Journal of Radiation and Cancer Research

REVIEW ARTICLE
Year
: 2022  |  Volume : 13  |  Issue : 4  |  Page : 232--236

Changing treatment paradigms of radiotherapy for the treatment of lung cancer


Atsuto Katano 
 Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan

Correspondence Address:
Dr. Atsuto Katano
Department of Radiology, The University of Tokyo Hospital, Tokyo
Japan

Abstract

Lung cancer is largely classified into two types according to its histology, small cell and nonsmall cell, and has diverse situations for which radiotherapy is indicated. Radiation therapy plays a major role in the treatment strategy for both types of lung cancer. Since the treatment of lung cancer is extremely complex, it is essential to develop an appropriate treatment strategy by combining surgery, radiotherapy, and systemic therapy (chemotherapy, immunotherapy, and molecular-targeted drugs) according to each stage of the disease. Radiotherapy is indicated, from curative intent to palliative treatment, at any stage of the disease. Current radiotherapy, which incorporates diagnostic imaging and physical engineering, has made significant progress, making it possible to increase the local control rate while reducing the radiation dose to at-risk organs. Herein, we review the basics of the current perspective of radiotherapy and the current role of radiotherapy in lung cancer treatment according to each stage of the disease.



How to cite this article:
Katano A. Changing treatment paradigms of radiotherapy for the treatment of lung cancer.J Radiat Cancer Res 2022;13:232-236


How to cite this URL:
Katano A. Changing treatment paradigms of radiotherapy for the treatment of lung cancer. J Radiat Cancer Res [serial online] 2022 [cited 2022 Dec 4 ];13:232-236
Available from: https://www.journalrcr.org/text.asp?2022/13/4/232/353191


Full Text

 Introduction



Lung cancer is the most common cause of cancer-related deaths, with an estimated 1.8 million deaths per year.[1] Radiotherapy is an important modality for the treatment of lung cancer. The main characteristic of radiotherapy is that it can preserve organ function and morphology and is less invasive than the surgical approach. In recent years, radiation therapy has developed rapidly owing to the sophistication of computer technology and high performance of treatment devices.[2] Intensity-modulated radiation therapy (IMRT) is an innovative treatment technique that uses advanced computer technology to focus a high dose on the lesion, while reducing the dose for the normal tissue around the lesion. This epoch-making treatment technique is expected to improve the tumor control rate and reduce complications. Volumetric-modulated arc therapy is an advanced form of IMRT, in which the rotational speed of the irradiation gantry and the dose rate are varied during irradiation, resulting in shorter irradiation times compared with conventional IMRT.[3]

In addition, four-dimensional computed tomography is increasingly used for treatment planning, which enables reliable irradiation even for physiologically fluctuating targets such as early-stage lung cancer. The development of a matching technique called image-guided radiation therapy has made it possible to apply with high accuracy the dose distribution created by the treatment planning machine to an actual patient during irradiation.[4] In conventional radiotherapy, very large margins are used to account for tumor movement and uncertainty, but with the improvement of such image processing technology, unnecessary doses to the surrounding normal tissues can be reduced, and a higher radiation dose can be focused on the tumor. Stereotactic body radiation therapy (SBRT), which uses a general linear accelerator, is currently being used in many facilities.

Although radiotherapy technology has developed, adverse effects are still inevitable and should be recognized as a disadvantage of radiotherapy.[5] Adverse events related to radiotherapy can be broadly divided into acute- and late-phase effects. Acute side effects that may occur during and after a couple of months of radiotherapy include fatigue, anorexia, esophageal mucositis, dermatitis, cough, bone marrow suppression, and radiation pneumonitis. Among the acute effects, radiation pneumonitis is relatively slow in onset and its onset is thought to peak several months later. The risk of developing radiation pneumonitis is related to the volume of normal lung irradiation, radiation dose, comorbid lung disease, and the use of concurrent chemotherapy.[6],[7],[8] Late adverse events that occur several months after the completion of irradiation are irreversible and include pulmonary fibrosis, esophageal stenosis, cardiovascular disorders, spinal cord injury, and brachial plexus injury. However, they rarely occur at clinically significant levels, as long as the prescribed tolerated dose for each organ is adhered to.

In this review article, the current role of radiotherapy in the treatment of lung cancer is reviewed.

 Stereotactic Body Radiation Therapy for Early-Stage Nonsmall Cell Lung Cancer



SBRT is a radiation therapy that concentrates a high dose of radiation on the tumor volume to complete the treatment in a short period of time. In the TROG 09.02 CHISEL trial, the local control rate was improved in the SBRT group compared with the conventional radiotherapy group.[9] SBRT is currently regarded as the standard of care for patients with early-stage nonsmall cell lung cancer (NSCLC) who are medically inoperable or refuse surgery. The 3-year local control rate is 70%–90%, and the incidence of serious side effects graded 3 or higher is approximately 10%.[10],[11],[12] While the standard SBRT method involves three to five fractionated irradiations, recently, single fractional SBRT for small lung cancers achieved clinical results comparable to the multifractional regime in phase II trials.[13],[14] SBRT is also administered for oligometastatic lung cancers and is considered an important treatment option for metastatic advanced cancer. Siva et al. reported promising clinical outcomes of single-fraction SBRT for oligometastatic lung cancer in the SAFRON II trial.[15]

To the best of our knowledge, no completed phase III randomized controlled trials have directly compared the clinical outcomes of surgery and SABR for early-stage NSCLC. Several phase III trials, such as the STARS and ROSEL trials, were terminated because of low patient recruitment. The pooled analysis of these trials has been a source of controversy among oncologists, and there is no definitive conclusion regarding priority of treatment.[16] Franks et al. concluded that a randomized phase III comparison of SABR and surgery was not feasible in their paper.[17] Chang et al. prospectively enrolled patients with operable, pathologically confirmed stage IA NSCLC, and compared the clinical outcomes of patients who underwent standard treatment surgery and those who underwent SBRT using propensity score-matched comparison in the revised STARS trial.[18] The 3-year and 5-year overall survival rates were 91% and 87%, respectively, for the SBRT arm, which was comparable to that of the surgery arm with a tolerable rate of adverse event incidence.

Tumors located in the central part of the body near the main bronchi, esophagus, and heart are known to have a high treatment-related mortality rate; this is an area in which standard SBRT is not appropriate.[19] In these centrally located cases, the SBRT regimen was modified to lower the single per-fraction dose and increase the number of irradiations by 4–10 times. According to the RTOG 0813 trial results, five fractionation SBRT schedules for centrally located cases resulted in similar clinical outcomes compared to peripherally located cases.[20] In addition, transient radiation pneumonitis is inevitable after irradiation to varying degrees, and respiratory function must be maintained so that it does not become fatal. Therefore, it is necessary to have a conference or consultation with respiratory medicine and respiratory surgery in advance. In addition, after irradiation, the true tumor size and pathological findings are unknown, unlike in the case of surgical resection, because the course is judged only by follow-up imaging. Since there is no complete consensus on the irradiation dose, fractionation, and schedule, these issues will be the subject of future research.

 Radiation Therapy with Chemotherapy in the Locally Advanced Stage



Concurrent chemoradiotherapy (CCRT) has traditionally been used for locally advanced-stage NSCLC. CCRT in the locally advanced stage has a larger irradiation area than SBRT, and the irradiation field includes the mediastinal area due to lymph node metastasis. Therefore, radiation esophagitis and pneumonia are frequently observed adverse events during the acute stage. CCRT is usually administered in combination with platinum-based chemotherapy at a dose of 1.8 Gy–2 Gy in conventional fractions, equivalent to 60–66 Gy.[21],[22] If radical CCRT is not feasible due to a large tumor volume or poor general health, including respiratory function, sequential chemotherapy, or radiotherapy alone could be a treatment option. According to the RTOG 0617 trial, a high-dose prescription of 74 Gy is not recommended for locally advanced stage NSCLC.[23] In recent years, the importance of adjuvant therapy in unresectable stage III NSCLC has been revealed, according to the results of the PACIFIC trial, which randomized patients with stage III NSCLC to durvalumab or placebo as adjuvant therapy after chemoradiation.[24] Durvalumab is an antiprogrammed cell death ligand-1 (PD-L1) antibody. In a recent long-term analysis, the overall survival and progression-free survival rates at four years in the durvalumab group were 49.6% and 35.3%, respectively,[25] and it is no exaggeration to say that it has revolutionized the treatment strategy for stage III NSCLC.

Further development of this adjuvant-based durvalumab strategy is underway. The COAST trial (NCT03822351) is currently investigating the efficacy of combination adjuvant therapy consisting of durvalumab and oleclumab or monalizumab. Oleclumab and monalizumab are an anti-CD73 and an anti-natural killer group 2A (NKG2A) antibody, respectively. The PACIFIC2 (NCT03519971) trial evaluated the clinical outcomes of concurrent durvalumab administration with CCRT.

CCRT is also used as a curative therapy for localized small cell lung cancer. In this case, accelerated hyperfractionated irradiation is known to improve the survival rate compared to that of conventional fractionated irradiation. The accelerated hyperfractionated irradiation consisted of 45 doses of 1.5 Gy twice daily for a total of 3 weeks. In a recent phase 2 trial, dose escalation to 60 Gy had clinical advantages, including improved overall survival rate without a significant increase in severe adverse events.[26]

 Radiation Therapy in Metastatic Advanced Stage



The main treatment for patients with advanced-stage lung cancer is systemic therapy, although palliative radiotherapy may also be used to manage local symptoms. Symptoms characteristic of advanced-stage lung cancer include hemoptysis, chest pain, dyspnea, cough, dysphagia, and superior vena cava compression, which are often associated with local tumor progression. As bone and brain metastases are also frequent, palliative radiotherapy is used to control them. In general, irradiation schedules such as 30 Gy in 10 fractions, 20 Gy in five fractions, and 8 Gy in one fraction are often used, but SBRT is said to have a high pain-relieving effect in painful spinal metastases in the SC.24 trial.[27] As for brain metastases, whole-brain irradiation is the mainstay of treatment; however, higher brain dysfunction as a late effect has been considered a problem. With the recent development of immunotherapies and molecular targeted therapies as well as the improvement of stereotactic radiotherapy techniques, a cautious stance is now required regarding the indications for whole brain radiotherapy.

A major paradigm shift in cancer treatment is stereotactic radiotherapy for oligometastases. Oligometastasis refers to a disease state that is limited to a small number of metastases, regardless of the primary pathology. In the SABR-COMET phase II trial, in which patients with oligometastases were randomly assigned to either palliative care or palliative care plus SBRT, the group that received additional SBRT showed significantly better overall survival and progression-free survival.[28] Iyengar et al. reported a significant improvement in progression-free survival rate with chemotherapy-added oligometastasis-directed SBRT compared to chemotherapy alone (9.7 months vs. 3.5 months, P = 0.01).[29] Gomez et al. found that local consolidation therapy, including SBRT, benefited overall survival compared to systemic therapy only (41.2 months vs. 17.0 months, P = 0.017).[30] These results suggest that addition of curative local treatment could improve clinical outcomes in patients with oligometastatic disease. Therefore, it is essential to evaluate the efficacy of local treatment. The classification of oligometastases was developed by an international team consisting of the European Society for Radiotherapy and Oncology and the European Organization for Research and Treatment of Cancer.[31] This is a new therapeutic strategy to break away from the strategy of distant metastasis resulting in systemic therapy, and further evidence is expected to be accumulated in the future.

 Radiation Therapy and Immunity



It has been pointed out that radiation may have an immunostimulatory effect by damaging tumor cells, activating tumor antigen production, and promoting T cell-mediated antitumor responses.[32],[33] The regression of nontarget lesions due to enhanced systemic antitumor responses caused by host immune stimulation is called the abscopal effect[34] and has been reported for a long time, but it is an extremely rare event in clinical practice.[35],[36] However, with the advent of new immunotherapies that modulate immune checkpoint mechanisms, this immunostimulatory effect has now been reconsidered.[37] A pooled analysis examining the effect of adding radiotherapy to the response to the anti-PD-1 antibody pembrolizumab in patients with metastatic NSCLC showed a benefit in response rate and survival in the combined radiotherapy group.[38] The favorable clinical results of the PACIFIC trial described earlier may also be due to the immunostimulatory effect of radiation, and prompt initiation of adjuvant immunotherapy after CCRT is required.

Morisada et al. reported that the higher the single per-fractional dose, the more effective the T cell-mediated antitumor immune activation.[39] The results of a phase 2 randomized clinical trial called PEMBRO-RT implicate the clinical benefit of stereotactic radiotherapy before pembrolizumab compared to pembrolizumab alone.[40] The relationship between radiotherapy and immunotherapy is interesting, and it is necessary to verify the therapeutic effect at a higher level of evidence in the future.

 Conclusion



The relationship between lung cancer and radiotherapy is very close and complex. [Table 1] represents the treatment outcomes of the trials outlined in this review. This includes prophylactic whole brain irradiation after the initial treatment of localized small cell lung cancer, palliative small source therapy for tumor-induced airway stenosis, preoperative CCRT for apex chest wall invasive cancer, gamma knife, and cyber knife therapy for brain metastasis.{Table 1}

Systemic treatment for lung cancer has also changed dramatically over the past few years, although radiotherapy equipment has continued to improve. To provide better cancer treatment, it is important to understand the need for radiotherapy for each patient and to consider the optimal combination of radiotherapy and chemotherapy, including immunotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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