervous system [4]. When given in combination with local treatment such as definitive chemoradiation or surgery in stage III NSCLC, two different approaches can potentially be pursued. One is to give a small number of chemotherapy cycles as induction prior to definitive local therapy [13,14], while alternatively the other method tries to give adjuvant chemotherapy as post-local treatment [2,15]. With the most effective cisplatin-based protocols, it has to be stated that no large randomised comparison between these two strategies within trials is currently available. However, single agent consolidation therapy with docetaxel following concurrent chemoradiation did not generate a survival benefit within a randomised trial of the Hoosier Oncology Group (HOG), although the multicentre phase-II pilot of the Southwest Oncology Group (SWOG) had generated encouraging longterm survival data [16]. The probable reason for the ultimate failure of the randomised trial was an increased treatment-related toxicity and toxic death rate in the single agent docetaxel consolidation arm during the pneumonitis phase of the post-radiation setting [17]. Currently, a randomised German trial is looking at consolidation cisplatin and oral vinorelbine versus observation following definitive concurrent chemoradiation [18]. However, it is probably unfair to expect definitive conclusions from this rather small randomised trial alone. In the adjuvant setting of early disease, a meta-analysis of more than 4000 patients was needed to prove a survival benefit of about 5% to 6% with adjuvant chemotherapy at 5 years [8]. When looking at the literature of currently published datasets, the largest and best selected patient group has been that from the chemoradiation arm of the Intergroup Trial 0139 [2]. Treatment was based on a concurrent chemoradiation of two cycles of cisplatin and etoposide together with 61 Gray (Gy) conventionally fractionated radiotherapy. Then, two cycles of consolidation chemotherapy with cisplatin and etoposide were added. A 5-year overall survival rate of 20.3% has been reached in stage IIIA(N2) patients with pathologically proven mediastinal N2status, representing probably the best survival data so far in a comparable patient population with chemoradiation within a randomised trial. Therefore, at the moment, the two-drug combinations with the largest evidence from randomised trials available in this concurrent chemoradiation setting are cisplatin and etoposide as well as cisplatin and vinorelbine [19]. There are also randomised trials including carboplatin and paclitaxel, but their results should be interpreted with caution as carboplatin lacks clinical data for being a significant radiation sensitiser in stage III (see Table 1) [9,10,20–22]. Furthermore, its systemic efficacy may be significantly inferior to platinumbased protocols on the micro-metastatic disease [12].