Vol.1, No.2, 5-10 (2012) Modern Chemotherapy
http://dx.doi.org/10.4236/mc.2012.12002
Raltitrexed + irinotecan as second-line chemotherapy
in elderly patients with advanced colorectal cancer
Barbara Vandendriessche1*, Filip Geurs2*, Ingeborg Hilderson3*
1Regionaal Ziekenhuis SINT MARIA, Halle, Belgium; *Corresponding Author:
2ZH Sint Maria, Brussel, Belgium; *Corresponding Author:
3Medical Oncology Department, REG ZH Sint Maria, Halle, Belgium; *Corresponding Author:
Received 7 August 2012; revised 14 September 2012; accepted 8 October 2012
ABSTRACT
Aims and Background: Irinotecan is a standard
option for relapsed/refractory advanced colo-
rectal cancer. Combination with raltitrexed and
irinotecan at lower than MTD doses should
preserve disease stabilisation while decreasing
toxicity. Patients and Methods: From January
2004 to April 2009, we analyzed, retrospectively,
our data on irinotecan + raltitrexed, fixed doses,
as a second-line chemotherapy in elderly pa-
tients (>70 years) with advanced colorectal can-
cer after failure of oxaliplatin based chemothera-
py twenty-three patients were evaluated. Iri-
notecan 350 mg + raltitrexed 2.6 mg were given
every 3 weeks. Tumo r measurements were ob-
tained after every third course of therapy. Toxic-
ity was assessed weekly using the National
Cancer Institute Common Toxicity Criteria, ver-
sion 2. Results: The median number of treatment
courses received per patient was 4 (range, 1 - 8).
All patients were assessable for toxicity and 21
for response. The most frequently observed
severetoxicities were diarrhea (grade 2, 13%) No
cases of significant neutropenia occurred. Ob-
jective partial responses were observed in 3 pa-
tients (13%). An additional 10 patients (43%) had
stable disease as their best response. To date,
12 patients have progressed with a median time-
to-progression of 4.3 months and a median sur-
vival of 8.3 months. Conclusions: A three weekly
irinotecan + raltitrexed administration can indu-
ce tumor control in elderly patients with advanc-
ed colorectalcancer that has progressed during
or shortly after oxaliplatin-based chemotherapy.
The diarrhea by irinotecan, seems mitigated by
coadministration of a smaller dose of raltitrexed
Keywords: Colorectal; Elderly; Irinotecan;
Second-Line; Unresectable
1. INTRODUCTION
Irinotecan (CPT-11), a DNA topoisomerase I inhibitor,
has demonstrated antitumor activity as a single agent in
the second-line treatment of advanced colorectal cancer
(ACC) [1,2]. In Europe, the drug was developed as a
3-weekly regimen (350 mg/m2 every 3 weeks), whereas
in the USA, a weekly regimen (100 - 125 mg/m2/week
for 4 consecutive weeks out of 6) wasevaluated 3 - 5. In
patients with 5-fluorouracil (5-FU)-refractory disease,
these phase II trials demonstrated objective response
rates of 12% to 15% and median survivals of 8 to 9
months. However, the major toxicities encountered with
these regimens were grade 3 for diarrhea, neutropenia,
nausea and vomiting, and alopecia. Several randomized
studies have studied the optimal regimen for single-agent
CPT-11. In the first study, CPT-11 was administered
weekly (125 mg/m2), once every 2 weeks (250 mg/m2) or
once every 3 weeks (350 mg/m2), or as a continuous in-
fusion (10 mg/m2/day, 14-day continuous infusion every
3 weeks). It was concluded that the 3-week and 2-week
regimens showed better tolerance and induced higher
response rates than the weekly regimen 6. In another stu-
dy, CPT-11 schedules of weekly (125 mg/m2) and of once
every 3 weeks (350 mg/m2) demonstrated similar effi-
cacy and quality of life. However, the 3-week regimen
was associated with a significantly lower incidence of se-
vere diarrhea 7. By adding raltitrexed to 3 weekly iri-
notecan, diarrhea and neutropenia were decreased. By
lowering the dose to the lowest one active for both drugs,
we hoped to avoid the neutropenia associated with three
weekly irinotecan, whilst maintaining an easy outpatient
regimen conceived for elderly patients risk. Due to the
physiological reduction of functional organ reserve and
the presence of comorbid conditions, elderly patients are
often excluded from clinical trials. These subjects fre-
quently suffer from tumor-related symptoms and need
some kind of palliative treatment. In clinical practice,
they often receive inadequate and untested treatments [9,
10]. The aforementioned trials did not obtain exhaustive

B. Vandendriessche et al. / Modern Chemotherapy 1 (2012) 5-10
6
information on the CPT-11 activity and tolerability in this
subset of patients. From January 2004 to April 2011, we
retrospectively collected our data on elderly patients with
ACC responding to defined selection criteria and treated
with irinotecan + raltitexed as second-line treatment fol-
lowing 5-FU/oxaliplatin-based therapy.
2. PATIENTS AND METHODS
2.1. Patient Selection
Patients with the following inclusion criteria were
considered for retrospective analysis: histologically con-
firmed ACC; age 70 years; performance status PS) 2
(Eastern Cooperative Oncology Group); at least one bidi-
mensionally measurable lesion; disease progression dur-
ing or within 6 months of 5-FU/oxaliplatin-based che-
motherapy for advanced disease; radiotherapy acceptable
if it was completed 3 weeks before the start of CPT-11
chemotherapy and not including the only site of measure
able disease; adequate hematologic reserve and hepatic
and renal function, documented by WBC 3000 mm3, abso-
lute neutrophil count 1500 mm3, hemoglobin level 9.0
g/dL, platelets 100,000 mm3, serum bilirubin 1.5 mg/dL,
AST (SGOT) 3x and 5x upper level of institutional nor-
mal if liver metastases were present), and serum crea-
tinine 2.0 mg/dL. Patients with metastatic involvement of
the CNS, a psychiatric disorder that could interfere with
treatment compliance, significant concurrent infection or
concurrent or previous malignancy, or significant cardiac
disease were excluded.
2.2. Staging, Response and Toxicity
Evaluation
Retrospectively analyzed patients were assessed ac-
cording to usual clinical practice including a complete
medical history and a general physical examination. Tu-
mor staging was assessed by a two-view chest X-ray,
upper abdomen ultrasound and, when appropriate, diag-
nostic scans (i.e., computed tomography, magnetic reso-
nance imaging, or bone scan). Complete blood cell
counts with platelet and differential counts were obtained
weekly during chemotherapy. Serum chemistries were
repeated at least once every course. Physical examination,
tumour marker levels (CEA and Ca 19.9) and radiologic
tumour parameter assessment were obtained every 3 cy-
cles of treatment. The World Health Organization (WHO)
criteria were used for the definition of response, response
duration, time to progression (TTP), and survival1. 1)
Decreased tumour marker levels were considered useful
for monitoring therapy in patients whose CEA and CA
19-9 had been elevated at baseline, but were not used to
evaluate the response. All adverse reactions were recorded
before each chemotherapy course. Toxicities were scored
according to the standard National Cancer Institute
common toxicity criteria, version. 2) The worst experi-
enced grade was recorded for each patient and type of
toxicity.
2.3. Statistical Methods
Duration of response was calculated from the first
documentation of response to disease progression or last
examination. TTP was determined by the interval from
the beginning of therapy to the date when disease pro-
gression was first documented. Survival was measured
from the date of registration to the date of death. Patients
dying before completion of restaging were defined as
“progressed” on the date of death.
Overall survival from the date of the beginning of 5-
FU/oxaliplatin-based first-line chemotherapy was also
calculated.
3. TREATMENT
The analysis was conducted in one centre. Patients re-
ceived irinotecan 350 mg (1 h infusion ) + raltitrexed 2.5
mg (15 min infusion ) on days 1 repeated every 3 weeks.
Corticosteroids and granisetrons were delivered before
each chemotherapy infusion to prevent emesis. Primary
prophylaxis with Granulocyte Colony-Stimulating Factor
(GCSF) was not allowed. On days 1 the minimum re-
quirements for chemotherapy administration were a neu-
trophil count of 1500 mm3, a platelet count of 100,000
mm3, a hemoglobin level 9.0 g/dL, and no sign of organ
toxicity (excluding alopecia).
For the patients who experienced hemoglobin levels
<10 g/dL, the recombinant human erythropoietin was
admitted. Loperamide, 2 mg orally every 2 hr, was rec-
ommended in the event of delayed diarrhoea and discon-
tinued 12 h after the last liquid stool. If diarrhoea was not
under control after 48 hr, other supportive measures, in-
cluding hospitalization for iv rehydration, were prescribed.
In case of appearance of grade 3 - 4 diarrhoea, a 20%
dose reduction was chosen for the subsequent courses.
Treatment was administered until evidence of disease
progression, unacceptable toxicity or patient refusal.
4. RESULTS
4.1. Patient Demographics
Twenty-three patients treated in the involved institution
were analyzed. Their characteristics are shown in Table 1.
The median age of patients was 75 years (range, 70 - 89),
and 10 patients (43%) were 75 years old or older. Patients
generally had widespread disease, with the most frequent
distant sites including liver, lung, and peritoneum. Six
patients (26%) had received prior radiotherapy.

B. Vandendriessche et al. / Modern Chemotherapy 1 (2012) 5-10 7
T able 1. Main characteristics of the study patients.
Characteristics All patients (%)
No. of patients 23 (100)
Gender
Male 11 (48)
Female 12 (52)
Age (yr)
Median 75
Range 70 - 79
Primary site
Colon 15 (65)
Rectum 8 (35)
Site of metastases
Liver 15 (65)
Local (recurrent) 5 (22)
Lung 5 (22)
Peritoneum 4 (17)
Lymph nodes 2 (9)
Bone 2 (9)
Involved sites
1 14 (61)
2 7 (30)
>2 2 (9)
ECOG performance status
0 11 (48)
1 12 (52)
Previous therapy
Surgery 23 (100)
First-line chemotherapy 23 (100)
Radiotherapy 4 (17)
4.2. Treatment Duration
A total of 114 cycles of treatment were administered,
with a median of 4 cycles per patient (range, 1 - 8). Four
patients (17.3%) received less than three cycles because
of disease progression, 2 patients (8.6%) received less
than three cycles because of adverse events.
Nevertheless, all of the patients evaluated were con-
sidered assessable for efficacy and toxicity. There were
no cases of significant delay or dose reduction due to
neutropenia.
The median relative dose intensity value was 95%.
4.3. Tumor Response and Survival
In our analysis, the overall response rate was 13%.The
median duration of response was 4.1 months (range, 3 -
7+). In addition, 10 patients (43.4%) maintained stable
disease, and another 10 patients (43.4%) had disease
progression. The median follow-up for alive patients was
10.4 months. At the time of analysis, the median TTP
was 4.3 months (range, 1 - 8+) and the median survival
was 8.3 months (range, 1 - 16+). Excluding those pa-
tients not truly assessable, the response rate reached was
14.2%. The overall median survival from the beginning
of the first-line chemotherapy exceeded 18 months.
5. SAFETY
The main severe hematologic toxicity was neutropenia,
which was grade 3 in 30.4% and no grade 4 toxicity. Di-
arrhoea was the main non-hematologic toxicity, but grade
2 diarrhoea occurred in 13% of patients. One patient re-
ported severe diarrhoea not responsive to rescue Anemia,
fatigue, and alopecia were frequent toxicities.
Table 2. Results.
Total no. (%)
Patients entered 23 (100)
Patients assessable 21 (97)
Response
CR - (0)
PR 3 (13)
SD 10 (43.4)
PD 10 (43.4)
Response rate 13.0
Median duration, months
Response rate 4.1
Range 3 - 7+
TTP 4.3
Range 1 - 8+
Survival, months 8.3
Range 1 - 16+
CR, complete response; PR, partial response; SD, stable disease; PD, pro-
gression of disease; TTP, time to progresion. s

B. Vandendriessche et al. / Modern Chemotherapy 1 (2012) 5-10
8
Table 3. Different authors on second line irinotecan (or combinations) after oxaliplatin.
author year 1st 2nd number RR PFS (months) reference
Tournigand 1999 folfox folfiri 34 6 4 21
Maindrault 2000 folfox folfiri 22 20 not 24
Louvet 2007 folfox pem/iri 44 14 not 23
Sorbye 2007 folfox folfiri 59 7 4.1 25
Recchia 2004 folfox folfiri 35 20 7.1 27
Marbro 2004 folfox Folfiri-3 65 17 4.1 26
our series 2009 xelox Tom-iri 23 13 4.2
No thromboembolic phenomena occurred. No treatment
high-dose loperamide administration. This required hos-
pital admission related death was reported. The incidence
of any cholinergic symptom was significantly low (2
patients, 8.6%).
6. DISCUSSION
The treatment of elderly patients is an emerging issue.
Although irinotecan monotherapy is recognized as the
treatment of choice in second-line therapy (after failure
of 5-FU) in ACC, unfortunately only a few studies have
evaluated its feasibility in elderly patients. Most of the
trials enrolled patients with a cut-off age ranging from 60
- 65 years, probably not representative of a real elderly
population. Nevertheless, a higher rate of adverse events
was detected in a CPT-11 study in patients 65 years
compared with patients younger than 65 years (rate of
grade 3 and 4 diarrhoea, 39% and 19%, respectively) [5],
although this has not been confirmed in other studies
[12,13]. The dose-limiting toxicities for CPT-11 are de-
layed diarrhea and neutropenia [14,15]. However, toxic-
ity patterns depend on the CPT-11 schedule. Grade 3 - 4
diarrhea occurred in 36% of the patients treated on a
weekly basis and in 19% of those treated once every 3
weeks (P = 0.002) in the trial of Fuchs et al. [7], provid-
ing comparative data on the efficacy, tolerability, and
effect on quality of life between the schedules. A higher
treatment-related mortality rate was noted among pa-
tients receiving weekly CPT-11 (5.3%) than among those
given the every-3-weeks schedule (1.6%), although this
difference was not statistically significant. In the weekly
group, at least three of five treatment-related deaths were
caused by diarrhoea and dehydration. In contrast, grade 3
- 4 neutropenia appeared slightly more frequent in the
every 3 weeks schedule (34% vs 29%), but this differ-
ence was not statistically significant. On the other hand,
the randomized phase II study of Schoe maker et al. [6]
reporting severe neutropenia in 34% of the patients
treated once every 3 weeks and in 25% of those treated
weekly , also supports the idea that these differences in
toxicity profile are probably related to the administration
schedule rather than the dose per cycle. Adding ral-
titrexed to three weekly irinotecan proved to decrease
diarrhoea. In our study, we used lower doses of both
drugs, while maintaining its efficacy; in comparison to
other second line regimens.
The objective response rate (13%) is consistent with
those reported in the analysis of pooled data from 455
patients from European studies and 304 patients from
American studies [4,18,19]. The median TTP of 4.3
months and the median survival of 8.3 months are simi-
lar to those of the aforementioned pooled data analysis
(Table 3). Interestingly, we observed that the overall
median survival from the beginning of the first chem-
therapy exceeded 18 months. These data prompted us to
use a second-line chemotherapy in the elderly after first-
line failure. This finding suggests that it is important to
make all drugs that have well-demonstrated clinical ac-
tivity in ACC available to all patients to guarantee
maximal benefit of systemic therapy for survival, as
mentioned in the analysis of Grothey et al. [19]. Actu-
ally, this schedule should be prospectively used as a
skeleton of active and lower dose of chemotherapy to
which targeted treatments should be added.
The advent of several biologic agents such as cetuxi-
mab and bevacizumab, which demonstrated to be benefi-
cial and tolerable without adding supplementary toxicity
has revolutionazed the management of metastatic colon
cancer. Determining a chemotherapeutic basis to whom
these drug can be added will become a major issue, es-
pecially in elderly patients. However, it is important to
bear in mind that our patients were a subpopulation of
elderly patients characterized by a good general condi-
tion. Therefore, these data cannot be extrapolated to the

B. Vandendriessche et al. / Modern Chemotherapy 1 (2012) 5-10 9
elderly population in general, but must be confirmed by
randomized prospective studies.
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