Lung cancer is the leading cause
of cancer-related morbidity and
mortality. The estimated incidences for the year 2000 are 164,100 new cases and
156,900 deaths in the United States alone. Five-year survival figures for
lung cancer have remained in the 15% range from 1974 through 1995; most of
these cures involve early cancers usually treated with surgery alone. However,
approximately 35% of patients present with locally advanced disease that is not
amenable to surgical therapy, but is nonetheless potentially curable.
Tradition- al treatment with radiation alone in these patients has yielded low
cure rates. This has spurred investigations of new methods to improve outcome.
Peckham and Steele outlined several possible mechanisms of
interaction between radiation and chemotherapies: spatial cooperation,
enhancement of tumor response, radioprotection, and nonoverlapping toxicities
are all ways that chemotherapy and radiation may interact to improve therapeutic
ratio. Spatial cooperation describes a situation where disease located in a
specific anatomic site is missed by one agent but treated by another.
Enhancement refers to the administration of an agent that increases the effect
of another agent, or when the effect of the combination is greater than would be
expected with either agent alone. Radioprotection refers to the administration
of a chemotherapeutic agent that would allow safe delivery of higher radiation
Finally, toxicity independence, or nonoverlapping toxicities,
describes when two partially effective agents can be used in combination without
having to substantially reduce dose levels to avoid unacceptable side effects.
Multiple phase III trials have shown benefits with the combined use of
chemotherapy and radiation in the treatment of non-small-cell lung cancer at
the expense of increased toxicity.[4-7] Overall, the meta-analysis from
Pritchard et al suggests that traditional chemotherapy added to radiotherapy
adds an average of 2 months to patient survival.
Several new active agents that hold promise for improving
outcome in lung cancer patients are emerging. These include paclitaxel (Taxol),
docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), and
irinotecan (Camptosar, CPT-11), which have demonstrated response rates ranging
from 20% to 54% as single agents in metastatic disease. Finding a cure for
this disease will require a better understanding of the mechanisms of action of
these agents and their interactions with ionizing radiation, and the proper
sequencing of these agents with other drugs and with radiation. This article
will review the literature on the use of irinotecan in combination with thoracic
irradition in the treatment of non-small-cell lung cancer.
Camptothecin and its derivatives target DNA topoisomerase I, the
DNA-relaxing enzyme.[9-12] This enzyme relaxes both positively and negatively
supercoiled DNA, which allows diverse essential cellular processes, including
DNA replication and transcription, to proceed. The key step for drug activity is
stabilization of the topoisomerase I-DNA intermediate that the enzyme forms
when cleaving DNA to allow for uncoiling to occur.[9-14] It is believed that
collision between the drug-trapped topoisomerase-DNA complex and the replication
material leads to G2-phase cell-cycle arrest and, ultimately, cell death.
Camptothecin is the prototype drug that was initially studied in
the 1970s as a chemotherapeutic agent; however, its use was discontinued because
of excessive toxicity. Ongoing research has begun to focus on camptothecin
derivatives that have antineoplastic activity with improved toxicity profiles.
This generation of drugs includes irinotecan. Irinotecan is a prodrug that is
metabolized intracellularly to its active metabolite, SN-38, by a
carboxylesterase- converting enzyme. This metabolite is more than 1,000
times more potent than irinotecan as an inhibitor of topoisomerase I. All of
the camptothecins have a terminal lactone ring that can be hydrolyzed to a less
active carboxylate species. Under acidic conditions, however, like that in the
tumor microenvironment, the active lactone species is favored.
The plasma half-life of SN-38 after a short IV infusion is 10.2
hours (range: 5.9 to 13.8 hours), so that nanomolar concentrations of the drug
persist for more than 2 days. This may affect its cytotoxicity. The major
method of elimination of SN-38 is hepatic glucuronidation; a decreased ability
to glucuronidate is thought possibly to correlate with increased
gastrointestinal side effects. Clinically, the dose-limiting toxicity of
irinotecan is delayed-onset diarrhea, which can be profuse and potentially life
threatening. The diarrhea is thought to be related to the high S-phase fraction
of the intestinal mucosa, as well as to the action of intestinal flora
glucuronidase in cleaving the camptothecin-glucuronidase conjugate, leading to
release of the drug in the intestinal lumen. Other common toxicities include
neutropenia, nausea, and vomiting.
In planning combined-modality chemoradiotherapy, it is important
to understand the mechanism of interaction between the two modalities. Several
investigators have reported that camptothecin enhances the cytotoxic effect of
radiation in vitro and in vivo.[20,21] Omura et al assessed the radiosensitizing
effects of SN-38 in HT-29 spheroids derived from a human colon cancer cell line.
Results showed significantly enhanced cell kill with combined radiation and
irinotecan; the largest gains in cytotoxicity occurred when irinotecan was
administered just before or just after the radiation. The data also suggest that
the mechanism of radiosensitization in the spheroids is through inhibition of
potentially lethal damage repair.
Chen et al showed that camptothecin derivatives radiosensitized
log-phased human MCF-7 breast cancer cells in a schedule-dependent manner.
Essentially, cells exposed to 20(S)-10,11 methylenedioxycamptothecin before or
during radiation had sensitization ratios of 1.6, while those treated with the
drug after radiation had substantially less enhancement of radiation-induced DNA
damage. The clinical implication of these results is that patients should be
treated with camptothecin derivative-based chemotherapy prior to or during
radiotherapy to receive the full benefits of combined-modality therapy. Emerging
data also show that other camptothecin derivativesincluding 9-nitro-
20(S)-camptothecin, 9-aminocamptothecin, and topotecan (Hycamtin)can
potentiate the lethal effects of radiation.
There are several hypotheses, with varying amounts of supportive
evidence, regarding the mechanism of interaction between radiation and
irinotecan. The first hypothesis suggests that inhibition of topoisomerase I by
camptothecin or its derivatives leads to inhibition of repair of
radiation-induced DNA strand breaks. The second hypothesis suggests that
camptothecin or its analogs causes redistribution of cells into the more
radiosensitive G2 phase of the cell cycle. The third hypothesis is that
topoisomerase I-DNA adducts are trapped by irinotecan at the sites of
radiation-induced single-strand breaks, leading to their conversion into
double-strand breaks. The primary mechanism involved with radiosensitization
may depend on which camptothecin derivative is being used; there is currently
insufficient evidence to identify the underlying mechanism with certainty.
Combined-modality treatment relies on the ability of focused
radiation and concurrent radiosensitizing agents to treat locally, while leaving
the potential micrometastatic disease for chemotherapy to control. As such, it
is also important to maximize the cytotoxic effects of chemotherapy while
minimizing toxicities. This requires an understanding of the mechanisms of
interaction between different drugs. Basic principles used in selecting drugs
include nonoverlapping toxicities, differing mechanisms of action, and non-cross-
resistance. Based on these criteria, both preclinical and clinical trials
have been undertaken to evaluate the cisplatin (Platinol)/irinotecan combination
in lung cancer.
In xenografts of the small-cell lung cancer tumor lines Mnsul
and LX1, Kudoh et al showed that irinotecan in combination with cisplatin led to
a larger reduction in tumor size than either agent alone. However, in
xenografts of Mnqul, a cell line developed from human squamous cell lung
carcinoma, combination cisplatin/irinotecan treatment was more effective than
cisplatin alone but not more effective than irinotecan alone. According to the
authors, the data clearly suggest that the combination of radiation and
irinotecan should be effective in small-cell lung cancer; however, they
cautioned that more data are needed, using a different non-small-cell lung
cancer model, prior to concluding that the combination is better than irinotecan
In patients with advanced lung cancer, early studies using
irinotecan alone have yielded favorable response rates (> 30%). The
combination of irinotecan and cisplatin has also been assessed in phase I and II
clinical trials; early data from phase II studies revealed a 48% response rate
in non-small-cell lung cancer and 78% in small-cell lung cancer. A
subsequent phase I trial looked at fractionation of both the cisplatin and
irinotecan doses, ie, 60 mg/m2 of cisplatin and escalating doses of irinotecan
were given on days 1 and 8. Cycles were repeated every 4 weeks. An impressive
78% response rate was seen in 18 patients with non-small-cell lung cancer.
A North American phase II trial examined the combination of cisplatin at 80 mg/m2 on day 1 and irinotecan at 60
mg/m2 on days 1, 8, and 15 in 4-week
courses, with the possibility of escalating the irinotecan dose according to
side effects. The irinotecan dose was ultimately modified to less than 40
mg/m2; the response rate was 28.8% in 52 patients.
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics,
2000. CA Cancer J Clin 50(1):7-33, 2000.
2. Stevens CW, Lee JS, Cox J, et al: Novel approaches to locally
advanced unresectable non-small cell lung cancer. Radiother Oncol 55(1):11-18,
3. Steele GG, Peckham MJ: Exploitable mechanisms in combined
radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol
Phys 5:85-91, 1979.
4. Dillman RO, Herndon J, Seagren SL, et al: Improved survival
in stage III non-small-cell lung cancer: Seven year follow up of Cancer and
Leukemia Group B 8433 trial. J Natl Cancer Inst 88:1210-1215, 1996.
5. Schaakae-Koning C, Vanden Bogart W, Dalesio O: Effects of
concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer.
N Engl J Med 326:524-530, 1992.
6. Sause WT, Scott C, Taylor S, et al: Radiation Therapy
Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588:
Preliminary results of a phase III trial in regionally advanced, unresectable
non-small cell lung cancer. J Natl Cancer Inst 87:198-205, 1995.
7. LeChevalier T, Arriagada R, Quoix E, et al: Radiotherapy
alone versus combined chemotherapy and radiotherapy in nonresectable
non-small-cell lung cancer: First analysis of a randomized trial in 353
patients. J Natl Cancer Inst 83:417-423, 1991.
8. Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy
compared with radiotherapy alone in the treatment of locally advanced,
unresectable, non-small cell lung cancer. A meta-analysis. Ann Intern Med
9. Hsiang Y-H, Hertzberg R, Hecht S, et al: Camptothecin induces
protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem
10. Hsiang Y-H, Liu LF: Identification of mammalian DNA
topoisomerase I as an intracellular target of the anticancer drug camptothecin.
Cancer Res 48:1722-1726, 1988.
11. Andoh T, Ishii K, Suzuki Y, et al: Characterization of a
mammalian mutant with a camptothecin resistant DNA topoisomerase I. Proc Natl
Acad Sci USA 84:5565-5569, 1987.
12. Nitiss J, Wang JC: DNA topoisomerase-targeting antitumor
drugs can be studied in yeast. Proc Natl Acad Sci USA 85:7501-7505, 1988.
13. Chen AY, Yu C, Gatto B, et al: DNA minor groove-binding
ligands: A different class of mammalian DNA topoisomerase I inhibitors. Proc
Natl Acad Sci USA 90:8131-8135, 1993.
14. Chen AY, Yu C, Bodley A, et al: A new mammalian DNA
topoisomerase I poison Hoechst 33342: Cytotoxicity and drug resistance in human
cell cultures. Cancer Res 53:1332-1337, 1993.
15. Chen AY, Choy H, Rothenberg ML: DNA topoisomerase
I-targeting drugs as radiation sensitizers. Oncology 13(10 suppl 5):39-46, 1999.
16. Chen AY, Leroy FL. DNA topoisomerases: Essential enzymes and
lethal targets. Annu Rev Pharmacol Toxicol 34:191-218, 1994.
17. Takimoto CH, Wright J, Arbuck SG: Clinical applications of
the camptothecins. Biochim Biophys Acta 1400(1-3):107-119, 1998.
18. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles of
SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor
effect of CPT-11. Cancer Res 51:4187-4191, 1991.
19. Araki E, Ishikawa M, Iigo M, et al: Relationship between
development of diarrhea and the concentration of SN-38, an active metabolite of
CPT-11, in the intestine and the blood plasma of athymic mice following
intraperitoneal administration of CPT-11. Jpn J Cancer Res 84(6):697-702, 1993.
20. Kudoh S, Takada M, Masuda N, et al: Enhanced antitumor
efficacy of a combination of CPT-11, a new derivative of camptothecin, and
cisplatin against human lung tumor xenografts. Jpn J Cancer Res 84(2):203-207,
21. Rich TA, Kirichenko AV: Camptothecin radiation
sensitization: Mechanisms, schedules, and timing. Oncology 12(8 suppl
22. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of the
camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in
human colon adenocarcinoma cells grown as spheroids. Radiat Oncol 43:197-201,
23. Chen AY, Okunieff P, Pommier Y, et al: Mammalian DNA
topoisomerase I mediates the enhancement of radiation cytotoxicity by
camptothecin derivatives. Cancer Res 57(8):1529-1536, 1997.
24. Amorino GP, Hercules SK, Mohr PJ, et al: Preclinical
evaluation of the orally active camptothecin analog, RFS-2000
(9-Nitro-20(S)-Camptothecin) as a radiation enhancer. Int J Radiat Oncol Biol
Phys 47(2):503-509, 2000.
25. Lamond JP, Wang M, Kinsella TJ, et al: Radiation lethality
enhancement with 9-aminocamptothecin: comparison to other topoisomerase I
inhibitors. Int J Radiat Oncol Biol Phys 36(2):369-376, 1996.
26. Mattern MR, Hofmann GA, McCabe Fl, et al: Synergistic cell
killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F
104864). Cancer Res 51(21):5813-5816, 1991.
27. De Vita VT, Hellman S, Rosenberg SA: Cancer. Priniciples and
Practice of Oncology, 5th ed, pp 333-348. Philadelphia, Lippincott-Raven, 1997.
28. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study of
CPT-11, a new derivative of camptothecin for previously untreated non-small-cell
lung cancer. J Clin Oncol 10(1):16-20, 1992.
29. Nakagawa K, Fukuoka M, Nitiani H, et al: Phase II study of
irinotecan (CPT-11) and cisplatin in patients with advanced non-small-cell lung
cancer (NSCLC). Proc Am Soc Clin Oncol 12:332, 1993.
30. Fujiwara Y, Yamakido M, Fukuoka M, et al: Phase II study of
irinotecan (CPT-11) and cisplatin (CDDP) in patients with small cell lung cancer
(SCLC). Proc Am Soc Clin Oncol 13:335, 1994.
31. Ueoka H, Tabata M, Kiura K, et al: Fractionated
administration of irinotecan and cisplatin for treatment of lung cancer: A phase
I study. Br J Cancer 79(5-6):984-990, 1999.
32. Devore RF, Johnson DH, Crawfors J, et al: Phase II study of
irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer.
J Clin Oncol 17(9):2710-2720, 1999.
33. Clamon G, Herndon J, Cooper R, et al: Radiosensitization
with carboplatin for patients with unresectable stage III non-small-cell lung
cancer: A phase III trial of the Cancer and Leukemia Group B and the Eastern
Cooperative Oncology Group. J Clin Oncol 17(1):4-11, 1999.
34. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of
concurrent versus sequential thoracic radiotherapy in combination with
mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell
lung cancer. J Clin Oncol 17(9):2692-2699, 1999.
35. Curran WJ, Jr, Scott C, Langer C, et al: Phase III
comparison of sequential vs concurrent chemoradiation for patients (Pts) with
unresected stage III non-small cell lung cancer (NSCLC): Initial report of
Radiation Therapy Oncology Group (RTOG) 9410 (abstract 1891). Lung Cancer
29(suppl 1):303a, 2000.
36. Takeda K, Negoro S, Kudoh S, et al: Phase I/II study of
weekly irinotecan and concurrent radiation therapy for locally advanced
non-small cell lung cancer. Br J Cancer 79(9-10):1462-1467, 1999.
37. Saka H, Shimokata K, Yoshida S, et al: Irinotecan (CPT-11)
and concurrent radiotherapy in locally advanced non-small cell lung cancer
(NSCLC): A phase II study of Japan Clinical Oncology Group (JCOG9504) (abstract
1607). Proc Am Soc Clin Oncol 16:447a, 1997.
38. Yokoyama A, Kurita Y, Saijo N, et al: Dose-finding study of
irinotecan and cisplatin plus concurrent radiotherapy for unresectable stage III
non-small-cell lung cancer. Br J Cancer 78(2):257-262, 1998.
39. Langer C, Movsas B, Huang C, et al. Phase I study of
irinotecan (CPT-11), cisplatin (cDDP) and radical thoracic radiation (TRT) in
the treatment of locally advanced non-small cell lung carcinoma (NSCLC). Lung
Cancer 29(suppl 1):334a, 2000.
40. Fukuda M, Fukuda Mi, Soda H, et al: Phase I study of
irinotecan (CPT-11) and cisplatin (CDDP) with concurrent thoracic radiotherapy
in locally advanced non-small cell lung cancer (NSCLC) (abstract 1796). Proc Am
Soc Clin Oncol 18:466a, 1999.
41.Yamamoto N, Fukuoka M, Negoro S, et al: A phase II study of
induction chemotherapy with CPT-11 and cisplatin followed by thoracic radiation
combined with weekly CPT-11 in patients with unresectable stage III non-small
cell lung cancer (abstract 1953). Proc Am Soc Clin Oncol 19:499a, 2000.
42. Yamada M, Kudoh S, Negoro S, et al: A phase I study of
irinotecan and carboplatin with concurrent thoracic radiotherapy for
unresectable non-small cell lung cancer (abstract 2035). Proc Am Soc Clin Oncol
43. Chakravarthy A, Choy H: A phase I trial of outpatient weekly
irinotecan/carboplatin and concurrent radiation for stage III unresectable
non-small-cell lung cancer: A Vanderbilt-Ingram Cancer Centre Affliliate Network
Trial. Clin Lung Cancer 1(4):310-311, 2000.
44. Chakravarthy A, Choy H, De Vore RD, et al: Phase I trial of
outpatient weekly irinotecan and carboplatin with concurrent radiation therapy
for stage III unresectable non-small cell lung cancer: A Vanderbilt Cancer
Center Affiliate Network Trial (VCCAN) Trial (abstract 2040). Proc Am Soc Clin
Oncol 19:520a, 2000.
45. Kinoshita A, Fukuda M, Kuba M, et al: Phase I study of
irinotecan (CPT-11) and cisplatin (CDDP) with concurrent thoracic radiotherapy
(TRT) in limited-stage small cell lung cancer (LS-SCLC) (abstract 1999). Proc Am
Soc Clin Oncol 19:511a, 2000.
46. Koukourakis MI, Bizakis JG, Skoulakis CE, et al: Combined
irinotecan, docetaxel and conventionally fractionated radiotherapy in locally
advanced head and neck cancer. A phase I dose escalation study. Anticancer Res