|Year : 2018 | Volume
| Issue : 2 | Page : 125-133
Radical radiotherapy or chemoradiotherapy for inoperable, locally advanced, non-small cell lung cancer: Analysis of patient profile, treatment approaches, and outcomes for 213 patients at a tertiary cancer center
Raj Kumar Shrimali1, Chandran Nallathambi1, Animesh Saha1, Avipsa Das1, Sriram Prasath2, Anurupa Mahata2, B Arun2, Indranil Mallick1, Rimpa Achari1, Deepak Dabkara3, Robin Thambudorai4, Sanjoy Chatterjee1
1 Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Radiotherapy Physics, Tata Medical Center, Kolkata, West Bengal, India
3 Department of Medical Oncology, Tata Medical Center, Kolkata, West Bengal, India
4 Department of Thoracic Surgery, Tata Medical Center, Kolkata, West Bengal, India
|Date of Web Publication||31-Dec-2018|
Dr. Raj Kumar Shrimali
Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Radical radiotherapy (RT) with curative intent, with or without chemotherapy, is the standard treatment for inoperable, locally advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively reviewed the data for all 288 patients who presented with inoperable, locally advanced NSCLC at our institution, between May 2011 and December 2016. RESULTS: RT alone or sequential chemoradiotherapy (SCRT) or concurrent chemoradiotherapy (CCRT) was used for 213 patients. Median age was 64 years (range: 27–88 years). Stage-III was the biggest stage group with 189 (88.7%) patients. Most patients with performance status (PS) 0 or 1 received CCRT, whereas most patients with PS 2 received RT alone (P < 0.001). CCRT, SCRT, and RT alone were used for 120 (56.3%), 24 (11.3%), and 69 (32.4%) patients, respectively. A third of all patients (32.4%) required either volumetric-modulated arc radiotherapy (VMAT) or tomotherapy. Median follow-up was 16 months. The median progression-free survival and median overall survival (OS) were 11 and 20 months, respectively. One-year OS and 2-year OS were 67.9% and 40.7%, respectively. Patients treated using CCRT lived significantly longer with a median survival of 28 months, compared with 13 months using SCRT and RT alone (P < 0.001). On multivariate analysis, OS was significantly affected by age, stage group, treatment approach, and response to treatment. CONCLUSION: RT including CCRT is feasible, safe, and well tolerated in our patient population and results in survival benefits comparable with published literature. CCRT should be considered for all patients with inoperable, locally advanced NSCLC, who are fit and have good PS.
Keywords: Concurrent chemoradiotherapy, radical radiotherapy, sequential chemoradiotherapy, lung cancer, volumetric-modulated arc radiotherapy
|How to cite this article:|
Shrimali RK, Nallathambi C, Saha A, Das A, Prasath S, Mahata A, Arun B, Mallick I, Achari R, Dabkara D, Thambudorai R, Chatterjee S. Radical radiotherapy or chemoradiotherapy for inoperable, locally advanced, non-small cell lung cancer: Analysis of patient profile, treatment approaches, and outcomes for 213 patients at a tertiary cancer center. Indian J Cancer 2018;55:125-33
|How to cite this URL:|
Shrimali RK, Nallathambi C, Saha A, Das A, Prasath S, Mahata A, Arun B, Mallick I, Achari R, Dabkara D, Thambudorai R, Chatterjee S. Radical radiotherapy or chemoradiotherapy for inoperable, locally advanced, non-small cell lung cancer: Analysis of patient profile, treatment approaches, and outcomes for 213 patients at a tertiary cancer center. Indian J Cancer [serial online] 2018 [cited 2019 Mar 18];55:125-33. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/125/249200
| » Introduction|| |
Lung cancer is a leading cause of cancer death across the world.,, Nonsmall cell lung cancer (NSCLC) accounts for over three-quarters of all lung cancers. Surgery is the treatment option of choice for early lung cancer (Stages - I, II, and some IIIA; AJCC Cancer Staging Manual, 7th Edition, 2010) although there are no published randomized phase-III data comparing surgery with chemo-radiotherapy. However, <20% of patients with NSCLC are suitable for surgery.
The majority of lung cancer patients in India present with locally advanced (Stage-IIIA and IIIB) and metastatic (Stage-IV) diseases.,, Radical radiotherapy (RT) with curative intent is the primary treatment option for most of these patients with stage-III disease, with the potential of providing long-term local disease control. The other usual reasons for using RT in patients without any distant metastases (Stages I to IIIA) are inoperability because of the stage, medically inoperable because of comorbidity, and patient preference. In Stage IIIB NSCLC and arguably many cases of Stage IIIA disease, surgery has no added survival advantage over radical chemo-radiotherapy. RT (with or without chemotherapy) with curative intent is the primary treatment option for these patients (Stages - I, II, and III), with the potential of providing long-term local disease control. RT schedule is usually at least 60 Gy in 30 fractions, using 2-Gy fractions daily over 6 weeks.
Concurrent cisplatin-based chemotherapy, in selected cases, has been shown to improve loco-regional control and overall survival (OS);, however, survival for Stage III NSCLC remains poor with a 3-year survival rate of 24%. The meta-analysis by Aupérin et al. and a subsequent Cochrane review established the superiority of concurrent chemoradiation therapy (CCRT) to sequential chemoradiation therapy (SCRT) for unresectable Stage III NSCLC, with 2- and 5-year absolute survival benefits of 10% and 4.5%, respectively., However, CCRT also has a higher rate of Grade 3 or 4 esophagitis than sequential CRT or RT alone.,
Despite advances in local and systemic therapies, the local control and survival remain poor, suggesting that a therapeutic plateau has been reached with conventional approaches. The radiotherapy strategies that aim to improve local control and survival of these patients with inoperable, locally advanced NSCLC are dose escalation, altered or modified fractionation, individualized radiotherapy administration, and advanced modern radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc radiotherapy (VMAT).,,,
We present our single-institution experience of treating NSCLC patients using RT with curative intent, using either radiotherapy alone or chemoradiation (sequential or concurrent). The management plan for each of these patients was decided by the lung cancer multidisciplinary team, guided by local protocols based on published evidence and guidelines. The objective of this large retrospective study was to assess outcomes in a large cohort of consecutive patients with inoperable and locally advanced NSCLC treated using radical doses of radiotherapy with curative intent, at our institution.
| » Materials and Methods|| |
All patients who presented with nonmetastatic (Stages I, II, and III) NSCLC and underwent RT for NSCLC with curative intent until December 2016 were searched from electronic medical records (EMRs) and radiotherapy records. From May 2011 to December 2016, 213 patients were identified as registered and treated with RT with curative intent for NSCLC at our hospital.
All patients with suspected lung cancer were staged using computed imaging, and histological or cytological diagnosis was obtained. Patients with no obvious metastases were further staged using a whole-body fludeoxyglucose-positron emission tomography (FDG-PET) and magnetic resonance imaging of the brain. Pulmonary function tests comprising forced expiratory volume in 1 s and lung diffusion capacity for carbon monoxide (DLCO) were also carried out to assess fitness for surgery or high-dose radiotherapy.
All these patients were discussed at the lung cancer multidisciplinary team (MDT) meeting, and the optimum course of treatment was discussed and decided upon. Patients with resectable tumors who were fit and willing for surgery underwent surgical resection. Stereotactic ablative radiotherapy (SABR) was used for patients with Stage I NSCLC who were medically inoperable because of comorbidities. Patients who were unresectable because of staging or technical reasons or medical reasons (comorbidities) or who decline surgery were considered for RT. Concurrent chemo-radiotherapy was the treatment of choice for all patients who were considered fit enough to tolerate this treatment. For patients who were comparatively frail or less fit, sequential chemo-radiotherapy was offered. For patients who were not suitable for chemotherapy because of comorbidity or had contraindications to chemotherapy, radiotherapy alone was used. Finally, some patients who were very frail, had suboptimal lung function, or had extensive nonmetastatic disease received palliative radiotherapy. This analysis excluded patients who received surgery, SABR, or palliative radiotherapy.
CCRT was delivered using conventional fractionation at 2 Gy per fraction (usually 60 Gy in 30 fractions), whereas SCRT was delivered using either accelerated hypofractionated radiation (55 Gy in 20 fractions, at 2.75 Gy per fraction) or conventional fractionation. Most RT-alone treatments were either accelerated hypofractionated radiation or continuous hyperfractionated accelerated radiation therapy (CHART) using 1.5 Gy per fraction, three times daily at least 6 h apart, for 12 consecutive days. Three-dimensional conformal radiotherapy (3D-CRT) was our default technique, and rotational IMRT using VMAT was used only if necessary, for adequately covering the planning target volume (PTV) while satisfactorily meeting the dose constraints for organs at risks (OARs). Our decision on choosing between 3D-CRT and VMAT and the radiotherapy treatment planning has been described in an earlier article. Image-guided treatment verification using orthogonal EPIDs or cone-beam imaging (CBCT) or megavoltage computed tomography (CT) (tomotherapy) was used for all these patients.
The concurrent chemotherapy is typically delivered with standard fractionation (2 Gy/fraction) and usually comprises cisplatin and etoposide. Most patients received cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 with etoposide 50 mg/m2 intravenously on days 1–5 and 29–33.,, The etoposide on days 2–5 and 30–33 was often changed to 100 mg/m2 orally, for patient convenience and easing chemotherapy workload.
During radiotherapy or CCRT, the patients are seen and reviewed by a clinical oncologist on a weekly basis and assessed for any toxicity and treated as appropriate. After completion of treatment, the patients are seen after 4 weeks to ascertain whether the side effects are settling as expected. Posttreatment response assessment CT is carried out at 10–12 weeks after treatment completion and response was documented according to the RECIST 1.1 criteria.
Data were entered in Microsoft Excel (Released 2016. Microsoft Excel for Windows, Version MSO 16.0. Washington, USA). Data obtained were checked for completeness and consistency. Statistical analysis was done using SPSS statistical software (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0, Armonk, NY, USA). Frequencies, percentages, mean, median, interquartile range, and range were calculated for categorical variables. Exact test was used to determine the relationship between treatment received and performance status (PS). Survival was analyzed using Kaplan–Meier method, and log-rank test was used to compare factors. Cox proportional hazards analysis was used for multivariate analysis of survival outcomes. Hazard ratios were reported along with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant.
| » Results|| |
Between May 2011 and December 2016, 288 patients were registered at our hospital with nonmetastatic (Stages I, II, and III) NSCLC. Of these, 37 patients received curative surgery and 9 patients received SABR for early NSCLC. A further 29 patients were treated with high-dose palliative radiotherapy (36–39 Gy using 3 Gy fractions) because they were found to be too frail (Eastern Cooperative Oncology Group [ECOG] PS 3 or 4) with comorbidity, had poor lung function, or the disease could not be encompassed within planning target volume that could be safely treated with a higher (curative) dose. All the remaining 213 patients were treated with RT with curative intent for NSCLC and have been analyzed.
RT with or without chemotherapy was administered to 213 patients with a median age of 64 years (range: 27–88 years). The patient characteristics have been described in [Table 1]. A significant number of patients with ECOG performance scores (PS) 0 and 1 received CCRT whereas most patients with PS 2 received RT alone (P < 0.001), as shown in [Figure 1].
CCRT was administered to 120 (56.3%) patients, SCRT to 24 (11.3%) patients, and RT alone was used for 69 (32.4%) patients. RT alone included patients who received standard fractionation, accelerated hypofractionation (55 Gy in 20 fractions), and CHART. The radiotherapy planning and delivery techniques included 3D-CRT in 144 (67.6%) patients and rotational IMRT (VMAT and tomotherapy) in 69 (32.4%) patients. The prescribed doses and the proportional breakdown of planning and delivery techniques are detailed in [Table 2].
Chemotherapy as a part of treatment
A total of 144 patients received some form of chemotherapy. Concurrent chemo-radiation was used in 120 patients. Cisplatin and etoposide,, were the most commonly used regimens for concurrent use with radiotherapy and were used in 131 (91%) of 144 patients. Paclitaxel and carboplatin were used in nine (6.25%) patients. Other regimens used were carboplatin and etoposide, paclitaxel and cisplatin, and single-agent paclitaxel. Sixteen patients from the CCRT group also received some form of neoadjuvant chemotherapy. Neoadjuvant chemotherapy before definitive radiation (SCRT) was used in 24 patients. The neoadjuvant chemotherapy was decided according to the histological diagnosis with platinum and pemetrexed doublet used for adenocarcinoma, platinum, and gemcitabine doublet used for squamous cell carcinoma, platinum and taxane (paclitaxel) doublet for NSCLC-NOS, or either of the other diagnoses. The overall incidence of anemia, leukopenia, and thrombocytopenia is described in [Table 3]. Twenty-six patients required admission into hospital for the management of febrile neutropenia. Dose reduction in chemotherapy was necessary for 14 patients, whereas 106 patients did not undergo any dose reduction. Granulocyte-colony-stimulating factors (G-CSFs) and PEGylated G-CSF (peg-Filgrastim) were used in 30 and 12 patients, respectively.
Median follow-up was 16 months (interquartile range: 8–25 months). The Kaplan–Meier curves showing the progression-free and OS for the entire cohort are displayed in [Figure 2]a and [Figure 2]b. The median progression-free survival and median OS were 11 (95% CI: 8.80–13.20) and 20 months (95% CI: 17.54–22.26), respectively. One-year and 2-year OS were 67.9% and 40.7%, respectively. Fourteen patients died within 90 days of completion of treatment, resulting in a 90-day mortality of 6.6%. RT and chemotherapy-related toxicity documented in EMR is detailed in [Table 4].
|Figure 2: Kaplan–Meier curves showing the following: (a) Overall survival. (b) Progression-free survival. (c) Overall survival, comparing concurrent chemoradiotherapy versus sequential chemoradiotherapy. (d) Progression-free survival, comparing concurrent chemoradiotherapy versus sequential chemoradiotherapy|
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The patients treated with CCRT lived significantly longer with a median survival (MS) of 28 months compared with both SCRT or RT-alone groups, with a MS of 13 months (P < 0.001), as displayed in [Table 3] and [Figure 2]c. The Kaplan–Meier curves comparing the progression-free and OSs for the CCRT and SCRT are displayed in [Figure 2]c and d. Patients with ECOG PS of 0 or 1 had significantly better outcomes compared with those with PS of 2 or 3. Patients who had at least stable disease (complete response, partial response, or stable disease) had better survival compared with patients who had progressive disease (P < 0.001).
Patients with Stage III disease formed the biggest subgroup with 189 (88.7%) patients, and comprised Stage IIIA (108 patients) and Stage IIIB (81 patients). MS for Stage IIIA patients was 22 months (95% CI: 19.45–24.54), compared with the MS for Stage IIIB patients at 17 months (95% CI: 11.89–22.12). This difference in the survival between IIIA and IIIB did not reach statistical significance (P = 0.256).
On multivariate analysis, the OS was found to be significantly affected by age (up to 70 years or more than 70 years), stage group, treatment approach (CCRT, SCRT, or RT alone), and response to treatment, as displayed in [Table 5].
| » Discussion|| |
The outcomes reported in this retrospective analysis suggest that radical dose of curative-intent thoracic radiotherapy (CCRT, SCRT, or RT alone) is a feasible treatment for inoperable, locally advanced NSCLC. If the patients are discussed in a multidisciplinary environment and the fitness, performance status, and comorbidities are carefully considered, the majority of patients can complete the prescribed treatment with manageable and acceptable toxicity. In the current study, the median OS for the entire study cohort was 20 months. Furthermore, CCRT was found to be significantly better, with a median OS of 28 months, than SCRT and RT-alone groups, both at 13 months (P < 0.001). In most of the trials that directly compared CCRT with SCRT, and were included in the meta-analysis by Aupérin et al., and the Cochrane review, the median OS was 16–17 months with CCRT and 13–15 months with SCRT.,, There were several other trials that reported the use of CCRT but did not directly compare CCRT with SCRT. These trials report the median OS for standard CCRT ranging from 20 to 28.7 months.,,, Several retrospective series on CCRT for NSCLC report the MS from 18 to 22 months.,,, The patient number (n = 213) in this study, near-universal use of tissue diagnosis, FDG-PET staging, and the multidisciplinary approach to treatment according to a clear departmental policy would suggest that these results are likely to reflect typical clinical practice for inoperable, locally advanced NSCLC in a tertiary-level cancer center from India.
The vast majority (88.7%) of patients with inoperable, locally advanced NSCLC in the current study consisted of Stage III disease, consistent with other reported data from India., Stage III NSCLC consists of a heterogeneous population, therefore a multimodality approach discussed and decided by multidisciplinary teams involving experts in surgery, radiation, and systemic agents is necessary. The distinction between Stage IIIA and IIIB disease is important because prognosis, treatment options, and long-term outcomes differ from one another. Furthermore, Stage IIIA disease needs to be differentiated as resectable or unresectable, usually depending on whether the nodal disease is single- or multi-station. A subgroup of stage IIIA patients is suitable for surgery., However, Stage IIIB (T1–T4 N3, or T4 N2) involves lymph node metastasis in the contralateral thorax or supraclavicular fossa and/or an unresectable primary tumor, making surgical resection inappropriate., Unresectable or inoperable Stage IIIA and Stage IIIB disease is treated using CCRT, while the management of potentially resectable IIIA is more complex and controversial and often debated. Treatment options for IIIA disease include surgery with neoadjuvant or adjuvant chemotherapy, radiation, or both as well as definitive chemoradiation., Long-term outcomes are poor, with a baseline 5-year OS of 15%–35% for Stage IIIA and 5%–10% for Stage IIIB.
In the landmark meta-analysis by Aupérin et al., CCRT improved OS over sequential CRT by an absolute benefit of 4.5% after 5 years, increasing 5-year OS rate from 10.6% to 15.1% (hazard ratio [HR] = 0.84). The locoregional progression was decreased by an absolute rate of 6.1% at 5 years, lowering the rate from 35% to 28.9% after CCRT. Although CCRT was found to improve OS and locoregional control, it did not lower distant disease progression compared to sequential CRT (HR = 1.04). CCRT, however, was associated with higher rates of Grade 3 or higher esophageal toxicity, which could reach up to 18%. The higher toxicity rates were deemed to be clinically acceptable and manageable.
Induction or consolidation chemotherapy in addition to CCRT has no additional benefit, as it has not been shown to improve 2-year OS or MS.,,, However, it could be considered in specific situations, especially for patients with bulky tumors where gross disease cannot be treated with radiation without leading to significant radiation-induced toxicity. CCRT is better suited for and tolerated by patients with minimal comorbidities, favorable performance statuses, and minimal weight loss., CCRT is used for relatively young patients (≤70 or 75 years old) with an ECOG PS of 0 or 1, weight loss <10% in the preceding 3 months, and minimal or no comorbidities. The use of CCRT in the current study is in line with this view, as more patients with better ECOG PS received CCRT, as displayed in [Figure 1].
An overview of 16 Phase II and III clinical trials by Stinchcombe et al. showed that elderly patients in CCRT trials experienced worse OS, more toxicity, and a higher rate of death, compared with younger patients. A retrospective study of 381 patients who received CCRT for Stage III lung cancer showed that age >75 years (P = 0.009), DLCO ≤80% (P = 0.011), and gross tumor volume ≥100 cm3 (P = 0.001) were statistically significant factors for poor OS. Severe esophageal and lung toxicity and interruption of radiotherapy were more frequent in patients with multiple adverse predictive factors. This finding was also consistent with earlier data from the Maastricht Cancer Registry, where older patients or patients with one or more serious comorbidity appeared to have inferior survival, and more than half of the patients with Stage III lung cancer were not eligible for CCRT. Although CCRT was reported to be the most commonly used treatment approach for patients with Stage IIIB NSCLC in the Netherlands, the authors could not obtain accurate information on whether CRT was sequential or concurrent from the registry, and therefore elucidating the criteria on which the treatment selection was based was not possible. However, Driessen et al. have reported comorbidity, poor performance score, and patient refusal as the most common motives for not using CCRT. Despite the fact that relatively fit and younger patients were assigned to CCRT, treatment tolerance was worse for patients receiving CCRT, especially for those with severe comorbidity. Only minor differences in survival between CCRT, SCRT, and RT were found, leading to suggestions that SCRT or RT alone might be more feasible options for the elderly. A recent systematic review and meta-analysis of three trials and subgroup data from one individual patient data meta-analysis have highlighted the importance of not excluding fit patients from more aggressive treatment on the basis of age alone. With the exception of increased hematological toxicity, CCRT appears to be tolerable in fit, elderly patients and should be the standard of clinical care. Patients who are unlikely candidates to tolerate CCRT should still receive sequential CRT since it could still add some benefit over radiotherapy alone by increasing 5-year OS from 5% to 10%.,,
Treatment was generally well tolerated in the current study, but admissions during treatment and chemotherapy dose modifications were still common. The overall incidence of hematological toxicity is described in [Table 4]. Twenty-six patients required admission into hospital for the management of febrile neutropenia. In the absence of routine nasogastric feeding tube insertion, it is possible that the severity of esophageal toxicity was underestimated. We accept that mild and moderate esophageal and lung toxicity is often underreported in retrospective reviews. The reported rate of Grades 3-4 esophagitis in this study (10%) is lower than many others reporting CCRT (18%–40%),,,, and although the esophageal dose constraints were not specified for planning and dosimetry, certain parameters were recorded. However, the low event rate precludes the identification of predictive factors for severe toxicity.
The radiotherapy may be difficult and challenging in inoperable, locally advanced (mostly Stage III) NSCLC because of the tumor size and complexity of shape, usually as a result of the following situations: primary separated from nodes (with normal lung in between), T3 or T4 disease that is very close to vulnerable organs, and multiple N2 or N3 (contralateral nodes) disease. Complex and advanced radiotherapy techniques may be necessary to satisfy the dose constraints for the OAR. A meta-analysis of 3795 patients with NSCLC randomized into 25 trials to compare higher (escalated) versus lower RT doses of curative intent showed that, in trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly related to high levels of toxicity. Where radiation therapy was used without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival. Therefore, modern radiation techniques should be considered to reduce toxicity wherever possible, such as IMRT, IGRT, respiration-gated RT, and adaptive RT. In the current series, VMAT was necessary for treating 61 patients and tomotherapy was used for 8 patients. Altered fractionation was also used, wherever feasible, for patients who did not receive CCRT, i.e., who received SCRT or RT alone. Thirty patients were treated using accelerated hypofractionated radiotherapy (typically using 55 Gy in 20 fractions, 2.75 Gy per fraction, 5 days a week) in the current series. CHART was used for 44 patients.
The mean lung dose (MLD) and the proportion of lung receiving 20 Gy expressed as a percentage (V20) are the most widely used and accepted lung dose constraints, with recommended MLD and V20 limits of <20–23 Gy and <30%–35%, respectively, in clinical practice.,, With IMRT gaining more acceptance for treating locally advanced lung cancers, monitoring the low dose bath to the normal lung is achieved by observing and recording the proportion of lung receiving 10 and 5 Gy expressed as a percentage (V10 and V5, respectively)., Although definite evidence-based guidance does not exist, some guidance is evolving around the dose volume constraints for V5 and V10. The RTOG 0617 study showed that, although the patients treated with IMRT had larger and more advanced tumors, IMRT was associated with less ≥ Grade 3 pneumonitis (7.9% vs. 3.5%, P = 0.039), and the lung volume receiving ≥5 Gy (V5) was not associated with any ≥ Grade 3 toxicity, whereas the lung V20 was associated with increased ≥ Grade 3 pneumonitis risk in multivariate analysis (P = 0.026). In the current series, 69 (32.4%) patients received rotational IMRT (VMAT and tomotherapy), with no difference in survival when compared with the 3D-CRT group.
An observational population-based study by Walraven et al has reported a large variation in non-surgical treatment for stage III NSCLC, across radiotherapy departments in Belgium and the Netherlands. A large variation was also observed between the two national registries of Netherlands and Belgium. Over half of the Stage III NSCLC patients in the Netherlands (55%) and more than a third (35%) in Belgium were treated with CCRT. Higher age and higher N-stage were found to be significantly associated with the choice for SCRT. Another study from Australia by Duggan et al. looked at guideline-recommended treatment (GRT) in routine clinical practice for 592 patients with Stage I–III NSCLC. One-third of the patients did not receive GRT, and it was identified that Stage I–IIIA patients who were ECOG 2 and Stage III patients aged 70 years and older were less likely to receive GRT. The MS was 30 months in the GRT group and 16 months in the non-GRT group (P < 0.001).
After carefully staging the patients with inoperable NSCLC, they must be assessed for fitness, ECOG PS, and considered for CCRT. The treatment must be in keeping with the current evidence-based recommendations and guidelines. This would help reduce variations in the treatment of patients with a similar clinical profile. These challenging and often complex multimodality treatment plans for the management of locally advanced NSCLC patients require the close coordination of health-care professionals and should ideally be performed at centers with an experienced team whenever possible.
| » Conclusion|| |
This large retrospective study suggests that using radical doses of thoracic radiotherapy with curative intent, either when used alone or when combined with sequential or concurrent chemotherapy for patients with inoperable, locally advanced NSCLC, is feasible and well tolerated in the patient population studied. Our outcomes are comparable to those published in randomized trials and large retrospective series. Given that progression-free and OS rates remain poor and both locoregional control and distant failure remain significant issues, continued progress is necessary with well-designed future studies.
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Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765-81.
Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al
. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): An analysis of population-based cancer registry data. Lancet 2011;377:127-38.
Walters S, Maringe C, Coleman MP, Peake MD, Butler J, Young N, et al.
Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: A population-based study, 2004-2007. Thorax 2013;68:551-64.
Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al.
The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706-14.
Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK. Quantified smoking status and non-small cell lung cancer stage at presentation: Analysis of a North Indian cohort and a systematic review of literature. J Thorac Dis 2012;4:474-484.
Noronha V, Dikshit R, Raut N, Joshi A, Pramesh CS, George K, et al
. Epidemiology of lung cancer in India: Focus on the differences between non-smokers and smokers: A single-centre experience. Indian J Cancer 2012;49:74.
] [Full text]
Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd
, Shepherd FA, Smith C, et al.
Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: A phase III randomised controlled trial. Lancet 2009;374:379-86.
Perez CA, Stanley K, Rubin P, Kramer S, Brady L, Perez-Tamayo R, et al.
A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the radiation therapy oncology group. Cancer 1980;45:2744-53.
Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al
. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non–small-cell lung cancer. J Clin Oncol 2010;28:2181-90.
O'Rourke N, Roqué i Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd.; 2010.
Chan C, Lang S, Rowbottom C, Guckenberger M, Faivre-Finn C, Committee IA, et al
. Intensity-modulated radiotherapy for lung cancer: Current status and future developments. J Thorac Oncol 2014;9:1598-608.
Bayman N, Blackhall F, McCloskey P, Taylor P, Faivre-Finn C. How can we optimise concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer? Lung Cancer 2014;83:117-25.
Hatton MQ, Martin JE. Continuous hyperfractionated accelerated radiotherapy (CHART) and non-conventionally fractionated radiotherapy in the treatment of non-small cell lung cancer : A review and consideration of future directions statement of search strategies used and source. Clin Oncol 2010;22:356-64.
Shrimali RK, Mahata A, Reddy GD, Franks KN, Chatterjee S. Pitfalls and challenges to consider before setting up a lung cancer intensity-modulated radiotherapy service: A Review of the reported clinical experience. Clin Oncol (R Coll Radiol) 2016;28:185-97.
Din OS, Harden SV, Hudson E, Mohammed N, Pemberton LS, Lester JF, et al.
Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: Results from 4 UK centres. Radiother Oncol 2013;109:8-12.
Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M, et al.
Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: Mature data from the randomised multicentre trial. CHART steering committee. Radiother Oncol 1999;52:137-48.
Jalal SI, Riggs HD, Melnyk A, Richards D, Agarwala A, Neubauer M, et al.
Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: Analysis of a phase III trial from the Hoosier oncology group (HOG) and US oncology. Ann Oncol 2012;23:1730-8.
Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, et al.
Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: The Hoosier oncology group and U.S. oncology. J Clin Oncol 2008;26:5755-60.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al.
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543-51.
O'Rourke N, Macbeth F. Is concurrent chemoradiation the standard of care for locally advanced non-small cell lung cancer? A review of guidelines and evidence. Clin Oncol (R Coll Radiol) 2010;22:347-55.
Hansen O, Knap MM, Khalil A, Nyhus CH, McCulloch T, Holm B, et al.
A randomized phase II trial of concurrent chemoradiation with two doses of radiotherapy, 60Gy and 66Gy, concomitant with a fixed dose of oral vinorelbine in locally advanced NSCLC. Radiother Oncol 2017;123:276-81.
Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al.
Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-99.
Trinh H, Pinkham MB, Lehman M, Zarate D, Dauth M, McGrath M, et al.
Outcomes treating stage III non-small cell lung carcinoma with curative-intent radiotherapy and concurrent carboplatin-paclitaxel chemotherapy. Clin Respir J 2016;10:428-34.
Dickhoff C, Dahele M, Smit EF, Paul MA, Senan S, Hartemink KJ, et al.
Patterns of care and outcomes for stage IIIB non-small cell lung cancer in the TNM-7 era: Results from the Netherlands cancer registry. Lung Cancer 2017;110:14-8.
Naito Y, Kubota K, Nihei K, Fujii T, Yoh K, Niho S, et al.
Concurrent chemoradiotherapy with cisplatin and vinorelbine for stage III non-small cell lung cancer. J Thorac Oncol 2008;3:617-22.
Iranzo V, Bremnes RM, Almendros P, Gavilá J, Blasco A, Sirera R, et al.
Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer. Lung Cancer 2009;63:63-7.
Detterbeck FC, Chansky K, Groome P, Bolejack V, Crowley J, Shemanski L, et al.
The IASLC lung cancer staging project: Methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (Eighth) edition of the TNM classification of lung cancer. J Thorac Oncol 2016;11:1433-46.
Ozcelik M, Korkmaz T, Odabas H, Gemici C, Ercelep O, Yuksel S, et al.
Comparison of efficacy and safety of three different chemotherapy regimens delivered with concomitant radiotherapy in inoperable stage III non-small cell lung cancer patients. Tumour Biol 2016;37:8901-7.
Antoni D, Mornex F. Chemoradiotherapy of locally advanced nonsmall cell lung cancer: State of the art and perspectives. Curr Opin Oncol 2016;28:104-9.
Burdett SS, Stewart LA, Rydzewska L. Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev 2007;3:CD006157.
Vokes EE, Herndon JE 2nd
, Kelley MJ, Cicchetti MG, Ramnath N, Neill H, et al.
Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and leukemia group B. J Clin Oncol 2007;25:1698-704.
Tsujino K, Kurata T, Kawaguchi T, Kubo A, Takada M, Ando M, et al.
Role of consolidation chemotherapy after concurrent chemo-radiotherapy in locally advanced non-small-cell lung cancer. J Thorac Oncol 2014;9:e7-8.
Belani CP, Wang W, Johnson DH, Wagner H, Schiller J, Veeder M, et al.
Phase III study of the eastern cooperative oncology group (ECOG 2597): Induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer. J Clin Oncol 2005;23:3760-7.
Rodrigues G, Choy H, Bradley J, Rosenzweig KE, Bogart J, Curran WJ Jr., et al.
Definitive radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol 2015;5:141-8.
Stinchcombe TE, Zhang Y, Vokes EE, Schiller JH, Bradley JD, Kelly K, et al.
Pooled analysis of individual patient data on concurrent chemoradiotherapy for stage III non-small-cell lung cancer in elderly patients compared with younger patients who participated in US national cancer institute cooperative group studies. J Clin Oncol 2017;35:2885-92.
Oh IJ, Ahn SJ. Multidisciplinary team approach for the management of patients with locally advanced non-small cell lung cancer: Searching the evidence to guide the decision. Radiat Oncol J 2017;35:16-24.
Kim YH, Ahn SJ, Kim YC, Kim KS, Oh IJ, Ban HJ, et al.
Predictive factors for survival and correlation to toxicity in advanced stage III non-small cell lung cancer patients with concurrent chemoradiation. Jpn J Clin Oncol 2016;46:144-51.
De Ruysscher D, Botterweck A, Dirx M, Pijls-Johannesma M, Wanders R, Hochstenbag M, et al.
Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: A prospective, population-based study. Ann Oncol 2009;20:98-102.
Driessen EJ, Bootsma GP, Hendriks LE, van den Berkmortel FW, Bogaarts BA, van Loon JG, et al.
Stage III non-small cell lung cancer in the elderly: Patient characteristics predictive for tolerance and survival of chemoradiation in daily clinical practice. Radiother Oncol 2016;121:26-31.
Dawe DE, Christiansen D, Swaminath A, Ellis PM, Rothney J, Rabbani R, et al.
Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis. Lung Cancer 2016;99:180-5.
Belderbos J, Uitterhoeve L, van Zandwijk N, Belderbos H, Rodrigus P, van de Vaart P, et al.
Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973). Eur J Cancer 2007;43:114-21.
Dillman RO, Herndon J, Seagren SL, Eaton WL Jr., Green MR. Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-5.
Curran WJ Jr., Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, et al.
Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: Randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011;103:1452-60.
Wang L, Wu S, Ou G, Bi N, Li W, Ren H, et al.
Randomized phase II study of concurrent cisplatin/etoposide or paclitaxel/carboplatin and thoracic radiotherapy in patients with stage III non-small cell lung cancer. Lung Cancer 2012;77:89-96.
Ramroth J, Cutter DJ, Darby SC, Higgins GS, McGale P, Partridge M, et al.
Dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer: Meta-analysis of randomized trials. Int J Radiat Oncol Biol Phys 2016;96:736-47.
Marks LB, Bentzen SM, Deasy JO, Kong FM, Bradley JD, Vogelius IS, et al.
Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010;76:S70-6.
De Ruysscher D, Faivre-Finn C, Nestle U, Hurkmans CW, Le Péchoux C, Price A, et al.
European organisation for research and treatment of cancer recommendations for planning and delivery of high-dose, high-precision radiotherapy for lung cancer. J Clin Oncol 2010;28:5301-10.
Budach V, Senan S, De Ruysscher D, Giraud P. Literature-based recommendations for treatment planning and execution in high-dose radiotherapy for lung cancer. Radiotherapy and oncology 2004;71:139-46.
Bezjak A, Rumble RB, Rodrigues G, Hope A, Warde P, Panel II, et al
. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508-20.
Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, et al
. Impact of intensity-modulated radiation therapy technique for locally advanced non–small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2016;35:56-62.
Walraven I, Damhuis RA, Ten Berge MG, Rosskamp M, van Eycken L, de Ruysscher D, et al.
Treatment variation of sequential versus concurrent chemoradiotherapy in stage III non-small cell lung cancer patients in the Netherlands and Belgium. Clin Oncol (R Coll Radiol) 2017;29:e177-85.
Duggan KJ, Descallar J, Vinod SK. Application of guideline recommended treatment in routine clinical practice: A Population-based study of stage I-IIIB non-small cell lung cancer. Clin Oncol (R Coll Radiol) 2016;28:639-47.
Schild SE, Hillman SL, Tan AD, Ross HJ, McGinnis WL, Garces YA, et al.
Long-term results of a trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small cell lung cancer: NCCTG N0028 (Alliance). J Thorac Oncol 2017;12:697-703.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]