Adding cisplatin to gemcitabine improved response and progression-free survival for people with locally advanced or metastatic pancreatic cancer

TREATMENT

Adding cisplatin to gemcitabine improved response and progression-free survival for people with locally advanced or metastatic pancreatic cancer Abstracted from: Colucci G,Giuliani F,GebbiaV, Biglietto M, Rabitti P,Uomo G,Cigolari S,Testa A, Maiello E, Lopez M.Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma.Cancer 2002; 94(4): 902^910.

BACKGROUND Overall 5-year survival for people with pancreatic cancer is less than 2%. Treatment with gemcitabine and cisplatin may be synergistic. In vivo studies suggest that gemcitabine inhibits DNA repair after cisplatin-induced genomic damage. Cisplatin may a¡ect gemcitabine catabolism by inhibiting ribonucleotide reductase. OBJECTIVE To assess whether adding cisplatin to gemcitabine improves time-to-disease-progression in people with advanced pancreatic adenocarcinoma. SETTING Multiple centers in Italy; timeframe not speci¢ed.

MAIN RESULTS Median time to progression was 8 weeks for the gemcitabine group and 20 weeks for the cisplatin group (p = 0.048). Response rate was 9.2% for gemcitabine and 26.4% for added cisplatin (p = 0.02; see Table 1). Toxicity was mild in both groups (seeTable 2). Grade 1^2 asthenia was higher in the cisplatin group (p = 0.046).There was no di¡erence in overall survival. AUTHORS’ CONCLUSIONS Cisplatin combined with gemcitabine may be the optimal therapy for people with advanced or metastatic adenocarcinoma of the pancreas. METHOD NOTES

METHOD Randomized controlled trial. PARTICIPANTS One hundred and seven people with measurable locally advanced or metastatic pancreatic adenocarcinoma, or both. Forty-two percent of participants were female; median age 62 years (range 33 to 75 years). Seventy-six percent had multiple disease sites. Exclusion criteria were previous chemotherapy, hormonal therapy or radiotherapy; age over 75 years; other malignant neoplasms; Karnofsky performance score under 50, or evidence of congestive heart failure, coronary artery disease, serious arrhythemia or severe uncontrolled metabolic, infectious or neurologic disease. INTERVENTION Gemcitabine alone or with added cisplatin. Gemcitabine was given as a 30-minute intravenous infusion of 1000 mg/m2 per week for 7 weeks. After a 2-week rest period, this dose was continued on days 1, 8 and 15 of a 28-day cycle for 2 cycles. Cisplatin (25 mg/m2 per week) was given 1 hour before gemcitabine. On day 22, only gemcitabine was administered. OUTCOMES Time-to-disease progression; response. 1363- 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved doi:10.1054/ebon.29, available online at http://www.idealibrary.com.on

Power calculation 80% power to detect a 30% increase in 4-month progressionfree survival with cisplatin at 5% level of signi¢cance. Actual recruitment may mean study is slightly underpowered Blinding Not speci¢ed Allocation Adequate concealment Generation of Adequate: central registry allocation sequence Balanced Groups appear balanced, although groups P-values are not reported for di¡erences Analysis Intention to treat and analysis of evaluable participants Sources offunding: American Society of Clinical Oncology. Correspondence to: Giuseppe Colucci, MD, Medical and Expirmental Oncology Unit, Oncology Institute, Via Amendola 209, 70125 Bari, Italy. Fax: +39-080-5555-483. (E-mail: colucci@ goim.it). Evidence-based Oncology (2002) 3,123^125

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Table 1 Response and survival among people with advanced or metastatic pancreatic cancer treated with gemcitabine plus or minus cisplatin

Outcome

Number needed to treat with % Gemcitabine added cisplatin to % Gemcitabine with cisplatin (n = 53) P-Value a¡ect one person alone (n = 54)

Complete response

1.8

0

Partial response

7.4

26.4

Objective response

9.2

26.4

8 weeks

20 weeks

20 weeks

30 weeks

Median time to progression Median overall survival

40.05

Not signi¢cant

0.48

Not signi¢cant

Change in absolute risk with cisplatin

Relative risk reduction with cisplatin

1.8% harm 100% RBR (2% bene¢t to 5% harm) (RI not calculable) o0.05 5 to bene¢t 19% bene¢t 257% RBI (3 to 19 to bene¢t) (5 to 33% bene¢t) (120% to 634% RBI) 0.02 6 to bene¢t 17.2% bene¢t 187% RBI (3 to 33 to bene¢t) (3 to 31% bene¢t) (89% to RBR to 463% RBI) 0.048 F F F F

F

Note: 95% con¢dence intervals are in parentheses. RBR = relative bene¢t reduction; RBI = relative bene¢t increase.

Table 2 Common adverse e¡ects among people with advanced or metastatic pancreatic cancer treated with gemcitabine plus or minus cisplatin Grade 3^4 adverse e¡ects

% Gemcitabine alone (n = 53)

% Gemcitabine with cisplatin (n = 51)

Change in absolute risk with cisplatin

Relative risk reduction with cisplatin

Mucositis

2

0

Diarrhea

0

4

100% RRR (CI not calculable) Not calculable

Nausea/vomiting

2

2

Leukopenia

4

4

Neutrophils

9

18

Anemia

4

6

Platelets

2

2

Transaminases

2

0

2% ARR (2% ARI to 6% ARR) 4% ARI (1% ARR to 9% ARI) 0% change (5% ARR to 5% ARI) 0% change (8% ARR to 8% ARI) 9% ARI (4% ARR to 22% ARI) 2% ARI (6% ARR to 10% ARI) 0% change (5% ARR to 5% ARI) 2% ARR (2% ARI to 6% ARR)

0% RRR (269% RRR to 269% RRI) 0% (188% RRR to 188% RRI) 100% RRI (107% RRR to 307% RRI) 50% RRI (206% RRR to 306% RRI) 0% (269% RRR to 269% RRI) 100% RRR (CI not calculable)

Note: 95% con¢dence intervals are in parentheses. Di¡erences are not statistically signi¢cant. RRR = relative risk reduction; RRI = relative risk increase; ARR = absolute risk reduction; ARI = absolute risk increase. A reduction in risk is a positive outcome.

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Evidence-based Oncology (2002) 3,123^125

Commentary People with pancreatic cancer have poor prognosis. Single agent chemotherapy with gemcitabine is standard care. Gemcitabine has an objective response rate of 0 to 17%, with median survival of 1 to 8 months. Combination approaches may disrupt the signal transduction pathways involved in cell proliferation, metastasis or angiogenesis. Colucci and colleagues found that objective response increased with a combined cisplatin and gemcitabine regimen. Overall survival was not affected, but mean time to progression

was significantly longer with combined therapy. The trial is well designed and the treatment arms are well balanced. The study suggests that tumor response and tumor control rates can be improved by exploiting the synergism between different drugs. This should prompt additional searches for combined chemotherapy for patients with pancreatic cancer. Carlo Riccardo Rossi University of Padova Padova, Italy Level and Quality of Evidence: 1C

Evidence-based Oncology (2002) 3,123^125

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