Patients self assessment of tolerance and quality of life during docetaxel based chemotherapy: results from a phase III trial in hormone-naïve metastatic prostate cancer patients

GETUG-AFU 15/0403 Trial F. Joly(1), G.Gravis(2), S. Oudard(3), M. Soulie(4), B. Esterni(5), C. Protiere(6), M. Habibian(7), I. Latorzeff(8), F. Priou(9), K. Fizazi(10)

A French national multicentric study sponsored by the National Federation of Comprehensive Cancer Centers (FNCLCC) with the collaboration of the French Association of Urologists (AFU).

ConClusion

The target accrual of the GETUG-AFU 15/0403 phase III trial testing Docetaxel in hormone-naïve prostate cancer was completed. From October 2004 to December 2009, 385 patients have been included.

Global Quality Of Life and functional scores were affected by the addition of Docetaxel during treatment but were equivalent to ADT arm at 12 months evaluation.

Self patients reported toxicity was increased in the combination of ADT + Docetaxel.

Sexual dysfunction, due to ADT, represented the most disturbing toxicity in both arms.

ACknowledgements The patients who have accepted to participate in this study.

All the participating investigational sites.

The Ligue Nationale Contre le Cancer.

The French Health Ministry (PHRC).

The IDMC members.

All the financial partners.

PARtiCiPAting CenteRs In FranceInstitut Gustave Roussy, Villejuif – Centre François Baclesse, Caen – Institut Paoli Calmettes, Marseille – Hôpital Georges Pompidou, Paris – Centre Hospitalier, La Roche sur Yon – Clinique du Parc, Toulouse – Centre Paul Papin, Angers – Centre Alexis Vautrin, Vandoeuvre les Nancy – Centre Eugène Marquis, Rennes – Centre René Gauducheau, Nantes – Hôpital Foch, Suresnes – Hôpital St Joseph, Paris – Centre Antoine Lacassagne, Nice – Centre Val d’Aurelle, Montpellier – Institut Claudius Régaud, Toulouse – Institut Curie, Paris – Centre Georges Leclerc, Dijon – Clinique Sainte Marguerite, Hyères – Hôpital Layné, Mont de Marsan – Centre Régional Hospitalier, Metz-Thionville – Hôpital Bretonneau, Tours – Centre Hospitalier Dupuytren, Limoges - Centre Catherine de Sienne, Nantes – Hôpital Saint André, Bordeaux – Clinique Saint-Jean Languedoc, Toulouse – Institut Jean Godinot, Reims – Clinique armoricaine de radiologie, Saint-Brieuc – Hôpital Saint-Louis, Paris.

In BelgiumClinique Saint-Luc, Bruxelles.

Randomized, open multicenter phase III study

Primary endpoints 36 months overall survival of the Docetaxel + ADT versus ADT alone in metastatic prostate cancer first

line treatment . The planned number of pts was 378 to detect a 15% difference in survival with a power of 80% and an

alpha of 0.05 (two-sided test).

Secondary endpoints Progression-free survival Economic evaluation Quality of life Toxicity Genomic and proteomic evaluation.

Minimization By ADT or chemotherapy received before metastatic disease By risk groups (Glass TR, et al. J Urol 2003)

enPoints And metHodologY

BackgroundTwo large phase III trials have demonstrated a survival benefit of Docetaxel (D) in hormone refractory prostate cancer patients (pts). D has become the standard of care in this setting. We recently evaluated the efficacy of D in hormone naïve metastatic prostate cancer (HNMPC) pts in a phase III multicentre trial. The aim of this sub analysis was to assess pts’ quality of life (QoL) and toxicity of D.

MethodsFrom 10/2004 to 12/2008, 385 pts with HNMPC were randomized between androgen deprivation therapy (ADT) and D: 75 mg/m²/ q3w (9 cycles) (arm A) vs. ADT alone (arm B). Pts’ QoL (EORTC QLQ-C30) was assessed at day 0, 3 months (M), 6M and twice a year. Toxicity was evaluated by self-assessment specific questionnaires at 3M and 6M.

ResultsPts QOL scores were comparable at inclusion (participation rate: 83.1%). Out of cognitive functioning overall scores were deteriorate at M3 and M6 for arm A. At 12M, no difference in regard of global score and functional scores were observed between the two arms (participation rate: 32.6%). Dyspnea was increased in arm A (p=0,02), appetite loss decreased in arm B (p=0,02) and constipation increased in arm B (p=0,02), others symptoms were not different at 12M evaluation. Regarding pts’ self-assessment toxicity: fatigue, alopecia, and taste changes were observed in more than 50% of all pts and were significantly higher in arm A (p<0,001). Sexual dysfunction, hot flushes, and weight gain were observed in more than 50% of pts with no difference between arms. Of all toxicities, sexual dysfunction reach the highest level of distress (> 33%) in both arms at 3M and 6M.

ConclusionsGlobal QoL and functional scores were affected by the addition of Docetaxel during treatment but were equivalent to ADT arm at 12 months evaluation. Self pts reported toxicity was increased in the combination of ADT + Docetaxel. Sexual dysfunction, due to ADT, represented the most disturbing toxicity in both arms.

AbstRACt # 48705

Risk gRouPsPrognosticFactors good intermediate Poor

Axial bone metastasis and or nodes ●Appendicular bone metastasis or visceral metastasis ● ● ● ●Performance status < 1 ● ●Performance status ≥ 1 ● ●Gleason score < 8 ●Gleason score ≥ 8 ●PSA < 65 (ng/ml) ●PSA ≥ 65 (ng/ml) ●

(Glass TR, et al. J Urol 2003)

Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to either arm A (ADT plus Docetaxel) or arm B (ADT alone).

Inclusion criteria Histologically proven adenocarcinoma of the prostate Metastatic disease with measurable or evaluable disease ECOG performance status ≤ 2 No chemotherapy for metastatic disease On ADT for < 60 days Androgen ablation or chemotherapy in neoadjuvant, adjuvant or in biological relapse provided the following: treatment

was stopped with more than one year without any metastases or PSA increase during this time Prior radiotherapy is allowed if achieved at least a day before inclusion Adequate hematological, renal and hepatic function Written informed consent

Exclusion criteria Peripheral neuropathy Active cardiac disease Brain metastasis Surgical castration

studY PoPulAtion

tReAtment Assessments

*Patient-assessed QOL (using the European Organization for Research and Treatment of Cancer QLQ-C30)** Indirect cost are evaluated by auto-questionnaire, direct cost by CRF information***Biopsy is done only for pts which have given specific informed consent. Biopsy performed initially and at the time of androgen independence. **** Serum proteomic analyses are performed before at the ninth month and at the time of androgen independence.

Inclusion C1 C2 C3 C4 C5 C6 C7 C8 C9 End of Docetaxel

/ 3 months for 3 years

/ 6 months until death

Informed consent ●Treatments

Docetaxel ● ● ● ● ● ● ● ● ●ADT

Evaluation

CT Scans ● ● ● ● ●Bone scans ● ● ● ● ●PSA ● ● ● ● ●QLQ-C30 * ● ● ● ●Toxicity evaluation (NCI) ● ● ● ● ● ● ● ● ● ● ●Auto evaluation of toxicity by questionnaire ● ●Cost evaluationQuestionnaire** ● ● ●Biopsy for genomic evaluation*** ●Proteomic**** ● ●

studY design And tReAtment

RANDOMIZATIONStratification: - Prior systemic TT - Risk group

Arm AADT + Chemotherapy

Arm BADT alone

C1

C1 = C2 = 21 days =Cndocétaxel : 75 mg/m²/d at d1

C2

C3

C4

C5

C6

C7

C8

C9

Androgen dependent metastatic prostate disease 378 pts planned

*- LHRH agonist - Or maximum androgen blockage - Or orchydectomy** Docetaxel: 75 mg/m² every 3 weeks for up to 9 cycles in the absence of disease progression or unacceptable toxicity

ADT*+

Docetaxel**ADT*

R e s u lt s

(1) Centre François Baclesse, CHU Caen, France; (2) Department of Medical Oncology, Institut Paoli Calmettte, INSERM URM 891, Marseille, France; (3)Medical Oncology Department, Georges Pompidou European Hospital and Inserm U674 Genomique Fonctionelle des Tumeurs Solides, Paris, France; (4) Centre Hospitalier Universitaire Rangueil, Toulouse, France; (5) Department of Biostatistics, Institut Paoli Calmettte, Marseille, France; (6) Research Unit UMR 912, Marseille, France; (7) FNCLCC, Paris, France; (8) Clinique Pasteur, Toulouse, France; (9) Centre Hospitalier Départemental, La Roche sur Yon, France; (10) Institut Gustave Roussy, Villejuif, France

PAtients eXPosuRe

ADT + Docetaxel / q3w (N= 189)

Nb of cycles (median/range) 9 [1-9]

Dose reduction (%) 53

Infusion delayed (%) 20Reasons for stopping treatment (%)

- Progression of disease- Adverse event - Withdrawal of consent - Death - Other*

2196118

*Reasons: medical investigator decision 74%

globAl And FunCtionAl sCAles

sYmPtom sCAles

Inclusion M3 M6 M12Completion questionnaire 83,10% 68,10% 63,30% 32,60%

SCORES Arm N Mean N Mean N Mean N Mean

Global Health Status

A 156 67,4 117 64,1 119 61,3 53 69,7B 143 65,4 125 71,1 100 70,9 58 67

p-value 0,006 <0,001

Physical functioning

A 158 88 114 80,2 126 74 54 81,9B 151 87,6 126 87,8 109 86,9 59 84,3

p value 0,001 <0,001

Role functioning

A 154 82,3 114 75,9 123 67,5 54 72,8B 145 82 129 83,9 107 84,6 59 77,7

p value 0,012 <0,001

Emotional functioning

A 156 75,5 116 75,2 120 73,1 52 80B 143 78 125 79,1 106 79,3 59 78,8

p value 0,038 Cognitive functioning

A 157 89,1 117 84,2 120 82,2 51 84B 145 88,4 127 85 106 84,3 57 84,5

Social functioning

A 154 85,9 115 76,8 117 73,9 53 79,6B 145 86,9 127 86,9 105 86 59 84,5

p value 0,001 <0,001

Inclusion M3 M6 M12SCORES Arm N Mean N Mean N Mean N Mean

FatigueA 158 24,5 116 39,8 126 46,8 52 31,6B 150 23,3 127 24,1 109 25,6 57 26,1

p-value <0,001 <0,001

Nausea and vomiting

A 158 2,3 121 6,2 125 4,7 55 3,3B 151 2,5 133 2,9 109 2,4 61 6,6

p-value 0,029

PainA 156 23,2 114 22,4 116 26,1 52 21,2B 143 23,4 126 16 103 20,7 57 24,3

p-value 0,045

DyspneaA 158 12,4 121 25,1 126 36,5 55 29,7B 150 14,2 132 18,9 109 21,4 61 18,6

p-value <0,001 0,022

InsomniaA 158 24,5 121 34,4 126 31 56 28B 151 24,1 132 25 110 28,5 61 28,4

p-value 0,014

Appetite lossA 158 6,3 121 12,7 126 13 56 2,4B 151 6,8 133 3 110 3,3 61 10,4

p-value <0,001 <0,001 0,017

ConstipationA 157 14 117 18,8 120 17,2 53 10,7B 147 14,5 127 13,4 106 16,7 59 22,6

p-value 0,024

DiarrhoeaA 156 8,1 115 15,4 120 16,1 53 9,4B 146 4,6 127 5,8 106 7,2 59 10,7

p-value 0,034 <0,001 0,001 Financial difficulties

A 155 7,1 117 8,3 119 10,1 53 8,8B 144 6,9 126 8,2 105 5,7 57 6,4

PAtients’ selF Assessment toXiCities

Inclusion

Arm A (%)M3

N = 106

Arm B (%)M3

N=106

p

Arm A (%)M6

N = 106

Arm B (%)M3

N=91

p

Completion questionnaire 58,4% 52,8%

Fatigue 86.8 58.5 <0.001 88.7 57.1 <0.001

Sexual dysfunction 82.1 73.6 NS 83 80.2 NS

Alopecia 76.4 6.6 <0.001 64.2 4.4 <0.001

Hot flashes 71.7 79.2 NS 73.6 82.4 NS

Muscular and joint pain 67,9 52,8 0,035 62,3 62,6 NS

Taste change 54,7 9,4 <0,001 63,2 4,4 <0,001

Weight gain 51,9 49,1 NS 54,7 53,8 NS

Paresthesia 47,2 33 0,047 60,4 34,1 <0,001

Diarrhea 44,3 16 <0,001 40,6 15,4 <0,001

Bone pain 40,6 30,2 NS 38,7 34,1 NS

Hand/foot pain 30,2 19,8 NS 40,6 15,4 <0,001

Stomach pain 29,2 15,1 0,02 19,8 9,9 0,048

Constipation 29,2 26,4 NS 32,1 28,6 NS

Anorexia 28,3 12,3 0,006 26,4 6,6 <0,001

Cutaneous allergy 27,4 14,2 0,028 33 14,3 0,002

Headache 27,4 12,3 0,09 15,1 14,3 NS

Nausea 22,6 12,3 ns 25,5 12,1 0,019

Mucositis 21,7 8,5 0,012 21,7 4,4 <0,001

Conjunctivitis 20,8 7,5 0,005 29,2 3,3 <0,001

Weight loss 19,8 12,3 ns 21,7 7,7 0,005

Fever 17 7,5 ns 12,3 3,3 0,034

Edema 16 13,2 ns 31,1 11 <0,001

Cystitis 10,4 7,5 ns 11,3 4,4 NS

Urinary dysfunction 9,4 19,8 0,049 19,8 17,6 NS

Vomiting 7,5 3,8 ns 4,7 6,6 NS

Nail loss 3,8 0 ns 25,5 2,2 <0,001

Qu

Al

itY

oF

liF

e s

Co

Re

s