Cetuximab in elderly patients.

Introduction

Since the demonstration that 5-fluorouracil (5FU)-based chemotherapy provides benefit in elderly patients suffering from metastatic colorectal cancer (MCRC), in the absence of severe comorbidities, as it does in younger patients, these regimens have been used increasingly more often [1,2]. The development of targeted therapies has raised the question of age limits for their use. Cetuximab, a chimeric humanised monoclonal antibody, is an epidermal growth factor receptor (EGFR) inhibitor. Its efficacy in terms of progression-free survival (PFS) has been demonstrated in MCRC resistant to irinotecan-based chemotherapy [3] and in first-line chemotherapy in combination with irinotecan, leucovorin and continuous infusion 5FU (FOLFIRI) [4]. However, little is known about the efficacy and tolerance of cetuximab in patients older than 70 years of age. To address this issue we have reviewed the cases of elderly patients treated with cetuximab in university hospitals, looking at efficacy and tolerance [5].

Patients and methods

A list of elderly patients (70 years and above) who were treated with cetuximab in seven university hospitals was obtained from the hospitals' pharmacy records. Data from these patients were collected retrospectively. EGFR expression was evaluated by immunohistochemistry and considered positive if at least 1% malignant cells stained for EGFR (Zymed Laboratories Inc., San Francisco, CA, USA or DakoCytomation, Glostrup, Denmark).

Cetuximab was given at an initial dose of 400 mg/[m.sup.2], followed by weekly infusions at a dose of 250 mg/[m.sup.2]. Cetuximab was administered with irinotecan (90-minute infusion of 180 mg/[m.sup.2] irinotecan, every two weeks), with FOLFIRI (2-hour infusion of 400 mg/[m.sup.2] leucovorin, bolus of 400 mg/[m.sup.2] 5FU and then a 46-hour infusion of 2400 mg/[m.sup.2] 5FU and a 90-minute infusion of 180 mg/[m.sup.2] irinotecan on the first day of a two-week cycle) or with leucovorin, 5FU and oxaliplatin (FOLFOX; 2-hour infusion of 200 mg/[m.sup.2] of leucovorin, bolus of 400 mg/[m.sup.2] of 5FU and then a 46-hour infusion of 2400 mg/[m.sup.2] of 5FU and 2-hour infusion of 85 mg/[m.sup.2] of oxaliplatin on day 1).

Data collection

The clinical characteristics and medical history of each elderly patient with MCRC were collected retrospectively from the patient's medical records. Details recorded were: date of diagnosis; primary tumour location (right or left colon, rectum); initial TNM classification; adjuvant radiochemotherapy for rectal cancer or chemotherapy for colon cancer and type of regimen received; date and type of relapse; type of chemotherapy regimen with dates of initiation and termination; best response with date of onset and duration; and type and date of local treatment for metastases (hepatic or pulmonary resection or thermal ablation, or other surgery).

Patients' characteristics were recorded at the time of the first infusion of cetuximab. These characteristics were: chemotherapy regimen (cetuximab alone, cetuximab with irinotecan, FOLFIRI or FOLFOX); clinical parameters [weight, World Health Organisation (WHO) performance status, number and type of metastatic sites]; biochemical parameters [blood count, total bilirubin concentration, alkaline phosphatase level, carcinoembryonic antigen (CEA) level and EGFR status].

Tolerance to cetuximab was evaluated during treatment; grade 3/4 toxic effects were assessed according to the National Cancer Institute Common Toxicity Criteria on haematological, digestive and skin toxicity. Reasons for stopping cetuximab treatment were recorded, when appropriate [allergy, patient decision, clinical progression, progression shown by computed tomography (CT) scan or other reasons].

Survival analysis and evaluation of tumour response

The primary endpoint of the study was PFS in the intention-to-treat population. Secondary endpoints were tumour response and overall survival (OS) after initiation of treatment with cetuximab.

PFS was defined as the time between the first administration of cetuximab and the first observation of disease progression, death from any cause or the date of the last follow-up visit. OS after initiation of treatment with cetuximab was defined as the time between the first administration of cetuximab and death or the date of the last follow-up visit.

Patients underwent physical examination and blood count was determined before each cycle. Tumour response was evaluated by CT scan in measurable lesions every 8 or 12 weeks, according to the centre. Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to assess tumour response [6].

Statistical analysis

Intent-to-treat analysis has been performed on the whole population of patients who received at least one administration of cetuximab. The Kaplan-Meier method was used to estimate PFS and OS, and comparisons have been made using the log-rank test [7].

Results

Patients' characteristics

Between January 2004 and August 2005, a total of 56 patients were treated in seven centres. Median age was 76 years (range, 70-84), and there were 33 males and 23 females. EGFR status was positive in 32 patients, unknown in 22 and negative in two. WHO performance status before cetuximab treatment was grade 0/1 in 46 patients (82%), grade 2 in seven patients (13%) and unknown in three (5%). Local treatment for liver metastases (surgical resection and/or local destruction by thermal ablation using radiofrequency) was carried out before cetuximab treatment in 23 patients (41%). The median number of metastatic sites was two (range, one to four) and the median number of previous chemotherapy regimens was three (range, one to six). Tumours were progressive with an irinotecan regimen (resistant) in 39 patients (70%) before cetuximab treatment. Median follow-up was 6.5 months after cetuximab initiation (range, 5.3-7.7 months).

Tumour response and adverse events with cetuximab treatment

Cetuximab was administered with irinotecan in 51 patients (91%), with FOLFIRI in three patients (5%) and with FOLFOX in two patients (4%). The median number of cetuximab infusions per patient was eight (range, one to 34). Anaphylaxis-like reaction leading to treatment cessation occurred in three patients (5%) and treatment was stopped for adverse events (diarrhoea or neutropenia) in six patients (11%). At the end of the follow-up period, 50 patients (89%) had experienced tumour progression and 27 were dead (48%).

Adverse events were mainly digestive; diarrhoea grade 3/4 was observed in 11 patients (20%) and vomiting grade 3 in one patient (2%). No grade 4 neutropenia and no febrile neutropenia were reported. Acneiform rash was observed in 42 patients (grade 1, 32%; grade 2, 32%; grade 3, 11%; grade 4, 0%).

Objective response rate (RR) according to RECIST criteria was 21.4%; this included one complete response (1.8%), 11 partial responses (19.6%), 19 stabilisations (33.9%) and 23 progressions (41%). Two patients were non-evaluable for response (3.6%). There was no difference in RR between the 70% of patients who progressed under treatment with irinotecan before administration of cetuximab and the RR observed in the other patients.

Survival

From the initiation of cetuximab treatment, median PFS was 4.4 months [95% confidence interval (CI), 3.0-5.7] and median OS was 16.0 months (95% CI, 13.5-18.5). No secondary resection was reported after cetuximab treatment in this population of elderly patients.

Discussion

Patients' characteristics in this retrospective study corresponded clearly in a selected population of elderly patients; however 12.5% were performance status (PS) 2, and the median number of previous chemotherapy regimens was three, which represents the classical number of chemotherapy lines offered to patients with MCRC. Progression under treatment with irinotecan-containing regimens was reported in only 70% of cases. None of these patients had severe comorbidities and they all corresponded to the group 1 ('fair') as defined by Balducci and Extermann [1].

The results of this retrospective study are very similar to those reported by Cunningham et al. for the BOND1 study (Phase II study comparing cetuximab alone to cetuximab plus irinotecan) in which the response rate was 22.9% and the PFS was 4.1 months for the group receiving irinotecan and cetuximab [3]; compared with 21.4% and 4.4 months, respectively, (95% CI, 3.0-5.7) in our retrospective study.

Tolerance was good in these elderly patients with no increase in the risk of diarrhoea or neutropenia; however, in some cases the irinotecan dose was reduced to 150 mg/[m.sup.2] for the first administration to test patients' tolerance.

Conclusion

Cetuximab combined with irinotecan is active in elderly patients failing on irinotecan-containing regimens. No age-specific complications have been observed and this combination may be used if elderly patients are considered to be fit for chemotherapy after geriatric evaluation. The benefit in PFS and OS appears to be of the same order as in younger patients. The use of cetuximab in first-line treatment in combination with FOLFIRI will depend on the final results of the CRYSTAL trial (Phase III study comparing FOLFIRI to FOLFIRI plus cetuximab) and subgroup analysis; however, the first results analysing prognostic factors did not show any differences between patients over 65 years old and younger patients [4]. The determination of predictive biological characteristics (K-ras status) may be a major help in the future to better select patients who will have the highest chance of good responses and tumour growth control [8] especially in the group of elderly patients for whom chemotherapy and targeted therapies are only recommended when the predicted benefit is likely to be clinically relevant.

References

[1.] Balducci L and Extermann M. Management of cancer in the older person: a practical approach. Oncologist, 2000, 5, 224-237.

[2.] Kohne CH, Grothey A, Bokemeyer C et al. Chemotherapy in elderly patients with colorectal cancer. Ann Oncol, 2001, 4, 435-442.

[3.] Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med, 2004, 351, 337-345.

[4.] Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. J Clin Oncol, 2007, 25 (suppl 18), 164S.

[5.] M Bouchada, Macarulla T, Spano J et al. Cetuximab and irinotecan-based chemotherapy as an active and safe treatment option for elderly patients with extensive pre-treated metastatic colorectal cancer. Proceedings of the 9th World Congress on Gastrointestinal Cancer, Ann Oncol, 2007, 18 (suppl 7), vii 71.

[6.] Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000, 92, 205-216.

[7.] Kaplan EL and Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc, 1958, 53, 457-481.

[8.] Lievre A, Bachet JB, Le Corre D et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res, 2006, 66, 3992-3995.

Jean Baptiste Bachet (1), Mohamed Bouchahda (2), Emmanuel Mitry (1), Tristan Cudennec (1), Jean Nicolas Vaillant (1) and Philippe Rougier (1)

(1) Hopital Ambroise-Pare, Boulogne, France and (2) Hopital Paul Brousse, Villejuif, France

Correspondence to: Philippe Rougier (email: [e-mail])