New Frontiers in Lung Cancer


NEW FRONTIER IN MANAGEMENT OF LUNG CANCER: RADIOTHERAPY ASPECT

Associate Professor Kanjana Shotelersuk, MD

Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand


SYNOPSIS

Lung cancer is the leading cause of cancer death worldwide. Non-Small Cell Lung Cancer (NSCLC) is approximately 80% of all lung cancer cases. Surgery has been considered standard treatment in early stage NSCLC. However, radiation therapy is increasingly used, especially Stereotactic Body Radiotherapy (SBRT) or Stereotactic Ablative Radiotherapy (SABR). It is an advanced radiotherapy technique to precisely deliver high dose radiation per fraction in small number, usually 1-5, of fractions. This technique has a radiobiological advantage in killing tumor cell. However, the suitable condition, which is a tumor of a small size (4 cms or less) and located in peripheral lung, is required.  

Several nonrandomized studies revealed good outcome of SBRT in early stage NSCLC. Local control at 2-3 years ranged from 40-80% and 3-year overall survival is around 50-60%. Therefore, SBRT is considered a standard of care for early stage medically inoperable NSCLC (T1-2, N0M0). Randomized studies, STARS, ROSEL and ACOSOG trials are attempted in operable NSCLC to compare between surgery and SBRT. Although there were not many patients recruited in these trials, the outcome was encouraging. Pool analysis of STARS and ROSEL studies reported that 3-year Relapse Free Survival and Overall Survival in SBRT arm was 86% and 95%, respectively. (1)

SBRT may be used cautiously in the tumor centrally located, 2 cms around the proximal bronchial tree, because of higher risk of treatment-related toxicity to critical mediastinal structures. RTOG 0813 has recently published the outcome of dose escalating study of five fractions SBRT schedule for centrally located NSCLC. The study revealed that radiation dose 50-60 Gy in 5 fractions is safely delivered with high rate of tumor control. (2)

In locally advanced NSCLC, concurrent chemoradiation has been considered standard treatment. However, the long term survival is not satisfied due to uncontrolled primary tumor in the lung and distant metastasis. Recently, PACIFIC study, showed promising outcome of adjuvant systemic immunotherapy after concurrent chemoradiation in locally advanced NSCLC. In the meantime, advanced radiotherapy techniques trying to improve treatment outcome has also been studied. Because radiation treatment target volume in locally advanced cases is quite large, delivering high dose radiation could increase radiation toxicities to adjacent normal tissues including heart, normal lung, spinal cord and esophagus. Advanced radiotherapy techniques including 3-Dimensional Conformal Radiotherapy, Intensity Modulated Radiation Therapy (IMRT) and recently Proton Therapy improve radiation dose delivery to the tumor. The physical property of proton, which is a type of particle beam, has significant dosimetric advantage comparing to photon therapy or X-ray beam. This results in decreasing radiation dose to critical normal structures. Since dose-escalating trial of photon therapy from 60 to 74 Gy, RTOG 0617, showed disappointing outcome, using proton therapy to increase radiation dose to tumor while maintain radiation dose to normal tissue might be beneficial in these patients. Favorable outcome of proton therapy has been reported in early and locally advanced stage NSCLC. Recently, retrospective study from National cancer Database Analysis of Proton therapy in NSCLC revealed better survival comparing with photon therapy. (3) 

In conclusion, new and advanced radiation techniques have become available. Ongoing and future studies are required to determine their optimal use. 

References:

  1. Chang JY, Senan S, Paul MA, et al. Stereotactic Ablative Radiotherapy versus Lobectomy for Operable Stage I Non-Small-Cell Lung Cancer: A Pool Analysis of Two Randomized Trials. Lancet Oncol. 2015: 630-637
  2. Bezjak A, Paulus R, Gaspar LE, et al. Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/ RTOG 0813 Trial. J Clin Oncol 2019: 1316-1325
  3. Higgins KA, O’Connell K, Liu Y, et al. National Cancer Database Analysi of Proton versus Photon Radiation Therapy in Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017: 128-137

NEW FRONTIER IN LUNG CANCER

Assistant Professor Thanyanan Reungwetwattana, MD, MSc

Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol, University, Bangkok, Thailand


SYNOPSIS

Even though, currently we have several novel and emerging therapies in lung cancer which improve the survival and quality of life for patients, but we also have a lot of unanswered questions that we need the global network research to explore the new knowledge. EGFR-TKI is the first effective targeted drug for treatment in EGFR-positive patients. The prevalence of EGFR mutation in NSCLC patients is higher in Asian population compared to the other population (55% vs. <20%). Currently, there are 3 generations of EGFR-TKI approved in the market for treating EGFR-positive patients specifically with sensitive mutation (exon19 deletion and exon21 L858R mutation) with the overall response rate of 60-70%. The acquired resistance could be occurred after 9-13 months of treatment. The majority of this group of patient (50-60%) develops T790M as the mechanism of resistance which is now we have the third-generation EGFR-TKI for overcoming this resistance. 

 The second approved targeted drugs for lung cancer is ALK inhibitors, which the history of development is similar to EGFR TKIs. Nowadays we do have 5 ALK inhibitors in the market to treat NSCLC with ALK fusion gene. The third and the forth targeted drugs are ROS inhibitor and BRAF inhibitors which are already approved for NSCLC patients with ROS fusion gene and with BRAF V600E mutation. Recently, larotrectinib was approved for treating NTRK fusion gene in solid tumor including lung cancer. Moreover, the other oncogenic driven mutation (MET amplification, HER2, PIK3CA mutation, RET, NTRK, FGFR fusion etc.) could be the target of treatment in NSCLC as well as EGFR gene. Currently, the potential targeted drugs for inhibiting these oncogenic driven mutations are developing in the early phase clinical studies. 

Each region of the world has the different in prevalence of oncogenic driven mutations in lung cancer. Our institute found the unique molecular profile in Thai lung cancer patients, which have the high prevalence of BRAF V600E mutation (10%) and METexon14 splice site (9%). In this study, we also found 68% (113/166) of EGFR mutation, 32.5% (54/166) of KRAS mutation, 4.8% (8/166) AKT mutation (E17K), 2.4% (4/166) of ROS1 mutation, 0.6% (1/166) of PIK3CA mutation (H1047R), and 0.6% (1/166) of PTEN mutation. We further validated the positive results by Real-Time PCR. 

Immunoterapy is currently approved for treatment in NSCLC both in adenocarcinoma and squamous cell carcinoma either with 1st or 2nd line treatment. The cost of the drug is one of the key issues together with the other important problem that we have not known the true predictive biomarkers for the immunotherapy. This is the urge of conducting the research to explore the real predictive and prognostic biomarkers.

In summary, the journey of personalized treatment in lung cancer is the good prototype for the cancer drugs development. I do believe that there will be the other effective emerging treatments for lung cancer approved in the near future which would improve the long term survival and QOL for patients.

Event Hours(1)

  • Lotus 5-6

    10:50 am – 12:00 pm

    Speakers:
    1. Assoc. Prof. Kanjana Shotelersuk (CU)
    2. Asst. Prof. Punnarerk Thongcharoen (SI)
    3. Asst. Prof. Thanyanan Reungwetwattana (Rama)
    4. Dr. Wisut Lamlertthon (CRA)

    Moderator:
    Assoc. Prof. Virote Sriuranpong (CU)

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