Il paziente anziano con malattia oncologica avanzata: il tumore del colon-retto

Milano 05.10.2018 Il paziente anziano con malattia oncologica avanzata: il tumore del colon-retto Salvatore Corallo U.O.C. Oncologia Medica IRCCS Istituto Nazionale dei Tumori Milano

CRC in elderly patients Siegel RL et al. Ca Cancer J Clin 2017

Inclusion of elderly patients in clinical trials 65 years 65 years Gouverneur A, Journal of Geriatric Oncology, 2018

Are all elderly patients the same? Fit Unfit Winther SB, et al. ESMO Open 2016

Challeges in treating elderly and frail patients Adjuvant Metastatic

Challeges in treating elderly and frail patients Adjuvant Metastatic

Surgery in elderly patients Chen T-C et al. Journal of Gatrointestinal Surgery, 2018

Adjuvant Therapy Goal: Eradicate potentially present micrometastases, thereby increasing the cure rate in those patients undergone potentially curative resection Benefits most clearly demonstrated in stage III disease ~ 22-30 % relative reduction in the risk of disease recurrence ~ 15-20% relative reduction in mortality Benefits are less certain in stage II Monga DK, et al. Ann Surg Oncol. 2006; André T, et al. J Clin Oncol. 2009; NCCN. Clinical practice guidelines in oncology: colon cancer.

What about elderly?

5-FU in the adjuvant setting Disease-free Survival Overall Survival Δ=32% Δ=24% 5-years free-relapse rates: 69 vs 58%; HR 0.68 (95%CI 0.60-0.76) p<0.001 5-years survival rates: 71 vs 64%; HR 0.76 (95%CI 0.68-0.85) p<0.001 Sargent DJ et al. N Engl J Med 2001

5-FU in the adjuvant setting DEATHS WITH AND WITHOUT THE RECURRENCE OF CANCER ACCORDING TO AGE GROUP Sargent DJ et al. N Engl J Med 2001

5-FU in the adjuvant setting Disease-free Survival 70 years Overall Survival 70 years >70 years >70 years Sargent DJ et al. N Engl J Med 2001

The MOSAIC study Disease-free Survival 73.3 % 67,4 % HR: 0.8 (95% CI: 0.68-0.93) P=0.003 Stage III HR 0.78 (95%CI: 0.65-0.93) p=0.005 Stage II HR 0.84 (95%CI: 0.62-1.14) p=0.258 Overall Survival 78,5% 76.0% HR: 0.84 (95% CI: 0.71-1.00) P=0.046 Stage III HR 0.80 (95%CI: 0.65-0.97) p=0.005 Stage II HR 1.00 (95%CI: 0.70-1.41) p=0.258 Andre T. et al; J Clin Oncol 2009

The MOSAIC study Andre T. et al; J Clin Oncol 2009

The ACCENT database Treatment Arm HR DFS 95% CI HR OS 95% CI HR TTR 95% CI All Age < 70 years (n=11953) 0.85 0.80 to 0.90 0.87 0.81 to 0.93 0.84 0.79 to 0.89 Age 70 years (n=2575) 1.05 0.94 to 1.19 1.08 0.95 to 1.23 1.06 0.93 to 1.22 p interaction 0.001 0.004 0.002 Oxaliplatin Age < 70 years (n=5420) 0.78 0.71 to 0.86 0.83 0.74 to 0.92 0.77 0.69 to 0.85 Age 70 years (n=1119) 0.94 0.78 to 1.13 1.04 0.85 to 1.27 0.86 0.69 to 1.06 p interaction 0.09 0.05 0.36 Oral Fluoropyrimidine Age < 70 years (n=5420) 0.91 0.80 to 1.02 0.90 0.79 to 1.03 0.90 0.80 to 1.02 Age 70 years (n=1119) 1.14 0.92 to 1.41 1.13 0.90 to 1.41 1.20 0.93 to 1.54 p interaction 0.13 0.16 0.09 Mc Cleary NJ et al. J Clin Oncol 2013

What about risk in elderly? How much? How can we measure it? How could we prevent it?

What about risk in elderly? How much? How can we measure it? How could we prevent it?

Recurrence Rate Stage II vs Stage III: Recurrence Rate 12 10 8 6 4 2 4.7 2 10.0 3.7 4 9.4 3.3 7.7 5.6 4.5 3.3 3.1 1.9 Stage II Stage III 1.5 2.4 1.9 1.7 1.3 1.2 1.1 Stage II: 67% of recurrences occur by 3 yrs Stage III: 75% of recurrences occur by 3 yrs 1.3 1.1 0.8 0.8 0.6 0.3 0 0.6 0.7 0.5 0.5 0.3 0.2 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Yr Sargent D, et al. J Clin Oncol. 2007

Stage II vs Stage III: Recurrence Rate Shah M. A., Journal of Clinical Oncology, 2016

What about risk in elderly? How much? How can we measure it? How could we prevent it?

5-FU in the adjuvant setting Overall Fit Medium-fit Unfit Majte A. et al. The Oncologist, 2017

G8 questionnaire Soubeyran et al. Journal of Clinical Oncology, 2008

What about risk in elderly? How much? How can we measure it? How could we prevent it?

DPYD Genotyping to predict Adverse Events Statistically significant associations were identified between grade 3 or greater fluorouracil AEs and both D949V and V732I variants. Grade 3 or greater overall hematologic adverse events were associated with V732Iand D949V and V732I was associated with grade 3 or greater neutropenia (OR, 1.8 [95%CI, 1.3-2.4]). JAMA Oncol, 2016; 2 (5): 655-662

Take Home Messages In stage III colon cancer a treatment with 5FU or Capecitabine should be proposed to "fit" or "medium-fit" elderly. The addition of Oxaliplatin to 5FU/Cape should be carefully evaluated In stage II colon cancer: - 75% to 80% cured with surgery alone - Benefit of chemotherapy is small and no consensus on whom to treat or on how to identify whom to treat - Anyway a treatment with only FU or Capecitabine should be proposed

Challeges in treating elderly and frail patients Trattamento in fase adiuvante Trattamento della malattia metastatica

5FU-based therapy in elderly patients < 70 years: 11.3 months 70 years: 10.8 months < 70 years: 5.3 months 70 years: 5.5 months Fit elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Folprecht G et al. Annals of Oncology, 2004

FOLFOX in elderly patients: a pooled analysis Progression-free survival Overall survival FOLFOX vs Control Goldeberg RM et al. Journal of Clinical Oncology, 2006

What about irinotecan in elderly patients? Aparicio T et al. Annals of Oncol, 2016

Intensity Modulation max max min min

Capecitabine 51 patients 70 years old PS (ECOG) 2 life expectancy 3 months; unsuitable for combination chemotherapy by their doctor or refusal of treatment by the patient creatinine clearance 50 ml/min capecitabine 1,250 mg/m2 twice daily (2,500 mg/m2 total daily dose) dd1-14q21 creatinine clearance: 30-50 ml/min capecitabine 950 mg/m2 twice daily (1,900 mg/m2 total daily dose) dd1-14q21 Feliu J et al. J Clin Oncol 2005

Capecitaibine and oxaliplatin 50 patients 70 years old PS (ECOG) 2 life expectancy 3 months; measurable disease creatinine clearance 50 ml/min Oxaliplatin 130 mg/m2 d1q21 Capecitabine 1000 mg/m2 twice daily (2000 mg/m2 total daily dose) dd1-14q28 creatinine clearance: 30-50 ml/min Oxaliplatin 130 mg/m2 d1q21 Capecitabine 750 mg/m2 twice daily (1500 mg/m2 total daily dose) dd1-14q28 PFS OS 5.8 months 13.2 months Feliu J et al. British Journal of Cancer 2006

What is the better treatment? Group A LV-5FU 459 patients - not candidate for standard full-dose combination therapy - PS (ECOG) 2 - measurable inoperable advanced or metastatic disease Group B FOLFOX Group C Capecitabine Group D XELOX Seymour MT et al. Lancet 2011

What is the better treatment? 4.5 5.8 Seymour MT et al. Lancet 2011

What is the better treatment? Seymour MT et al. Lancet 2011

What about target therapy for frail patients?

bevacizumab in elderly: AVEX trial Previously untreated mcrc, age 70 years N=280 Randomize 1:1 Stratification factors: ECOG PS (0 1 vs 2) Geographic region Capecitabine 1000 mg/m 2 b.i.d. days 1 14, q21d + Bevacizumab 7.5 mg/kg day 1, q21d Capecitabine 1000 mg/m 2 b.i.d. days 1 14, q21d Key inclusion criteria ECOG PS 0 2 Prior adjuvant chemotherapy allowed if completed >6 month before inclusion Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin Cunningham D, Lancet Oncol, 2013

bevacizumab in elderly: AVEX trial Cunningham D, Lancet Oncol, 2013

How to select?

bevacizumab in elderly: PRODIGE-20 Previously untreated mcrc, age 75 years PS (ECG) 2 N=102 Randomize 1:1 Stratification factors: CT ( 5FU vs doublet therapy) primary tumour resected Spitzer QoL score (0-3 versus 4-7 versus 8-10) CT (LV-5FU2, mfolfox, FOLFIRI) + Bevacizumab 5 mg/kg day 1, q21d CT (LV-5FU2, mfolfox, FOLFIRI) Aparicio T. European Journal of Cancer, 2018

bevacizumab in elderly: PRODIGE-20 Survival without deteriorated autonomy Survival without deteriorated QoL Aparicio T. European Journal of Cancer, 2018

Anti-EGFR in elderly patients A pooled analysis of the CRYSTAL (FOLFIRI +/- cetuximab) and OPUS (FOLFOX +/- cetuximab) trials. Younger (<70 y) Elderly ( 70 y) Cet + CT n=320 CT n=380 Cet + CT n=78 Median PFS (months) 10 7.7 8.9 7.2 CT n=67 Median OS (months) 23.6 20.2 23.3 15.1 Grade 3/4 toxicity (%) Neutropenia 31.2 23.7 33.3 35.8 Diarrhea 12.8 7.9 23.1 14.9 Fatigue 4.0 4.7 2.6 7.5 All skin toxicity 25.2 0.8 23.1 1.5 60-day mortality 2.2 2.1 1.3 3.0 Grade 3/4 toxicity increased in both treatment arms for elderly patients, but there was no obvious interaction between age (< 70 vs 70 years) and the differences for treatment toxicity between the arms. Folprecht G, Ann Oncol, 2010

Anti-EGFR in elderly patients Douillard YJ, Ann Oncol, 2015

Panitumumab in frail patients Sep/2010-Feb/2015 40 patients 75 years frailty status RAS and BRAF wild-type life expectancy 12 weeks ECOG performance Status 2. Stratum A Never treated with absolute contraindication to any chemotherapy Stratum B After failure of a first line treatment (FU or Capecitabine +/- oxaliplatin or bevacizumab) and contraindication to irinotecan Panitumumab 6 mg/kg every 2 weeks Panitumumab 6 mg/kg every 2 weeks DISEASE PROGRESSION Pietrantonio F et al, The Oncologist, 2015

Panitumumab in frail patients Pietrantonio F et al, The Oncologist, 2015

Panitumumab in frail patients Progression-free survival Overall survival Pietrantonio F et al, The Oncologist, 2015

And what about tumour-related frailty?

Treatments options in patients with liver dysfunction ~ 50% of patients with CRC will develop liver metastases during their lifetime - 20% synchronous - 30% metachronous Mechanism of liver dysfunction in CRC patients is multifactorial: - direct reduction of the volume of functional liver - intra-hepatic and extra-hepatic biliary obstruction - portal vein occlusion due to thrombosis Field KM, The Lancet, 2008; Roderburg C, Clin. Colorectal Cancer, 2011

Treatments options in patients with liver dysfunction Walia T et al, Therapeutics and Clinical Risk Management, 2008

Treatments options in patients with liver dysfunction Faugeras L, Critical reviews in Oncology/Hematology, 2017

Treatments options in patients with liver dysfunction Treatment Liver toxic effects Frequency Severity Capecitabine Hyperbilirubinaemia, usually without increased alkaline phosphatase and gammaglutamyltransferase; might be related to haemolysis Common (23 25% of patients) Grade 3 4 in up to 23% of patients Fluorouracil Steatosis Common Usually subclinical Hepatotoxicity Rare Usually subclinical Increased aminotransferases and alkaline phosphatase Common Irinotecan Steatosis and steatohepatitis Common (25 50% of patients) Increased aminotransferases and bilirubin Oxaliplatin Vascular changes; sinusoidal obstruction or dilatation syndrome Up to 25% of patients Common (20 80% of patients) Usually reversible Steatohepatitis can increase morbidity if used before liver resection Usually reversible Might increase morbidity, but not mortality, after liver resection Field KM, The Lancet, 2008; Faugeras L, Critical reviews in Oncology/Hematology, 2017

Treatments options in patients with liver dysfunction 5-FU: 1000, 1800 or 2600 mg/m(2) as a 24-h infusion plus Leucovorin (LV) at 500 mg/m(2) fixed dosage 1 2 3 creatinine >1.5 but 3.0 mg/dl normal creatinine normal creatinine normal bilirubin bilirubin >1.5 but <5.0 mg/dl bilirubin 5.0 mg/dl Fleming GF, Ann Oncol, 2003

Treatments options in patients with liver dysfunction Shitara K, Japanese Journal of Clinical Oncology, 2010

What s new for the future?

What s new for the future? Panda Study Randomized phase 2 study of first-line FOLFOX plus panitumumab versus 5FU plus pan in elderly RAS and BRAF wild-type metastatic colorectal cancer patients

What s Trattamenti new for(ii the linea) future?

What s Trattamenti new for(ii the linea) future?

to be continued. salvatore.corallo@istitutotumori.mi.it