key: cord-0016185-po5kkm5b
authors: Couñago, Felipe; de la Pinta, Carolina; Gonzalo, Susana; Fernández, Castalia; Almendros, Piedad; Calvo, Patricia; Taboada, Begoña; Gómez-Caamaño, Antonio; Guerra, José Luis López; Chust, Marisa; González Ferreira, José Antonio; Álvarez González, Ana; Casas, Francesc
title: GOECP/SEOR radiotherapy guidelines for small-cell lung cancer
date: 2021-03-24
journal: World J Clin Oncol
DOI: 10.5306/wjco.v12.i3.115
sha: 83aaac4d75bac80befdee0448db4223e74a56f03
doc_id: 16185
cord_uid: po5kkm5b

Small cell lung cancer (SCLC) accounts for approximately 20% of all lung cancers. The main treatment is chemotherapy (Ch). However, the addition of radiotherapy significantly improves overall survival (OS) in patients with non-metastatic SCLC and in those with metastatic SCLC who respond to Ch. Prophylactic cranial irradiation reduces the risk of brain metastases and improves OS in both metastatic and non-metastatic patients. The 5-year OS rate in patients with limited-stage disease (non-metastatic) is slightly higher than 30%, but less than 5% in patients with extensive-stage disease (metastatic). The present clinical guidelines were developed by Spanish radiation oncologists on behalf of the Oncologic Group for the Study of Lung Cancer/Spanish Society of Radiation Oncology to provide a current review of the diagnosis, planning, and treatment of SCLC. These guidelines emphasise treatment fields, radiation techniques, fractionation, concomitant treatment, and the optimal timing of Ch and radiotherapy. Finally, we discuss the main indications for reirradiation in local recurrence.

Small cell lung cancer (SCLC) was first described by Barnard [1] in 1926. Prior to that time, SCLC was considered a mediastinal lymphosarcoma and later it was known as "oat cell carcinoma of the bronchus" [2] . The treatment of SCLC has evolved over time and this evolution is reflected in published randomised controlled trials (RCT). Table 1 summarizes the main clinical trials carried out to date to evaluate the treatment of SCLC. Based on advances in thoracic surgery during World War II, surgery became the treatment of choice in SCLC until 1960 [3] .

The first RCT comparing surgery to radiotherapy (RT) in SCLC was performed in the 1960s [4, 5] . After that, the Veterans Administration Lung Study Group (VALSG) defined SCLC as either limited-stage (LS) or extensive-stage (ES) disease depending on whether or not the disease could be encompassed within a single RT field [6] .

Later, a RCT comparing cyclophosphamide (CP) to placebo found that CP significantly improved overall survival (OS) [7] . In a subsequent clinical trial, combined therapy (RT + CP) increased survival vs RT alone [8] . Other RCTs later confirmed those findings [9, 10] , while the findings of a subsequent RCT conducted by Perez et al [11] suggested that prophylactic cranial irradiation (PCI) could further prolong survival.

Polychemotherapy (PCh) regimens were evaluated in various clinical trials [12] [13] [14] , one of which concluded that PCh was superior to CP [15] . As a result, RT was relegated to being used as consolidation therapy [16, 17] . Other studies found that combining chemotherapy (Ch) and RT (chemoradiotherapy; CRT) resulted in median survival outcomes of 12-15 mo and 5-year OS rates ranging from 10%-15%. While CRT seemed to yield comparable OS outcomes, treatment-related toxicity was substantially greater when the two treatment modalities were combined [18, 19] . Two meta-analyses (MTA) found that adding RT to Ch improved 3-year OS [20] [21] [22] . Based on previous experience with PCh regimens, a treatment protocol involving RT to the brain and thorax combined with high dose Ch [CP, Adriamycin and Vincristine (CAV)] was developed, achieving greater local control (LC) than either treatment alone [23] . However, that approach was abandoned due to high levels of treatment-related toxicity [24] . Cisplatin-etoposide Ch combined with RT has shown to be effective in the treatment of SCLC with a manageable toxicity profile [25] .

The next advance in treatment protocols for LS-SCLC came from a RCT comparing early thoracic RT (TRT) to late TRT, both groups received concurrent PCh, showing a significant benefit in 5-year OS for early TRT [26] . A phase II trial compared once-daily TRT to twice-daily (1.5 Gy/session) accelerated hyperfractionated RT (AHF-RT) (45 Gy). All patients received concurrent cisplatin-etoposide PCh [27] . The median survival in the AHF-RT group was 23 mo, with a 3-year OS of 30% [28] .

Another RCT [29] was performed to compare initial (weeks 1 to 4) to delayed (weeks 6-9) AHF-RT (54 Gy), with all patients receiving concurrent low-dose PCh. Median survival in the early group was 34 mo vs 26 mo in the delayed group; 5-year OS was 30% vs 15%, respectively (P = 0.027). Another RCT [30] compared AHF-RT combined with cisplatin-etoposide administered concurrently or sequentially. The results of that trial showed that concurrent CRT was associated with significantly better OS outcomes

Two important studies were published in 2007: The first proposed staging SCLC according to the AJCC (American Joint Committee on Cancer) TNM (tumor-nodemetastasis) criteria [37] . The second study reported improved OS outcomes in patients with ES-SCLC who had a confirmed response to PCh and subsequently received PCI [38] . Based on those findings, PCI became the standard treatment for patients with LS-SCLC who showed a partial response (PR) to treatment.

Regarding diagnostic techniques, 18 F -fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET/CT) was incorporated into clinical practice because it provides more accurate staging of supraclavicular and distant disease, thus reducing the need for prophylactic mediastinal irradiation [39, 40] .

In recent years, the results of two landmark RCT were published: CREST and CONVERT [41] [42] [43] . CREST was performed to evaluate consolidative TRT in patients with ES-SCLC who respond to Ch. Median survival was significantly longer in the treatment group with better 5-year OS rates. In the CREST trial [41, 42] , patients were randomised to consolidative TRT (30 Gy in 10 fractions) or no TRT (control group). All patients received PCI. Thoracic recurrences were significantly reduced in the intervention group vs control (80% vs 44%). The 2-year OS was 13% vs 3%. A post hoc analysis revealed a greater survival benefit in patients who underwent thoracic RT after PCh [44] and in patients with ≤ 3 extrapulmonary metastases who received consolidative TRT [45] .

In the CONVERT trial [43] , patients were randomised to twice-daily AHF-RT (45 Gy) vs once-daily RT (66 Gy). Both groups received PCI. There were no significant differences between the groups in OS, progression-free survival (PFS), LC, or metastatic progression. Based on these findings, the Turrisi scheme remained the treatment of choice due to higher compliance rates (98% vs 83%) with the TRT dose. A subsequent MTA showed that OS was better in patients treated with early vs late TRT in patients who complied with the prescribed dose intensity of the Ch regimen [46] .

SCLC is commonly diagnosed in advanced stages. Early detection of SCLC with computed tomography has not shown to provide any benefit. Given the aggressive nature of advanced SCLC, the diagnosis should be made in a few weeks, but treatment should not be initiated until histological confirmation [52] is done.

In patients with SCLC, the following key variables should be registered: Age, comorbidities, tobacco use, and ECOG status. Patients should undergo a complete physical examination with comprehensive blood tests. Molecular markers provide little value, although pro-gastrin-releasing peptide has shown specificity in the diagnosis and follow-up of some patients with SCLC [53] .

Paraneoplastic syndromes can occur due to the production of polypeptides (syndrome of inappropriate antidiuretic hormone secretion or Cushing's syndrome), or autoimmune phenomena (Lambert-Eaton syndrome, anti-Hu-associated encephalomyelitis, among others).

Staging is performed via thoracoabdominal computed tomography with intravenous contrast (IVC), unless contraindicated. Preferably, magnetic resonance imaging (MRI) should be used to perform the brain study due to its greater sensitivity and better definition of brain structures. Brain metastases (BM) are present in more than 12% of patients previously classified with LS-SCLC.

18 F -FDG PET/CT imaging is recommended in LS-SCLC, but considered optional in ES-SCLC if it implies a delay in treatment. This imaging modality provides the best mediastinal staging and distant localization of metastases (adrenal and bone) [54] . Due to its high sensitivity (close to 100%) and specificity (90%), 18 F -FDG PET/CT imaging changes the therapeutic approach in 28% of patients [55] , including re-staging in 15% of cases [95% confidence interval (CI): 9-21] [56] .

18 F -FDG PET/CT images should be acquired under the same positioning and immobilization conditions of the planned treatment. This imaging modality can help to optimize radiation doses and treatment volumes [57] . One study reported a higher risk of supraclavicular lymph node (LN) recurrence when CT-based nodal irradiation was omitted [58] . It has been suggested that better definition of volumes could influence both LC and OS [59] . Although this improvement in OS has not been demonstrated in prospective studies [60] , some have reported lower rates of esophagitis [57] . In patients who undergo sequential treatment, Ch can reduce glucose consumption; consequently, restaging with 18 F -FDG PET/CT may underestimate mediastinal involvement, which is why this imaging modality is not appropriate for planning RT [61, 62] .

Bony metastases are often present in these patients. A bone scan is indicated if 18 F -FDG PET/CT is not available [63] . If there is suspected bone marrow involvement, a biopsy is indicated (level of evidence V, grade of recommendation C) [64] . Abdominal MRI with IVC may be necessary to identify hepatic or adrenal lesions (level of evidence V, grade of recommendation C).

Histologic confirmation is generally obtained through bronchoscopy, endobronchial ultrasound (EBUS), or transesophageal endoscopic ultrasound (level of evidence III, grade of recommendation C) [65] . EBUS-guided needle aspiration is highly effective, with a sensitivity of 97.4%, specificity of 100%, negative predictive value of 60%, and positive predictive value of 100% [66] . Peripheral nodal biopsy, mediastinoscopy, or diagnostic thoracoscopy will rarely be necessary. In patients with ES-SCLC, it is recommended to biopsy the soft tissue lesions that offer the highest yield with the least risk (e.g., skin, liver). Prior to surgery or RT, all patients should undergo respiratory function testing. Table 2 summarizes the imaging tests recommended for staging SCLC.

According to the World Health Organization [67] , SCLC is an epithelial neoplasm of neuroendocrine origin, with small cells on Alcian blue staining, scant cytoplasm, dispersed chromatin, inconspicuous nucleoli, numerous mitoses (> 10/2 mm 2 ) and abundant necrosis. These lesions may be found as well in adenocarcinoma cells or squamous cell carcinoma. Immunohistochemistry will clarify diagnostic uncertainty based on expression of chromogranin, synaptophysin, and CD56, although these markers may be absent in 5%-10% of cases. CK7 is present in 25% and TTF-1 in 85%-90% of cases. Ki-67 Levels are elevated in most patients, thus facilitating differential diagnosis with other neuroendocrine tumours. Programmed death ligand 1 expression is currently being studied to determine if immunotherapy can be added to current treatment approaches. To identify new therapeutic targets, other molecular profiles can be considered in nonsmokers with ES-SCLC. Not recommended for restaging after chemotherapy in sequential treatment

Brain MRI is preferable Brain CT with IV contrast (without contrast is inadequate)

Only indicated to assess uncertain liver or adrenal lesions (V, C)

Invasive tests used as appropriate according to tumour location Follow WHO criteria for cell typing. Immunohistochemistry for differential diagnosis 

Staging for SCLC is based on the VALSG classification system. However, the TNM staging described in the AJCC 8 th edition (level of evidence I, grade of recommendation A) should also be utilized [68, 69] . Tables 3 and 4 summarize TNM staging for SCLC.

In patient with LS-SCLC, the tumour is confined to the hemithorax (stages I-III). All other cases of SCLC are considered ES-SCLC (stage IV). However, there are discrepancies between the various guidelines (NCCN/CSCO, ESMO) with regard to the presence of pleural effusion, large primary tumour, or contralateral supraclavicular LNs. If the only evidence of metastasis is pleural or pericardial effusion without the presence of malignant cells, these cases should be considered non-metastatic (M0) (level of evidence V, grade of recommendation B).

In patients with a single metastatic site, initiation of PCh should not be delayed. The patient should be re-evaluated after two cycles of PCh to determine the status of the target lesion (level of evidence V, grade of recommendation C). Single extrathoracic metastasis (including non-regional lymph node)

Multiple extrathoracic metastases TNM: Tumor-node-metastasis; AJCC: American Joint Committee on Cancer.

Surgery: Patients with stage I (T1-2N0) disease may benefit from surgery [70] . These patients should undergo invasive mediastinal staging with 18 F -FDG PET/CT imaging [71] . Surgery consists of lobectomy with mediastinal lymphadenectomy (level of evidence II, grade of recommendation A). Based on data from retrospective studies, 5year OS is approximately 57% [70] .

Stereotactic body radiation therapy: CRT are indicated in patients with inoperable stage cT1-2N0M0 SCLC. Data from the National Cancer Data Base showed that there are no differences in OS between patients treated with stereotactic body radiation therapy (SBRT) followed by PCh and those treated with concurrent CRT [72] . As a result of those findings, the proportion of patients treated with SBRT increased sharply from 2004 (0.4%) to 2013 (6.4%). A multicenter study reported that SBRT (50 Gy, 5 fractions) yielded a LC rate of 97.4% at 1 year and 96.1% at 3 years, with a median PFS at 1 and 3 years of 58.3% and 53.2%, respectively [73] . The median survival was 17.8 mo (69.9% at 1 year and 34% at 3 years), with only minimal toxicity (grade 2 pneumonitis: 5.2%). Thus, SBRT achieves a high LC rate in patients with early, inoperable SCLC; however, sequential treatment with PCh is essential [74] .

Adjuvant treatment: Adjuvant PCh should be administered after surgical resection. RT should be included in patients with mediastinal nodal involvement. Figure 1 shows the evaluation algorithm for adjuvant TRT.

A review of studies that included adjuvant TRT found that the addition of this treatment modality improved median OS in pN1 and pN2 disease [75] . Adjuvant TRT was associated with a lower risk of death in both pN1 [hazard ratio (HR): 0.79; 95%CI: 0.63-1.00, P = 0.05] and pN2 disease (HR: 0.60; 95%CI: 0.48-0.75, P < 0.0001), but not with better OS in patients without nodal involvement. OS was better (HR 0.72, 95%CI: 0.57-0.90, P = 0.004) in patients who underwent sublobar resection.

The standard treatment for stage IIB and IIIC is concomitant CRT (level of evidence I, grade of recommendation A).

Two MTA concluded that PCh plus TRT improve OS [20, 21] in LS-SCLC. Another MTA [36] demonstrated that early TRT is superior to late TRT in patients receiving concomitant CRT. Ideally, TRT should start with the first or second cycle of PCh (level of evidence I, grade of recommendation A). However, PCh should not be delayed in order to initiate concomitant TRT. Another study [76] found that a shorter interval between initiation of PCh and completion of TRT is associated with a better OS (level of evidence I, grade of recommendation A).

A recent MTA [77] compared the efficacy and toxicity of twice-daily to once-daily CRT, finding significantly better overall survival with the twice-daily regimen and no differences in toxicity.

AHF-RT (45 Gy) with an interfraction interval of ≥ 6 h is recommended for normal tissue repair. Alternatively, higher dose (66 Gy) normofractionated RT can be considered as an individual option for each patient. AHF-RT is preferable in patients with a good performance status (PS) and baseline lung function. 

Consolidative TRT: Prior to the introduction of immunotherapy, the main treatment for ES-SCLC was platinum-based PCh, preferably with carboplatin rather than cisplatin due to the more tolerable toxicity profile. The median OS ranges from 8-13 mo [78] .

Although platinum-based PCh is the mainstay of treatment for ES-SCLC, 80% of patients present residual intrathoracic disease or progression. For this reason, consolidative TRT has been evaluated in these patients. This approach should be considered in patients with ES-SCLC who present residual thoracic disease and low volume extrathoracic metastatic disease with a complete or good response to PCh (level of evidence I, grade of recommendation A). One meta-analysis found that consolidative TRT prolongs both OS and PFS, with only a small increase in the risk of esophagitis [79] .

BM are treated with whole-brain RT (WBRT). In asymptomatic patients, the recommended approach is PCh followed by WBRT. For symptomatic patients, the recommendation is WBRT +/-concomitant PCh.

In selected cases with only a few BM, stereotactic radiosurgery (SRS) followed by active surveillance with MRI can be considered in order to avoid PCI/WBRT; SRS can also be performed to treat new BM [80] . The FIRE SCLC study [81] was a multicenter cohort study comparing SRS to WBRT. In that study, although WBRT prolonged the interval to brain progression, it did not improve OS. ENCEPHALON (NCT03297788) is an ongoing phase II RCT designed to compare WBRT to SRS in patients with 1-10 BM. Another trial (NCT03391362) is currently underway to compare SRS in patients diagnosed with ES-SCLC and 1-6 BM.

Oligometastatic disease: The number of metastases is a prognostic factor [82] , but the differences in OS between oligometastatic and polymetastatic SCLC remain unclear. In one trial, patients with stage IV SCLC and ≤ 4 extracranial metastases after response to PCh were randomised to PCI with or without consolidative TRT and irradiation of extracranial metastases. TRT reduced the risk of the first thoracic recurrence (62.5% vs 25.8%) and the risk of recurrence in previous metastases (78.1% to 41.9%).

The incidence of SCLC increases as a function of age, with patients ≥ age 70 accounting for approximately one-third of cases. Data on the treatment of these patients are limited because the elderly are underrepresented in clinical trials [83] . The use of CRT in elderly patients has been limited because these patients are less likely to be able to tolerate the potential toxicity of treatment due to lower functional reserve levels. However, elderly patients with LS-SCLC who are in good general condition can be treated with CRT and modern RT techniques such as 3-dimensional (3D)-RT or intensity modulated RT (IMRT). A RCT found that disease-free survival and response rates among elderly patients were similar to those observed in patients younger than age 70 [84] . Even though 5-year OS was higher in younger patients, 16% of patients ≥ age 70 remained alive at 5 years. In the CONVERT trial, elderly and younger patients presented comparable OS outcomes (29 vs 30 mo; P = 0.38) [85] . Although many elderly patients with LS-SCLC have comorbidities, they are generally able to tolerate CRT as well as younger patients, though they present a higher risk of asthenia and myelosuppression [86] . Patients with ES-SCLC with good PS and adequate supportive treatment can tolerate standard PCh.

The ESTRO/ACROP guidelines for the target volume delineation for non-SCLC (NSCLC) categorised the recommendations as follows: Mandatory (M), recommended (R); optional (O); and discouraged (D) [87] . Some of these indications have been adopted for the treatment of SCLC [52] .

Treatment planning should be based on computed tomography with the patient placed in the treatment position (M) with IVC (R) and a slice thickness ≤ 3 mm (M). Preferably, 4D-CT (R) should be used to evaluate the gross tumour volume (GTV) displacement in the respiratory cycle, or with breathing coordination methods (ABC) or gating techniques (R).

The primary GTV (GTVp) is the macroscopic tumour visible on CT or 18 F -FDG PET/CT. The LN GTV (GTVn) corresponds to the LNs involved prior to PCh (M) that are visible on CT or 18 F -FDG PET/CT (short axis > 10 mm on CT or with significant uptake), and/or have been histologically confirmed. Grouped nodes with a short axis < 10 mm adjacent to the tumour are considered to be involved (R).

The GTVp and GTVn must be contoured separately (O). The recommended lung window parameters (R) are: W = 1600 and L= -600 for lung parenchymal tumour. W = 400 and l = 20 for involved LNs/tumours invading the mediastinum.

At present, there are no validated data to support the fusion of diagnostic 18 F -FDG PET/CT with treatment planning CT [88] . There may be discrepancies between these images, for the following reasons: (1) The GTV on 18 F -FDG PET/CT frequently corresponds to areas of normal tissue on the CT. The 18 F -FDG PET/CT images are acquired over several minutes, which allows us to define the motion of the primary tumour. When these images are associated with those obtained in a 3D planning CT, some areas of the GTV on 18 F -FDG PET/CT may correspond to "air" areas on the CT due to lesion movement; (2) When the tumour is contiguous to areas of similar density, it must be defined by 18 F -FDG PET/CT; in cases in which FDG uptake is not due to the tumour (e.g., heart, active infection), this should be contoured on CT; and (3) LNs that are enlarged on CT but negative on 18 F -FDG PET/CT imaging should not be considered part of the GTV unless pathological data is available. Small nodes without uptake adjacent to the primary tumour or those located between pathological nodes, or with evident growth on consecutive CT scans, should be considered part of the GTV [89, 90] .

Postoperative RT: To date, postoperative RT (PORT) after surgery and sequential PCh of early -stage SCLC (N0) has not been shown to improve OS [91] [92] [93] .

PORT can improve 5-year OS in pN2 disease [94] [95] [96] , but does not significantly improve OS in stage pN1 [75] . A MTA [97] concluded that PORT improves 1-3 year LC rates in pN1 and pN2 and 1-5 year OS in pN2 disease. However, PORT provides no benefit in pN0 [98, 99] . Clinical guidelines recommend PORT for the treatment of microscopic or macroscopic residual disease (R1 or R2) or pN2+ disease (level of evidence V, grade of recommendation C) [100, 101] .

The recommended treatment volumes are as follows: Bronchial stump, ipsilateral hilum, preoperatively involved regions, and pathologically-positive areas [102] [103] [104] . The treatment fields proposed in the randomised Lung ART trial for PORT in patients with pN2+ NSCLC [105] could be applied to patients with SCLC. However, PORT should be used cautiously in the treatment of SCLC given the negative results reported in a recent RCT in NSCLC [106] . Consequently, the treatment approach should be individualised and determined by consensus decision at the thoracic tumour board at each hospital.

The margin added to the clinical target volume (CTV) to define the planning target volume (PTV) will depend on the immobilization system used and other centrespecific factors. A 5 mm margin added to the involved LNs may be sufficient [107] . A 3 mm margin may be recommended for nodes < 2 cm and 12 mm for nodes > 2 cm [108] .

Respiratory motion should be compensated for by defining the internal target volume (ITV) based on reconstruction of the phases of the respiratory cycle obtained through 4D-CT imaging [109] . Published series for SBRT do not differentiate between the GTV and CTV. The CTV margin for the PTV is 5 mm (range, 3-7 mm).

In the 1980s, studies were performed to determine whether delimitation of the GTV should be based on the pre-or post-induction PCh tumour volume [110] , with the available evidence suggesting that there were no apparent differences in OS or relapse patterns. One study [111] evaluated 59 patients treated with neoadjuvant CT followed by CRT; 31 patients received TRT to the pre-PCh volume and 28 to the post-PCh volume. The use of the post-PCh volume did not increase out-of-field margin failures or thoracic recurrences. These data suggest that reduced fields are an acceptable strategy.

In a recent RCT [112] patients with stage I-III SCLC (92.9% stage III) underwent neoadjuvant PCh and were then randomised to TRT to the primary pre-PCh GTV (control arm) or the post-PCh GTV (experimental arm). Initially involved nodal regions were included in both treatments. There were no differences in locoregional PFS or OS at 3 and 5 years, although significant grade 3 esophagitis was observed in the pre-PCh arm. In the CONVERT and CALBG30610/RTOG 0538 trials, the treatment volume was the residual post-PCh GTV.

Another controversy surrounds the use of elective irradiation of mediastinal and supraclavicular LNs [27, 28] . The study conducted by Baas et al [113] was the first to omit elective mediastinal irradiation. The volume irradiated was the involved primary tumour and LNs with a diameter ≥ 1 cm. In that study, 16% of patients developed local recurrence within the RT field. Updated data from that trial [114] reported out-of-field nodal recurrences in two patients and in-field recurrences in 9 (sole site of recurrence in 4). From the out-of-field relapses, one occurred in the ipsilateral supraclavicular fossae. The incidence of recurrences in the elective mediastinum is low (range, 2%-11%) and in more than 50% of cases these occur in the ipsilateral supraclavicular fossae, which underscores the crucial importance of accurate staging (with 18 F -FDG PET/CT and/or supraclavicular ultrasound) [115] . In the CONVERT trial, elective mediastinal irradiation was not permitted. In the CALBG 30610/RTOG 0538 (NCT00632853) trial, the CTV included the ipsilateral hilum. Staging with 18 F -FDG PET/CT was not mandatory in either trial.

The post-PCh primary GTV and pre-PCh nodal areas should be included in the treatment volume. For the primary GTV, if the tumour invades the mediastinum, the pre-PCh volume should be contoured at the tumour-parenchyma interface; only the residual post-PCh GTV should be considered. If CR in the primary tumour has been achieved, the primary CTV (CTVp) should be contoured on the pre-PCh image. Elective irradiation of areas located between involved mediastinal stations is optional, as is irradiation of the ipsilateral supraclavicular fossae in cases with extensive mediastinal involvement (level of evidence II, grade of recommendation B).

To account for microscopic disease after neoadjuvant CT, an adequate GTVp margin would be 1.4 mm. To reduce the irradiation volume, the CTV can be omitted with no significant differences in the recurrence rate. Micrometastases in the CTV may be small enough to be sterilized by PCh. In most studies, a 5-8 mm margin is added to the GTVp or ITV to establish the CTVp. When contouring the CTVn, the entire area encompassing the pathological nodes should be included with a 5-8 mm margin. The PTV margin is generally obtained by adding 5-10 mm to the CTV.

The optimal treatment volume for consolidation TRT in ES-SCLC has not been established [116] [117] [118] [119] [120] [121] . Table 5 shows the volumes used in recent studies. According to ESTRO/ACROP recommendations, the following should be included: Post-CT GTVp, the hilar region, and the mediastinum (not only the involved area), in all cases accounting for the decreased nodal volume after Ch (R).

The indication for PCI in ES-SCLC is controversial [122] . Standard WBRT is recommended. To protect the hippocampus, this structure should be contoured according to the RTOG atlas [123] on a T1-weighted 3D contrast-enhanced MRI. For hippocampal protection, the planning CT should have a slice thickness ≤ 1.25-1.3 mm to ensure correct fusion with the MRI. In this case, the CTV should be defined as the whole brain minus the bilateral hippocampus + 5 mm [124, 125] . To define the PTV, a 3-5 mm margin is added to the CTV to protect the outer table of the skull to avoid alopecia. 

A fundamental aspect of RT planning in SCLC is to delineate the organs-at-risk (OAR) with adequate dose limitations.

The dose limits on the dose/volume histogram (DVH) for the lung are based on both lungs minus the target volume (GTV) [126, 127] . DVH dosimetric parameters in TRT [V5, V13, V30, V20 and mean lung dose (MLD)] may be associated with the risk of pneumonitis, mainly grade ≥ 3. The most commonly used parameters are the V20 and MLD. When V20 is limited to ≤ 30%-35% and MLD ≤ 20-23 Gy, the reported rate of radiation pneumonitis is ≤ 20% [128] . The incidence of grade 5 pneumonitis is extremely low and associated with dose fractions totalling > 2 Gy, elevated V20 values, and lower lobe tumours.

Based on RTOG 0813 and 0915 recommendations, the 2016 SABR guidelines 2016, and data from TG 101 [126] , the recommended dose limits for SBRT per fraction are as follows: One fraction: 7 Gy/1500 cc, 7.4 Gy/1000 cc; three fractions: 11.6 Gy/1500 cc, 12.4 Gy/1000 cc, V20 < 10%, V12.5 < 15%; four fractions: 11.6 Gy/1500 cc, 12.4 Gy/1000 cc, V20 ≤ 12%, MLD < 6 Gy; five fractions: 12.5 Gy/1500 cc, 13.5 Gy/1000 cc, V12.5 < 15%, V20 < 10%; and eight fractions: V12.5 < 15%, V20 < 10%.

The trachea should be contoured in the mediastinal window, including all layers. The upper limit is the cricoid cartilage and the lower limit is the upper border of the proximal bronchial tree (2 cm above the carina). The bronchial tree includes 2 cm distal from the trachea, the carina, the right and left main bronchi to the lower-lobe bronchi. Contouring ends at the segmental bifurcation.

The RTOG recommends the following dose/volume parameters for the trachea and ipsilateral bronchus: 20.2 Gy (Dmax)/10.5 Gy (< 4 cm 3 ) in one-fraction; 30 Gy (Dmax)/15 Gy (< 4 cm 3 ) in three fractions; 34.8 Gy (Dmax)/15.6 Gy (< 4cm 3 ) in four fractions; 105% of the prescribed dose to the PTV/18 Gy (< 4 cm 3 ) in five fractions; and 44 Gy (Dmax) in eight fractions [129] .

Esophagus: All layers of the esophagus should be contoured from the cricoid to the gastroesophageal junction. Several factors-concomitant boost; AHF-RT; concurrent CRT-may increase the risk of severe acute esophagitis (grade ≥ 3), which can occur in up to 15%-25% of cases [130] . The V60 is the most accurate predictor of grade 3 esophagitis [131] : V60 < 0.07% = 4%, V60 0.07%-17% = 10%, and V60 > 17% = 22%. Dmean < 34 Gy may be associated with ≥ grade 3 acute esophagitis in 5%-20% cases; V35 < 50%, V50 < 40%, and V70 < 20% may limit ≥ grade 2 esophagitis to less than 30% [132] . The maximum dose is a better predictor of severe late toxicity than Dmean. In SBRT treatments, the incidence of ≥ G3 esophagitis is low; studies of single-fraction RT suggest that D2.5 cm 3 to the esophagus < 14 Gy will maintain a rate less than 5% and a Dmax < 22 Gy [133] . Other studies with one or more fractions report dose/volume limits as follow: D5cc <14.5 Gy; D2cc 15-20 Gy; and Dmax < 19 Gy [134] .

The spinal cord is contoured in the mediastinal window from the cricoid to below L2. The structure should be contoured following the bony limits of the spinal canal. Another possibility is to delineate the visible spinal cord on the CT and apply a 2 mm margin for the DVH analysis to estimate all uncertainties. In tumours located close to this organ, or for SBRT treatments, fusion with MRI is useful [126, 127] The use of a planning OAR volume margin around a critical organ such as the spinal cord is sufficient to avoid overdose (level of evidence IV, grade of recommendation C).

In normofractionated treatments (1.8-2 Gy/day) that include the cord circumference, myelopathy rates of 0.2%, 6%, and 50% have been described after 50 Gy, 60 Gy, and 69 Gy, respectively. The NCCN recommends Dmax ≤ 50 Gy. In SBRT for tumours in which only part of the spinal cord is irradiated, the risk of myelopathy is < 1% with Dmax 13 Gy/1 fraction or 20 Gy/3 fractions. RTOG 0915 establishes limits of 14 Gy in one fraction and 30 Gy in 5 fractions; a strict limit of 22 Gy in five fractions should also be considered [135] . Although the main variable associated with myelopathy is the maximum dose, the volume irradiated is also important. When the D0.1cc parameter is used, lower dose levels are established in each fraction.

The brachial plexus is divided into five nerve roots, including C5 at the exit through the neural hole, and C4-C5 to T1 as they exit through the T1-T2 foramen. To delineate the brachial plexus in the mediastinal window setting, it is preferable to use IV contrast to distinguish the nerves from the adjacent vessels. If no contrast is used, the subclavian and axillary arteries and veins should be used for reference. In the treatment of apical tumours with SBRT, CT-MRI fusion is recommended [126, 127] . The upper limit is the exit point of the C5 root through the C4-C5 neural foramen, while the lower limit is the subclavian and axillary neurovascular bundle not including the vessels to identify the lateral border, and the second rib as the medial limit; external limit: Space between the anterior and middle scalene muscles from the vertebral body of C5 to its insertion at the first rib; internal limit: At the space at the conjunction of the lateral border of the spinal canal and the space or soft tissue between the scalene muscles at the vertebral body. To reduce the risk of radiationinduced plexopathy [136] , the Dmedian should be ≤ 69 Gy with a Dmax at 2 cm 3 < 75 Gy. The risk of plexopathy is greater for brachial plexus doses > 26 Gy in 3-4 fractions, and for maximum doses > 35 Gy and V30 > 0.2 cm 3 .

The entire pericardial sac should be contoured, including the atria and ventricles. The upper limit is below the aortic arch (aorto-pulmonary window) and the lower limit is the cardiac apex, excluding the pulmonary artery trunk, aorta, and superior vena cava [126] . The trade-off between protecting the heart and the likelihood of controlling the lung cancer must always be considered.

In normofractionated RT, the risk of toxicity for Dmean values < 10 Gy, 10-20 Gy, and ≥ 20 Gy is 4%, 7%, and 21%, respectively. V50 values ≤ 25% and Dmean ≤ 20 Gy are recommended and the risk of pericarditis increases with pericardial Dmean > 26 Gy and V30 > 46% according to QUANTEC. In SBRT, dose/volume limits [135] are as follows: Four fraction treatments: Dmax < 45 Gy, V40 ≤ 1 cm 3 , and V20 ≤ 5 cm 3 . RTOG 0618, 0813, and 0915 used Dmax values of 22 Gy/16 Gy < 15 cm for single fractions, Dmax 30 Gy/24 Gy < 15 cm 3 in 3 fractions, Dmax 34 Gy/< 15 cm 3 in 4 fractions, and 105% of the dose prescribed at PTV/32 Gy < 15 cm 3 in 5-fraction regimens [129] .

Great vessels: The great vessels are contoured in SBRT, including the aorta and vena cava, from 10 cm above the PTV to 10 cm below it. Dose limits are Dmax 37 Gy/31 Gy < 10 cm 3 in single fraction treatments, Dmax 45 Gy/39 Gy < 10 cm 3 in three fractions, Dmax 49 Gy/43 Gy < 10 cm 3 in four fractions and 105% of the dose prescribed at PTV/47 Gy < 10 cm 3 in five fractions.

Chest wall: In peripheral tumours treated with SBRT, the chest well is considered an OAR. Each rib should be contoured at 5 cm from the PTV, excluding the intercostal space. Descriptive parameters are: Dmax 30 Gy/22 Gy < 1 cm 3 in a single fraction, Dmax 36.9 Gy/28.8 Gy/< 1 cm 3 in three fractions, and Dmax 40 Gy/32 Gy < 1 cm 3 in four fraction schemes.

The capacity of standard PCh agents (cisplatin-etoposide) to penetrate the blood-brain barrier is limited and 60% of patients will develop BM within two years of diagnosis, which explains the importance of PCI. The value of PCI is supported by the highest quality scientific evidence. Aupérin et al [33] performed a MTA of seven clinical trials (mostly LS-SCLC), finding that PCI resulted in an absolute decrease of 25.3% in BM and a 5.4% improvement in 3-year OS.

A RCT conducted in Japan compared PCI to MRI-based observation in patients with ES-SCLC [122] , finding that PCI did not provide any survival benefit, thus calling into question the role of PCI in these patients. Nevertheless, while PCI is considered standard in LS-SCLC, some patients-such as those older than age 75 or with high risk factors for neurotoxicity due to pre-existing disorders-may opt for close follow-up with MRI.

Prior to initiating PCI after completion of CRT, a brain MRI should be performed for re-evaluation. In patients with chest CR, MRI performed after CRT shows an incidence of BM ranging from 20%-32% [137, 138] .

Another MRI-based study found that the cumulative incidence (prior to PCI) of BM was 6.67% 4 mo after the initial treatment, rising to 12.2% at month 5 (1 mo later) until gradually reaching 21.82% at month 9 [139] . These data indicate that PCI should be administered after completion of CRT. BM were detected in 10% of SCLC patients in the computed tomography era vs 24% in the MRI era. The emergence of MRI reduced the use of PCI from 42% of patients to only 13% [140] .

Recent data from non-randomised studies suggest that PCI significantly benefits patients with LS disease, with better OS in patients re-evaluated with MRI [141] .

Data from retrospective studies involving patients with LS-SCLC who achieve CR after CRT suggest that PCI does not improve OS, provided that MRI and SRS are available; however, those same data show that PCI reduces the incidence of BM [142] . SRS is an effective treatment for selected cases of SCLC with BM [143] .

A MTA of seven randomised trials involving > 2000 patients found that PCI improved OS and significantly decreased the incidence of BM compared to observation [144, 145] . However, it is important to note that those trials were highly heterogeneous in terms of the OS analyses due to the wide range of imaging tests utilized.

PCI is the standard treatment for most patients with LS-SLC who respond to radical CRT (level of evidence I, grade of recommendation A). Although the MTA by Aupérin et al [33] included only patients who achieved CR after CRT, the role of PCI can be extrapolated to patients with partial response based on current radiological tests. The NVALT-11/DLCRG-02 Study and SWOG S1827 phase III (MAVERICK) noninferiority trial (NCT04155034) are currently being performed to determine whether active surveillance with MRI yields similar survival outcomes to MRI plus PCI [146] .

The use of PCI in patients with ES-SCLC is controversial. The EORTC study [38] showed that PCI reduced the incidence of BM from 40% to 15%, prolonged median survival (from 5.4 mo to 6.7 mo) and improved OS rates (27% to 13%). However, prior to initiation of PCI, no imaging test was required in that study. In the study conducted by Takahashi et al [122] all patients underwent MRI prior to PCI. The cumulative incidence of BM in the two arms (PCI vs observation) was 48% and 69%, respectively. Despite the lower rate of BM with PCI, this did not improve OS (Table 6) .

The PCI dose in ES-SCLC is 2500 cGy in 10 fractions (level of evidence I, grade of recommendation A) and 2000 cGy in 5 fractions [38] ; however, the neurocognitive effects of the latter scheme have not been fully investigated.

Although two MTA and one pooled analysis have shown that PCI improves OS in patients with ES-SCLC , the result of another MTA called into question the value of PCI [150] . Consequently, the decision to use PCI or not should be discussed with the radiation oncologist. Patients with ES-SCLC who progress after PCh should not receive PCI.

PCI is associated with several acute toxicities, including alopecia, headache, fatigue, and, in rare instances, nausea and vomiting. Long-term sequelae such as severe memory loss, intellectual impairment, or even dementia and ataxia (both rare) have been reported. Chronic neurotoxicity (CNT) [151] may be associated with age, high total doses, dose fractions > 3 Gy, and concomitant PCh. In the prospective RTOG 0212 trial [152] , age was the most significant factor for the development of CNT, with 83% of patients over age 60 developing CNT at 12 mo compared to only 56% of younger patients.

A recent systematic review assessed the risk factors for CNT after PCI [153] , concluding that there is a lack of sufficient quality data to define these factors. However, disease-related factors (paraneoplastic syndromes, undiagnosed cerebral micrometastases, steroid use, etc.) are known to influence the development of CNT. Numerous factors have been shown to exacerbate the toxicity of cancer treatment, including treatment-related factors (CT or CT-induced anemia); smoking; excessive alcohol intake; comorbidities (e.g., depression and anxiety); hypertension; hyperlipidemia; and diabetes caused by vascular damage and cerebral hypoperfusion.

A dose escalation study [154] found no significant reduction in the 2-year incidence of BM at doses > 25 Gy, but did find an increase in mortality. A neurocognitive analysis of data from RTOG 0212 (2500 vs 3600 cGy) showed a significant increase in CNT with higher doses [152] .

In patients with stage I SCLC, the risk of BM is minimal and there does not appear to be any survival benefit associated with PCI in surgically-treated stage pT1-2N0M0 disease [155] [156] [157] . Consequently, follow-up in this patient population should be limited to brain MRI.

Few studies have evaluated the impact of PCI on survival outcomes in elderly patients. Eaton et al [158] evaluated PCI in 1926 patients, finding that this treatment improved OS in patients ≥ 75 years of age but not in those ≥ age 80. Other series suggest that patients older than 65-70 years of age-especially those with large tumours and/or women-are unlikely to achieve an OS benefit even after a good response to CRT [159, 160] . One study suggested that patients with LS-SCLC and incomplete response to CRT may not benefit from PCI [161] . Active surveillance with brain MRI is preferable in elderly patients and in those with limited functional status, pre-existing neurocognitive disorders, or significant comorbidities.

Neurocognitive deterioration associated with PCI [162] is caused in part by irradiation of the hippocampus. For this reason, hippocampal sparing techniques have been evaluated, with promising results in metastatic patients treated with WBRT and hippocampal avoidance [163, 164] . As a result, several multicenter RCTs are currently underway. NCT01780675 is a trial [165] performed to assess the safety of PCI and its impact on memory with or without hippocampal avoidance in patients with SCLC. That trial included 168 patients, finding that the rate of cognitive decline [Hopkins Revised Verbal Learning Test (HVLT-R)] at 4 and 8 mo did not significantly differ for PCI alone vs PCI with hippocampal avoidance (28% vs 29%). Moreover, the incidence of metastases did not significantly differ between the groups, and none of the patients developed BM in the hippocampus [166] .

The Spanish PREMER trial (NCT02397733) reported contrary results. Among the 118 eligible patients, a significant decrease in memory was observed in the PCI group vs the hippocampal avoidance group, as follows: At 3 mo: 21.7% vs 5.1%; at 6 mo: 32.6 vs 7.3%; and 12 mo: 18.5 vs 3.8%). That trial used the Free and Cued Selective Reminding Test (FCSRT) to test neurocognitive function, but this test (FCSRT) was not used in the other randomised trial [167] .

The study endpoints of the NRG-CC003 trial (NCT02635009) were 12-mo intracranial relapse and 6-mo impairment of delayed recall on the HVLT-R [168] .

The latest NCCN guidelines recommend hippocampal avoidance and the use of memantine during and after PCI because this delayed the time to cognitive deterioration in patients who received WBRT for BM (RTOG 0614) [169] .

For the radiation oncologist, the decision to recommend PCI or not is challenging, as it is not always clear which patients are likely to benefit and which can be offered MRI surveillance. In some cases, surveillance with MRI may be preferred, especially for patients who show a CR to the initial treatment [80] . Risk assessment should be individualized and decision-making should be shared with patients [100, 101] .

Published evidence on the role of image-guided radiation therapy (IGRT) in SCLC is limited. One study involving a series of 132 patients with SCLC [170] found no significant differences in OS between patients treated with or without IGRT. No toxicity information was reported.

There are no randomised studies comparing IMRT to 3D-RT in LS-SCLC. Data from retrospective studies [171] suggest that OS is comparable, although IMRT is associated with a significantly lower rate of percutaneous feeding tube placement due to esophagitis (5% vs 17%).

Comparative dosimetric studies between IMRT and volumetric modulated arc therapy (VMAT), including patients with SCLC [172] , show that each technique has specific advantages depending on the tumour location. In peripheral tumours, the lung V5 (%) is lower with VMAT than IMRT while the lung V30 (%) is lower with IMRT. In central locations with mediastinal involvement, VMAT has a lower V20 (%) than IMRT.

The first prospective study of proton therapy with concomitant CT in LS-SCLC was published in 2017 [173] . The median dose was 63.9 cobalt gray equivalents (range, 45-66.6) in 33-37 fractions administered once [n = 18 (60.0%)] or twice daily [n = 12 (40.0%)]. Compared to IMRT, proton RT achieved a statistically significant reduction in mean doses to the spinal cord, heart, and lung, but not in mean esophageal dose or V20. At a median follow-up of 14 mo, LC and OS survival rates were 85% and 72% at one year and 63% and 58% at two years, respectively. There was only one case each (3.3%) of grade ≥ 3 esophagitis and pneumonitis. Grade 2 pneumonitis and esophagitis occurred in 10% and 43% of patients, respectively. 

At least five studies have been published on compensation for treatment interruptions in SCLC. Of these, four have shown that delays in completing RT can have deleterious effects on the following: (1) Significant loss of locoregional control and worse OS/PFS outcomes, especially in patients who do not receive PCI after TRT and in patients with a SER (start and end of RT) interval ≥ 30-31 d [175] [176] [177] ; (2) Significant decrease in 5-year OS, especially in men, (> 6 times higher) [178] ; (3) Delays > 7 d for hypofractionated (40 Gy in 15 fractions) and normofractionated (50 Gy in 25 fractions) schemes, as well as delays > 29-30 d in patients treated with accelerated regimens (Turrisi scheme) appear to be deleterious [175] [176] [177] ; (4) The only study that does not show a deleterious effect (subanalysis of CALGB-9235, F-III) involved normofractionated CRT (50 Gy), with RT initiated in the 4 th cycle of CT (possible effect due to accelerated repopulation at the start of "late" RT after CT [179] ; and (5) No values have been reported for Tk (time from the start of RT at which accelerated repopulation begins) or K (estimated loss of biological efficacy in Gy per day of delay that would need to be added to compensate). Similarly, compensation techniques for the Turrisi scheme have not been described.

The potential loss of radiobiological effectiveness due to treatment interruption should be considered as a risk exposure to potentially avoidable threats. Thus, this would not be subject to the rules of evidence-based medicine, which refers to the evaluation of the benefits of therapeutic/diagnostic techniques [180] . However, the following recommendations can be made: (1) Avoid and/or compensate if the interruption is > 7 d in hypofractionated (40 Gy, 15 fractions) or normofractionated (50 Gy, 25 fractions) schemes. By extension, this rule should apply to normofractionated schemes > 60 Gy (perhaps even when the interruption is > 5-7 d); (2) Avoid/ compensate if total treatment time > 29 days in patients treated with accelerated schemes (Turrisi); (3) Avoid/compensate for interruptions, especially in men; and (4) compensation methods: In the absence of published studies, the following recommendations should be considered as general guidelines. For normofractionated schemes, any compensation method would be, in principle, appropriate. However, each case should be evaluated individually; the absence of Tk and K values makes it difficult to perform radiobiological calculations in cases in which it is necessary. For this reason, it would be preferable to use double treatment sessions and/or to perform RT on holidays/Saturdays whenever possible. For hyperfractionated schemes, compensation is more challenging for the same reasons, especially given the nature of such schemes. In addition to considering treatment on holidays/Saturdays, a reasonable alternative would be to increase the number of sessions (add 1-2 more days of treatment, which would mean 32 to 34 fractions rather than 30), or to increase the dose per fraction for the remaining sessions (increased the dose from 1.5 to 1.6-1.8 Gy/fraction), or to combine both approaches. In all cases, it is essential to assess OAR tolerances. If it is not feasible to continue with AHF-RT, another alternative would be to switch to a hypofractionated scheme (≥ 2.67 Gy/d).

Very few studies have been published on reirradiation (reRT) in lung cancer. As a result, most of the available data come from retrospective studies, which are highly heterogeneous in terms of histology (both SCLC and NSCLC), disease stage, treatments received (time interval between RT treatments, doses, fractionations, techniques, use of PCh or not, etc.) and in the parameters used to assess treatment response [181] .

Approximately 30% of patients with SCLC are diagnosed with LS disease; of these 30%, will progress locally [32] . LC is an important factor that may influence OS. Thoracic recurrence can produce symptoms that affect the patient's quality of life and may even require emergency treatment. The review that included the largest number of lung cancer patients (any histological type) to date was published in 2017 [182] . That study reviewed data from 13 clinical trials involving 435 patients treated with 3D-RT or IMRT and another 10 trials (253 patients) of SBRT.

Below we review and discuss the published reports on reRT that provide specific data for SCLC. One of the limited recommendations from these studies is the need to assess the indication for reRT in SCLC independently from other histologies due to the unique behavior of SCLC [183] . Reirradiation is especially indicated to treat hemoptysis and vena cava syndrome, but it is less effective for dyspnea [184] . Hypofractionated schemes are recommended, with doses > 40 Gy (EQD2) [185] . If the patient is in poor general condition (PS > 3) or presents extrathoracic metastases, reRT should only be performed in selected symptomatic patients. In these cases, reRT vs supportive treatment should be assessed.

In terms of the recommended doses and fractionations for reRT, reported treatment schemes range from 25-37.5 Gy in 9-15 fractions for symptomatic patients or those with metastatic disease. In general, the reported benefits of reRT in terms of symptom palliation lasts only for approximately 1 mo, probably due, in part, to the short OS in these patients [media survival: 1.7 mo (1.0-4.0)]. The risk of chronic toxicity is greater if there are overlapping fields in central tumours. Cumulative doses of 90-150 Gy in central structures should be avoided. If less than 6 mo have elapsed between one RT treatment and reRT, the spinal cord dose should be < 50 Gy (EQD2) [184] . However, if more than 6 mo have passed, doses of 40-45 Gy have been used in 20-25 fractions, with a safe cumulative mean dose of 87.4 Gy.

The following factors are associated with better OS: KPS > 70%; asymptomatic patient without metastatic disease; reRT dose > 40 Gy (EQD2); cumulative dose > 90 Gy (EQD2) [185] . Predictors of good response are PS, small recurrence, and a long interval between RT.

Based on the available data, we can conclude that reRT for SCLC at palliative doses (< 40 Gy) is useful to treat symptoms such as hemoptysis, vena cava syndrome, and rib pain; however, this technique should only be used in selected patients. In asymptomatic patients without distant disease and good PS, higher doses may improve both quality of life and OS. Thus, we recommend treating selected asymptomatic patients without metastatic disease with radical intent RT; in other cases, we recommend considering hypofractionated reRT vs supportive treatment to prevent toxicity.

The present review was carried out by Spanish radiation oncologists from the GOECP/SEOR to review RT and combined treatment of SCLC. This review is based on a quality analysis of the published literature according to internationally-accepted classification of the levels of recommendation and the grades or quality of scientific evidence [188] . 

Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer

Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer

What margins are necessary for incorporating mediastinal nodal mobility into involvedfield radiotherapy for lung cancer?

Determining optimal clinical target volume margins on the basis of microscopic extracapsular extension of metastatic nodes in patients with non-small-cell lung cancer

ESTRO ACROP consensus guideline on implementation and practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer

Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study

Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy

Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses

Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study

Reply: Patterns of nodal recurrence after omission of elective nodal irradiation for limited-stage small-cell lung cancer

Locoregional failures following thoracic irradiation in patients with limited-stage small cell lung carcinoma

Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis

Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer

Benefit from thoracic radiotherapy in patients with extensive-disease small-cell lung cancer with elevated lactate dehydrogenase

Efficacy of 3D conformal thoracic radiotherapy for extensive-stage small-cell lung cancer: A retrospective study

Timing of thoracic radiotherapy in the treatment of extensive-stage small-cell lung cancer: important or not?

Consolidative thoracic radiotherapy for extensive stage small cell lung cancer

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial

Hippocampal-sparing whole-brain radiotherapy: a "how-to" technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy

Prospective Study of Hippocampal-Sparing Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer

Treatment Design and Rationale for a Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for SCLC: PREMER Trial on Behalf of the Oncologic Group for the Study of Lung Cancer/Spanish Radiation Oncology Group-Radiation Oncology Clinical Research Group

Organs at risk in lung SBRT

Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus

Radiation dose-volume effects in the lung

Serious complications associated with stereotactic ablative radiotherapy and strategies to mitigate the risk

Radiation dose-volume effects in the esophagus

Predicting esophagitis after chemoradiation therapy for non-small cell lung cancer: an individual patient data meta-analysis

Use of normal tissue complication probability models in the clinic

Esophageal toxicity from high-dose, singlefraction paraspinal stereotactic radiosurgery

Esophageal tolerance to high-dose stereotactic ablative radiotherapy

Stereotactic body radiation therapy: a comprehensive review

Dose constraints to prevent radiation-induced brachial plexopathy in patients treated for lung cancer

Frequency of Silent Brain Metastasis Before Prophylactic Cranial Irradiation in Small Cell Lung Cancer

Prevalence of brain metastases immediately before prophylactic cranial irradiation in limited disease small cell lung cancer patients with complete remission to chemoradiotherapy: a single institution experience

Patterns of brain metastasis immediately before prophylactic cranial irradiation (PCI): implications for PCI optimization in limited-stage small cell lung cancer

Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI)

Treatment Response and Prophylactic Cranial Irradiation Are Prognostic Factors in a Real-life Limited-disease Small-cell Lung Cancer Patient Cohort Comprehensively Staged With Cranial Magnetic Resonance Imaging

Management of brain metastasis with magnetic resonance imaging and stereotactic irradiation attenuated benefits of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer

Limited-Stage Small Cell Lung Cancer: Is Prophylactic Cranial Irradiation Necessary?

Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: analysis of 505 randomized patients

Prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study

Prophylactic cranial irradiation in small-cell lung cancer: findings from a North Central Cancer Treatment Group Pooled Analysis

Thirty years of prophylactic cranial irradiation in patients with small cell lung cancer: a meta-analysis of randomized clinical trials

The effects of prophylactic cranial irradiation versus control on survival of patients with extensive-stage small-cell lung cancer: a meta-analysis of 14 trials

The Role of Prophylactic Cranial Irradiation in Patients With Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy

Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer

Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: A systematic review

Prophylactic Cranial Irradiation (PCI) Collaborative Group. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial

Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer

Prophylactic Cranial Irradiation in Resected Early-Stage Small Cell Lung Cancer

Prophylactic cranial irradiation in resected small cell lung cancer: A systematic review with meta-analysis

Prophylactic cranial irradiation for patients with limited-stage small-cell lung cancer with response to chemoradiation

Longitudinal Brain Changes Associated with Prophylactic Cranial Irradiation in Lung Cancer

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial

Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001

Neuro-cognitive (HVLT-R total recall) functioning in localized vs. metastatic small-cell lung cancer with or without hippocampus sparing PCI: Results from a phase III trial

The Incidence and Location of Brain Metastases Following HA-PCI Compared with Standard PCI in Small Cell Lung Cancer (SCLC): A Phase III Trial

Phase III Trial of Prophylactic Cranial Irradiation with or without Hippocampal Avoidance for SMALL-CELL LUNG Cancer

NRG Oncology CC003: A randomized phase II/III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small cell lung cancer

Memantine for the prevention of cognitive dysfunction in patients receiving wholebrain radiotherapy: a randomized, double-blind, placebo-controlled trial

Effectiveness of image-guided radiotherapy for locally advanced lung cancer patients treated with definitive concurrent chemoradiotherapy

Comparison of 2 common radiation therapy techniques for definitive treatment of small cell lung cancer

Dosimetric comparison between IMRT and VMAT in irradiation for peripheral and central lung cancer

Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer

Optimizing lung cancer radiation treatment worldwide in COVID-19 outbreak

Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control

Duration of Twice-Daily Thoracic Radiotherapy and Time From the Start of Any Treatment to the End of Chest Irradiation as Significant Predictors of Outcomes in Limited-Disease Small-Cell Lung Cancer

Effects of thoracic radiotherapy timing and duration on progression-free survival in limited-stage small cell lung cancer

Does sex influence the impact that smoking, treatment interruption and impaired pulmonary function have on outcomes in limited stage small cell lung cancer treatment?

Interruptions of once-daily thoracic radiotherapy do not correlate with outcomes in limited stage small cell lung cancer: analysis of CALGB phase III trial 9235

The Royal College of Radiologists. Timely delivery of radical radiotherapy: guidelines for the management of unscheduled treatment interruptions

Thoracic reirradiation for lung cancer: a literature review and practical guide

Re-Irradiation: New FrontiersSpringer

High-dose re-irradiation following radical radiotherapy for non-small-cell lung cancer

Re-irradiation for Locally Recurrent Lung Cancer: Evidence, Risks and Benefits

Prognostic factors and outcome of reirradiation for locally recurrent small cell lung cancer-a multicenter study