Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Fizazi K, Pagliaro L, Laplanche A, et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncol 2014; published online Nov 3. http://dx.doi.org/10.1016/s1470-2045(14)70490-5
Web extra material List of contributing centers Center Principal Investigator Number of patients Institut Gustave Roussy Prof Karim FIZAZI 48 MD Anderson, Houston Dr Lance PAGLIARO 28 Centre Léon Bérard Dr Aude FLECHON 26 NCI Brastilava Prof Jozef MARDIAK 25 Centre Alexis Vautrin Dr Lionnel GEOFFROIS 21 Centre Eugène Marquis Prof Pierre KERBRAT 19 Institut Claudius Régaud Dr Christine CHEVREAU 16 Centre Paul Papin Dr Rémy DELVA 11 Centre René Gauducheau Dr Frédéric ROLLAND 11 Hôpital Foch Dr Christine THEODORE 10 Institut Bergonié Dr Guilhem ROUBAUD 9 Institut Paoli Calmettes Dr Gwenaëlle GRAVIS 7 1
Hôpital Morvan Dr Jean-Pierre MALHAIRE 5 Centre Val d'aurelle Dr Jean-Pierre BLEUSE 5 Institut Jean Godinot Dr Jean-Christophe EYMARD 5 Hôpital Bretonneau Prof Claude LINASSIER 4 Hôpital du bon secours Dr Christian PLATINI 3 Centre François Baclesse Dr Emmanuel SEVIN 3 Centre Henri Becquerel Dr Cécile GUILLEMET 2 Hopital de la Pitié Salpétrière Dr Thibault de la Motte Rouge 2 Centre G.F. Leclerc Dr Sylvie ZANETTA 1 Centre hospitalier Rodez Dr Laurent MOSSER 1 2
List of investigators Pr. Culine APHP CHU Hôpital Henri Mondor Dr Pouessel APHP CHU Hôpital Henri Mondor Dr AUVRIGNON APHP Hôpital Armand-Trousseau Dr Landman-Parker APHP Hôpital Armand-Trousseau Dr TABONE APHP Hôpital Armand-Trousseau Dr CONFORTI APHP Hôpital Pitié-Salpétrière Dr de la Motte Rouge APHP Hôpital Pitié-Salpétrière dr Spano APHP Hôpital Pitié-Salpétrière Dr VIGNOT APHP Hôpital Pitié-Salpétrière Dr BLANC C.H.U. de Poitiers Dr GEOFFROIS Centre ALEXIS VAUTRIN Dr. UWER Centre ALEXIS VAUTRIN Dr. Peyrade Centre ANTOINE LACASSAGNE Dr. Thyss Centre ANTOINE LACASSAGNE Pr. Kerbrat Centre EUGENE MARQUIS Dr. LAGUERRE Centre EUGENE MARQUIS Dr. Joly Centre FRANCOIS BACLESSE - Caen Dr. Sevin Centre FRANCOIS BACLESSE - Caen Dr. LADOIRE Centre GEORGES FRANCOIS LECLERC Dr ZANETTA Centre GEORGES FRANCOIS LECLERC Dr. Blot Centre HENRI BECQUEREL Dr. Chinet-Charrot Centre HENRI BECQUEREL Dr Debled Centre HENRI BECQUEREL Dr. Guillemet Centre HENRI BECQUEREL Dr. Benhaddou Centre hospitalier de Rodez Dr. Marre Centre hospitalier de Rodez Dr. Mosser Centre hospitalier de Rodez Dr CAILLERES Centre Hospitalier du Pays d'aix Dr NAHON Centre Hospitalier du Pays d'aix Pr Droz Centre LEON BERARD Dr Fléchon Centre LEON BERARD Dr BAGATTINI Dr BERTUCCI Dr CAMERLO Dr CAPPIELLO-BATALLER Dr GONCALVES Dr GRAVIS Dr. MADROSZYK-FLANDIN Dr. TARPIN Dr TOPART Dr VIENS Dr. VIRET Dr. Abadie-Lacourtoisie Centre PAUL PAPIN Dr. Delva Centre PAUL PAPIN Dr. BOMPAS Centre RENE GAUDUCHEAU 3
Dr ROLLAND Dr COSTA Dr TIMAR-DAVID Dr. Botton Dr. Labat Dr. LUCAS Dr. Malhaire Dr METGES Dr. SIMON Dr BERGER Dr. Narciso Raharimanana Dr. Bourgeois Dr Linassier Dr. BLEUSE Dr. CHAPELLE Pr. Culine Dr. Hervé Dr Pouessel Dr. Platini Dr WALTER Dr Mignot Dr. Théodore Dr Bui Dr HOUEDE Dr ITALIANO Dr. Chevreau Dr. Couteau Dr. Dalenc Dr. Mourey Dr. Di Palma Pr Fizazi Dr Dr GROSS GOUPIL LORIOT Dr. MASSARD Dr Plantade Dr Eymard Dr. Yazbek Dr. CHEN MD Pagliaro Dr. BROZMANOVA Dr Mardiak Dr. MEGO Dr. OBERTOVA Dr. RECKOVA Dr. SYCOVA MILA Centre RENE GAUDUCHEAU CHU - Hôpital Caremau - Nimes CHU - Hôpital Caremau - Nimes CHU de St Etienne - Hôpital Bellevue CHU de Tours - Centre de Pédiatrie Clocheville CHU de Tours - HÔPITAL BRETONNEAU CHU de Tours - HÔPITAL BRETONNEAU CRLC Val d'aurelle - Montpellier CRLC Val d'aurelle - Montpellier CRLC Val d'aurelle - Montpellier CRLC Val d'aurelle - Montpellier CRLC Val d'aurelle - Montpellier Hopital du Bon secours Hopital du Bon secours Hôpital Foch - Suresnes Hôpital Foch - Suresnes Institut Bergonie - Bordeaux Institut Bergonie - Bordeaux Institut Bergonie - Bordeaux Institut CLAUDIUS REGAUD Institut CLAUDIUS REGAUD Institut CLAUDIUS REGAUD Institut CLAUDIUS REGAUD Institut GUSTAVE-ROUSSY - Villejuif Institut GUSTAVE-ROUSSY - Villejuif Institut GUSTAVE-ROUSSY Villejuif Institut GUSTAVE-ROUSSY Villejuif Institut GUSTAVE-ROUSSY - Villejuif Institut GUSTAVE-ROUSSY - Villejuif Institut JEAN GODINOT Institut JEAN GODINOT MD Anderson Cancer Center MD Anderson Cancer Center 4
Methods Pretreatment evaluation The pretreatment evaluation included a complete history and physical examination, CBC, electrolytes, renal and liver function, hcg, AFP, LDH, pulmonary function test including diffusion of CO (DLCO/VA), CT scan of the pelvis, the abdomen, the thorax, and the brain. A brain MRI could replace the CT scan. Imaging could be delayed by a week following the initiation of treatment if it was started in an emergency. Patients also had to have adequate renal function (creatinine clearance> 60 ml/min), absolute granulocyte count 1,500/mm 3, platelets 100,000 mm 3, and bilirubin 1.5x the upper limit of normal value. A known infection by the Human Immunodeficiency Virus was an exclusion criterion. Methodology for tumour marker decline calculation (Fizazi K, et al. J Clin Oncol 2004; 22: 3868-76) A software to help calculate tumour marker decline can be downloaded for free at http://www.gustaveroussy.fr/calculation-tumor/nsgct.html Definition of favourable and unfavourable pattern of decrease in the serum tumour markers: Decline rates are calculated and expressed as a theoretical time to normalization, using a logarithmic formula: We define M 0 the initial marker value and M 1 the marker value at the first evaluation (at 3 weeks). Then the Time to Normalization (TN M ) for marker M can be obtained according to the following formula TN M = 3 A / B Where A is the difference between M 0 and the normal value M N on the logarithm scale (A = log(m 0 )- log(m N )) and B is the difference between M 0 and the value M 1 at the start of cycle 2 (3 weeks after) on the logarithm scale (B = log(m 0 )-log(m 1 )). In the case where the time between marker values is different from 3 weeks, the formula needs to be modified by replacing the number 3 with the number of weeks separating the two measurements. Patients can then be classified into 4 categories as follows: A M Normal at cycle 1 and at cycle 2 B M Abnormal at cycle 1 and Normalization at cycle 2 C M Abnormal cycle 1 and TN M < T M D M Abnormal cycle 1 and TN M T M or abnormal and increasing marker at cycle 2 Time to Normalization cut-off points (T M ) vary for each marker: T AFP = 9, T HCG = 6 and T LDH = 4 weeks for AFP, b-hcg and LDH respectively. A favourable pattern of decrease is defined as HCG and AFP being both A, B, or C. Particular medical settings requiring specific management Patients with major lung involvement by cancer (like those with the choriocarcinoma syndrome ) were not to receive frontline bleomycin in order to avoid acute respiratory distress syndrome (ARDS). It was recommended that these patients be managed using only cisplatin and etoposide for 3 days at the first cycle (with the last 2 days of cisplatin-etoposide and bleomycin being introduced around day 10, when doable), followed by full-dose chemotherapy in the second cycle if lung function allows such treatment. Also, these patients could receive cycle 2 beginning day 18. 5
Patients with ureteral compression could be managed either by primary ureteral derivation, uretero-bladder catheter, or front-line chemotherapy according to the presentation and creatinine clearance. Dose modification of chemotherapy was not recommended. Patients with brain metastases were to be treated with steroids and primary chemotherapy. However, if symptoms did not improve, a cycle could be delayed to allow radiotherapy or surgery to be performed, if this was medically necessary according to the investigator s opinion. Patients with a poor performance status (PS 3-4) could be included in the trial and treated in the standard manner. However, the investigator could consider modifying the doses of the first cycle of chemotherapy, if medically justified. Additional detailed results Eight patients were not evaluable for tumour marker decline assessment: 6 early deaths during the first three weeks, 1 consent withdrawal, and 1 screen failure. An additional patient (with a favourable tumour marker decline) was included by mistake by a centre that was no longer covered by IRB approval. This patient was not treated according to the protocol and he was excluded from all analyses. Twelve patients did not receive the last cycle of dose-dense chemotherapy due to toxicity (n=6), cancer progression (n=3), or patient/investigator decision (n=3). 6
Tables Unfav-BEP Unfav-DoseDense Fav-BEP Q1 Median Q3 Q1 Median Q3 Q1 Median Q3 Cycle 1-21 -20-19 -21-20 -19-21 -20-20 Cycle 2 0 1 2 0 1 2 0 0 1 Cycle 3 21 22 24 21 22 23 21 21 22 Cycle 4 42 43 45 42 43 45 42 42 44 Cycle 5 63 64 69 Q1=First quartile; Q3=Third quartile Table 1: Timing of chemotherapy cycles (days) Unfav-BEP (n=98) Unfav-DoseDense (n=105) Fav-BEP (n=51) ccr pcr scr PRm- PRm+ Incomplete resection Progression or stable disease Non evaluable 0 (0%) 25 (26%) 4 (4%) 19 (19%) 14 (14%) 6 (6%) 22 (22%) 8 (8%) 6 (6%) 32 (30%) 4 (4%) 11 (10%) 16 (15%) 7 (7%) 23 (22%) 6 (6%) 3 (6%) 17 (33%) 3 (6%) 12 (24%) 6 (12%) 1 (2%) 9 (18%) 0 (0%) Table 2: Response to treatment 7
Figures BEP 1 Cisplatin 20 mg/m 2 /d d1-5 Etoposide 100 mg/m 2 /d d1-5 Bleomycin 30 mg/w Paclitaxel-BEP + Oxaliplatin + G-CSF / 3 weeks 2 cycles Paclitaxel 175 mg/m 2 d1 BEP as above Oxaliplatin 130 mg/m 2 d10 G-CSF 263 μg/d (excepted chemo days) Cisplatin, Ifosfamide, Bleomycin + G-CSF / 3 weeks 2 cycles Cisplatin 100 mg/m 2 d1 Ifosfamide 2g/m 2 d10,12,14 Mesnum Bleomycin 25 mg/d d10-14 (continuous IV) G-CSF as above Figure 1: Dose-dense regimen 8
Figure 2: Example of tumour marker decline assessment using the calculator available online at http://www.gustaveroussy.fr/calculation-tumor/nsgct.html 9