Raltitrexed + irinotecan as second-line chemotherapy in elderly patients with advanced colorectal cancer

doi:10.4236/mc.2012.12002

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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: [email protected]

2ZH Sint Maria, Brussel, Belgium; *Corresponding Author: [email protected]

3Medical Oncology Department, REG ZH Sint Maria, Halle, Belgium; *Corresponding Author: [email protected]

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

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

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

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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