Practice changing publications
All areas of the UCCH are continuously active in clinical research and in conducting clinical trials. The researchers are involved in national and international consortia. The impact of these joint activities can be seen in the contribution of UCCH researchers as co-authors in groundbreaking studies and publications for the continuous development of cancer treatment.
In the following, we present selected publications of the most important practice-changing studies, i.e. studies in the field of oncology, which represent a significant improvement of the current standard of treatment. Listed here are publications from the years 2018 - 2020 with UCCH participation that have appeared in the leading journals (e. g. New England Journal of Medicine, Lancet Oncology or Journal of Clinical Oncology).
Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial
Shitara K,Van Cutsem E, Bang J-Y, Fuchs C, Wyrwicz L, Lee K-W, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J, JAMA Oncol. 2020 Sep 3., PubMed
The Keynote 062 trial is the first large randomized trial to evaluate the role of first line immunotherapy with pembrolizumab either alone or in addition to standard first line chemotherapy both compared to chemotherapy alone, pointing out the high relevance of CPS and MSI status.
Randomized comparison of pazopanib and doxorubicin as first line treatment in metastatic soft tissue sarcoma patients ≥60 years of age - results of an German intergroup study
Grünwald V, Karch A, Schuler M, Schöffski P, Kopp H-G, Bauer S, Kasper B, Lindner LH, Chemnitz J-M, Crysandt M, Stein A, Steffen B, Richter S, Egerer G, Ivanyi P, Zimmermann S, Liu X, Kunitz A, J Clin Oncol. 2020 Aug 24; JCO2000714., PubMed
This randomized German intergroup study showed comparable efficacy for single agent pazopanib or doxorubicin in elderly patients with previously untreated metastatic soft tissue sarcoma and thus established an additional treatment option in this patient group.
Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer
Cremolini C, Antoniotti C, Stein A, Bendell J, Gruenberger T, Rossini D, Masi G, Ongaro E, Hurwitz H, Falcone A, Schmoll H-J, Di Maio M, J Clin Oncol. 2020 Aug 20; JCO2001225., PubMed
This large meta analysis defines the role of FOLFOXIRI and bevacizumab in first line metastatic colorectal cancer and will lead to a revision of current guidelines still recommending this regimen in BRAF mutant tumors despite no impact on survival.
Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Jäger E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators., Lancet. 2019 May 11;393(10184):1948-1957., PubMed
This German multicenter DKH-funded trial showed that in locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT in comparison to perioperative ECF/ECX improved overall survival.
Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.
Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B; RELIVE Investigators., Lancet Gastroenterol Hepatol. 2019 Jun;4(6):454-465., PubMed
This is a negative trial showing that doxorubicin-loaded nanoparticles are not active in the treatment of sorafinib resistant hepatocellular carcinoma.
Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.
Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA; RAINFALL Study Group., Lancet Oncol. 2019 Mar;20(3):420-435., PubMed
This large trial showed no beneficial impact of the addition of ramucirumab to standard first line chemotherapy, despite the clear effect seen in second and third line esophagogastric adenocarcinoma.
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.
Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, Fornaro L, Olesiński T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS, Lancet. 2018 Jul 14;392(10142):123-133., PubMed
This phase 3 trial showed an overall similar efficacy but better tolerability of pembrolizumab compared to paclitaxel and established the clinical relevance of PD-L1 combined positivity score (CPS) in esophagogastric adenocarcinoma.
Sequential Versus Combination Therapy of Metastatic Colorectal Cancer Using Fluoropyrimidines, Irinotecan, and Bevacizumab: A Randomized, Controlled Study-XELAVIRI (AIO KRK0110).
Modest DP, Fischer von Weikersthal L, Decker T, Vehling-Kaiser U, Uhlig J, Schenk M, Freiberg-Richter J, Peuser B, Denzlinger C, Peveling Genannt Reddemann C, Graeven U, Schuch G, Schwaner I, Stahler A, Jung A, Kirchner T, Held S, Stintzing S, Giessen-Jung C, Heinemann V; XELAVIRI/AIO KRK0110 Investigators., J Clin Oncol. 2019 Jan 1;37(1):22-32., PubMed
This trial demonstrated the clinical relevance of an upfront combination compared to a sequential escalation strategy in mainly elderly patients with metastatic colorectal cancer based on RAS/BRAF status.
Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
Subbiah V, Lassen U, Élez E, Italiano A, Curigliano G, Javle M, de Braud F, Prager GW, Greil R, Stein A, Fasolo A, Schellens JHM, Wen PY, Viele K, Boran AD, Gasal E, Burgess P, Ilankumaran P, Wainberg ZA, Lancet Oncology 2020 August 17, 2020., PubMed
This phase 2 trial established BRAF/MEK inhibition as new standard of care in previously treated BRAF mutated biliary tract cancers.
Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer.
Burzykowski T, Coart E, Saad ED, Shi Q, Sommeijer DW, Bokemeyer C, Díaz-Rubio E, Douillard JY, Falcone A, Fuchs CS, Goldberg RM, Hecht JR, Hoff PM, Hurwitz H, Kabbinavar FF, Koopman M, Maughan TS, Punt CJA, Saltz L, Schmoll HJ, Seymour MT, Tebbutt NC, Tournigand C, Van Cutsem E, de Gramont A, Zalcberg JR, Buyse M; Aide et Recherche en Cancerologie Digestive Group., JAMA Netw Open. 2019 Sep 4;2(9):e1911750, PubMed
This study indicates that the deepness of response and continuous evaluation of the size of lesions may be good surrogate parameters for the individual prediction of overall survival in metastatic colorectal cancer patients.
Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project.
Sjoquist KM, Renfro LA, Simes RJ, Tebbutt NC, Clarke S, Seymour MT, Adams R, Maughan TS, Saltz L, Goldberg RM, Schmoll HJ, Van Cutsem E, Douillard JY, Hoff PM, Hecht JR, Tournigand C, Punt CJA, Koopman M, Hurwitz H, Heinemann V, Falcone A, Porschen R, Fuchs C, Diaz-Rubio E, Aranda E, Bokemeyer C, Souglakos I, Kabbinavar FF, Chibaudel B, Meyers JP, Sargent DJ, de Gramont A, Zalcberg JR; Fondation Aide et Recherche en Cancerologie Digestive Group (ARCAD)., J Natl Cancer Inst. 2018 Jun 1;110(6):638-648, PubMed
The study group has developed a nomogram to predict survival outcome of patients based on several patient and disease characteristics in metastatic colorectal cancer undergoing first line chemotherapy plus/minus targeted antibody-based therapy.
Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database.
Renfro LA, Goldberg RM, Grothey A, Sobrero A, Adams R, Seymour MT, Heinemann V, Schmoll HJ, Douillard JY, Hurwitz H, Fuchs CS, Diaz-Rubio E, Porschen R, Tournigand C, Chibaudel B, Hoff PM, Kabbinavar FF, Falcone A, Tebbutt NC, Punt CJA, Hecht JR, Souglakos J, Bokemeyer C, Van Cutsem E, Saltz L, de Gramont A, Sargent DJ; ARCAD Clinical Trials Program., J Clin Oncol. 2017 Jun 10;35(17):1929-1937., PubMed
Based on the results of this pooled data set upfront identification of patient at risk for early mortality was established.
Germ cell cancer
Outcome of Men With Relapses After Adjuvant Bleomycin, Etoposide, and Cisplatin for Clinical Stage I Nonseminoma.
Fischer S, Tandstad T, Cohn-Cedermark G, Thibault C, Vincenzi B, Klingbiel D, Albany C, Necchi A, Terbuch A, Lorch A, Aparicio J, Heidenreich A, Hentrich M, Wheater M, Langberg CW, Ståhl O, Fankhauser CD, Hamid AA, Koutsoukos K, Shamash J, White J, Bokemeyer C, Beyer J, Gillessen S; Global Germ-Cell Cancer Group., J Clin Oncol. 2020 Apr 20;38(12):1322-1331., PubMed
This investigation shows that even after adjuvant chemotherapy the few patients who relapse have an excellent outcome.
Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study.
Dieckmann KP, Radtke A, Geczi L, Matthies C, Anheuser P, Eckardt U, Sommer J, Zengerling F, Trenti E, Pichler R, Belz H, Zastrow S, Winter A, Melchior S, Hammel J, Kranz J, Bolten M, Krege S, Haben B, Loidl W, Ruf CG, Heinzelbecker J, Heidenreich A, Cremers JF, Oing C, Hermanns T, Fankhauser CD, Gillessen S, Reichegger H, Cathomas R, Pichler M, Hentrich M, Eredics K, Lorch A, Wülfing C, Peine S, Wosniok W, Bokemeyer C, Belge G., J Clin Oncol. 2019 Jun 1;37(16):1412-1423., PubMed
This milestone paper establishes a novel Marker, the micro RNA 371 as a potential novel serum marker for disease stage and response to therapy in both seminomatous and non-semino´matous germ cell tumors.
Questioning the Value of Fluorodeoxyglucose Positron Emission Tomography for Residual Lesions After Chemotherapy for Metastatic Seminoma: Results of an International Global Germ Cell Cancer Group Registry.
Cathomas R, Klingbiel D, Bernard B, Lorch A, Garcia Del Muro X, Morelli F, De Giorgi U, Fedyanin M, Oing C, Haugnes HS, Hentrich M, Fankhauser C, Gillessen S, Beyer J., J Clin Oncol. 2018 Oct 4:JCO1800210., PubMed
This re-evalution shows that the role of FDG-PET to study residual vital disease in seminoma pts after chemotherapy is less secure as initially thought.
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.
Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Müller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP., N Engl J Med. 2020 Feb 13;382(7):597-609., PubMed
This trial showed, that addition of the highly selective HER2 inhibitor tucatinib to standard treatment with capacetabine and trastuzumab resulted in heavily pretreated HER2-positive metastatic breast cancer patients in better progression-free survival and overall survival than adding placebo with a median 1 year PFS of 33.1% in the tucatinib-combination group compared to 12.3% in the placebo-combination group.
A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.
Harter P, Sehouli J, Lorusso D, Reuss A, Vergote I, Marth C, Kim JW, Raspagliesi F, Lampe B, Aletti G, Meier W, Cibula D, Mustea A, Mahner S, Runnebaum IB, Schmalfeldt B, Burges A, Kimmig R, Scambia G, Greggi S, Hilpert F, Hasenburg A, Hillemanns P, Giorda G, von Leffern I, Schade-Brittinger C, Wagner U, du Bois A., N Engl J Med. 2019 Feb 28;380(9):822-832., PubMed
In this trial, a randomized comparison of systematic pelvic and paraaortic lymphadenectomy versus no lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery showed, that additional lymphadenectomy was not associated with longer overall or progression-free survival than no lymphadenectomy but was associated with a higher incidence of postoperative complications.
Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.
von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wülfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators., N Engl J Med. 2019 Feb 14;380(7):617-628., PubMed
Her-2 positive breast cvancer patients received in this trial in case of residual invasive disease after completion of neoadjuvant therapy in a randomized comparison either trastuzumab or trastuzumab emtansine. It was shown, that treatment with trastuzumab emtansine led to a 50% reduction in progression compared to trastuzumab.
Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.
Pfisterer J, Shannon CM, Baumann K, Rau J, Harter P, Joly F, Sehouli J, Canzler U, Schmalfeldt B, Dean AP, Hein A, Zeimet AG, Hanker LC, Petit T, Marmé F, El-Balat A, Glasspool R, de Gregorio N, Mahner S, Meniawy TM, Park-Simon TW, Mouret-Reynier MA, Costan C, Meier W, Reinthaller A, Goh JC, L'Haridon T, Baron Hay S, Kommoss S, du Bois A, Kurtz JE; AGO-OVAR 2.21/ENGOT-ov 18 Investigators., Lancet Oncol. 2020 May;21(5):699-709., PubMed
In this randomized phase III trial, the combination of carboplation with pegylated liposomal doxorubicin and bevacizumab was established as a new standard of care in the treatment of recurrent platinum sensitive ovarian cancer.
Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
Chekerov R, Hilpert F, Mahner S, El-Balat A, Harter P, De Gregorio N, Fridrich C, Markmann S, Potenberg J, Lorenz R, Oskay-Oezcelik G, Schmidt M, Krabisch P, Lueck HJ, Richter R, Braicu EI, du Bois A, Sehouli J; NOGGO; AGO TRIAS Investigators., Lancet Oncol. 2018 Sep;19(9):1247-1258., PubMed
In this randomized trial, the role of antiangiogenesis in the treatment of platinum-resistant ovarian cancer was investigated. Sorafenib, in combination with topotecan and continued as maintenance therapy, showed a statistically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer.
Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial.
Friedlander M, Gebski V, Gibbs E, Davies L, Bloomfield R, Hilpert F, Wenzel LB, Eek D, Rodrigues M, Clamp A, Penson RT, Provencher D, Korach J, Huzarski T, Vidal L, Salutari V, Scott C, Nicoletto MO, Tamura K, Espinoza D, Joly F, Pujade-Lauraine E., Lancet Oncol. 2018 Aug;19(8):1126-1134., PubMed
In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy.The here conducted prospective analyyses showed that olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo despite the known side effects of olaparib.
Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial.
Oza AM, Matulonis UA, Malander S, Hudgens S, Sehouli J, Del Campo JM, Berton-Rigaud D, Banerjee S, Scambia G, Berek JS, Lund B, Tinker AV, Hilpert F, Vázquez IP, D'Hondt V, Benigno B, Provencher D, Buscema J, Agarwal S, Mirza MR., Lancet Oncol. 2018 Aug;19(8):1117-1125., PubMed
The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial in patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy and investigated either niraparib as a maintenance treatment or placebo. In this analyis, PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.
Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial.
Lin NU, Borges V, Anders C, Murthy RK, Paplomata E, Hamilton E, Hurvitz S, Loi S, Okines A, Abramson V, Bedard PL, Oliveira M, Mueller V, Zelnak A, DiGiovanna MP, Bachelot T, Chien AJ, O'Regan R, Wardley A, Conlin A, Cameron D, Carey L, Curigliano G, Gelmon K, Loibl S, Mayor J, McGoldrick S, An X, Winer EP., J Clin Oncol. 2020 May 29:JCO2000775., PubMed
In this randomized, controlled trial in patients with HER2-positive breast cancer with brain metastases, the addition of tucatinib to trastuzumab and capecitabine significantly improved response, reduced risk of intracranial progression and reduced risk of death. This is the first regimen to demonstrate improved antitumor activity against brain metastases in patients with HER2-positive breast cancer.
Prospective, Multicenter, Randomized Phase III Trial Evaluating the Impact of Lymphoscintigraphy as Part of Sentinel Node Biopsy in Early Breast Cancer: SenSzi (GBG80) Trial.
Kuemmel S, Holtschmidt J, Gerber B, Von der Assen A, Heil J, Thill M, Krug D, Schem C, Denkert C, Lubitz J, Blohmer JU, Reinisch M, Hötzeldt M, Seither F, Nekljudova V, Schwidde I, Uhrhan K, Von Minckwitz G, Rezai M, Mulowski J, Loibl S, Kuehn T., J Clin Oncol. 2019 Jun 10;37(17):1490-1498., PubMed
In this German prospective, multicenter, randomized phase III trial, patients with cN0 early breast cancer or extensive/high-grade ductal carcinoma in situ planned for standard radioactive-labeled colloid Lymphoscintigraphy (LSG) with subsequent Sentinel Node Biopsy (SLNB) were randomly assigned biopsy either with knowledge of the LSG findings or without. It was shown, that SLNB is equally effective irrespective of the surgeon's knowledge of preoperative LSG results.
BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study.
Fasching PA, Loibl S, Hu C, Hart SN, Shimelis H, Moore R, Schem C, Tesch H, Untch M, Hilfrich J, Rezai M, Gerber B, Costa SD, Blohmer JU, Fehm T, Huober J, Liedtke C, Weinshilboum RM, Wang L, Ingle JN, Müller V, Nekljudova V, Weber KE, Rack B, Rübner M, von Minckwitz G, Couch FJ., J Clin Oncol. 2018 Aug 1;36(22):2281-2287., PubMed
The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with triple-negative breast cancer with BRCA1/2 mutations.
Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44).
Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG and the AGO-B Study Group., J Clin Oncol. 2018 May 1;36(13):1308-1316., PubMed
In this analysis, it was shown, that in patients with hormone receptor-positive tumors, prolonged anti-HER2 treatment-neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months-significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.
Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.
Bidard FC, Michiels S, Riethdorf S, Mueller V, Esserman LJ, Lucci A, Naume B, Horiguchi J, Gisbert-Criado R, Sleijfer S, Toi M, Garcia-Saenz JA, Hartkopf A, Generali D, Rothe F, Smerage J, Muinelo-Romay L, Stebbing J, Viens P, Magbanua MJM, Hall CS, Engebraaten O, Takata D, Vidal-Martinez J, Onstenk W, Fujisawa N, Diaz-Rubio E, Taran FA, Cappelletti MR, Ignatiadis M, Proudhon C, Wolf DM, Bauldry JB, Borgen E, Nagaoka R, Caranana V, Kraan J, Maestro M, Brucker SY, Weber K, Reyal F, Amara D, Karhade MG, Mathiesen RR, Tokiniwa H, Llombart-Cussac A, Meddis A, Blanche P, d'Hollander K, Cottu P, Park JW, Loibl S, Latouche A, Pierga JY, Pantel K., J Natl Cancer Inst 2018;110: 560-7., PubMed
In this multi-national metaanalysis on thousands of breast cancer patients receiving neoadjuvant therapy from 21 studies showed that the CTC count was an independent, strong prognostic factor for disease-free and overall survival. As highlighted in the accompanying Editorial, the results of this study will refine the paradigm of prognosis and treatment individualization. CTCs have been included into the AJCC Cancer Staging Manual 2018 for breast cancer as new staging category (cM0(i+), which allows now a better risk stratification.
Leukemia, stem cell transplantation, lymphoma and myeloma
Clinical Features Associated with COVID-19 Outcome in MM: First Results from International Myeloma Society Dataset
Chari A, Samur MK, Martinez-Lopez J, Cook G, Biran N, Yong KL, Tietsche de Moraes Hungria V, Engelhardt M, Gay F, Garcia-Feria A, Oliva S, Oostvogels R, Gozzetti A, Rosenbaum CA, Kumar SK, Stadtmauer E, Einsele H, Beksac M, Weisel KC, Anderson KC, Mateos M-V, Moreau P, San Miguel J, Munshi NC, Avet-Loiseau H, Blood 2020 Nov 6; blood.2020008150., PubMed
Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.
Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S., N Engl J Med. 2019 Aug 22;381(8):727-738., PubMed
In this pivotal trial for highly refractory multiple myeloma, treatment with Selinexor and dexamethasone was established as a new standard of care.
Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.
Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators., N Engl J Med. 2019 May 30;380(22):2104-2115., PubMed
This large phase III trial established with the combination treatment of the monoclonal Antibody Daratumumab to the standard of care regimen of lenalidomide and dexamethasone an new standard of care for first-line treatment of non-transplant eligible patients with multiple myeloma after showing significant benefit in response and PFS compared to lenalidomide and dexamethasone.
Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study.
Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ., Lancet. 2020 Jul 18;396(10245):186-197., PubMed
In this large phase III trial, the addition of the monolonal antibody daratumumab to carfilzomib and dexamethasone lead to a significant benefit in response and PFS compared to carfilzomib and dexamethasone in 1.-3. Relapse of multiple myeloma and so set a new standard of care in this indication.
Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.
Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance., Lancet. 2019 Dec 21;394(10216):2271-2281., PubMed
The FLYER trial established in a non-inferiority setting the treatment of 4 cycles R-CHOP in patients with stage I-II disease and favorable prognosis with a comparable outcome to the 6 cycle treatment with significant reduction of overall toxicity.
Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study.
Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, Suvannasankha A, Weisel K, Karlin L, Libby E, Arnulf B, Facon T, Hulin C, Kortüm KM, Rodríguez-Otero P, Usmani SZ, Hari P, Baz R, Quach H, Moreau P, Voorhees PM, Gupta I, Hoos A, Zhi E, Baron J, Piontek T, Lewis E, Jewell RC, Dettman EJ, Popat R, Esposti SD, Opalinska J, Richardson P, Cohen AD., Lancet Oncol. 2020 Feb;21(2):207-221., PubMed
Belantamab mafodotin is the first anti-BCMA immunoconjugate showing marked efficacy in refractory multiple myeloma. Results of this phase II pivotal trial will lead to approval in this indication.
Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial.
Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, Lindsay J, Weisel K, White D, Facon T, San Miguel J, Sunami K, O'Gorman P, Sonneveld P, Robak P, Semochkin S, Schey S, Yu X, Doerr T, Bensmaine A, Biyukov T, Peluso T, Zaki M, Anderson K, Dimopoulos M; OPTIMISMM trial investigators., Lancet Oncol. 2019 Jun;20(6):781-794., PubMed
After showing a significant benefit in response and PFS compared to bortezomib and dexamethasone, the triple combination treatment of pomalidomide, bortezomib and dexamethasone was established as a new standard of care for patients with 1.-3. Relapse of multiple myeloma after treatment with lenalidomide.
PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group.
Borchmann P, Goergen H, Kobe C, Lohri A, Greil R, Eichenauer DA, Zijlstra JM, Markova J, Meissner J, Feuring-Buske M, Hüttmann A, Dierlamm J, Soekler M, Beck HJ, Willenbacher W, Ludwig WD, Pabst T, Topp MS, Hitz F, Bentz M, Keller UB, Kühnhardt D, Ostermann H, Schmitz N, Hertenstein B, Aulitzky W, Maschmeyer G, Vieler T, Eich H, Baues C, Stein H, Fuchs M, Kuhnert G, Diehl V, Dietlein M, Engert A., Lancet. 2018 Dec 23;390(10114):2790-2802., PubMed
This German multicenter trial established the PET-guided treatment in advanced stage Hodgkin’s disease allowing treatment shortening in PET negative patients when evaluated after two treatment cycles.
Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN).
Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, Wollmer E, Wäsch R, Bornhäuser M, Berg T, Lang F, Ehninger G, Serve H, Zeiser R, Wagner EM, Kröger N, Wolschke C, Schleuning M, Götze KS, Schmid C, Crysandt M, Eßeling E, Wolf D, Wang Y, Böhm A, Thiede C, Haferlach T, Michel C, Bethge W, Wündisch T, Brandts C, Harnisch S, Wittenberg M, Hoeffkes HG, Rospleszcz S, Burchardt A, Neubauer A, Brugger M, Strauch K, Schade-Brittinger C, Metzelder SK., J Clin Oncol. 2020 Jul 16:JCO1903345., PubMed
In this randomized, phase II trial patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive sorafenib or placebo maintenance treatment. It was shown, that sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.
Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome.
Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, Pollyea DA, DesJardins P, Ottmann O, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Heuser M., Leukemia. 2019 Feb;33(2):379-389., PubMed
This is the only randomized study of glasdegib in AML. Since a clear survival advantage for the combination low dose Ara-C (LDAC) plus glasdegib vs. LDAC plus placebo was demonstrated, glasdegib was approved by the FDA.
Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study.
Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, Leis C, Fiedler W, Kindler T, Schroeder T, Mayer K, Lübbert M, Wattad M, Götze K, Horst HA, Koller E, Wulf G, Schleicher J, Bentz M, Greil R, Hertenstein B, Krauter J, Martens U, Nachbaur D, Abu Samra M, Girschikofsky M, Basara N, Benner A, Thol F, Heuser M, Ganser A, Döhner K, Döhner H., J Clin Oncol. 2020 Feb 20;38(6):623-632., PubMed
This randomized phase III study showed a clear increase in CR rate and EFS by addition of Gemtuzumab Ozogamicin to standard chemotherapy in a molecularly defined subgroup of AML patients.
Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.
Wei AH, Strickland SA Jr, Hou JZ, Fiedler W, Lin TL, Walter RB, Enjeti A, Tiong IS, Savona M, Lee S, Chyla B, Popovic R, Salem AH, Agarwal S, Xu T, Fakouhi KM, Humerickhouse R, Hong WJ, Hayslip J, Roboz GJ., J Clin Oncol. 2019 May 20;37(15):1277-1284., PubMed
Although venetoclax had been approved by the FDA in combination with low dose Ara-C due to our preceding phase I/II study, this randomized phase III definitely proved the advantage of addition of venetoclax to low doses ARA-C in elderly AML patients.
Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation.
Frick M, Chan W, Arends CM, Hablesreiter R, Halik A, Heuser M, Michonneau D, Blau O, Hoyer K, Christen F, Galan-Sousa J, Noerenberg D, Wais V, Stadler M, Yoshida K, Schetelig J, Schuler E, Thol F, Clappier E, Christopeit M,Ayuk F, Bornhäuser M, Blau IW, Ogawa S, Zemojtel T, Gerbitz A, Wagner EM, Spriewald BM, Schrezenmeier H, Kuchenbauer F, Kobbe G, Wiesneth M, Koldehoff M, Socié G, Kroeger N, Bullinger L, Thiede C, Damm F., J Clin Oncol. 2019 Feb 10;37(5):375-385., PubMed
In patients with AML who underwent allogeneic stem cell transplantation, clonal donor hematopoiesis of unknown significance significantly influences relapse and GvHD risk.
Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell LungCancer.
Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA., J Clin Oncol. 2020 Aug 1;38(22):2530-2542., PubMed
Updated analysis of the efficacy data, extended and updated safety analysis on induction and maintenance treatment as well as Quality of Life analysis of the IMpower 150 trial. No relevant worsening of Symptom and Quality of Life parameter during treatment were reported and in particular no impact by the addition of bevacizumab to the combination of atezolizumab and chemotherapy. No new safety signals were reported.
Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell LungCancer.
Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC., J Clin Oncol. 2020 May 10;38(14):1505-1517., PubMed
Efficacy of the combination Carboplatin/Pemetrexed/Pembrolizumab was confirmed in this updated analysis. No new safety signals were reported with longer follow up.
Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lungcancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.
Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D.,Lancet Oncol. 2020 Mar;21(3):387-397., PubMed
No Impact on Quality of Life and Symptom scores by the addition of pembrolizumab to carboplatin/pembrolizumab was observed, in some Quality of Life and Symptom categories patient reported better outcomes for this combination.
Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lungcancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators., Lancet Oncol. 2019 Dec;20(12):1655-1669., PubMed
Combination of ramucirumab and erlotinib compared to erlotinib and placebo demonstrated a significant improvement of PFS and an improvement of DOR with comparable response rates. No new safety signals were observed.
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell LungCancer.
Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS., N Engl J Med. 2019 Nov 21;381(21):2020-2031., PubMed
In this second analysis a significant prolongation of survival was observed for the combination of nivolumab and ipilimumab compared to platinum based chemotherapy in untreated patients with advanced non oncogenic addicted PDL expressing NSCLC. Consistent efficacy was observed in PD-L 1 negative patients. Efficacy was independent from TMB.
First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell LungCancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.
Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, Brahmer J, Rabinowitz I, Reddy PS, Chesney J, Orcutt J, Spigel DR, Reck M, O'Byrne KJ, Paz-Ares L, Hu W, Zerba K, Li X, Lestini B, Geese WJ, Szustakowski JD, Green G, Chang H, Ramalingam SS., J Clin Oncol. 2019 Apr 20;37(12):992-1000., PubMed
Feasibility and tolerability of nivolumab and low dose ipilimumab in NSCLC was confirmed. TMB threshold of =/> 10 mut/MB was determined as threshold for efficacy assessed by response and PFS.
Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell LungCancer With PD-L1 Tumor Proportion Score of 50% or Greater.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR., J Clin Oncol. 2019 Mar 1;37(7):537-546., PubMed
Consistent survival benefit for pembrolizumab monotherapy compared to platinum based chemotherapy in untreated patients with oncogenic wild type high PD-L1 expressing (=/> 50% TPS score) was confirmed with longer follow-up. No relevant safety signals were observed.
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M; PACIFIC Investigators., N Engl J Med. 2018 Dec 13;379(24):2342-2350., PubMed
Besides PFS also the second coprimary endpoint survival was significantly prolonged by a consolidation treatment with durvalumab in patients with locally advanced NSCLC after simultaneous chemoradiotherapy.
First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell LungCancer.
Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group.,N Engl J Med. 2018 Dec 6;379(23):2220-2229., PubMed
Combination of atezolizumab with carboplatin and etoposide led to a significant improvement of PFS and survival in untreated patients with metastatic SCLC compared to chemotherapy alone.
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group., N Engl J Med. 2018 Jun 14;378(24):2288-2301., PubMed
Combination of atezolizumab, bevacizumab, carboplatin and paclitaxel led to a significant improvement of PFS and OS in untreated population of patients with advanced non squamous NSCLC. Safety results were as expected and enhanced efficacy was seen in patients with liver metastases.
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell LungCancer.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators., N Engl J Med. 2018 May 31;378(22):2078-2092., PubMed
Combination of pembrolizumab with carboplatin and pemetrexed led to a significant improvement of PFS and OS in untreated oncogenic wild type patients with advanced non squamous NSCLC. Efficacy was seen across all PD-L1 expression levels and safety signals were as expected.
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden.
Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L., N Engl J Med. 2018 May 31;378(22):2093-2104., PubMed
Combination of nivolumab and ipilimumab led to a significant improvement of PFS in patients with untreated TMB high NSCLC independent from PD-L1 expression compared to platinum based chemotherapy. In addition DOR was in favor of this combination and no new safety signals were observed.
Molecular Testing Guideline for the Selection of Patients With LungCancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of LungCancer/Association for Molecular Pathology Clinical Practice Guideline Update.
Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington J, Leighl NB, Lew M, Pantelas J, Ramalingam SS, Reck M, Saqi A, Simoff M, Singh N, Sundaram B., J Clin Oncol. 2018 Mar 20;36(9):911-919., PubMed
Update of the joint molecular testing guidelines of ASCO, CAP, ASCO and the Association for Molecular Pathology for patients with NSCLC implementing new and larger testing panels including testing for ROS-1, RET, ERB2, KRAS and MET.
Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations.
Menzer C, Menzies AM, Carlino MS, Reijers I, Groen EJ, Eigentler T, de Groot JWB, van der Veldt AAM, Johnson DB, Meiss F, Schlaak M, Schilling B, Westgeest HM, Gutzmer R, Pföhler C, Meier F, Zimmer L, Suijkerbuijk KPM, Haalck T, Thoms KM, Herbschleb K, Leichsenring J, Menzer A, Kopp-Schneider A, Long GV, Kefford R, Enk A, Blank CU, Hassel JC., J Clin Oncol. 2019 Nov 20;37(33):3142-3151., PubMed
This paper describes respoonse and efficacy of targeted therapy in unusual non-V600 BRAF mutations in melanoma.
PubMed Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group.
Hoeben BA, Carrie C, Timmermann B, Mandeville HC, Gandola L, Dieckmann K, Ramos Albiac M, Magelssen H, Lassen-Ramshad Y, Ondrová B, Ajithkumar T, Alapetite C, Balgobind BV, Bolle S, Cameron AL, Davila Fajardo R, Dietzsch S, Dumont Lecomte D, van den Heuvel-Eibrink MM, Kortmann RD, Laprie A, Melchior P, Padovani L, Rombi B, Scarzello G, Schwarz R, Seiersen K, Seravalli E, Thorp N, Whitfield GA, Boterberg T, Janssens GO., Lancet Oncol. 2019 Mar;20(3):e155-e166., PubMed
This is a consensus recommendation of paediatric radiation oncologists from leading centres in 11 European countries based on available information on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimize the risk of long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia.
Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial.
Goschzik T, Schwalbe EC, Hicks D, Smith A, Zur Muehlen A, Figarella-Branger D, Doz F, Rutkowski S, Lannering B, Pietsch T, Clifford SC., Lancet Oncol. 2018 Dec;19(12):1602-1616., PubMed
In order to achieve a more risk-adapted and personalized therapeutic approach in the treatment of medulloblastoma, out of the HIT-SIOP PNET 4 trial a whole chromosomal signature was developed that allows the assignment of non-WNT/non-SHH medulloblastoma patients normally classified as standard-risk into favourable-risk and high-risk categories. A subgroup of children was defined according to the chromosomal and molecular signature who should be considered for therapy de-escalation in future biomarker-driven, risk-adapted clinical trials.
Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group.
Rutkowski S, Modena P, Williamson D, Kerl K, Nysom K, Pizer B, Bartels U, Puget S, Doz F, Michalski A, von Hoff K, Chevignard M, Avula S, Murray MJ, Schönberger S, Czech T, Schouten-van Meeteren AYN, Kordes U, Kramm CM, van Vuurden DG, Hulleman E, Janssens GO, Solanki GA, van Veelen MC, Thomale U, Schuhmann MU, Jones C, Giangaspero F, Figarella-Branger D, Pietsch T, Clifford SC, Pfister SM, Van Gool SW., Lancet Oncol. 2018 Aug;19(8):e419-e428., PubMed
During the last decade new methods of molecular tumor tissue analysis have been developed in order to improve the identification of high-risk and low-risk diseases and subsequent treatment-stratification. Therefore, retrospective analysis of tumor material according to new methods is a key determinant in this improvement process. However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours. Thus, the authors recommend to implement practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Furthermore, procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grund KB, Brugières L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra YS, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng HK, Perry A, MacDonald TJ, Hernáiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schüz J, Johansen C, Andersen TV, Röösli M, Kuehni CE, Grotzer M, Kjaerheim K, Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO, Pfister SM., Lancet Oncol. 2018 Jun;19(6):785-798., PubMed
Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not yet been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. The authors aimed to assess and define these genes to provide evidence for future screening guidelines. The analysis of 1022 cases from retrospective and prospective studies let to the conclusion, that genetic counselling and testing should be used as a standard-of-care procedure in patients with MB-WNT and MB-SHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. Criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics are proposed by the authors.
Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial.
Knörr F, Brugières L, Pillon M, Zimmermann M, Ruf S, Attarbaschi A, Mellgren K, Burke GAA, Uyttebroeck A, Wróbel G, Beishuizen A, Aladjidi N, Reiter A, Woessmann W; European Inter-Group for Childhood Non-Hodgkin Lymphoma., J Clin Oncol. 2020 Jul 30:JCO2000157., PubMed
To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial stratified patients according to the time of relapse and CD3 expression to prospectively test re-induction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy. The results of this study showed, that allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. Nevertheless, for early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy also achieved cure in patients with late relapse; however, it was again not effective for early relapses.
Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics.
Eckert C, Groeneveld-Krentz S, Kirschner-Schwabe R, Hagedorn N, Chen-Santel C, Bader P, Borkhardt A, Cario G, Escherich G, Panzer-Grümayer R, Astrahantseff K, Eggert A, Sramkova L, Attarbaschi A, Bourquin JP, Peters C, Henze G, von Stackelberg A; ALL-REZ BFM Trial Group., J Clin Oncol. 2019 Dec 20;37(36):3493-3506., PubMed
Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The authors presumed that more detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice. Therefore, MRD was assessed after induction treatment and at different times during relapse treatment until allo-HSCT in 413 patients. The MRD-response was then used for further treatment stratification. Results showed, that after induction treatment, MRD-based treatment stratification resulted in excellent survival in patients with late relapsed BCP-ALL and prognosis could be further improved in very poor responders by intensifying treatment directly after induction. Furthermore, TP53 alterations was identified as a novel genetic high-risk marker in all MRD response groups in late relapsed BCP-ALL. Furthermore the authors proposed to consider early and late non-responders as events in future trials.
Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.
Begemann M, Waszak SM, Robinson GW, Jäger N, Sharma T, Knopp C, Kraft F, Moser O, Mynarek M, Guerrini-Rousseau L, Brugieres L, Varlet P, Pietsch T, Bowers DC, Chintagumpala M, Sahm F, Korbel JO, Rutkowski S, Eggermann T, Gajjar A, Northcott P, Elbracht M, Pfister SM, Kontny U, Kurth I., J Clin Oncol. 2020 Jan 1;38(1):43-50., PubMed
The authors describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MB-SHH in infants.
Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study.
Pieters R, De Lorenzo P, Ancliffe P, Aversa LA, Brethon B, Biondi A, Campbell M, Escherich G, Ferster A, Gardner RA, Kotecha RS, Lausen B, Li CK, Locatelli F, Attarbaschi A, Peters C, Rubnitz JE, Silverman LB, Stary J, Szczepanski T, Vora A, Schrappe M, Valsecchi MG., J Clin Oncol. 2019 Sep 1;37(25):2246-2256., PubMed
Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. In this study, early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.
High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008.
Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-E.W.I.N.G.99 and EWING-2008 Investigators., J Clin Oncol. 2018 Sep 6;36(31):JCO2018782516., PubMed
For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. It was shown by this study that, BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.
MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.
Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, Briganti A, Budäus L, Hellawell G, Hindley RG, Roobol MJ, Eggener S, Ghei M, Villers A, Bladou F, Villeirs GM, Virdi J, Boxler S, Robert G, Singh PB, Venderink W, Hadaschik BA, Ruffion A, Hu JC, Margolis D, Crouzet S, Klotz L, Taneja SS, Pinto P, Gill I, Allen C, Giganti F, Freeman A, Morris S, Punwani S, Williams NR, Brew-Graves C, Deeks J, Takwoingi Y, Emberton M, Moore CM; PRECISION Study Group Collaborators. N Engl J Med. 2018 May 10;378(19):1767-1777. doi: 10.1056/NEJMoa1801993. Epub 2018 Mar 18, PubMed
This randomized controlled trial established MRI guided biopsy in the diagnostic of prostate cancer. In comparison to ultrasound-guided biopsy, the use of risk assessment with MRI before biopsy and MRI-targeted biopsy showed significant superiority in men at clinical risk for prostate cancer who had not undergone biopsy previously.
Persistent Prostate-Specific Antigen After Radical Prostatectomy and Its Impact on Oncologic Outcomes.
Preisser F, Chun FKH, Pompe RS, Heinze A, Salomon G, Graefen M, Huland H, Tilki D., Eur Urol. 2019 Jul;76(1):106-114. doi: 10.1016/j.eururo.2019.01.048. Epub 2019 Feb 14. PMID: 3077203, PubMed
A persistently increased PSA value after surgery is associated with a higher risk of biochemical relapse (BCR), metastatic disease and overall mortality. Recently published data from Martini Clinic confirmed these findings of earlier clinical trials: Thus, in this single center trial, 8.8% (n=1025) of 11 604 patients were identified with persistent PSA value after radical prostatectomy. Metastasis-free survival rates, OS and CSS rates were 53.0 vs. 93.2% (p < 0.001), 64.7 vs. 81.2% (p < 0.001) and 75.5 vs. 96.2% (p < 0.001) for persistent vs. undetectable PSA 15 years after surgery. Salvage radiotherapy was associated with improved OS (HR: 0.37, p=0.02) and CSS (HR: 0.12, p<0.01). Based on these results salvage radiotherapy is now recommended for patients with persistent PSA with no evidence of metastatic disease in EAU guidelines (EAU guidelines 18.104.22.168. Recommendations for the management of persistent PSA after radical prostatectomy).
External Validation of the European Association of Urology Biochemical Recurrence Risk Groups to Predict Metastasis and Mortality After Radical Prostatectomy in a European Cohort.
Tilki D, Preisser F, Graefen M, Huland H, Pompe RS., Eur Urol. 2019 Jun;75(6):896-900. doi: 10.1016/j.eururo.2019.03.016. Epub 2019 Apr 5., PubMed
In this retrospective analysis of 1125 patients, the European Association of Urology biochemical risk (BCR) stratification was verified. In fact, 5yr. metastatic progression free survival and prostate cancer specific mortality free survival rates were significantly higher in patients with low BCR risk compared to their high-risk counterparts. Consequently, the EAU guidelines now recommend that patients with PSA recurrence assigned to the low risk BSC category can be monitored without immediate intervention (EAU guidelines 6.3.3 Natural History of PSA recurrence and 6.3.9 Guidelines for second-line therapy after treatment with curative intend)
Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial
Azzouzi A-R, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FMJ, Fromont G, Gratzke C, Emberton M, PCM301 Study Group, Lancet Oncol. 2017 Feb;18(2):181-191. doi: 10.1016/S1470-2045(16)30661-1., PubMed
Padeliporfin vascular-targeted photodynamic therapy as a tissue-preserving approach is a safe and effective treatment for low-risk, localised prostate cancer and may defer or avoid radical therapy.