Assessing the Impact of Chemotherapy on Tumor- Related Symptoms in Advanced Colorectal Cancer

Assessing the Impact of Chemotherapy on Tumor- Related Symptoms in Advanced Colorectal Cancer

ABSTRACT: In all patients with advanced colorectal cancer, disease eventually progresses following fluorouracil (5-FU) therapy, with a worsening of disease-related symptoms and quality of life (QOL). Irinotecan (CPT-11[Camptosar]) has produced response rates of 16% to 27% in patients with 5-FU-refractory colorectal cancer, along with a modest survival gain and possible palliative benefit. Disease-related symptoms and QOL are major end points of palliation, although few studies have assessed them as primary end points of response. The concept of palliative response benefit has been applied successfully to randomized trials of systemic therapy in prostate and pancreatic cancers. This article will describe how this concept has been used in the design of a current phase II trial assessing the palliative benefit of irinotecan in patients with 5-FU-refractory colorectal cancer. This trial uses disease-related symptoms and performance status as primary end points. Palliative response was defined prospectively as one or more of the following: (1) 50% decrease in pain score; (2) 50% decrease in narcotic analgesic usage; or (3) 10-point increase in Karnofsky performance scale from baseline for 4 weeks, without deterioration of any of these parameters. The difficulties in using patient-oriented end points as response criteria in this trial and in the clinic will be addressed. [ONCOLOGY 12(Suppl 6):121-128,1998]


Colorectal cancer is the second most common cause of cancer-related
death in industrialized populations. Despite intensive investigation,
the prognosis of patients with metastatic disease has not improved
over the past 30 years. Estimated 5-year survival is 5%,[1] and
systemic therapy affords only a modest survival advantage over
supportive care alone.[2] Systemic therapy is therefore given with
palliative intent. Disease-related symptoms and quality of life (QOL)
are the most relevant end points of palliation and are of major
concern to patients with advanced disease.[3,4]

For the first time in many years, a number of new agents are now
available for the treatment of advanced colorectal cancer. Assessment
of drug efficacy is usually based on the standard criteria of
radiologic response, time to progression, and overall survival. These
end points do not always correspond to palliation. The assessment of
these new agents, therefore, should include a measure of the impact
of therapy on disease-related symptoms and quality of life. In this
article, we will discuss the basis of this approach and its use in
the design of a phase II trial to assess the palliative benefit of
irinotecan (CPT-11 [Camptosar]) in patients with colorectal cancer
refractory to fluorouracil (5-FU).

Systemic Therapy for Colorectal Cancer

Fluorouracil-Based Therapy

The antimetabolite 5-FU is the most widely used cytotoxic agent in
advanced colorectal cancer. It acts through the binding of its
metabolite, 5-fluorodeoxyuridylate monophosphate (FdUMP), to
thymidylate synthase, which results in the depletion of substrates
for DNA synthesis. Response rates of between 15% and 20% have been
reported for 5-FU as initial monotherapy.[5]

Over the last decade, biochemical modulators, including leucovorin,
have been used to enhance the therapeutic efficacy of 5-FU. A
published meta-analysis of nine trials randomizing 1,381 patients to
5-FU and leucovorin vs 5-FU alone confirmed overall response rates of
23% and 11%, respectively. There was no survival advantage reported
for either regimen.[6] Improved tumor response rates have also been
achieved by varying the administration regimen of 5-FU, especially by
using a continuous infusion.[7,8]

In all patients with advanced colorectal cancer, disease eventually
progresses on 5-FU therapy, with worsening of disease-related
symptoms and QOL. The role of systemic therapy in this patient
population is poorly defined, given the poor activity of currently
available standard cytotoxic agents.[9] Of the newer agents currently
under evaluation, the camptothecin derivatives have generated
considerable clinical attention, especially in this population with
refractory/resistant disease.

Camptothecin and Its Analogs

The camptothecins act by inhibiting topoisomerase I, an enzyme that
forms a covalently linked cleavable complex with DNA, resulting in a
single-strand break.[10] Then, the enzyme-DNA complex allows for
swiveling of the single strand, followed by replication and
subsequent repair. The camptothecin derivatives stabilize this
complex, maintaining the single-strand break.[11] With prolonged
exposure to the camptothecins, the replication fork collides with the
drug-stabilized cleavable complex, inducing a lethal double-strand
DNA break.[12]

Irinotecan is a semisynthetic analog of camptothecin that has better
water solubility, an improved toxicity profile, and greater
activity.[13] In vivo, irinotecan is converted by hepatic
carboxylesterase to its active metabolite, 7-ethyl 10-hydroxy-campothecin
(SN-38), [14,15] which has demonstrated a greater than 250-fold
antitumor activity than the prodrug in vitro.[16] Phase I studies of
irinotecan have been carried out in Japan, the United States, and
France using various administration schedules. Activity has been
observed in non-small-cell lung, breast, colon, and cervical cancers,
with minor activity in other malignancies.[16]

The toxicities reported include delayed-onset diarrhea, neutropenia,
nausea, vomiting, an acute cholinergic syndrome, fatigue, and
alopecia; these have been discussed in detail in a recent review.[17]
The principal toxicity in the pivotal US phase II trials in
colorectal cancer was delayed diarrhea, which has the potential to
diminish QOL. It has a median onset of 11 days from the commencement
of therapy, with 31% of patients suffering National Cancer Institute
(NCI) grade 3 or 4 toxicity.[18]

The severity of delayed diarrhea has been reduced by the use of
intensive, high-dose antidiarrheal medications.[19] In the
aforementioned phase II trials, the incidence of severe diarrhea was
reduced from 17.5% to 9.8% of courses when this regimen was begun at
the onset of diarrhea.[18]

Irinotecan in Previously Treated Colorectal Cancer

Phase II Trials

Phase II trials of irinotecan in patients with previously treated
colorectal cancer have been completed in Japan, France, and multiple
centers within the United States. A Japanese phase II study evaluated
irinotecan at a dose of 100 mg/m² weekly or 150 mg/m² every
2 weeks in 67 colorectal cancer patients, including 51 who had
previously received chemotherapy (oral fluoropyrimidines, intravenous
5-FU, or 5-FU and leucovorin). Irinotecan produced an overall partial
response rate of 27%, with a median duration of response of 50 days
(range, 9 to 120 days). The response rate in patients previously
treated with chemotherapy or radiotherapy was 25%.[20]

Pooled data have been analyzed from US multicenter single-agent
trials involving 304 patients with cancers that were refractory or
resistant to 5-FU (ie, those who progressed during or relapsed
following initial chemotherapy). Irinotecan was administered in a
6-week regimen (weekly treatment for 4 weeks, followed by 2
weeks’ rest) at a starting dose of 100, 125, or 150 mg/m².
Of the 304 patients, 193 commenced treatment at a dose of 125
mg/m². On an intent-to-treat analysis, response rates based on
starting dose were as follows: 22% for the 150-mg/m² dose, 15%
for 125 mg/m², and 8% for 100 mg/m². Overall, 49% of
patients had stable disease for at least 2 months. The median
duration of response was 6.0 months.[18]

The European experience with a 3-week regimen in previously treated
patients has also been reported. Of 130 pretreated patients enrolled
in the trial, 62 patients had progressed while receiving prior
5-FU-based chemotherapy and were defined as 5-FU-resistant. Similar
to the US trials, the European investigators observed a response rate
to irinotecan of 17.7% in pretreated patients, including a response
rate of 16.1% in the 5-FU-resistant subset. The median time to
response was 9.3 weeks, and median survival duration was 10 months.[21]

Phase III Trial of Irinotecan as Second-Line Therapy

As reported by Cunningham et al,[22] an inter-European phase III
randomized trial comparing irinotecan to best supportive care and to
best second-line 5-FU-based therapy in patients with 5-FU-refractory
disease has been completed. This trial is described in detail in
another article in this supplement ; this article will focus on the
trial’s results
with respect to QOL and disease-related symptoms.

Both studies prospectively assessed, as secondary end points, the
effect of irinotecan on patients’ QOL and disease-related
symptoms using the European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 version 2.0
instrument.[23] In the comparison of irinotecan to best second-line
therapy, the irinotecan arm demonstrated an improvement in pain-free
survival of 10.3 vs 8.5 months (P = .06), with a reduction in
analgesic requirements and an improvement in performance status.[22]

In the comparison of second-line irinotecan vs best supportive care,
there was a significant improvement in the global QOL score in favor
of irinotecan. In addition, the irinotecan-treated patients
demonstrated a significant improvement in pain intensity, as measured
by the EORTC QLQ-C30 instrument (P = .002), which was associated with
a decrease in analgesic requirements.[22]


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