Phase I Study of Irinotecan and Concurrent Radiation Therapy for Upper GI Tumors
Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly
ABSTRACT: Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly irinotecan combined with concurrent radiotherapy for patients with locally advanced, unresectable gastric, gastroesophageal junction, or esophageal cancer. Patients who received previous chemotherapy (excluding irinotecan) or who experienced recurrent cancer after surgery were eligible for this protocol. The total dose of radiation did not exceed 50.4 Gy (28 fractions of 1.8 Gy each). The starting dose level of irinotecan was 30 mg/m2 infused over 90 minutes given weekly for 5 weeks. Subsequent dose levels were increased in 10 mg/m2 increments to 40, 50, 60, and 70 mg/m2. Of 15 patients who have been enrolled to date, all are evaluable for toxicities and 12 for response. Major hematologic toxicities (grade 3/4) were neutropenia, chills, hemorrhage, and anemia. Grade 3/4 gastrointestinal toxicities included nausea, vomiting, dehydration, anorexia, and constipation. Other severe nonhematologic toxicities included fatigue, hypotension, and hypothermia, as well as cardiovascular toxicities. There was no severe diarrhea and no treatment-related deaths. Of the 12 evaluable patients, 7 (58%) responded, including 2 complete responses; 4 (30%) had no change and 1 had progressive disease. Survival ranged from 1 month to 15 months, with a median survival of 8 months. When the total dose of irinotecan given concurrently with radiotherapy was higher than 250 mg/m2, patients experienced significantly more severe grade 3/4 toxicities than with lower doses (P = .04), with no improvement in response rate. It was concluded that weekly doses of irinotecan of up to 60 mg/m2 with concurrent radiotherapy given over 5 weeks was feasible and demonstrated good response. This regimen did not cause severe diarrhea or pneumonitis, but neutropenia and fatigue were major toxicities. The study continues to accrue. [ONCOLOGY 14(Suppl 14):34-37, 2000]
Introduction
Although the incidence of gastric carcinoma has declined in theUnited States over the past 40 years, it remains the eighth leading cause ofcancer death. In addition, for reasons that are as yet unclear, the incidence ofgastroesophageal and esophageal carcinoma (particularly adenocarcinoma) appearsto be increasing.[1] Smoking has recently been implicated, but the evidenceappears weak.[2,3] Fifty percent of patients with upper gastrointestinal (GI)malignancies present with unresectable locally advanced or metastatic cancer.[4]A recent approach for the treatment of locally advanced upper GI tumors ismultidisciplinary. However, patients with coincidental medical problems, elderlypatients, and those with a history of smoking and/or heavy alcohol consumptionmay not be appropriate candidates for radical surgery. These patients especiallywill need chemoradiotherapy for their upper GI tract tumors.
Irinotecan (Camptosar) is a plant alkaloid that was isolatedfrom Camptotheca acuminata.[5] Irinotecan has strong anticancer activity invitro[6] and in various experimental animal cancer models.[7] Because it haddemonstrated minimal efficacy in early clinical trials and severe toxicity, thischemotherapeutic agent was not popular in the United States.[8-13] There havebeen many attempts to synthesize derivatives of camptothecin in order toreinforce its anticancer activity and to decrease its toxicity.[14,15]
The water-soluble derivative of camptothecin,7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (irinotecan)has been shown to have high antitumor activity and low toxicity in murinetumors.[7,16] Furthermore, Tsuruo et al have demonstrated that irinotecan iseffective against pleiotropic drug-resistant tumors in vitro and in vivo.[17] Itappears that camptothecin and irinotecan strongly inhibit mammalian DNAtopoisomerase I.[18,19]
A phase I clinical study of irinotecan, in which the drug wasgiven intravenously in a weekly dose, has shown that leukopenia andunpredictable diarrhea are dose-limiting toxicities, and that 100 mg/m2is the maximum tolerated dose (MTD).[20,21] A partial response was observed inpatients with advanced non-small-cell lung cancer (NSCLC) who were treatedwith 100 mg/m2 or more of irinotecan in thisphase I study.[21]
A recent publication reports the outcome of the investigationaluse of irinotecan to increase tumor radiosensitivity.[22] Human lung tumorxenografts were treated with either irinotecan 10 mg/kg intraperitoneally ondays 1, 5, and 9; single-dose radiation (10 Gy/leg) on day 1; or a combinationregimen of both treatments, with radiation given 1 hour after the first dose ofirinotecan. DNA flow cytometry studies were performed to define the cell cyclechanges following treatment for 1 to 12 hours with 0, 0.5, 2.0, or 8.0 ng/mLSN-38, the major active metabolite of irinotecan. In the small-cell andsmall-cell/large-cell carcinoma xenografts, combination treatment resulted insignificant tumor regression compared with the use of irinotecan or radiationtreatment alone.
No severe weight loss or increased skin reaction was observedfollowing the combined treatment. Flow cytometry studies showed that theproportion of cells in G2/M-phase, the most radiosensitive phase, increasedafter 1-hour exposure to the lowest dose of SN-38 (0.5 ng/mL). These findingssuggest that irinotecan is a potent radiosensitizing agent, and that itsactivity is related to the cell cycle.[22]
Based on the preclinical data and a few phase I studiesindicating irinotecan to be an active chemotherapeutic agent as well as aradiosensitizer for upper GI tumors, we conducted a phase I study to assess theMTD of weekly irinotecan given with concurrent daily continuous radiotherapy forupper GI tumors.
Patients and Methods
This phase I study was initiated in January 1998. Patients wereeligible after the histology of their tumors was confirmed. They were to haveadvanced, unresectable gastric, gastroesophageal, or esophageal carcinoma.Patients previously treated by chemotherapy without irinotecan or those withrecurrent unresectable tumors were eligible. Patients had to be 18 years of ageor older with a performance status of 0, 1, or 2 (Zubrod performance scale) anda life expectancy of at least 12 weeks.
Additional eligibility requirements included a pretreatmentgranulocyte count >1,500/mL, hemoglobin level ³ 9g/dL, a platelet count ³ 100,000/mL, adequate renalfunction as documented by serum creatinine £ 2.0mg/dL, and adequate hepatic function as documented by a serum bilirubin level< 1.5 mg/dL regardless of liver involvement secondary to tumor. In addition,serum glutamic-oxaloacetic transaminase (SGOT) had to be £3 times the institutional upper limit of normal (ULN) unless the liver wasinvaded with tumor, in which case the SGOT had to be £5 times the institutional ULN. Patients who had received up to two priorregimens of systemic chemotherapy (excluding irinotecan) were eligible for studyentry.
Exclusion criteria included previous treatment with irinotecanor topotecan (Hycamtin), or prior radiation therapy to the thorax or upperabdomen. Also excluded were patients with any active or uncontrolled infection,including known infection with human immunodeficiency virus, patients withpsychiatric disorders that would interfere with consent or follow-up, orpatients with a history of myocardial infarction within the previous 6 months orcongestive heart failure that required therapy. Patients with a history of priormalignancy (except for adequately pretreated basal cell carcinoma, squamous cellskin cancer in situ, or other cancer for which the patient was disease-free forat least 5 years) were also barred from the study.
Baseline measurement of the tumor site and all known metastaticdisease had to be documented by computed tomography (CT) scans, x-ray, or otherradiographic assessments before treatment could be instituted, and an informedconsent form had to be signed by the patient before registration into the study.
Treatment Plan
Chemotherapy
At least three patients were treated at each irinotecan doselevel. Doses were escalated in sequential groups of three patients until the MTDwas established or the highest intended dose level was tested. Dose escalationwas not allowed for individual patients. All three patients at each dose levelwere to receive all five doses of irinotecan before the next cohort was startedat the next higher dose level. Cohorts could be expanded to six patients asnecessary. The starting dose level of irinotecan was 30 mg/m2/wkinfused over 90 minutes. All patients were premedicated prior to irinotecandosing to prevent nausea and vomiting.
The following dose levels were employed: dose level 1, 30 mg/m2;level 2, 40 mg/m2; level 3, 50 mg/m2;level 4, 60 mg/m2; level 5, 70 mg/m2.
A weekly dose of irinotecan was given if the granulocyte countwas ³ 1,000/µL, the platelet count was ³100,000/µL, and any other treatment-related toxicities were £grade 1.
Radiotherapy
The treatment plan for radiation therapy was to give a totaltumor dose of 45-50.4 Gy in 1.8 Gy fractions for a total of 25-28 fractions,delivered over 5 weeks. The dose was calculated at the midplane. All patientswere reassessed at 4 weeks after completion of chemoradiation therapy.Irinotecan was administered 1 hour prior to administration of radiation therapyon day 1 of each week of 5 treatment weeks.
The linear accelerator generated 6 MV or 18 MV photons. Theminimum target skin distance was 80 cm. Field placements wereanterior-posterior/posterior-anterior and anterior with two posterior obliquesto avoid high dosing to the heart. The two sharp posterior angles were used tominimize the volume of the lung included within the irradiated fields. Targetvolume was based on the size of individual tumors. The 2-cm lateral margin and3-cm margin along the vertical axis of the target mass were used.
Radiation therapy was withheld on any planned treatment day onwhich the patients exhibited grade 3 toxicity. A toxicity that delayed plannedradiation therapy for more than 2 weeks was considered dose-limiting for thepurpose of this study.
All patients were seen weekly in the Radiation OncologyDepartment and every 2 weeks in the GI Center during chemoradiation therapy.
Results
There were 18 patients enrolled in this study between Januaryand November 1998. All patients were evaluable for toxicities and 12 forresponse. Male to female ratio was 16:2; ages ranged from 30 to 76 years with amedian of 59 years. Of these, 6 patients had esophageal malignancies, 9 hadlesions in the gastroesophageal junction, and 3 had cancer of the stomach. Tumorpathology included 1 squamous, 14 adenocarcinoma (1 well differentiated, 9moderately differentiated, and 4 poorly differentiated), and 3 signet ringcarcinomas. In all, 12 patients had T3 and 6 had T4 lesions; 6 patients had N0disease and 12 had N1 disease.
Dose levels of irinotecan were as follows: three patientsreceived 30 mg/m2, three patients received 40mg/m2, four patients received 50 mg/m2,and six patients received 60 mg/m2, one patientreceived 70 mg/m2. Radiation doses ranged from30 Gy to 50.4 Gy.
There were 4 patients who received 50.4 Gy in 28 fractions, 12received 45 Gy in 25 fractions, 1 patient received 27 Gy in 15 fractions, andanother received 34 Gy in 19 fractions.
Major toxicities (grade 3/4) were hematologic. Three patientsdeveloped neutropenia, including one patient with neutropenic fever, one patienthad sepsis, and one patient developed chills. Two patients hemorrhaged, and twohad severe anemia. Patients with grade 3/4 GI toxicities included two withnausea, four with vomiting, three with dehydration, three with anorexia, and onewith constipation. No patient experienced severe pneumonitis.
Of 12 evaluable patients, 7 (58%) had a response, including 2complete responses; 4 patients (30%) had no change. Only 1 patient hadprogressive disease. Median time to progression was 27.5 weeks. Survival rangedfrom 1 to 15 months; median survival was 8 months.
Discussion
Among the camptothecins, irinotecan appears active as a singleagent in patients with advanced gastric carcinoma.[23] Irinotecan plus cisplatin(Platinol) was also reported to have a response rate of 42%.[24]
Camptothecin is an alkaloid obtained from plants such as the Camptothecaacuminata tree. The original clinical preparation, camptothecin sodium, wasevaluated in clinical trials in the late 1960s and early 1970s, but wasabandoned due to severe and unpredictable hemorrhagic cystitis.[25-27]Irinotecan is a semisynthetic derivative of camptothecin that possesses greateraqueous solubility, greater in vitro and in vivo activity, and is associatedwith less severe and more predictable toxicity than camptothecin.[28-30]
Both camptothecin and irinotecan are potent inhibitors oftopoisomerase I, a nuclear enzyme that plays a critical role in DNA replicationand transcription. The enzyme normally functions during DNA replication causingtransient breaks in a single strand of DNA that release the torsional straincaused by synthesis of a new strand of DNA or RNA around a double helix. Thecamptothecins target this topoisomerase I-DNA complex, stabilize it, and theninhibit reannealing of the parent DNA. When an advancing replication forkcollides with the camptothecin-topoisomerase I-DNA complex, double-stranded DNAbreaks occur that lead to cell death.[31,32] Preclinical studies in human lungtumor xenografts have shown that irinotecan is a potent radiosensitizing agent,and that its activity is related to the cell cycle.[22]
Preliminary, preclinical, and clinical studies demonstrate asynergistic effect of irinotecan and radiation and further substantiate theradiosensitizing activity of irinotecan. Interaction with cellular processessuch as DNA replication, RNA transcription, and DNA repair may transformpotentially sublethal DNA damage into sublethal DNA damage. It is plausible thatsuch sublethal DNA damage could then be converted into lethal DNA damage withthe addition of radiation-induced DNA damage.[22]
A phase I/II study of weekly irinotecan given concurrently withradiation in patients with locally advanced NSCLC demonstrated response andmanageable toxicities. Doses of irinotecan started at 30 mg/m2and were escalated to 45 and 60 mg/m2/week. In26 eligible patients, the dose-limiting toxicities were esophagitis,pneumonitis, and diarrhea. The MTD was estimated to be 60 mg/m2and the recommended dose for a phase II study was 45 mg/m2.In this phase II study, 2 of 24 evaluable patients achieved a complete responseand 16 attained a partial response, resulting in an overall response rate of76%.
The investigators concluded that a combination of concurrentweekly irinotecan and radiotherapy is feasible and active for locally advancedNSCLC.[33] These results were extended in a phase II trial in previouslyuntreated patients with stage IIIA/B NSCLC where 24 eligible patients receivedirinotecan 60 mg/m2 weekly and a total of 60 Gychest radiation therapy. The response rate was 79%, with pneumonitis andesophagitis being the principle toxicities.[33]
Administering up to 60 mg/m2irinotecan with concurrent radiation therapy of 45 Gy over 5 weeks has beenshown to be a feasible approach in previously treated patients.
In the future, cell proliferation rates must be considered whenproviding accelerated radiation therapy or conventional radiation therapy incombination with radiosensitizing agents. Combined treatment with moreefficacious systemic agents and more aggressive locoregional treatments toproduce 5-year survival rates better than 25% with less than 10%treatment-related mortality is warranted. The combination of irinotecan andconcurrent radiotherapy can be given safely for esophageal and gastric cancers.It should also be investigated for the treatment of lung and other cancers.
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