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%, and
systemic therapy affords only a modest survival advantage over
supportive care alone. 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).
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.
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. 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. Of the newer agents currently
under evaluation, the camptothecin derivatives have generated
considerable clinical attention, especially in this population with
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. 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. With prolonged
exposure to the camptothecins, the replication fork collides with the
drug-stabilized cleavable complex, inducing a lethal double-strand
Irinotecan is a semisynthetic analog of camptothecin that has better
water solubility, an improved toxicity profile, and greater
activity. 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. 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.
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.
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.
The severity of delayed diarrhea has been reduced by the use of
intensive, high-dose antidiarrheal medications. 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.
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%.
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.
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.
Phase III Trial of Irinotecan as Second-Line Therapy
As reported by Cunningham et al, 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
trials 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. 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.
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.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics. CA Cancer
J Clin 48:6-29, 1997.
2. Scheithauer W, Rosen H, Kornek G-V, et al: Randomized comparison
of combination therapy plus supportive care with supportive care
alone in patients with metastatic colorectal cancer. Br Med J
3. Guyatt GH, Thompson PJ, Berman LB, et al: How should we measure
function in patients with chronic heart and lung diseases? J Chron
Dis 38:517-524, 1985.
4. Guyatt GH, Feeney DH, Patrick DL: Measuring health-related quality
of life. Ann Intern Med 118:622-629, 1993.
5. Moertel CG: Chemotherapy of gastrointestinal cancer, in Tajnon HJ,
Staquet MJ (eds): Recent Advances in Cancer Treatment, vol 3, pp
311-323. New York, Raven, 1977.
6. Advanced Colorectal Cancer Meta-Analysis project: Modulation of
fluorouracil by leucovorin in patients with advanced colorectal
cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992.
7. Lokich JJ, Ahlgren JD, Gullo JJ, et al: A prospective randomized
comparison of continuous infusion fluorouracil with a conventional
bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic
Oncology program study. J Clin Oncol 7:425-432, 1989.
8. De Gramont A, Bosset JF, Milan C, et al: A prospectively
randomized trial comparing 5-FU bolus with low dose folinic acid and
5-FU bolus plus continuous infusion with high-dose folinic acid for
advanced colorectal cancer (abstract). Proc Am Soc Clin Oncol 14:455, 1995.
9. Hermann R: Systemic treatment of colorectal cancer. Eur J Cancer
10. Hsiang JH, Hertzberg R, Hecut S, et al: Campothecin induces
protein-limited DNA breaks via mammalian DNA topoisomerase I. J Biol
Chem 260:14873-14878, 1985.
11. Eng WK, Faucette L, Johnson RK, et al: Evidence that DNA
topoisomerase I is necessary for the cytotoxic effects of
camptothecin. Mol Pharmacol 34:755-760, 1988.
12. Hsiang YH, Likou MG, Liu LF, et al: Arrest of replication forks
by drug stabilized topoisomerase-I-DNA cleavable complexes as a
mechanism of cell killing by camptothecin. Cancer Res 49:5077-5082, 1989.
13. Kunimoto T, Nitta K, Tanaka T, et al: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin,
a novel water-soluble derivative of camptothecin, against murine
tumors. Cancer Res 47:5994-5997, 1987.
14. Tsuji T, Kaneda, Kado K, et al: CPT-11 converting enzyme from rat
serum: Purification and some properties. J Pharmocobiodyn 14:341-349, 1991.
15. Kawato J, Aonuma M, Hiroto Y, et al: Intracellular roles of
SN-38, a metabolite of the camptothecin derivative CPT-11, in the
anti-tumour effect of CPT-11. Cancer Res 51:4187-4191, 1991.
16. Creemers GJ, Lund B, Verweij J: Topoisomerase I inhibitors:
Topotecan and irinotecan. Cancer Treat Rev 20: 73-96, 1994.
17. Rothenberg ML: Topoisomerase I inhibitors: Review and update. Ann
Oncol 8:837-855, 1997.
18. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irinotecan therapy
for patients with previously treated colorectal cancer: Overall
results of FDA-reviewed pivotal US trials (abstract). Proc Am Soc
Clin Oncol 16:803, 1997.
19. Abigerges D, Chabot GG, Armand JP, et al: Phase I and
pharmacologic studies of camptothecin analogue irinotecan
administered every three weeks in cancer patients. J Clin Oncol
20. Shimada Y, Yoshino M, Wakui, et al: Phase II study of CPT-11, a
new camptothecin derivative in metastatic colorectal cancer. J Clin
Oncol 11:909-913, 1993.
21. Rougier P, Culine S, Bugat R, et al: Multicenter phase II study
of phase II study of first line CPT-11 in advanced colorectal cancer:
Preliminary results (abstract). Proc Am Soc Clin Oncol 13:200, 1994.
22. Cunningham D, Pyrhonen S, James RD, et al: A phase III
multicenter randomized study of CPT-11 versus supportive care (SC)
alone in patients with 5-FU resistant metastatic colorectal cancer
(abstract). Proc Am Soc Clin Oncol 17:1a, 1998.
23. Aaaronson NK, Ahmedzai S, Bergman B, et al: The European
Organization for Research and Treatment of cancer QLQ-C30: A
quality-of-life instrument for use in international trials in
oncology. J Natl Cancer Inst 85:365-376, 1993.
24. Campbell A. Subjective measures of well being. Am Psychol
25. Outcome Working Group, Health Service Committee: Outcomes of
cancer treatment for technology assessment and cancer treatment
guidelines. J Clin Oncol 14:671-679, 1996.
26. Stephens RJ, Hopwood P, Girling DJ, et al: Randomized trials with
quality of life endpoints: Are doctors ratings of patients
physical symptoms interchangeable with patients self-ratings?
Qual Life Res 6:225-236, 1997.
27. Slevin ML, Plant H, Lynch D, et al: Who should measure quality of
life, the doctor or the patient? Br J Cancer 57:109-112, 1988.
28. Warr D, McKinney S, Tannock I: Influence of measurement error in
assessment of response to anticancer chemotherapy: Proposal for new
criteria of tumor response. J Clin Oncol 2:1040-1046, 1984.
29. Priestman TJ, Baum M: Evaluation of quality of life in patients
receiving treatment for advanced breast cancer. Lancet 1:899-900, 1976.
30. Coates A, Thomson D, McLeod GRM, et al: Prognostic value of
quality-of-life scores in a trial of chemotherapy with and without
interferon in patients with malignant melanoma. Eur J Cancer
31. Ruckdeschel JC, Piantadosi S, and the Lung Cancer Study Group:
Quality of life assessment in lung surgery for bronchogenic
carcinoma. Thorac Surg 6:201-205, 1991.
32. Tannock IF, Osoboa D, Stockler MR, et al: Chemotherapy with
mitoxantrone plus prednisone or prednisone alone for symptomatic
hormone-resistant prostate cancer: A Canadian randomized trial with
palliative endpoints. J Clin Oncol 14:1756-1764, 1996.
33. Coates A, Porzsolt F, Osoba D: Quality of life in oncology
practice: Prognostic value of EORTC QLQ-C30 score in patients with
advanced malignancy. Eur J Cancer 33:1025-1030, 1997.
34. The Nordic Gastrointestinal Tumour Adjuvant Therapy Group:
Expectant or primary chemotherapy in patients with advanced
asymptomatic colorectal cancer: A randomized trial. J Clin Oncol
35. Glimelius B, Graf W, Hoffman K, et al: General condition of
asymptomatic patients with advanced colorectal cancer receiving
palliative chemotherapy: A longitudinal study. Acta Oncol 31:645-651, 1992.
36. Glimelius B, Hoffman K, Graf W, et al: Quality of life during
chemotherapy in patients with symptomatic advanced colorectal cancer:
The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer
37. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival
and clinical benefit with gemcitabine as first-line therapy for
patients with advanced pancreas cancer: A randomized trial. J Clin
Oncol 15:2403-2413, 1997.
38. Rothenberg ML, Abbruzzese JL, Moore MJ, et al: A rationale for
expanding the endpoints for clinical trials in advanced pancreatic
carcinoma. Cancer 78:627-632, 1996
39. Andersen JS, Burris HA, Casper E, et al: Development of a new
system for assessing clinical benefit for patients with advanced
pancreatic cancer (abstract). Proc Am Soc Clin Oncol 13:461, 1994.
40. Karnofsky DA, Abelamn WH, Craver LF, et al: The use of nitrogen
mustards in palliative treatment of carcinoma with particular
reference to bronchogenic carcinoma. Cancer 1:634-656, 1948.
41. Selby PJ, Chapman J-AW, Etazadi-Amoli J, et al: The development
of a method for assessing quality of life in cancer patients. Br J
Cancer 50:13-22, 1984.
42. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial of
irinotecan in patients with progressive or rapidly recurrent
colorectal cancer. J Clin Oncol 14:1128-1135, 1996.
43. Fayers PM, Jones DR: Measuring and analyzing quality of life in
cancer clinical trials: A review. Stat Med 2:429-446, 1983.
44. Osoba D, Zee B, Pater J, et al: Psychometric properties and
responsiveness of the EORTC Quality of Life Questionnaire (QLQ-C30)
in patients with breast, ovarian and lung cancer. Qual Life Res
45. Bergman B, Sulivan M, Sorenson S: Quality of life during
chemotherapy for small-cell lung cancer: II. A longitudinal study of
the EORTC Core Quality of Life Questionnaire and comparison with the
Sickness Impact Profile. Acta Oncol 31:19-28, 1992.
46. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of
cancer treatment. Cancer 47:207-214, 1981.