Preoperative Chemoradiotherapy vs. Chemotherapy Alone in NSCLC Patients

Preoperative Chemoradiotherapy vs. Chemotherapy Alone in Non-small Cell Lung Cancer (NSCLC) Patients With Mediastinal Lymph Node Metastases (Stage IIIA, N2): A Randomized Prospective Phase III Trial

RATIONALE: Drugs used in chemotherapy, such as docetaxel and cisplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving chemotherapy with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known if chemotherapy plus radiation therapy is more effective than chemotherapy alone before surgery in treating non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying docetaxel and cisplatin with or without radiation therapy to see how well they work when given before surgery in treating patients with stage IIIA non-small cell lung cancer that has spread to lymph nodes in the chest.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: Chemotherapy; Radiation: Radiotherapy; Procedure: Surgery

Detailed Description

The main objective of this trial is to compare feasibility and efficacy of sequential neoadjuvant chemoradiotherapy with 44 Gy concomitant boost to neoadjuvant chemotherapy alone.

Secondary objectives are to assess the value of PET in predicting pathological response and eventfree survival in stage IIIA NSCLC, and a health economic analysis of the two regimens. Further to compare the amount of serum DNA in patients with stage IIIA, pN2 NSCLC before chemotherapy, before surgery and at the second follow-up visit (i.e. four months after surgery or treatment failure for patients who can not be operated) in patients randomized into the trial SAKK 16/00 and to correlate the DNA variation with tumor response, remission duration and overall survival.

OUTLINE: This is a prospective randomized phase III trial. Patients are stratified according to mediastinal bulk (5 cm or more vs less than 5 cm), weight loss in the past 6 months (5% or more vs less than 5%), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Study Type: Interventional
• Enrollment (Actual): 232
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Löwenstein, Germany, 74245
    • Klinik Loewenstein gGmbH
  • Mannheim, Germany, D-68135
    • Klinikum der Stadt Mannheim
• Serbia
  • Sremska Kamenica, Serbia, 21204
    • Institut za plucne bolesti
  • Sremska Kamenica, Serbia, 21204
    • Institute of Oncology
• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonsspital Aarau
  • Baden, Switzerland, CH-5404
    • Kantonsspital Baden
  • Baden, Switzerland, CH-5404
    • Kantonsspital
  • Basel, Switzerland, CH-4016
    • Saint Claraspital AG
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bellinzona, Switzerland, 6500
    • Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Freiburg, Switzerland, 1708
    • Kantonsspital Freiburg
  • Geneva, Switzerland, CH-1211
    • Hopital Cantonal Universitaire de Geneve
  • Lausanne, Switzerland, 1011
    • Centre Pluridisciplinaire d' Oncologie
  • Liestal, Switzerland, CH-4410
    • Kantonsspital Liestal
  • Olten, Switzerland, CH-4600
    • Kantonsspital Olten
  • Rheinfelden, Switzerland, 4310
    • FMH Onkologie/Haematologie
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • Regionalspital
  • Winterthur, Switzerland, CH-8400
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8038
    • Onkozentrum
  • Zurich, Switzerland, CH-8063
    • City Hospital Triemli
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer

  • Squamous, adenosquamous, large cell, or poorly differentiated

• Stage IIIA (T1-3, N2, M0)

  • N2 disease confirmed by 1 of the following:

    • Mediastinoscopy

    • Bronchoscopy with fine-needle aspiration or esophagoscopy

      • All N3 lymph nodes must be negative by positron-emission tomography (PET) AND CT scan (< 1 cm in the largest diameter)

    • PET scan

      • Both the primary tumor and at least 1 N2 lymph node must be positive in PET scan
      • At least 1 of the PET scan positive N2 lymph nodes is positive in the CT scan (> 1 cm in the largest diameter)
      • All N3 lymph nodes negative in PET scan

PATIENT CHARACTERISTICS:

Age:

• 18 to 75

Performance status:

• WHO 0-1

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 4,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin normal
• AST/ALT no greater than 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 2.5 times ULN

Renal:

• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• Cardiac function normal
• No unstable cardiac disease requiring treatment
• No congestive heart failure
• No angina pectoris even if medically controlled
• No significant arrhythmia
• No myocardial infarction in the past 3 months

Pulmonary:

• Lung function appropriate

Neurologic:

• No history of significant neurologic or psychiatric disorders
• No psychotic disorders
• No dementia
• No seizures

Other:

• No other prior or concurrent malignancies except nonmelanoma skin cancer, adequately treated carcinoma in situ of the cervix, or any other neoplastic disease with a disease-free interval ≥ 5 years
• No active uncontrolled infection
• No uncontrolled diabetes mellitus
• No gastric ulcers
• No pre-existing peripheral neuropathy greater than grade 1
• No contraindications to corticosteroids
• No other serious underlying medical condition that would preclude study participation
• No socioeconomic or geographic condition that would preclude study participation
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior cytostatic chemotherapy

Endocrine therapy:

• No concurrent prednisone except for treatment of acute hypersensitivity reactions or chronic low-dose treatment initiated more than 6 months prior to study entry (i.e., no greater than 20 mg methylprednisolone or equivalent)

Radiotherapy:

• No prior radiotherapy to chest

Surgery:

• Not specified

Other:

• At least 30 days since participation in another clinical study
• No other concurrent experimental drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A; Neoadjuvant Chemoradiotherapy + Chemotherapy + Surgery	Drug: Chemotherapy; Docetaxel (Taxotere®) 85 mg/m2 1 hour iv infusion d1 Cisplatin 100 mg/m2 1 hour iv infusion d1 Schedule: 3 cycles repeated every 21 days; Radiation: Radiotherapy; Radiotherapy (3 weeks after last chemotherapy administration) 44 Gy in 22 fractions concomitant boost technique in 3 weeks; Procedure: Surgery; 3-4 weeks after termination of radiotherapy
Active Comparator: Arm B; Neoadjuvant Chemotherapy + Surgery	Drug: Chemotherapy; Docetaxel (Taxotere®) 85 mg/m2 1 hour iv infusion d1 Cisplatin 100 mg/m2 1 hour iv infusion d1 Schedule: 3 cycles repeated every 21 days; Procedure: Surgery; 3-4 weeks after termination of radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival	Time from randomization to relapse/progression/second tumor/death, whichever occurs first (for all randomized patients). If no event is observed, the patients will be censored at the last time they were known to be alive.	1 month after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative mortality assessed	All deaths occurring within 30 days of the thoracic surgery to remove the primary tumor	1 month after surgery
Toxicity (hematological, renal and neurological toxicities, nausea and vomiting, weight changes as well as esophageal toxicities)	Assessed according to the NCIC-CTG Expanded Common Toxicity Criteria grading. Special attention shall be given to hematological, renal and neurological toxicities, nausea and vomiting, weight changes as well as esophageal toxicities.	During treatment
Complete resection rate after surgery	Assessed according to the NCIC-CTG Expanded Common Toxicity Criteria grading.	1 month after surgery
Objective response rate measured after completion of chemoradiotherapy	Response rate will be evaluated according to the; WHO response criteria; TNM classification after surgery.	43 days
Operability	Patients who are able to undergo radical resection of their lung cancer after neoadjuvant therapy, as assessed by the thoracic surgeon.	1 month after chemo
Overall survival	Calculated from randomization to the date of death from any cause. Patients not experiencing an event will be censored at the last time they were known to be alive.	Life-long follow-up until death of patient (up to 30 years)
Failure pattern	Defined as location of first tumor progression or relapse. Failure can be local relapse (area of primary tumor or mediastinum), distant relapse (all others) or the combination thereof.	Life-long follow-up until death of patient (up to 30 years)

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Miklos Pless, MD, Kantonsspital Winterthur KSW; Principal Investigator: Hans-Beat Ris, MD, Centre Hospitalier Universitaire Vaudois; Principal Investigator: Diana Naehrig, MD, Universitaetsspital-Basel; Principal Investigator: Roger Stupp, MD, Centre Hospitalier Universitaire Vaudoise

Publications and helpful links

General Publications

• Tieu BH, Sanborn RE, Thomas CR Jr. Neoadjuvant therapy for resectable non-small cell lung cancer with mediastinal lymph node involvement. Thorac Surg Clin. 2008 Nov;18(4):403-15. doi: 10.1016/j.thorsurg.2008.07.004.
• Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Fruh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015 Sep 12;386(9998):1049-56. doi: 10.1016/S0140-6736(15)60294-X. Epub 2015 Aug 11. Erratum In: Lancet. 2015 Sep 12;386(9998):1040.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2001
• Primary Completion (Actual): April 9, 2014
• Study Completion (Actual): September 15, 2023

Study Registration Dates

• First Submitted: February 14, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Estimated): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: stage IIIA non-small cell lung cancer; squamous cell lung cancer; large cell lung cancer; adenosquamous cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms
• Other Study ID Numbers: SAKK 16/00; SWS-SAKK-16/00 (Other Identifier: SAKK); EU-20138

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No