Randomized study of sequential versus combination chemotherapy with

capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer

a study of the Dutch Colorectal Cancer Group (DCCG)

CJA Punt, M Koopman, J Douma, J Wals, AH HonkoopFLG Erdkamp, RS de Jong, CJ Rodenburg,

L Mol, NF Antonini

ASCO 2007

Effective cytotoxic drugs in advanced CRC

• Effective cytotoxic drugs in CRC: fluoropyrimidines, irinotecan, oxaliplatin

• Median overall survival is increased when these drugs are made available to patients with advanced CRC1

• No comparative data on sequential versus combined use of these drugs

1Grothey et al. J Clin Oncol 2004

Background

• Salvage treatments have not been a prospective part of phase III studies in 1st line treatment of colorectal cancer

• Results on overall survival of these studies may be biased by imbalances in salvage treatments1

• UK FOCUS study2 only evaluates sequential versus combined use of either irinotecan or oxaliplatin with 5FU (amended during accrual period) 1 Punt Ann Oncol 2004

2 Seymour et al. ASCO 2005

DCCG CAIRO study

• Primary objective: to determine whether 1st line combination treatment is superior in terms of overall survival compared to the sequential use of the same drugs

• This is the first phase III study in advanced colorectal cancer patients that prospectively evaluates sequential versus combination treatment when all three cytotoxic drugs with known efficacy are made available

CAIRO study CKTO 2002-07

Arm A Arm B

Randomize

capecitabine

capecitabine +oxaliplatin

irinotecancapecitabine +

oxaliplatin

capecitabine +irinotecan1st line

2nd line

3rd line

Dose/schedule of drugsall cycles given 3 weekly

• Capecitabine monotherapy: 1250 mg/m2 b.i.d. day 1-14

• Irinotecan monotherapy: 350 mg/m2 day 1

• CAPIRI1: capecitabine 1000 mg/m2 b.i.d. day 1-14 + irinotecan 250 mg/m2 day 1

• CAPOX2: capecitabine 1000 mg/m2 b.i.d. day 1-14 + oxaliplatin 130 mg/m2 day 1

1 Rea et al. Ann Oncol 20052 Borner et al. J Clin Oncol 2002

Endpoints, statistics

Primary endpoint:

• overall survival

Secondary endpoints:

• progression-free survival

• response rate

• safety, quality of life

Statistics

• Designed to detect a difference in median overall survival of 3.5 months with 80% power, =0.05, 2- tailed test

Inclusion criteria

• Histologically proven colorectal cancer

• Advanced disease not amenable to curative surgery

• Measurable or evaluable disease parameters (serum CEA as the only parameter for disease activity was not allowed)

• No previous systemic treatment for advanced disease

• Previous adjuvant chemotherapy was allowed provided that the last administration was given > 6 months prior to randomisation

• Age 18 years

• WHO performance score 0-2

• Adequate hepatic, bone marrow, and renal function

Exclusion criteria

• Serious concomitant disease preventing the safe administration of chemotherapy or likely to interfere with the study assessments

• Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix, and squamous or basal cell carcinoma of the skin

• Pregnancy or lactation; patients (M/F) with reproductive potential not implementing adequate contraceptives measures

• Central nervous system metastases

• Serious active infections

• Inflammatory bowel disease or other diseases associated with chronic diarrhoea

• Previous extensive irradiation of the pelvis or abdomen

• Concomitant (or within 4 weeks before randomization) administration of any other experimental drug

• Concurrent treatment with any other anti-cancer therapy

Evaluation schedule

• Toxicity was evaluated at the start of each cycle (every 3 weeks)

• Tumor response was evaluated every 9 weeks (every 3 cycles)

• Central review of all patient files when death occurred < 30 days within the last administration of study drugs with death not directly related to disease progression

Accrual

• 820 patients were randomized in 75 participating Dutch hospitals within 2 years (jan. ’03 - dec. ’04)

• Ineligible patients N=17

• Eligible patients N=803

Trial profile

Arm A Arm B

Randomize

capecitabineN=397

capecitabine +oxaliplatin

N=143 (36%)

irinotecanN=251 (62%)

capecitabine +oxaliplatin

N=213 (53%)

capecitabine +irinotecan

N=398

1st line

2nd line

3rd line

Baseline characteristics

Number of eligible pts Sequential (N=401) Combination (N=402)

Median age 64.0 63.0

Gender

Male

Female

63%

37%

63%

37%

Performance status

PS0/1

PS2

95%

5%

96%

4%

Predominant localisation of metastases

Liver

Extrahepatic

Unknown

69%

29%

2%

71%

29%

<1%

LDH at randomization

Normal

Abnormal

64%

36%

64%

36%

Prior adjuvant therapy

Yes

No

14%

86%

14%

86%

Median overall survival

Combination treatment 17.4 months (15.2-19.2)

----------- Sequential treatment 16.3 months (14.3-18.2)

p = 0.33

Efficacy results

Sequential

N=401

Combination

N=402

p value

Median overall survival (months) 16.3 17.4 0.33

Hazard ratio for death 1.08

One-year survival rate (%) 64 67

Median PFS (months) 1st line 5.8 7.8 0.0002

Overall response rate (CR + PR)*

1st line

2nd line

3rd line

77 (20%)

23 (10%)

5 (4%)

139 (41%)

24 (12%)

-

Disease control rate (CR + PR + SD)*

1st line

2nd line

3rd line

280 (74%)

162 (71%)

72 (57%)

297 (87%)

121 (63%)

* Percentages are based on patients evaluable for response

Grade 3-4 toxicity over all lines

Toxicity

SequentialN = 397

Combination N = 398 p value

Hand-foot syndrome 13% 7% 0.004

Diarrhea 23% 27% 0.23

Nausea 8% 9% 0.45

Vomiting 7% 10% 0.16

Stomatitis 3% 2% 0.15

Thrombosis/embolism 9% 10% 0.48

Febrile neutropenia 5% 7% 0.18

Mortality

SequentialN = 401

CombinationN = 402

60-day mortality 3.0% 4.5%

Death probably related to treatment *

sepsis **

diarrhea

neutropenic fever

8

6

1

1

3

2

1

0

Sudden death *** 1 5

* In 9/11 patients major protocol violations were detected

** In 7/8 patients neutropenia was present

*** In 4/6 patients cardiopulmonary risk factors were present

Grade 3-4 toxicities in first line

Toxicity

Arm Acapecitabine

N = 397

Arm B capiri

N = 398p value

Hand-foot syndrome 12% 6% 0.002

Diarrhea 11% 26% <0.001

Nausea 4% 10% 0.004

Vomiting 3% 9% 0.0002

Stomatitis <1% 2% 0.16

Thrombosis/embolism * 7% 10% 0.20

Febrile neutropenia <1% 7% <0.001

* All grades

Quality of life

• Participation to this part of the study was proposed to the first 620 patients entered in the study (QLQ-C30 questionnaire of the EORTC)

• 403 patients were evaluable for quality of life

• Quality of life scores were comparable between the two arms, except for diarrhoea which was reported more frequently in combination treatment

Conclusions

• Combination treatment is not superior in terms of efficacy to sequential treatment in patients with advanced colorectal cancer

• Our results on median overall survival for sequential treatment are the highest reported when a fluoropyrimidine is administered as monotherapy in 1st line

• Sequential treatment is a useful alternative for combination treatment

• Our results may be useful for strategies in which chemotherapy is combined with targeted agents

DCCG CAIRO study acknowledgements

Investigators:C.Rodenburg, Amersfoort; J.van der Hoeven, Amstelveen; D.Richel, M.Schweitzer, B.de Valk, M.Soesan, Amsterdam; J.Douma, Arnhem; P.Nieboer,Assen; F.Valster, Bergen op Zoom; R.Rietbroek, Beverwijk; G.Ras, O.Loosveld, Breda; D.Kehrer, Capelle a/d IJssel; M.Bos, Delft; Z.Erjavec, Delfzijl; H.Sinnige, C.Knibbeler, Den Bosch; W.Van Deijk, F.Jeurissen, H.Sleeboom, Den Haag; H.de Jong, Den Helder; A.Imholz, Deventer; E.Muller, Doetinchem; H.van Kamp, Drachten; E.Balk, Ede; G.Creemers, M.Dercksen, Eindhoven; M.Legdeur, Enschede; H.van Halteren, Goes; A.van der Torren, Gouda; G.Hospers, R.de Jong, Groningen; P.Zoon, Harderwijk; J.Wals, Heerlen; V.Derleyn, Helmond; C.Gerrits, Hengelo; C. de Swart, Hoofddorp; J.Haasjes, Hoogeveen; W.Meijer, Hoorn; C.de Swart, Haarlem; M.Polee, Leeuwarden; M.Tesselaar, Leiden; G.Jonkers, Leiderdorp; R.Brouwer, Leidschendam; R.Jansen, Maastricht; P.de Jong, Nieuwegein; C.Punt, H.Oosten, Nijmegen; J.van Wissen, Oosterhout; M.Kuper, Oss; M.den Boer, Roermond; A.Planting, A.vander Gaast, J.Stouthard, F.de Jongh, T.Kok, Rotterdam; J.Braun, Schiedam; F.Erdkamp, Sittard; G.Veldhuis, Sneek; C.Geers, Spijkenisse; P.van der Werf, Stadskanaal; A.van Reisen, Terneuzen; H.Roerdink, Tilburg; D.ten Bokkel Huinink, R.Oltmans, S.van der Vegt, E.Voest, Utrecht; L.van Hulsteijn, Veghel; G.Vreugdenhil, Veldhoven; M.Werter, Venlo; J.Ruit, Vlaardingen; L.Kerkhofs, Vlissingen; W.Jaspers, Winschoten; P.Schiphorst, Winterswijk; J.Holleman, Woerden; A.van Bochove, Zaandam; O.van Dobbenburgh, Zutphen; J.de Graaf, A.Honkoop, Zwolle. Statistician: O.Dalesio, Amsterdam Central Datamanagement: J.Akkermans, F.van Leeuwen, IKO NijmegenIndependent Data Monitoring Committee: P.De Mulder, D.Sleijfer, G.Stoter