Irinotecan and Radiation in Combined-Modality Therapy for Solid Tumors

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]

Introduction

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.

Camptothecins

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.

Conclusions

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.

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