Cetuximab in elderly patients.Introduction
Since the demonstration that 5-fluorouracil (5FU)-based chemotherapy provides benefit in elderly patients suffering from metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
Mentioned in: Coagulation Disorders
pertaining to or of the nature of a metastasis. colorectal cancer colorectal cancer
Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. (MCRC MCRC Metastatic Colorectal Cancer
MCRC Marine Corps Recruiting Command (USMC)
MCRC Malicious Code Research Center (Finjan Software)
MCRC Motorcycle Racing Club ), 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 chi·mer·ic
1. Relating to a chimera.
2. Composed of parts of different origin. humanised monoclonal antibody monoclonal antibody, an antibody that is mass produced in the laboratory from a single clone and that recognizes only one antigen. Monoclonal antibodies are typically made by fusing a normally short-lived, antibody-producing B cell (see immunity) to a fast-growing , is an epidermal growth factor receptor This article is about a cell suface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate.
The epidermal growth factor receptor (EGFR EGFR Epidermal Growth Factor Receptor (a kinase enzyme)
EGFR Estimated Glomerular Filtration Rate ) inhibitor. Its efficacy in terms of progression-free survival (PFS PFS,
n post facilitation stretch; therapeutic approach utilized during proprioceptive neuromuscular facilitation in which the patient begins the stretch midway between the fully relaxed and fully stretched position and uses maximum level of effort to ) has been demonstrated in MCRC resistant to irinotecan-based chemotherapy  and in first-line chemotherapy in combination with irinotecan, leucovorin and continuous infusion 5FU (FOLFIRI FOLFIRI Folinic Acid, Fluorouracil & Irinotecan (chemo treatment) ) . 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 .
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 bolus /bo·lus/ (bo´lus)
1. a rounded mass of food or pharmaceutical preparation ready to swallow, or such a mass passing through the gastrointestinal tract.
2. a concentrated mass of pharmaceutical preparation, e. 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 FOLFOX 5-Fluorouracil, Leucovorin and Oxaliplatin (chemo treatment) ; 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).
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 TNM classification Oncology An international system for staging malignancy which measures 3 major parameters of a cancer: T–size or extent of the primary tumor, as determined by clinical exam, endoscopy, laparoscopy, biopsy or resective procedures, ; adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant)
1. assisting or aiding.
2. a substance that aids another, such as an auxiliary remedy.
3. radiochemotherapy for rectal cancer Rectal Cancer Definition
The rectum is the portion of the large bowel that lies in the pelvis, terminating at the anus. Cancer of the rectum is the disease characterized by the development of malignant cells in the lining or epithelium of the rectum. or chemotherapy for colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States. 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 Metastasis (plural, metastases)
A tumor growth or deposit that has spread via lymph or blood to an area of the body remote from the primary tumor.
Mentioned in: Malignant Melanoma (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 Bilirubin
The predominant orange pigment of bile. It is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin in red blood cells, and other chromoproteins such as myoglobin, cytochrome, and catalase. concentration, alkaline phosphatase alkaline phosphatase /al·ka·line phos·pha·tase/ (ALP) (fos´fah-tas) an enzyme that catalyzes the cleavage of orthophosphate from orthophosphoric monoesters under alkaline conditions. level, carcinoembryonic antigen (CEA CEA carcinoembryonic antigen.
CEA (Carcinoembryonic antigen) ) 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 Common Toxicity Criteria (CTC) is a standardised classification of side effects used in assessing drugs for cancer therapy. Most US drug trials base their observations on this system which has a range of grades from 0-5, 5 usually equating to death. Currently version 3. on haematological Adj. 1. haematological - of or relating to or involved in hematology
hematologic, hematological , 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 Response Evaluation Criteria In Solid Tumors (RECIST) - is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stable"), or worsen ("progression") during treatments. (RECIST RECIST Response Evaluation Criteria in Solid Tumors (oncology review criteria) ) criteria were used to assess tumour response .
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 .
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 Neutropenia Definition
Neutropenia is an abnormally low level of neutrophils in the blood. Neutrophils are white blood cells (WBCs) produced in the bone marrow that ingest bacteria. ) 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 febrile /feb·rile/ (feb´ril) pertaining to or characterized by fever.
Of, relating to, or characterized by fever; feverish. 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.
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.
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 .
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 ; 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.
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 . 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  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.
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tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. 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.
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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: firstname.lastname@example.org)