Summary
The aim of this study was to retrospectively analyze the long‐term effectiveness of combined chemoradiation as the definitive treatment of locally advanced cancers of the cervical esophagus. ...Patients received high‐dose external beam radiotherapy and concurrent cisplatin‐based chemotherapy. Some patients received intraluminal brachytherapy as a boost. In addition, a majority of the patients received cisplatin‐based induction chemotherapy before definitive chemoradiation. Fifty‐five patients (46 men, 9 women, median age 58 years, range 35–72 years) with cancers of the cervical esophagus (stage II: 20; stage III: 35 patients) were treated with definitive chemoradiation (median dose 60 Gy, range 50–70 Gy). Actuarial overall survival rates at 2, 3, 5, and 10 years were 35%, 29%, 25%, and 10%, respectively. Thirteen long‐term survivors were observed with a follow‐up of more than 5 years. Neither gender nor age, tumor length, tumor grade, or clinically detectable lymph node metastases was significant prognostic factors for survival. Twenty‐four patients (44%) developed local or regional recurrences, 15 (27%) distant metastases, and 8 (15%) patients developed a second malignancy. Acute and late toxicity of this treatment schedule was moderate. Concurrent chemoradiation offers a chance of long‐term survival for locally advanced unresectable carcinomas of the cervical esophagus, with long‐term survival rates above 24% and acceptable toxicity. These results substantiate the use of chemoradiation as a curative treatment option for cervical esophageal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This trial was designed to prove superiority of irinotecan over etoposide combined with carboplatin in extensive-disease small-cell lung cancer.
Patients were randomly assigned to receive carboplatin ...area under the curve 5 mg ·min/ml either in combination with irinotecan 50 mg/m2 on days 1, 8, and 15 (IP) or etoposide 140 mg/m2 on days 1–3 (EP). Primary end point was progression-free survival (PFS) at 6 months. Secondary end points were overall survival (OS), response rate, and toxicity.
Of 226 patients, 216 were eligible. Median PFS was 6.0 months 95% confidence interval (CI) 5.0–7.0 in the IP arm and 6.0 months (95% CI 5.2–6.8) in EP arm (P = 0.07). Median survival was 10.0 months (95% CI 8.4–11.6) and 9.0 months (95% CI 7.6–10.4) in the IP and EP arm (P = 0.06), respectively. Hazard ratios for disease progression and OS were 1.29 (95% CI 0.96–1.73, P = 0.095) and 1.34 (95% CI 0.97–1.85, P = 0.072), respectively. No difference in response rates was observed. Grade 3 and 4 hematologic toxicity favored the IP arm, whereas diarrhea was significantly more frequent in the IP arm.
This trial failed to show superiority of irinotecan over etoposide in combination with carboplatin.
We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised ...AIO-PK0104 study.
AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash.
Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash.
The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.
Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell ...lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure.
Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m2 either with standard paclitaxel at 200 mg/m2 (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure time above a plasma concentration of 0.05 µM (Tc>0.05) determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS).
Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m2, P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS 5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91–1.49, P = 0.228 and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81–1.37, P = 0.682).
PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit–risk profile in patients with advanced NSCLC.
NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
Temsirolimus showed clinical efficacy in refractory squamous cell carcinoma of the head and neck (SCCHN), who failed platinum and epidermal growth factor receptor inhibition. Tumor shrinkage in 39% ...and a progression-free survival rate of 40% at 12 weeks warrants future studies in SCCHN, which may define a novel treatment paradigm in SCCHN. However, no predictive molecular marker was identified.
Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K–AKT–mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN.
The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence.
A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0–54.6). The median PFS and OS were 56 days (95% CI 36–113 days) and 152 days (76–256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF.
Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K–AKT–mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies.
NCT01172769.
The aim of the present study is to examine the impact of kV-CBCT-based online adaptive radiation therapy (ART) on dosimetric parameters in comparison to image-guided-radiotherapy (IGRT) in ...consecutive patients with tumors in the head and neck region from a prospective registry.
The study comprises all consecutive patients with tumors in the head and neck area who were treated with kV-CBCT-based online ART or IGRT-modus at the linear-accelerator ETHOS™. As a measure of effectiveness, the equivalent-uniform-dose was calculated for the CTV (EUD
) and organs-at-risk (EUD
) and normalized to the prescribed dose. As an important determinant for the need of ART the interfractional shifts of anatomic landmarks related to the tongue were analyzed and compared to the intrafractional shifts. The latter determine the performance of the adapted dose distribution on the verification CBCT2 postadaptation.
Altogether 59 consecutive patients with tumors in the head-and-neck-area were treated from 01.12.2021 to 31.01.2023. Ten of all 59 patients (10/59; 16.9%) received at least one phase within a treatment course with ART. Of 46 fractions in the adaptive mode, irradiation was conducted in 65.2% of fractions with the adaptive-plan, the scheduled-plan in the remaining. The dispersion of the distributions of EUD
-values from the 46 dose fractions differed significantly between the scheduled and adaptive plans (Ansari-Bradley-Test, p = 0.0158). Thus, the 2.5th percentile of the EUD
-values by the adaptive plans amounted 97.1% (95% CI 96.6-99.5%) and by the scheduled plans 78.1% (95% CI 61.8-88.7%). While the EUD
for the accumulated dose distributions stayed above 95% at PTV-margins of ≥ 3 mm for all 8 analyzed treatment phases the scheduled plans did for margins ≥ 5 mm. The intrafractional anatomic shifts of all 8 measured anatomic landmarks were smaller than the interfractional with overall median values of 8.5 mm and 5.5 mm (p < 0.0001 for five and p < 0.05 for all parameters, pairwise comparisons, signed-rank-test). The EUD
-values for the larynx and the parotid gland were significantly lower for the adaptive compared with the scheduled plans (Wilcoxon-test, p < 0.001).
The mobile tongue and tongue base showed considerable interfractional variations. While PTV-margins of 5 mm were sufficient for IGRT, ART showed the potential of decreasing PTV-margins and spare dose to the organs-at-risk.
In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and ...neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1.
Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes.
Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative 2.7 versus 1.6 months; HR 0.70 (95% CI 0.50–0.97),EGFR-amplified 2.8 versus 1.5 months; HR 0.53 (0.33–0.85), HER3-low 2.8 versus 1.8 months; HR 0.57 (0.37–0.88), and PTEN-high 1.6 versus 1.4 months; HR 0.55 (0.29–1.05) tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative andEGFR-amplified tumors 2.7 versus 1.5 months; HR 0.47 (0.28–0.80), and patients with p16-negative tumors who were EGFR therapy-naïve 4.0 versus 2.4 months; HR 0.55 (0.31–0.98). PFS was improved in afatinib-treated patients who were VeriStrat ‘Good’ versus ‘Poor’ 2.7 versus 1.5 months; HR 0.71 (0.49–0.94), but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35).
Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative,EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings.
NCT01345682.
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses &agr;v&bgr;5 integrin. Cilengitide selectively inhibits &agr;v&bgr;3 and &agr;v&bgr;5 integrins and ...is investigated as a treatment strategy.
The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity.
One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome.
Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.
Abstract Purpose Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown ...activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. Methods Patients received cetuximab 250 mg/m2 (loading dose: 400 mg/m2 ) days 1, 8 and 15; pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival PFS) and toxicity were evaluated. Results Sixty-six patients received ⩾1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval CI: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. Conclusions Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.
Purpose
The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical ...treatments and gave recommendations.
Methods
A systematic review of published evidence for medical treatment of mRCC was performed (July 2016–August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN (
http://www.sign.ac.uk/pdf/sign50.pdf
). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate.
Results
Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated.
Conclusion
ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.
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