The role of radiotherapy in lung cancer: Where is the evidence?

doi:10.1016/j.radonc.2007.04.004

Radiotherapy and Oncology

Volume 83, Issue 2, May 2007, Pages 203-213

https://doi.org/10.1016/j.radonc.2007.04.004 Get rights and content

Abstract

Radiotherapy is one of the main treatment modalities in lung cancer, contributing to both its cure and palliation. Thoracic irradiation has traditionally been considered the mainstay of treatment in inoperable stage III non-small cell lung cancer. However, despite technical developments and the addition of chemotherapy, the curative potential of radiotherapy in this subset of patients is disappointingly poor. The role of radiotherapy as an adjunct to pulmonary resection (preoperative and postoperative) is questionable, but well-designed and executed phase III studies are lacking. An important application of radiotherapy is palliation of tumor-related symptoms in the chest and in metastatic sites, such as bones and brain. In small cell lung cancer, routine applications of radiotherapy include chest radiotherapy in limited disease and prophylactic cranial irradiation in complete responders to chemotherapy, each increasing survival by about 5%.

Section snippets

Preoperative radiotherapy

The theoretical objective of applying radiation prior to surgery in NSCLC is the reduction of tumor volume to convert marginally resectable or unresectable disease or to make tumor resection easier and more efficacious. Preoperative radiotherapy was compared with immediate surgery in a series of randomized studies performed in the 1960s and early 1970s [23], [71], [84]. Although in some patients radiotherapy was able to sterilize tumor in the chest, there was no survival benefit with this

Postoperative radiotherapy

The likelihood of local relapse after surgery increases substantially with tumor advancement and is particularly high in cases with regional nodal involvement. It has been believed that radiation may sterilize small deposits of lung cancer, thus leading to a reduction of locoregional relapse rate and prolongation of survival. Based on this rationale, postoperative radiotherapy has commonly been used in patients with positive lymph nodes or with tumor invasion into adjacent structures. A number

Management of stage IIIA-N2 NSCLC

The management of IIIA-N2 is a matter of controversy. Generally, treatment outcomes with surgery alone in this category are poor with 5-year survival rates of 7–24% [2]. Recent achievements with the use of induction chemotherapy or concomitant chemoradiation in locally advanced NSCLC led to numerous phase II studies in which this combination was tested in preoperative setting. It was demonstrated that the triple-modality approach is feasible, although its toxicity is considerable. In a recent

Definitive radiotherapy in stage III NSCLC and in less-advanced medically inoperable disease

In unresectable locally advanced or locally recurrent NSCLC, the efficacy of radiotherapy in terms of long-term tumor control is disappointing. The median survival in patients treated with radiotherapy is below 10 months and the 5-year survival probabilities vary between 5% and 10%. In less-advanced medically inoperable disease, the results are better but still far below the outcomes of surgery. Two major reasons for the low efficacy of radiotherapy in NSCLC are the limited radiosensitivity of

Combining radiotherapy and chemotherapy

Within the last 2 decades, a subject of intense clinical research in locally advanced NSCLC has been a strategy of combining chemotherapy and radiation. The major expectation from the addition of chemotherapy to radiation is to increase survival by improving tumor control in the thorax and by eliminating the emergence of metastatic disease. The two most frequently investigated strategies of combined chemotherapy and radiation include primary chemotherapy followed by radiation, and concurrent

Management of Pancoast tumor

Pancoast tumors have traditionally been managed with radiotherapy followed by en-block resection. However, complete resection was achieved in only 60% of patients and overall 5-year survival was in the range of 30% [65]. Another approach included radiotherapy alone, with local control and survival seemingly inferior to those reported in surgical series. The interpretation of these results was difficult due to retrospective character of particular studies, small numbers of patients, different

Palliative radiotherapy

Thoracic radiotherapy has been documented in numerous studies to provide effective palliation of local symptoms (particularly hemoptysis and pain) in patients with locally advanced or recurrent NSCLC [32], [48], [50], [72], [76]. In this category of patients radiotherapy rather than more toxic and expensive chemotherapy should generally be considered as the treatment of choice [47]. A series of randomized studies has been performed to determine the optimal regimens of palliative radiotherapy in

Radiotherapy for small cell lung cancer

Small cell lung cancer (SCLC) accounts for 20–25% of all lung cancer cases, with only one-third of patients presenting with limited disease. The mainstay of treatment in SCLC is chemotherapy. Radiotherapy is used as an adjunctive method in patients with limited disease. A series of phase III studies has indicated that the addition of radiotherapy to chemotherapy significantly reduces the risk of intrathoracic relapse, but most of them did not have enough statistical power to detect a difference

Key points

•
Radiotherapy is an important component of lung cancer management and most of its applications are based on the evidence from clinical studies (Table 6).
•
Radiotherapy has a major role in locally advanced inoperable NSCLC; its efficacy in this setting, however, is far from satisfactory.
•
Adding chemotherapy to radiation in stage III inoperable NSCLC is associated with survival benefit.
•
The role of radiotherapy adjunctive to pulmonary resection (preoperative, postoperative) is questionable.
•

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SPECT V/Q in Lung Cancer Radiotherapy Planning
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Curative-intent lung cancer radiation therapy either alone (RT) or combined with immuno-chemotherapy is associated with potential risk of serious radiation-induced lung injury. This review provides a summary of the role of SPECT ventilation perfusion (V/Q) imaging as an emerging adjunct to lung cancer RT planning and treatment dosimetry. Denoted “functional lung avoidance RT” it is hypothesized that preferential dosimetric avoidance of physiologically functional lung may reduce the frequency of radiation-induced lung injury. SPECT V/Q imaging datasets available during the planning process allows the prioritization (or “personalization’) of RT dose to minimize the volume of functional lung probabilistically exposed to injurious radiation dose. Selective escalation of target dose and adaptive planning and replanning is also enabled. The emergent importance of the tumor-lung microenvironment and its biologic relationship to local immune effectors in lung cancer provides further incentive to individualize RT planning and delivery. This review examines important normal tissue dosimetric constraints that are part of current standards-of-care and the new dosimetric parameters associated with functional lung avoidance RT. SPECT V/Q has been a valuable tool in investigating the feasibility and efficacy of functional lung avoidance RT but is yet to become main stream due to the lack of large clinical trials. It is encouraging however that functional lung avoidance is feasible in RT dose-target delineation and some of the more promising studies are discussed.
Palliative thoracic radiotherapy for patients with advanced non-small cell lung cancer and poor performance status
2015, Lung Cancer
Citation Excerpt :
In the presented group of patients, the efficacy of PTR in reducing symptoms of tumor growth in chest was clearly lower than in the other groups of patients with advanced NSCLC, but with KPS equal or over 50. The palliative effect in our patients in comparison to the data from literature on some symptoms were lower: on cough 22.2% vs 48–70%, on haemoptysis 29.4% vs 60–97%, on thoracic pain 18.2% vs 50–88%, on dyspnoe and dysphagia 0% vs 36–66% and 4–10%, respectively [11,12,16,20–26,43]. The tolerance of PTR in our group of patients with poor performance status (KPS: 40–30) was poor.
The evaluation of efficacy of palliative thoracic radiotherapy (PTR) in patients with advanced non-small cell lung cancer (NSCLC) and to compare it with efficacy of supportive care (SC) alone.
Between 2000 and 2012, 235 patients with advanced NSCLC (IIIB and IV) and Karnofsky Performance Status accounted 40–30, were qualified to PTR. In fact, 125 (53.2%) out of them were treated with PTR, and 110 (46.8%)—with SC alone, in accordance with patients expectations. There were no differences between PTR and SC group with respect to patient and tumor characteristics as well as with respect to the type and incidence of symptoms related to the local growth of NSCLC. In all 125 PTR patients the delivered tumor dose was 20 Gy given in five daily fractions over five treatment days. All 110 patients who refused PTR were treated with SC in another hospital (28.2%), in a hospice (21.8%) or by general practitioners at home (50.0%).
The 90-day overall survival rate in the group of PTR patients was 20.0%, and in the group of SC patients it was 18.2%. Median survival amounted 58 and 59 days, respectively. The efficacy of PTR and SC, relative to the symptoms associated with the local growth of NSCLC, was comparable. Tolerance of PTR was poor and early toxicity—significant. Moreover 41.6% of irradiated patients received PTR within the last 30 days of their lives and 16.0% of these patients—within the last 15 days prior to death.
The life expectancy of patients with advanced NSCLC and poor performance status (Karnofsky 40–30), who presenting moderate or severe symptoms related to the local growth of cancer, is measured in days or weeks. The effective method of treatment for these patients is modern supportive care rather than PTR.
Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage Non-Small Cell Lung Cancer (NSCLC): A European survey conducted by the European Society for Medical Oncology (ESMO) Young Oncologists Committee
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Early stage Non-Small Cell Lung Cancer (NSCLC) is potentially curable with surgery. ESMO guidelines recommend cisplatin-based adjuvant chemotherapy (CT) for completely resected stage II–III NSCLC. There is limited evidence for the use of adjuvant CT and/or radiotherapy (RT) in incompletely resected (R1) early stage NSCLC.
A European survey of thoracic oncologists was conducted to evaluate use of adjuvant CT and RT for R1-resected NSCLC and to identify factors influencing treatment decisions. Demographics and information on clinical stage, regimens, cycles planned, radiotherapy sites, multidisciplinary management and discussion about inconclusive evidence with the patient were collected. Univariate and multivariate analyses were performed.
768 surveys were collected from 41 European countries. 82.9% of participants were medical oncologists; 49.3% ESMO members; 37.1% based in University Hospitals; 32.6% practicing oncology for over 15 years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT and mostly cisplatin/vinorelbine (81.2%) or cisplatin/gemcitabine (42.9%). 85% discussed limited clinical evidence with the patient. In the univariate analysis, a statistically significant association with CT prescription was found for medical oncology specialty (p < 0.001), ESMO membership (p < 0.001), activity in clinical research (p = 0.002) and increased frequency of ESMO guidelines consultation (p for trend <0.001). 48.3% of participants prescribed adjuvant RT and its prescription were associated with radiation oncology specialty (p < 0.001), not being an ESMO member (p < 0.001), years practicing specialty (p for trend = 0.001), workload of lung cancer patients (p for trend = 0.027) and decreased frequency in consulting ESMO guidelines (p < 0.001). In the multivariate analysis, medical oncology and radiation oncology were the best discriminator for prescription of adjuvant CT and RT, respectively.
This survey demonstrates that adjuvant CT and RT are commonly used in clinical practice for R1-resected NSCLC despite limited evidence. Prospective trials are necessary to clarify optimal management in this setting.
Changes in functional lung regions during the course of radiation therapy and their potential impact on lung dosimetry for non-small cell lung cancer
2014, International Journal of Radiation Oncology Biology Physics
To study changes in functional activity on ventilation (V)/perfusion (Q) single-photon emission computed tomography (SPECT) during radiation therapy (RT) and explore the impact of such changes on lung dosimetry in patients with non-small cell lung cancer (NSCLC).
Fifteen NSCLC patients with centrally located tumors were enrolled. All patients were treated with definitive RT dose of ≥60 Gy. V/Q SPECT-CT scans were performed prior to and after delivery of 45 Gy of fractionated RT. SPECT images were used to define temporarily dysfunctional regions of lung caused by tumor or other potentially reversible conditions as B3. The functional lung (FL) was defined on SPECT by 2 separate approaches: FL1, a threshold of 30% of the maximum uptake of the patient's lung; and FL2, FL1 plus B3 region. The impact of changes in FL between initiation of RT and delivery of 45 Gy on lung dosimetry were analyzed.
Fourteen patients (93%) had larger FL2 volumes than FL1 pre-RT (P<.001). Dysfunctional lung became functional in 11 patients (73%) on V SPECT and in 10 patients (67%) on Q SPECT. The dosimetric parameters generated from CT-based anatomical lung had significantly lower values in FL1 than FL2, with a median reduction in the volume of lung receiving a dose of at least 20 Gy (V₂₀) of 3%, 5.6%, and mean lung dose of 0.95 and 1.55 on V and Q SPECT respectively.
Regional ventilation and perfusion function improve significantly during RT in centrally located NSCLC. Lung dosimetry values vary notably between different definitions of functional lung.
Image guided hypofractionated 3-dimensional radiation therapy in patients with inoperable advanced stage non-small cell lung cancer
2013, International Journal of Radiation Oncology Biology Physics
Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT.
Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed total dose of 60 Gy in 20 fractions of 3 Gy each. Radiation treatment was delivered using an image guided radiation therapy technique to verify correct position. Toxicities were graded according to Radiation Therapy Oncology Group morbidity score. Survival rates were estimated using the Kaplan-Meier method.
The median follow-up was 13 months (range, 4-56 months). All patients completed radiation therapy and received the total dose of 60 Gy to the primary tumor and positive lymph nodes. The overall response rate after radiation therapy was 83% (3 patients with complete response and 22 patients with partial response). The 2-year overall survival and progression-free survival rates were 38.1% and 36%, respectively. Locoregional recurrence/persistence occurred in 11 (37%) patients. Distant metastasis occurred in 17 (57%) patients. Acute toxicities occurred consisting of grade 1 to 2 hematological toxicity in 5 patients (17%) and grade 3 in 1 patient; grade 1 to 2 esophagitis in 12 patients (40%) and grade 3 in 1 patient; and grade 1 to 2 pneumonitis in 6 patients (20%) and grade 3 in 2 patients (7%). Thirty-three percent of patients developed grade 1 to 2 late toxicities. Only 3 patients developed grade 3 late adverse effects: esophagitis in 1 patient and pneumonitis in 2 patients.
Hypofractionated curative radiation therapy is a feasible and well-tolerated treatment for patients with locally advanced NSCLC. Randomized studies are needed to compare HypoRT to conventional treatment.
The influence of time of radio-chemotherapy and other therapeutic factors on treatment results in patients with limited disease small cell lung cancer
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The evaluation of effect of therapeutic parameters such as time of starting thoracic radiotherapy in relation to chemotherapy, schedule of combination chemo- and radiotherapy and SER, on treatment results in patients with limited disease small cell lung cancer (LD SCLC).
Between 2000 and 2007, 212 patients with LD SCLC received combined therapy: chemotherapy and thoracic radiotherapy. All patients received chemotherapy according to PE schedule (4–6 cycles), in combination with thoracic radiotherapy. The total dose applied to GTV was 54 Gy given in 27–30 fractions using fraction dose of 1.8–2.0 Gy. The concurrent treatment was performed in 112 patients (52.8%): the conventional fractionation (once a day, every five days a week) in 35 patients while 77 patients received “moderate” accelerated fractionation (one fraction a day, every four days a week and two fractions within one day, a week apart, with 6 h gap). The remaining 100 patients (47.2%) received sequential treatment. The time from the first day of chemotherapy to the end of thoracic radiotherapy (SER) was evaluated in all patients. The SER ranged from 57 to 337 days with the median value of 121 days.
The complete response in the thorax was observed in 143 out of 212 patients (67.5%). Out of these, 82 patients received concurrent chemo-radiotherapy (given in 22 patients as conventional dose fractionation and in 60 patients according to “moderate” accelerated dose fractionation), and the remaining 61 patients were treated with sequential therapy. The 5-year survival rates were: 17.7% for overall survival (OS), and 19.3% for disease-free survival (DFS). The relationship of therapeutic factors to survival rates showed statistically significant improvement of survival ratios in relation to early starting of thoracic radiotherapy and application of concurrent chemo-radiotherapy. The results of logistic regression revealed significant relationship between the value of SER and OS and DFS. The analysis shows that each day of extension of the SER resulted in increased probability of death (decrease of OS) by 0.28% and in increased the risk of development failure (decrease of DFS) by 0.31%. The influence of SER on lowered probability of complete response frequency was not statistically significant.
The concurrent chemo-radiotherapy with early administration of thoracic radiotherapy, results in improved complete response in the thorax and increase of overall and disease-free survival rates. The 5-year survival rates were: 17.7% for overall survival and 19.3% for disease-free survival. Our analysis and data from the literature suggest that shorter SER may play prognostic role in patients with LD SCLC treated with combination chemo- and radiotherapy. However, these observations require the confirmation in following studies.

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^☆: Presented in part at the 25th meeting of the European Society for Radiotherapy and Oncology (ESTRO) held in Leipzig, Germany, between the 9 and 12 October 2006.

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Educational reviewThe role of radiotherapy in lung cancer: Where is the evidence?☆

Abstract

Section snippets

Preoperative radiotherapy

Postoperative radiotherapy

Management of stage IIIA-N2 NSCLC

Definitive radiotherapy in stage III NSCLC and in less-advanced medically inoperable disease

Combining radiotherapy and chemotherapy

Management of Pancoast tumor

Palliative radiotherapy

Radiotherapy for small cell lung cancer

Key points

Recommended readings

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Int J Radiat Oncol Biol Phys

Lancet Oncol

Ann Thor Surg

Radiother Oncol

Radiother Oncol

Radiother Oncol

Eur J Cancer Clin Oncol

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Clin Oncol

J Thorac Cardiovasc Surg

Lancet

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Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

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Lung Cancer

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Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications

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N Engl J Med

Continuous hyperfractionated accelerated radiotherapy – weekend less (CHARTWEL) versus conventionally fractionated (CF) radiotherapy in non-small-cell lung cancer (NSCLC): first results of a phase III randomised multicentre trial (ARO 971)

Eur J Cancer

Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol

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Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells

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Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma

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Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group

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Mitomycin, ifosfamide and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life

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Long-term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected stage III nsclc: RTOG 9410

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J Natl Cancer Inst

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Results of a controlled clinical trial for evaluation of intensive preoperative irradiation in operable bronchial cancer

Archiv Geschwulst

Educational review
The role of radiotherapy in lung cancer: Where is the evidence?☆