Irinotecan and Radiation in Combined-Modality Therapy for Solid Tumors

July 1, 2001

Irinotecan (CPT-11, Camptosar) is a camptothecin derivative thatis thought to exert its cytotoxic effects by targeting topoisomerase

ABSTRACT: Irinotecan (CPT-11, Camptosar) is a camptothecin derivative thatis thought to exert its cytotoxic effects by targeting topoisomerase I. It isbelieved that irinotecan stabilizes a DNA-topoisomerase I cleavable complex,and that interactions between this complex and the replication machinery maylead to cell death. There is a significant volume of in vitro and in vivo datademonstrating that irinotecan acts as a radiosensitizer. The exact mechanism ofthis radiosensitization is currently unknown. The increasing amount of datademonstrating improved outcomes with concurrent chemoradiation treatment ofmalignancies like lung cancer and head and neck cancer provide impetus forpursuing the addition of other drugs as radiosensitizers to improve localcontrol further. Irinotecan is undergoing early clinical trials in thecombined-modality setting in several disease sites. This article will provide anoverview of the current status of irinotecan used concurrently with radiotherapyin the treatment of a variety of solid tumors. [ONCOLOGY 15(Suppl 8):22-28,2001]


Solid tumors account for the majority of all malignancies and areresponsible for a large proportion of deaths in the industrialized world. In theUnited States in the year 2001, 1,268,000 new cases of invasive cancer will bediagnosed and 553,400 Americans are expected to die from their cancers.[1] Whilecurrently about half of all patients are cured, the other 50% will die of theirdisease.[1] Current treatments are based on one of three modalities: surgery,radiation, or chemotherapy. Surgical treatments often fail because either thetumor recurs in the tumor bed, since an insufficient margin of normal tissue wasremoved in order to preserve function and cosmesis, or distant metastasesdevelop. Radiation treatments fail because distant metastatic disease developsor the dose required to sterilize the tumor is limited by the surrounding normaltissues, and the tumor recurs locally. Chemotherapy tends to have less of acurative effect on gross disease but may be able to decrease the risk of distantrelapse when administered in an adjuvant setting.

More traditional treatments like cisplatin (Platinol) anddoxorubicin are now being joined by a new generation of drugs active against abroad range of solid tumors. These new agents—including paclitaxel (Taxol),docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), irinotecan(CPT-11, Camptosar), and others—are associated with promising response ratesof 20% to 50% in the setting of metastatic disease.[2] It is hoped that theseagents may improve outcomesin patients with earlier-stage diseaseas well.

Multiple Treatment Modalities

Modern clinical trials are focusing more on integrating multipletreatment modalities to maximize outcomes. Steele and Peckham outlined severalmechanisms for the possible interaction of radiation and chemotherapies: spatialcooperation, enhancement of tumor response, radioprotection, and nonoverlappingtoxicities (or toxicity independence).[3] Spatial cooperation describes asituation in which disease located in a specific anatomic site is missed by oneagent but treated by another. Enhancement occurs when the administration of oneagent increases the effect of another agent, or when the effect of thecombination is greater than would be expected with either agent alone.Radioprotection refers to administration of a chemotherapeutic agent that allowsfor safe delivery of increased radiation.

Ample literature exists on the ability of different drugs toenhance radiation effect when the two modalities are delivered concurrently.This article will provide an overview of concurrent administration of irinotecanand radiation to patients with solid tumors, with a focus on irinotecan’smechanism of action, its radiosensitizing effects, and current clinical trialsevaluating concurrent irinotecan and radiation.


Background and Mechanism of Activity

Irinotecan is a member of a relatively new group of anticanceragents, the camptothecins, whose activity is believed to be achieved bytargeting DNA topoisomerase I.[4-7] The human DNA topoisomerase I is a monomeric100-kDa protein that relaxes supercoiled DNA by introducing a single-strandbreak in DNA, followed by the passing of the intact strand through the breakprior to re-ligation.[4-9] This activity is key in many aspects of DNAmetabolism, including transcription, replication, and regulation of DNAsupercoiling, which is important in maintaining genomic stability. It isbelieved that the camptothecins function by stabilizing a topoisomerase I-DNAintermediate, called the cleavable complex, such that the 5¢phosphoryl end ofthe DNA single-strand break is bound covalently to a topoisomerase I tyrosineresidue.[10] It is believed that collision of this drug-trapped complex with theDNA replication machinery will lead to G2 phase cell-cycle arrest and celldeath.[10]

Camptothecin, the parent compound, was initially isolated fromthe tree Camptotheca acuminata and found to have a broad spectrum of activity ina variety of solid tumors.[11] However, early clinical trials with the ring-openform of the drug showed excessive toxicity and the trials were terminated.[12]More recently, interest has been rekindled in these drugs with the advent ofderivatives that have significant antitumor activity and much less toxicity.Irinotecan, one of these derivatives, is actually a prodrug that is metabolizedintracellularly intoSN-38.[13] SN-38 is approximately 1,000 times more potent than irinotecan ininhibiting topoisomerase I.[14] All of the camptothecins have a terminal lactonering that can be hydrolyzed to a less active carboxylate species. Under acidicconditions, however, like those expected in the tumor microenvironment, theactive lactone species is favored.[13]

The plasma half-life of SN-38 by intravenous infusion is 5.9 to13.8 hours,[13] and this may have implications in terms of both directcytotoxicity and radiosensitization. SN-38 is eliminated primarily through hepaticglucuronidation and it is thought that a decreased ability to glucuronidate thedrug correlates with increased gastrointestinal side effects.[13] One of themajor side effects of irinotecan is late-onset diarrhea, which is possiblyrelated to the high S-phase fraction of the intestinal mucosa as well as actionof intestinal flora glucuronidase in cleaving the camptothecin-glucuronidaseconjugate, leading to the drug’s release into the intestinal lumen.[15] Othercommon toxicities include neutropenia, nausea, vomiting, anorexia, fatigue,asthenia, and elevation of hepatic transaminase levels.[13]

Several other camptothecin derivatives have been shown to havesignificant cytotoxic effects and are at varying stages of development. Theseinclude topotecan (Hycamtin),[16,17] 9-aminocamptothecin (9 A-C),[18] and9-nitrocamptothecin (RFS-2000).[19] Of these, topotecan has undergone the mostextensive clinical testing; it is indicated for treatment of patients withplatinum-resistant ovarian cancer and small-cell lung cancer after failure offirst-line therapy.[16]

Irinotecan Activity

Response rates with irinotecan have ranged from 18% to 32% inmetastatic colorectal cancer,[20,21] 15% to 32% in non-small-cell lungcancer,[22,23] and 10% to 47% in small-cell lung cancer.[24,25] It is alsoactive in other malignancies, including cervical, gastric, ovarian, and centralnervous system tumors.[13] While its activity in advanced disease is promising,convincing evidence now indicates that the camptothecins—including irinotecan—havesignificant radiosensitizing properties.[10,17] This discovery may potentiallylead to improved local control of solid tumors when irinotecan is usedconcurrently with radiation. In the setting of localized and potentially curabledisease, it is hoped that this enhanced activity will translate into improvedsurvival.

Several hypotheses exist regarding the mechanism of interactionbetween radiation and irinotecan, each with varying amounts of supportiveevidence. One hypothesis suggests that inhibition of topoisomerase I bycamptothecin or its derivatives leads to inhibition of repair ofradiation-induced DNA strand breaks.[18,26,27] A second hypothesis suggests thatcamptothecin or its analogs causes redistribution of cells into the more radiosensitive G2 phase of the cell cycle.[28]

Another hypothesis is that topoisomerase I-DNA adducts aretrapped by irinotecan at the sites of radiation- induced single strand breaks,leading to their conversion into double-strand breaks.[29-31] In essence, thedrug-stabilized cleavable complex, with a concealed single-strand DNA break, maypotentially act as a point of sublethal DNA damage. Interaction with cellularprocesses like transcription and DNA repair may act to turn this"potentially sublethal damage" into "sublethal damage." Itis possible that the addition of radiation may in turn change this"sublethal damage" into "lethal damage."[10] It is alsosuggested that high levels of topoisomerase I are associated with high levels ofcleavable complex formation.[32] These high enzyme levels have been documentedin several tumor specimens,[33] suggesting that irinotecan use may be beneficialin improving the therapeutic ratio vis-à-vis normal tissue effects.

Johnson and McNerney initially reported in 1985 thattopoisomerase I activity increased by about 300-fold after irradiation of humanperipheral blood lymphocytes or cultured lymphoblastoid cells.[34] Otherinvestigators have not found any increase in activity.[34] This variance couldbe related to the cell population or to the genomic location of thetopoisomerase pool under examination. The predominance of the particularmechanism involved in radiosensitization may depend on which camptothecinderivative is used; now, there is insufficient evidence to identify theunderlying mechanism with certainty.

Irinotecan Radiosensitization

Chen et al showed that camptothecin derivatives radiosensitizedlog-phased human MCF-7 breast cancer cells in a schedule-dependent manner.[35]Essentially, cells that were exposed to 20(S)-10,11 methylene dioxycamptothecinbefore or during radiation showed sensitization ratios of 1.6, while thosetreated with the drug after radiation had substantially less enhancement ofradiation-induced DNA damage. These results suggest that patients should receivethe drug shortly before or during radiation to reap the full radiosensitizationpotential of combination treatment. Other investigators found similar results:in one study, for example, the major increase in radiosensitization in humanmalignant melanoma (U1-Mel) cells treated with 9-aminocamptothecin occurred inthe first hour after irradiation.[36]

Amorino et al examined the interaction between radiation and9-nitro-20(S)-camptothecin (9-NC), which is an orally active camptothecinderivative.[19] Results showed a concentration-dependent dose-enhancement ratioof up to 2.0 in the human lung cancer cell line H460. They also found that9-NC partially inhibited split-dose recovery in the same cell line, suggestinginhibition of sublethal damage recovery. Furthermore, interesting early datashow that SN-38 sensitized proliferating WHO3 cells (a human esophageal cancercell line) to radiation under hypoxic conditions.[37]

Other evidence of the radiosensitizing abilities ofcamptothecins comes from more complex model systems. Omura et al examinedradiosensitization with SN-38 in HT-29 spheroids derived from a human coloncancer cell line.[27] Cell kill was significantly enhanced when radiation wascombined with irinotecan. The largest gains in cytotoxicity occurred whenirinotecan was given just before or just after the radiation. Results alsosuggested that the mechanism of radiosensitization in the spheroids is throughinhibition of potentially lethal damage repair. Evidence from human small-celland mixed small- and large-cell lung cancer xenografts also indicates thatsignificant radiosensitization occurs with the combination of irinotecan andradiation. According to flow cytometry, the proportion of cells in the G2/Mphase increases 1 hour after treatment with SN-38, suggesting that some of theradiosensitization occurs through cell-cycle-related mechanisms.[28]

Clinical Trials

The large volume of in vitro and in vivo evidence of irinotecan’sradiosensitizing abilities has led to clinical trials. It is hoped thatirinotecan would improve the therapeutic ratio by selectively targeting tumorcells, which tend to be more acidic and which may have higher topoisomeraselevels. Clinical trials in this area have begun and early reports of responserates are encouraging.

Non-Small-Cell Lung Cancer

The majority of clinical studies of irinotecan combined withradiation have involved patients with non-small-cell lung cancer. Importantresults from large multicenter trials suggested that concurrent chemotherapy andradiation is a reasonable treatment strategy to potentially improve outcome withacceptable side effects.[38-40]

Takeda and colleagues examined weekly irinotecan at escalatingdoses with concurrent thoracic radiation (60 Gy in 30 fractions over 6 weeks) ina phase I/II trial.[41] Patients with stage III non-small-cell lung cancer andEastern Cooperative Oncology Group (ECOG) performance status 0 to 2 receivedirinotecan at the initial dose of 30 mg/m2 IV weekly for 6 weeks, with the doseescalated in 15-mg/m2 increments in successive cohorts. Five patients receivedthe maximum tolerated dose of 60 mg/m2, two of whom had World HealthOrganization (WHO) grade 3/4 esophagitis and three, grade 3/4 pneumonitis. Anadditional 10 patients treated in the phase II portion of the trial receivedirinotecan at 45 mg/m2, for a total of 17 patients treated at this dose level.Toxicities in the phase II portion included one case of fatal pneumonitis andone case of grade 3 diarrhea. The overall response rate was 76.9%; the 1-yearsurvival rate was 61.5% at 22 months of follow-up.

Saka and colleagues performed a phase II trial in which patientswith locally advanced non-small-cell lung cancer received irinotecan at 60mg/m2 IV weekly with concurrent thoracic radiation (60 Gy).[42] Among all 24patients, 71% completed the planned chemotherapy and 88% completed the plannedradiotherapy. Partial responses were seen in 79% of patients. Toxicitiesincluded three cases of grade 3 pneumonitis, two cases of grade 3 esophagitis,two cases of grade 3 neutropenia, and one case of grade 3 fever. No grade 4toxicities were observed. The investigators concluded that this was a tolerableand active regimen for patients with non-small-cell lung cancer.

Evaluation of irinotecan plus concurrent thoracic irradiationhas expanded to include platinum compounds based on their established activityin non-small-cell lung cancer, their radiosensitizing effects, as well aspreclinical data.[43] Yokoyama and colleagues in the Japan Clinical OncologyGroup conducted a phase I trial in which 12 patients received escalating dosesof irinotecan and cisplatin with 60 Gy of concurrent thoracic radiation.[44] Sixpatients received the level 1 doses of 60 mg/m2 (cisplatin) and 40mg/m2(irinotecan) with the radiation. The chemotherapy was discontinued, however, intwo patients before the three planned cycles were completed because of toxicity.At dose level 2 (60 mg/m2 of cisplatin and 60 mg/m2 of irinotecan), only threepatients received all three chemotherapy cycles. The three patients who did notcomplete chemotherapy also did not complete radiotherapy, in contrast to doselevel 1 where all patients completed their planned radiation treatment. Due tothe low-dose intensity of irinotecan in dose levels 1 and 2 (irinotecan wasoften omitted on days 8 and 15 because of leukopenia or diarrhea), the lowcompletion rate for radiation therapy, and the high rate of toxicities(including one death), the study was closed at dose level 2. Although theoverall response rate was 67% (8/12 partial responses), overall survival at 1year was only 33%. An ongoing phase I study being conducted at the Fox ChaseCancer Center may provide further insight into the tolerability of concurrentirinotecan, cisplatin, and thoracic radiation.[45]

Three other Japanese trials of concurrent platinum drugs,irinotecan, and radiation in non-small-cell lung cancer have been reported. Ina study by Fukuda et al, 24 patients received two courses of chemotherapy withsplit-course radiation (irinotecan at 60 mg/m2 days 1, 8, and 15 and cisplatinat 80 mg/m2 on day 1 were the recommended doses for phase II study).[46] Theoverall response rate was 65% with some cases of neutropenia, thrombocytopenia,and esophagitis. A follow-up study by the Japanese Lung Cancer Group involvedinduction cisplatin and irinotecan for two cycles followed by concurrent weeklyirinotecan and thoracic radiation.[47] Among 68 enrolled patients, neutropenia(6% incidence of grade 4), esophagitis (4%, grade 3), and pneumonitis (2%, grade4) were the significant toxicities. The response rate was 63.3% and theestimated 1-year survival was 71.7%. They concluded that induction chemotherapyfollowed by concurrent thoracic radiation and irinotecan was a promisingstrategy that merited evaluation in randomized trials.

Finally, a trial assessed combining 60 Gy of thoracic radiationwith carboplatin (Paraplatin) and irinotecan.[48] Thirty enrolled patientsreceived carboplatin at 20 mg/m2/d × 5 and irinotecan at a starting dose of 30mg/m2 IV weekly. Both drugs were given weekly for 4 weeks. The irinotecan dosewas escalated in 10-mg/m2 increments. The maximum tolerated dose of irinotecanwas 60 mg/m2; dose-limiting toxicities included pneumonitis, esophagitis,neutropenia, and thrombocytopenia. Three patients had complete responses and 15had partial responses, for an overall response rate of 60%. Median survival hasnot been reached, and the 2-year survival is encouraging at 51.3%.

Outside of Japan, there has been one reported trial ofirinotecan plus carboplatin and concurrent thoracic radiation. For the first 18patients treated on this trial at the Vanderbilt Cancer Center, the responserate has been 61%, and nausea, vomiting, and esophagitis have been the majortoxicities (Table 1).[49] While one patient at the first dose level developedgrade 5 esophagitis, a further six patients in the expanded cohort did notdevelop this problem. The maximum tolerated dose of concurrent chest radiationand irinotecan was found to be 40 mg/m2/wk for 6 weeks.

Small-Cell Lung Cancer

The combination of cisplatin and irinotecan has been found tohave significant activity in refractory disease, [50] as well as in de novodisease.[52] Data recently presented by the Japanese Clinical Oncology Groupshowed that four cycles of cisplatin/irinotecan every 4 weeks in extensive-stagesmall-cell lung cancer significantly increased 1-year survival to 60% (from 40%with standard cisplatin/etoposide therapy).[53] It follows that this combinationmight improve cure rates if combined with thoracic radiation in limited-stagedisease. So far, there is a report of a phase I trial in which patients receivedcisplatin on day 1 and irinotecan on days 1, 8, and 15 for four 28-day cycles.

Patients also received 20 Gy of radiation to the chest with eachof the first three cycles (total dose: 60 Gy). Of 16 evaluable patients, 4 had acomplete response, 11 partial response, and 1 stable disease, for an overallresponse rate of 94%. The recommended schedule was 40 mg/m2 of irinotecan and 60mg/m2 of cisplatin, because at higher doses the limiting toxicity was fatigue.Further follow-up of these patients and assessment of this combination in aphase II study are warranted.

Head and Neck Cancer

Concurrent chemotherapy and radiation have been shown to bebeneficial for head and neck cancer patients when agents with radiosensitizingproperties, such as fluorouracil (5-FU), cisplatin, mitomycin (Mutamycin), orhydroxyurea (Hydrea), were included in the regimen. Koukourakis and colleaguespublished results of a phase I trial of combination docetaxel and irinotecanwith radiation for locally advanced squamous cell carcinoma of the head andneck.[54] The planned radiation dose of 66 to 70 Gy was delivered in 6.5 to 7weeks in combination with chemotherapy. The docetaxel starting dose was 20 mg/m2/wk with planned increases of 5mg/m2 every eight patients (two cohorts)for a total of seven doses. The irinotecan starting dose was 25 mg/m2/wk for 7weeks and was increased by 15 mg/m2 every four patients until dose-limitingtoxicities occurred.

All four patients at the third dose level (docetaxel at 25 mg/m2/wk and irinotecan at 55mg/m2/wk) developed grade 3/4 mucositis requiring> 7-day treatment delays. This delay may partially explain why the lowestcomplete response rate was seen in patients at this dose level. At the first andsecond dose levels, grade 2 mucositis was experienced by 7 of 8 patients (theother patient had grade 3 mucositis), and grade 2 asthenia and anorexia occurredin at least half the patients. Interestingly, 9 of 12 patients had documentedcomplete responses based on the post-treatment computed tomography (CT) scans,and three had partial responses. The investigators recommended that the maximumtolerated doses for weekly docetaxel and irinotecan should be 20 and 40 mg/m2,respectively, during standard radiotherapy for head and neck cancer.

Another phase I trial examined combining irinotecan with anestablished regimen of twice-daily radiation,5-FU, and hydroxyurea.[55] Irinotecan was administered IV daily on days 1 to 5every 2 weeks for 4 to 5 cycles. Irinotecan was given prior to the radiation ata starting dose of 5 mg/m2/d and was escalated to a maximum dose of 15mg/m2/d.Of 16 patients entered in the trial, 14 were evaluable for toxicity; 10developed grade 3/4 mucositis and 8 developed grade 3/4 dermatitis by the thirdto fifth cycle. Of 8 patients evaluable for response, 6 had either a partial orcomplete response. The authors concluded that the dose-limiting radiosensitizingcontribution of irinotecan was seen at 15 mg/m2. Additional patients are beingtreated in a phase II fashion with irinotecan at 10 mg/m2/d.

Both of these trials show that irinotecan in combination withconcurrent radiation and other agents, ie, docetaxel, or 5-FU and hydroxyurea,yields high response rates in locally advanced disease. Dose escalation ofirinotecan is limited by mucositis as would be expected with radiosensitization.Further study of irinotecan with concurrent radiotherapy is needed, possiblywith incorporation of a mucosal protection agent like amifostine (Ethyol)[56,57]to help ameliorate toxicities.

Gastrointestinal Cancer

The role of chemoradiotherapy in locally advancedgastrointestinal cancer—which often carries a grim prognosis—is worthy ofstudy. Certainly, the activity of irinotecan in metastatic colorectal cancers isencouraging.[58] An ongoing phase I trial at the M. D. Anderson Cancer Center isexamining the role of escalating weekly doses of irinotecan with concurrentradiation to a total dose of 45 to 50.4 Gy in locally advanced uppergastrointestinal cancers.[59] The irinotecan starting dose was 10 mg/m2/wk andhas been escalated to 70 mg/m2/wk without yet reaching the maximum tolerateddose. Median time to progression has been 27.5 weeks in 18 patients. Only 8% ofthe planned irinotecan doses have been withheld due to side effects.

Another ongoing phase I trial at the Memorial Sloan-KetteringCancer Center has the following major objectives: determine the dose-limitingtoxicity of irinotecan when given weekly with cisplatin and concurrentradiotherapy in patients with locally advanced carcinoma of the esophagus orgastroesophageal junction; determine the maximum tolerated dose and therecommended phase II dose of irinotecan in this regimen; and evaluate thecomplete response rate after one course of induction chemotherapy followed byconcurrent chemotherapy and radiotherapy.[60] Patients receive cisplatininduction chemotherapy followed by irinotecan on days 1, 8, 15, and 22. After 2weeks of rest, patients begin chemoradiation with cisplatin and irinotecan asabove on days 1, 8, 22, and 29, and radiotherapy once daily 5 days a week for 5to 6 weeks. It is hoped that the results of these studies will provide areasonable basis for future phase II trials.

Cervical Cancer

Carcinoma of the cervix is another tumor for which irinotecanhas the potential to improve local control. Several randomized trials have shownthe benefit of concurrent cisplatin-based chemotherapy and radiation inincreasing tumor control and overall survival in this disease.[61-64] It islogical to add irinotecan to current protocols based on its radiosensitizingeffects, its nonoverlapping toxicities with cisplatin, and impressive responserates of the combination of irinotecan, cisplatin, and radiation in otherdisease sites.[2,17]

In a study by the European Organization for the Research andTreatment of Cancer (EORTC), patients with histologically confirmed, inoperable,progressive, metastatic, or recurrent squamous cell carcinoma of the cervix withno radiation in the preceding 3 months were treated with irinotecan.[65] Resultsshowed a 23.5% response rate in a patient population with one or more lesions inan unirradiated area. The response rate was lower in the previously irradiatedareas. These results are similar to those from a phase II trial conducted by theGynecologic Oncology Group.[66]

Sugiyama et al also incorporated irinotecan into a regimen foradvanced or recurrent disease.[67] They treated 29 patients with cisplatin at 60mg/m2 on day 1 every 4 weeks and irinotecan at 60 mg/m2 on days 1, 8, and 15.The response rate was 59% (complete response in two patients), with majortoxicities of neutropenia, anemia, nausea/vomiting, and diarrhea. The fact thatthese advanced-disease patients (some of whom had received up-front radiationtherapy) responded significantly to chemotherapy alone makes it appealing to trythe addition of irinotecan to concurrent radiation and cisplatin regimens inlocalized disease.


In early studies, radiation has been combined withirinotecan-based chemotherapy for several solid tumor types. This approach seemslogical, given data indicating that irinotecan acts as a radiosensitizer.Emerging clinical data from phase I and II trials in non-small-cell lungcancer show response rates of at least 60% and promising1-year survival rates. Toxicity assessments from these early trials have alsodemonstrated that these regimens are feasible and tolerable for most patients.Concurrent irinotecan-incorporating chemotherapy regimens may soon be tested inrandomized phase II or III trials in patients with non-small-cell lung cancer.Similar promising results with irinotecan-based concurrent chemoradiotherapyregimens have also been seen in trials of head and neck cancer patients. Giventhe activity of irinotecan in other tumors, including gastrointestinal andcervical cancers, continued assessment of this agent with concurrentradiotherapy is warranted in these malignancies as well.


1. Greenlee RT, Hill-Harmon MB, Taylor M, et al: Cancerstatistics 2001. CA Cancer J Clin 50:7-33, 2001.

2. Stevens CW, Lee JS, Cox J, et al: Novel approaches to locallyadvanced unresectable non-small cell lung cancer. Radiother Oncol 55(1):11-18,2000.

3. Steele GG, Peckham MJ: Exploitable mechanisms in combinedradiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol BiolPhys 5:85-91, 1979.

4. Hsiang Y-H, Hertzberg R, Hecht S et al: Camptothecin inducesprotein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem260:14873-14878, 1985.

5. Hsiang Y-H, Liu LF: Identification of mammalian DNAtopoisomerase I as an intracellular target of the anticancer drug camptothecin.Cancer Res 48:1722-1726, 1988.

6. Andoh T, Ishii K, Suzuki Y, et al: Characterization of amammalian mutant with a camptothecin resistant DNA topoisomerase I. Proc NatlAcad Sci USA 84:5565-5569, 1987.

7. Nitiss J, Wang JC: DNA topoisomerase-targeting antitumordrugs can be studied in yeast. Proc Natl Acad Sci USA 85:7501-7505, 1988.

8. Chen AY, Yu C, Gatto B, et al: DNA minor groove-bindingligands: A different class of mammalian DNA topoisomerase I inhibitors. ProcNatl Acad Sci USA 90:8131-8135, 1993.

9. Chen AY, Yu C, Bodley A, et al: A new mammalian DNAtopoisomerase I poison Hoechst 33342: Cytotoxicity and drug resistance in humancell cultures. Cancer Res 53:1332-1337, 1993.

10. Chen AY, Choy H, Rothenberg ML: DNA topoisomeraseI-targeting drugs as radiation sensitizers. Oncology (Huntington) 13(10 suppl5):39-46, 1999.

11. Chen AY, Leroy FL: DNA topoisomerases: Essential enzymes andlethal targets. Annu Rev Pharmacol Toxicol 34:191-218, 1994.

12. Muggia FM, Creaven PJ, Hansen HH, et al: Phase I clinicaltrial of weekly and daily treatment with camptothecin (NSC-100880): Correlationwith preclinical studies. Cancer Chemother Rep 56:515-521, 1972.

13. Takimoto CH, Wright J, Arbuck SG: Clinical applications ofthe camptothecins. Biochem Biophys Acta 1;1400(1-3):107-119, 1998.

14. Kawato Y, Aonuma M, Hirota Y, et al: Intracellular roles ofSN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumoreffect of CPT-11. Cancer Res 51:4187-4191, 1991.

15. Araki E, Ishikawa M, Iigo M, et al: Relationship betweendevelopment of diarrhea and the concentration of SN-38, an active metabolite ofCPT-11, in the intestine and the blood plasma of athymic mice followingintraperitoneal administration of CPT-11. Jpn J Cancer Res 84(6):697-702, 1993.

16. De Vita VT, Hellman S, Rosenberg SA: Cancer. Principles andPractice of Oncology, 5th ed, pp 921 and 1528. Philadelphia, Lippincott-Raven,1997.

17. Rich TA, Kirichenko AV: Camptothecin radiationsensitization: Mechanisms, schedules, and timing. Oncology (Huntington) 12(8suppl 6):114-120, 1998.

18. Lamond JP, Wang M, Kinsella TJ, et al: Radiation lethalityenhancement with 9-aminocamptothecin: Comparison to other topoisomerase Iinhibitors. Int J Radiat Oncol Biol Phys 36(2):369-376, 1996.

19. Amorino GP, Hercules SK, Mohr PJ, et al: Preclinicalevaluation of the orally active camptothecin analog, RFS-2000(9-nitro-20(S)-camptothecin) as a radiation enhancer. Int J Radiat Oncol BiolPhys 47(2):503-509, 2000.

20. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II trial ofirinotecan in patients with progressive or rapidly recurrent colorectal cancer.J Clin Oncol 14(4):1128-1135, 1996.

21. Rougier P, Bugat R, Douillard JY, et al: Phase II study ofirinotecan in the treatment of advanced colorectal cancer in chemotherapy-naivepatients and patients pretreated with fluorouracil-based chemotherapy. J ClinOncol 15(1):251-260, 1997.

22. Fukuoka M, Niitani H, Suzuki A, et al: A phase II study ofCPT-11, a new derivative of camptothecin for previously untreated non-small-celllung cancer. J Clin Oncol 10(1):16-20, 1992.

23. Baker L, Khan R, Lynch T, et al: Phase II study ofirinotecan in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol16:461a, 1997.

24. Le Chevalier T, Ibrahim N, Chomy P, et al: A phase II studyof irinotecan in patients with small cell lung cancer progressing after initialresponse to first-line chemotherapy. Proc Am Soc Clin Oncol 16:450a, 1997.

25. Masuda N, Fukuoka M, Kusunoki Y, et al: CPT-11: A newderivative of camptothecin for the treatment of refractory or relapsedsmall-cell lung cancer. J Clin Oncol 10(8):1225-1229, 1992.

26. Ng CE, Bussey AM, Raaphorst GP, et al: Inhibition ofpotentially lethal and sublethal damage repair by camptothecin and etoposide inhuman melanoma cell lines. Int J Radiat Biol 66(1):49-57, 1994.

27. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of thecamptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation inhuman colon adenocarcinoma cells grown as spheroids. Rad Oncol 43:197-201, 1997.

28. Tamura K, Takada M, Kawase I, et al: Enhancement of tumorradio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res88(2):218-223, 1997.

29. Boothman DA, Wang M, Schea RA, et al: Posttreatment exposureto camptothecin enhances the lethal effects of x-rays on radioresistant humanmalignant melanoma cells. Int J Radiat Oncol Biol Phys 24(5):939-948, 1992.

30. Boothman DA, Fukunaga N, Wang M, et al: Down-regulation oftopoisomerase I in mammalian cells following ionizing radiation. Cancer Res54(17):4618-4626, 1994.

31. Boothman DA: Enhanced malignant transformation isaccompanied by increased survival recovery after ionizing radiation in Chinesehamster embryo fibroblasts. Radiat Res 138(1 suppl):S121-S125, 1994.

32. Pommier Y: Eukaryotic DNA topoisomerase I: Genome gatekeeperand its intruders, camptothecins. Semin Oncol 23(1 suppl 3):3-10, 1996.

33. Potmesil M: Camptothecins: From bench research to hospitalwards. Cancer Res 54(6):1431-1439, 1994

34. Smith PJ: DNA topoisomerases and radiation responses. Int JRadiat Biol 58(4):553-559, 1990.

35. Chen AY, Okunieff P, Pommier Y, et al: Mammalian DNAtopoisomerase I mediates the enhancement of radiation cytotoxicity bycamptothecin derivatives. Cancer Res 57(8):1529-1536, 1997.

36. Lamond JP, Wang M, Kinsella TJ, et al: Radiation lethalityenhancement with 9-aminocamptothecin: Comparison to other topoisomerase Iinhibitors. Int J Radiat Oncol Biol Phys 36(2):369-376, 1996.

37. Jansen van Rensburg CE: SN-38 potentiates the cytotoxiceffect of radiation in a human oesaphageal cancer cell line, under hypoxicconditions (abstract 2628). Proc Am Soc Clin Oncol 19:666a, 2000.

38. Clamon G, Herndon J, Cooper R, et al: Radiosensitizationwith carboplatin for patients with unresectable stage III non-small-cell lungcancer: A phase III trial of the Cancer and Leukemia Group B and the EasternCooperative Oncology Group. J Clin Oncol 17(1):4-11, 1999.

39. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study ofconcurrent versus sequential thoracic radiotherapy in combination withmitomycin, vindesine, and cisplatin in unresectable stage III non-small-celllung cancer. J Clin Oncol 17(9):2692-2699, 1999.

40. Curran WJ Jr, Scott C, Langer C, et al: Phase III comparisonof sequential vs concurrent chemoradiation for patients with unresected stageIII non-small cell lung cancer: Initial report of Radiation Therapy OncologyGroup 9410 (abstract 1891). Proc Am Soc Clin Oncol 19:484a, 2000.

41. Takeda K, Negoro S, Kudoh S, et al: Phase I/II study ofweekly irinotecan and concurrent radiation therapy for locally advancednon-small cell lung cancer. Br J Cancer 79(9-10):1462-1467, 1999.

42. Saka H, Shimokata K, Yoshida S, et al: Irinotecan andconcurrent radiotherapy in locally advanced non-small cell lung cancer: A phaseII study of Japan Clinical Oncology Group (JCOG9504) (abstract 1607). Proc AmSoc Clin Oncol 16:447a, 1997.

43. Kudoh S, Takada M, Masuda N, et al: Enhanced antitumorefficacy of a combination of CPT-11, a new derivative of camptothecin, andcisplatin against human lung tumor xenografts. Jpn J Cancer Res 84(2):203-207,1993.

44. Yokoyama A, Kurita Y, Saijo N, et al: Dose-finding study ofirinotecan and cisplatin plus concurrent radiotherapy for unresectable stage IIInon-small-cell lung cancer. Br J Cancer 78(2):257-262, 1998.

45. Fox Chase Cancer Center. Phase I Trial ofRadical Thoracic Radiation, Weekly CPT-11 (Irinotecan) and Cisplatin in LocallyAdvanced Non-Small Cell Lung Carcinoma (97-6475-125 CPT 11). Ongoing trial.

46. Fukuda M, Fukuda Mi, Soda H, et al: Phase I study ofirinotecan and cisplatin with concurrent thoracic radiotherapy in locallyadvanced non-small cell lung cancer (abstract 1796). Proc Am Soc Clin Oncol18:466a, 1999.

47. Yamamoto N, Fukuoka M, Negoro S, et al: A phase II study ofinduction chemotherapy with CPT-11 and cisplatin followed by thoracic radiationcombined with weekly CPT-11 in patients with unresectable stage III non-smallcell lung cancer (abstract 1953). Proc Am Soc Clin Oncol 19:499a, 2000.

48. Yamada M, Kudoh S, Negoro S, et al: A phase I study ofirinotecan and carboplatin with concurrent thoracic radiotherapy forunresectable non-small cell lung cancer (abstract 2035). Proc Am Soc Clin Oncol18:528a, 1999.

49. Chakravarthy A, Choy H, De Vore RD, et al: Phase I trial ofoutpatient weekly irinotecan and carboplatin with concurrent radiation therapyfor stage III unresectable non-small cell lung cancer: A Vanderbilt CancerCenter Affiliate Network Trial (abstract 2040). Proc Am Soc Clin Oncol 19:520a,2000.

50. Nakanishi Y, Takayama K, Takano K, et al: Second-linechemotherapy with weekly cisplatin and irinotecan in patients with refractorylung cancer. Am J Clin Oncol 22(4):399-402, 1999.

51. Kudoh S, Fujiwara Y, Takada Y, et al: Phase II study ofirinotecan combined with cisplatin in patients with previously untreatedsmall-cell lung cancer. West Japan Lung Cancer Group. J Clin Oncol16(3):1068-1074, 1998.

52. Noda K , Nishiwaki Y, Kawahara M, et al: Randomized phaseIII study of irinotecan and cisplatin versus etoposide and cisplatin inextensive-disease small-cell lung cancer: Japan Clinical Oncology Group study(JCOG9511) (abstract 1887). Proc Am Soc Clin Oncol 19:483a, 2000.

53. Kinoshita A, Fukuda M, Kuba M, et al: Phase I study ofirinotecan and cisplatin with concurrent thoracic radiotherapy in limited-stagesmall cell lung cancer (abstract 1999). Proc Am Soc Clin Oncol 19:511a, 2000.

54. Koukourakis MI, Bizakis JG, Skoulakis CE, et al: Combinedirinotecan, docetaxel and conventionally fractionated radiotherapy in locallyadvanced head and neck cancer: A phase I dose escalation study. Anticancer Res19:2305-2309, 1999.

55. Humerickhouse RA, Haraf D, Stenson K, et al: Phase I studyof irinotecan, 5-FU, and hydroxyurea with radiation in recurrent or advancedhead and neck cancer (abstract 1650). Proc Am Soc Clin Oncol 19:418a, 2000.

56. Bourhis J, De Crevoisier R, Abdulkarim B, et al: Arandomized study of very accelerated radiotherapy with and without amifostine inhead and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys46(5):1105-1108, 2000.

57. Schonekas KG, Wagner W, Prott FJ, et al: Amifostine—Aradioprotector in locally advanced head and neck tumors. Strahlenther Onkol175(suppl 4):27-29, 1999.

58. Douillard JY, Cunningham D, Roth AD, et al: Irinotecancombined with fluorouracil compared with fluorouracil alone as first-linetreatment for metastatic colorectal cancer: A multicentre randomised trial.Lancet 355(9209):1041-1047, 2000.

59. Blumenschein GR, Ajani JA, Fairweather J, et al: Phase Istudy of CPT-11 plus radiotherapy in patients with locally advanced upper GIcarcinomas (abstract 1274). Proc Am Soc Clin Oncol 19:322a, 2000.

60. Cancer Trials. NCI. Phase I study of irinotecan andcisplatin with concurrent radiotherapy in patients with locally advancedcarcinoma of the esophagus or gastroesophageal junction. Ongoing.

61. Keys HM, Bundy BN, Stehman FB, et al: Cisplatin, radiation,and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy forbulky stage IB cervical carcinoma. N Engl J Med 340:1154-1161, 1999.

62. Rose PG, Bundy BN, Watkins EB, et al: Concurrentcisplatin-based radiotherapy and chemotherapy for locally advanced cervicalcancer. N Engl J Med 340:1144-1153, 1999.

63. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation withconcurrent chemotherapy compared with pelvic and para-aortic radiation forhigh-risk cervical cancer. N Engl J Med 340:1137-1143, 1999.

64. Peters WA III, Liu PY, Barrett RJ II, et al: Concurrentchemotherapy and pelvic radiation therapy compared with pelvic radiation therapyalone as adjuvant therapy after radical surgery in high-risk early-stage cancerof the cervix. J Clin Oncol 18(8):1606-1613, 2000.

65. Lhomme C, Fumoleau P, Fargeot P, et al: Results of aEuropean Organization for Research and Treatment of Cancer/Early ClinicalStudies Group phase II trial of first-line irinotecan in patients with advancedor recurrent squamous cell carcinoma of the cervix. J Clin Oncol17(10):3136-3142, 1999.

66. Look KY, Blessing JA, Levenback C, et al: A phase II trialof CPT-11 in recurrent squamous cell carcinoma of the cervix: A GynecologicOncology Group study. Gynecol Oncol 70(3):334-338, 1998.

67. Sugiyama T, Yakushiji M, Noda K, et al: Phase II study ofirinotecan and cisplatin as first-line chemotherapy in advanced or recurrentcervical cancer. Oncology 58(1):31-37, 2000.