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Data from the Radiation Therapy Oncology Groupand Eastern Cooperative Oncology Group indicate that increased survival
ABSTRACT: Data from the Radiation Therapy Oncology Groupand Eastern Cooperative Oncology Group indicate that increased survivalmay be achieved in patients with surgically unresectable stage II, IIIA,or IIIB non-small-cell-lung cancer when exposed to hyperfractionated radiationtherapy schedules, as compared with single daily-fraction radiotherapy.In addition, an increase in survival has been noted in patients with unresectabledisease or resectable adenocarcinoma following exposure to cisplatin (Platinol)and fluorouracil (5-FU) with concomitant radiotherapy. Both docetaxel (Taxotere)and paclitaxel (Taxol) have activity in patients with non-small-cell lungcancer and/or esophageal adenocarcinoma. Preclinical studies have shownthat these agents may be potent radiation enhancers by inducing cell-cyclearrest in the G2/M-phase of the cell cycle. Thus, we initiateda phase I study to define the maximum tolerated dose and dose-limitingtoxicities of docetaxel when administered with concomitant chest radiation.Results from this phase I trial may provide a basis for integrating sucha regimen into a curative-intent treatment approach for intermediate-stagemalignancies of the chest. [ONCOLOGY 11(Suppl 7):23-26, 1997]
There is an intermediate stage during the natural history of many solidtumors during which patients have locally or regionally advanced diseasewithout clinically overt, systemic metastasis. Traditional treatmentfor these patients consisted of surgery and/or radiotherapy; however, onlya small percentage of patients were cured, and treatment failures due toinadequate locoregional or systemic control of the disease occurred ina high percentage of patients.
Therefore, patients with intermediate-stage solid tumors require moreeffective locoregional therapy, as well as the administration of systemictherapy to eradicate microscopic metastases. These observations have ledto the widespread investigation of multimodality therapies, including induction(neoadjuvant) chemotherapy and concomitant chemoradiotherapy.
Among the common malignancies in the chest, non-small-cell lung cancerfrequently is diagnosed in an intermediate stage (stages IIIA and IIIB).The majority of these patients develop systemic disease outside the ipsilateralside of the chest, and a significant proportion fail to achieve locoregionalcontrol.
The administration of induction chemotherapy utilizing cisplatin (Platinol)and vinblastine for two cycles has been demonstrated in two studies toresult in a significant increase in median and long-term survival, as comparedwith radiotherapy alone.[3,4] Another study investigating induction chemotherapyhas suggested that improved survival occurs as a function of decreasedsystemic recurrence rate. Locoregional control, on the other hand, doesnot appear to be increased through the use of induction chemotherapy.
Randomized studies investigating concomitant chemoradiotherapy vs radiotherapyalone have frequently focused on cisplatin administered as a single agent.Daily, weekly, and monthly administration of the drug during radiotherapyhave been investigated. To date, only one study has shown an increasein survival.
In this study, improved survival occurred as a function of an increasein locoregional control. These data suggest that increasing locoregionalcontrol may translate into a survival benefit for some patients with intermediatenon-small-cell lung cancer and that concomitant chemoradiotherapy may beone tool to achieve that goal. This is further substantiated by recentreports indicating increased survival in patients treated with hyperfractionatedradiation therapy schedules or the regimen of continuous hyperfractionatedaccelerated radiation therapy (CHART), as opposed to single daily-fractionradiotherapy.[7,8]
Similar observations supporting the use of combined-modality therapyhave been made in esophageal cancer. Results from two studies investigatingthe use of cisplatin and fluorouracil (5-FU) with concomitant radiotherapydemonstrated an increase in survival in patients with unresectable diseaseor resectable adenocarcinoma.[9,10] In addition, an increase in locoregionaland systemic tumor control was reported.
In recent years, several new chemotherapeutic agents with activity innon-small-cell lung cancer and/or esophageal cancer have been identified,including the taxanes docetaxel (Taxotere) and paclitaxel (Taxol). Inthe preclinical setting, the taxanes appear to be potent radiation enhancersby inducing cell-cycle arrest in the G2/M-phase.[11,12] Studieshave shown that cells in the G2/M-phase are more sensitive toradiation than cells in other phases of the cell cycle.
In addition, concurrent administration of chemotherapy and radiationhas resulted in promising data in intermediate-stage chest malignancies.Thus, the investigation of new chemotherapeutic compounds with concomitantradiation therapy is a high priority.
Because the clinical interactions of docetaxel and concomitant chestradiotherapy had not been described previously, we initiated a phase Istudy to define the maximum tolerated dose and dose-limiting toxicitiesof docetaxel when administered with concomitant chest radiation. In addition,we investigated the administration of docetaxel on a variety of schedulesto determine the most feasible schedule of administration in a clinicalsetting.
Patients and Methods
This ongoing study began in 1994 at the University of Chicago, and patientenrollment continues. Criteria for study participation includes patientswith histologically or cytologically confirmed advanced solid tumors andthose who require chest radiotherapy as a component of their overall treatmentplan. Also eligible are patients with metastatic or local/regionally advanceddisease in the chest, as well as those requiring adjuvant radiation therapyfollowing surgical resection of an advanced intrathoracic malignancy.
Further eligibility criteria include a Cancer and Leukemia Group B statusof 0 to 2, normal bone marrow, and normal hepatic and renal function. Althoughpatients are not to have received hormonal or chemotherapy within 4 weeksof study initiation, prior radiation therapy to less than 25% of the activebone marrow is allowed.
Patients with known brain metastases or meningeal involvement are excluded.In addition, patients with symptomatic peripheral neuropathy (more thangrade 1) or serious additional medical disease are excluded. Similarly,prior therapy with a taxane is not allowed. All patients signed an informedconsent.
Pretreatment staging procedures include routine physical examinationand hematologic and serum chemistry blood tests.
The dose-escalation schedule is shown in Table1. The overall goals of this study are to determine the optimal scheduleand maximum tolerated dose of docetaxel. Radiation therapy is administeredat 180 to 200 Gy/fraction, administered Monday through Friday for eachof 5 to 6 consecutive weeks. The total planned radiation dose is 50 to60 Gy. The docetaxel dose has been escalated from 40 to 60 to 75 mg/m²per 3-week cycle (administered twice during a 6-week course of radiotherapy).Beginning 24 hours prior to each dose of docetaxel, oral dexamethasoneis administered at 8 mg twice daily for a total of 6 doses.
A minimum of three evaluable patients are entered at each dose level.There is no dose escalation in individual patients. The maximum tolerateddose is defined as the dose at which less than 33% of patients experiencedose-limiting toxicity. Grade 3 or 4 nonhematologic toxicity (excludingnausea, vomiting, anemia, and alopecia) and grade 4 neutropenia exceeding4 days' duration or complicated by a neutropenic fever or grade 4 thrombocytopeniarepresent dose-limiting toxicities.
This study investigating docetaxel as a single agent with concomitantradiotherapy to the chest opened in 1994. To date, 29 patients have beenenrolled, including 19 men and 10 women (Table2). Of the 29 patients, 20 had non-small-cell lung cancer and 9 hadesophageal cancer. Only 1 patient has received prior chemotherapy; 7 patientshave undergone previous surgery. The study data are currently undergoingfinal analysis regarding the recommended phase II doses and the optimaladministration schedule.
This phase I study of docetaxel with concomitant radiotherapy is designedto define the optimal dose and schedule of docetaxel with standard chestradiotherapy. Following completion of the study, the integration of thisregimen into a curative-intent treatment approach for intermediate-stagemalignancies of the chest should be pursued.
Regarding non-small-cell lung cancer, induction chemotherapy resultsin increased median and long-term survival rates. Similarly, increasedtumor control within the chest may be of benefit to the patient. Therefore,it would appear to be of interest to investigate docetaxel-based inductionchemotherapy to be followed by docetaxel with concomitant chest radiotherapy.
In particular, two to three cycles of docetaxel with cisplatin or carboplatin(Paraplatin), followed by docetaxel with radiotherapy, may be of interest.The Cancer and Leukemia Group B is currently pursuing this sequencing strategy,utilizing several of the new chemotherapeutic agents.
In this randomized phase II study, patients receive two cycles of anew chemotherapeutic agent, plus cisplatin as induction chemotherapy, followedby two additional cycles of the same chemotherapy regimen with concomitantstandard chest radiotherapy. Patients are randomized to receive eitherpaclitaxel, vinorelbine (Navelbine), or gemcitabine (Gemzar) with the cisplatindose. A similar study design utilizing docetaxel would be of great interest,given the higher efficacy reported in cisplatin-resistant patients withadvanced non-small-cell lung cancer.
At the same time, integration of concomitant docetaxel with radiotherapyinto the management of patients with esophageal cancer is currently beingexamined in a phase II multicenter study. Patient enrollment is ongoing.Eligible patients with advanced but nonmetastatic esophageal cancer receivethree cycles of cisplatin/docetaxel followed by docetaxel with concomitantchest radiotherapy. Patients with resectable disease undergo esophagectomyfollowing the completion of radiotherapy, and patients with unresectabledisease complete concomitant chemoradiotherapy with a boost dose of radiation.Preliminary results are expected in the near future.
1. Hellman S, Vokes EE: Improving conventional therapy. Sci Am 275(3):83-89,1996.
2. Ginsberg R, Vokes EE, Raben A: Non-small cell cancer, in DeVita JrVT, Hellman S, Rosenberg SA (eds): Cancer Principles & Practice ofOncology, 5th ed, pp 858-910. Philadelphia, JB Lippincott, 1997.
3. Dillman RO, Seargren SL, Propert K: A randomized trial of inductionchemotherapy plus high-dose radiation versus radiation alone in stage IIInon-small cell lung cancer. N Engl J Med 323:940-945, 1990.
4. Sause W, Scott C, Taylor S, et al: Radiation Therapy Oncology Group(RTOG) 88-08 and Eastern Cooperative Oncology group (ECOG) 4588: Preliminaryresults of a phase III trial in regionally advanced unresectable non-small-celllung cancer. J Natl Cancer Inst 87:198-205, 1995.
5. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versuscombined chemotherapy and radiotherapy in nonresectable non-small-celllung cancer: First analysis of a randomized trial in 353 patients. J NatlCancer Inst 83:417-423, 1991.
6. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects ofconcomitant cisplatin and radiotherapy on inoperable non-small-cell lungcancer. N Engl J Med 326: 24-530, 1992.
7. Sause W, Scott C, Taylor S, et al: RTOG 8808 and ECOG 4588: Preliminaryanalysis of a phase III trial in regionally advanced unresectable non-smallcell lung cancer with minimum three year follow-up. Int Radiat Oncol BiolPhys 32 (suppl 1):195, 1995.
8. Saunders MI, Dische S, Barrett A, et al: Randomised multicentre trialsof chart vs conventional radiotherapy in head and neck and non-small-celllung cancer: An interim report. Br J Cancer 73:1455-1462, 1996.
9. Al-Sarraf M, Martz K, Herskovic A, et al: Progress report of combinedchemoradiotherapy alone in patients with esophageal cancer: An intergroupstudy. J Clin Oncol 15:277-284, 1997.
10. Walsh T, Noonan N, Hollywood D, et al: A comparison of multimodaltherapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467,1996
11. Tishler RB, Schiff PB, Geard CR, et al: Taxol: A novel radiationsensitization. Int J Radiat Oncol Biol Phys 22:613-617, 1992.
12. Hennequin C, Giocanti N, Favaudon V: Interaction of ionizing radiationwith paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells.Cancer Res 56:1842-1850, 1996.
13. Vokes EE, Leopold KA, Herndon II JE, et al: A CALGB randomized phaseII study of gemcitabine or paclitaxel or vinorelbine with cisplatin asinduction chemotherapy (XRT) in stage IIIB non-small cell lung cancer (NSCLC):Feasibility data (CALGB study #9431) (abstract 1636). Proc Am Soc ClinOncol 16:455a, 1997.