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Clinical Trial
. 2017 Oct 1;3(10):1358-1365.
doi: 10.1001/jamaoncol.2017.0982.

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial

Feng-Ming Kong  1   2 , Randall K Ten Haken  1 , Matthew Schipper  1   3 , Kirk A Frey  4 , James Hayman  1 , Milton Gross  4   5 , Nithya Ramnath  5   6 , Khaled A Hassan  6 , Martha Matuszak  1 , Timothy Ritter  1   5 , Nan Bi  1 , Weili Wang  1   2 , Mark Orringer  7 , Kemp B Cease  5   6 , Theodore S Lawrence  1 , Gregory P Kalemkerian  6
Affiliations
Clinical Trial

Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non-Small-Cell Lung Cancer: A Phase 2 Clinical Trial

Feng-Ming Kong et al. JAMA Oncol. .

Abstract

Importance: Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival.

Objective: To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non-small-cell lung cancer (NSCLC).

Design, setting, and participants: A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT.

Intervention: Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation.

Main outcomes and measures: The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population.

Results: The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45-83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63-86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%-92%) and 62% (95% CI, 43%-77%), respectively. Median overall survival was 25 months (95% CI, 12-32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%-66%) and 30% (95% CI, 16%-45%), respectively.

Conclusions and relevance: Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion.

Trial registration: clinicaltrials.gov Identifier: NCT01190527.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kong and Dr Ten Haken report grants from National Institutes of Health (NIH) during the conduct of the study; grant and travel support from Varian Medical System, outside the submitted work. Dr Frey reports Grant support from NIH/NCI and NIH/NINDS, common stock ownership in General Electric, Bristol-Myers Squibb, Novo Nordisk, and Merck, and consultation positions at Siemenns Medical, Avid Radiopharmaceuticals, and MIM Software, Inc. Dr Matuszak reports grants from NIH, National Cancer Institute, during the conduct of the study and grants from Varian Medical Systems outside the submitted work. Dr Kalemkerian reports grants from Millennium, Pfizer, GlaxoSmithKline, Astex, OncoMed, and Merck outside the submitted work.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram of Study Enrollment
IRB indicates institutional review board; PET/CT, positron emission tomography in conjunction with computed tomography.
Figure 2.
Figure 2.. Radiation Dose Prescriptions
The dose was prescribed so that every patient had an opportunity of receiving a maximum dose of 86 Gy to during RT PET-PTV in 30 daily fractions of 2.1 to 3.8 Gy. Dose was also limited by tolerances of other organs at risk, such as heart, esophagus, and cord per standard practice. CT indicates computed tomography; CTV, clinical target volume; MLD, mean lung dose; NCTP, normal tissue complication probability; PET, positron emission tomography; PTV, planning target volume; RT, radiation therapy.
Figure 3.
Figure 3.. Escalating Dose to Tumor Without Increasing Dose to Normal Tissues
Pretreatment and midtreatment PET/CT-guided RT planning in a patient who was oxygen dependent after a futile thoracotomy. Based on the midtreatment PET-CT, the patient received an added 11 Gy to the residual 18F-fludeoxyglucose–avid tumor while maintaining normal tissue toxicity probability (NTCP) of the lung at 17.2%. This patient remains alive and off oxygen therapy more than 4 years after treatment. In addition to dose-marked color lines, the purple line represents planning target volume or pretreatment, and the yellow line is the target volume during treatment planning. CT Indicates computed tomography; PET, positron emission tomography; RT, radiotherapy.
Figure 4.
Figure 4.. Tumor Control and Survival After Adaptive Treatment
A, Local tumor control (corresponding to infield local-regional control). B, Overall local regional control. C, Local regional progression-free survival. D, Overall survival.
Figure 5.
Figure 5.. Patterns of First Failure
Venn diagram with number and percentage of patients in each category.
See this image and copyright information in PMC

Comment in

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