The role of radiation therapy in the management of small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive form of lung cancer. SCLC treatment requires multidisciplinary management and timely treatment. Radiation therapy is an important part of management of all stages of SCLC, in the curative as well as in the palliative setting. The role of radiation therapy in all stages of SCLC has changed in recent years; this article describes these changes and highlights the role of radiation therapy in the management of SCLC.

Lung cancer is the leading cause of cancer death worldwide [1]. Small cell lung cancer (SCLC) makes up ∼15% of all lung cancer cases [2] and smoking is its main cause [3]. SCLC is a rapidly progressing disease with high recurrence rates and poor outcomes [4, 5]. About one-third of patients will present with TNM (tumour, node, metastasis) stage I–III SCLC at the time of diagnosis (mostly corresponding to limited disease (LD), which is defined as a tumour burden able to fit within a radiation field) [6-8] and two-thirds will present with stage IV disease (mostly corresponding to extensive disease (ED), i.e. a tumour burden not covered by one radiation field, including malignant pleural effusion and/or distant metastases).

The role of radiotherapy in all stages of SCLC has changed in recent years; this article describes the role of radiotherapy in SCLC.

Standard of care for LD-SCLC

Once the diagnosis of LD-SCLC is established the standard treatment for fit patients will be concurrent radiochemotherapy [9]. Two meta-analyses have demonstrated that combined modality treatment improves survival over radiotherapy alone [10, 11], with further improvements when delivered concurrently [12, 13]. The current standard chemotherapy regime in the treatment of LD-SCLC consists of etoposide and cisplatin (EP) [14-16].

Timing

While concurrent radiochemotherapy is the standard, the ideal timing of radiotherapy combined with chemotherapy is debated. SCLC is a chemo-sensitive tumour and rapid responses are often observed; chemotherapy is often initiated first to rapidly counter symptoms and fast tumour growth [17]. Early radiotherapy (starting with the first or second cycle of cisplatin-based chemotherapy) has been shown to lead to improved overall survival compared with delayed radiotherapy [8, 12, 18, 19]. However, a randomised trial by Sun et al. [20] did not confirm a benefit with early RT.

Early concurrent radiochemotherapy may not be suitable for all patients. In patients with large tumour volumes or poor performance status, early radiotherapy may increase acute and late toxicities. In these cases a deferred start to radiotherapy or even sequential treatment are the preferred options. Bulky tumours may require large treatment volumes; these can be reduced if initial chemotherapy shrinks the tumour, potentially reducing toxicity to the lungs and oesophagus. Several randomised controlled trials showed no difference in relapse rates when these smaller volumes were treated [21-23].

Most guidelines support early thoracic radiotherapy, beginning with the first or second cycle when cisplatin-based chemotherapy is used [6, 12, 18, 24, 25]. The time between the start of any therapy and the end of radiation therapy is an important predictor of survival in LD-SCLC: prolongation correlates to a decrease in overall survival of 1.9% per week [18, 24]. An updated meta-analysis, based on individual patient data, confirmed increased 5-year survival rates when early and hyper-fractionated irradiation is administered with good chemotherapy compliance [25].

Radiotherapy dose in curative intent

In 1999, Turrisi et al. [26] reported a 5-year overall survival benefit of 10% with four cycles of EP and concurrent twice-daily (1.5 Gy twice-daily, 30 fractions) when compared to once-daily radiotherapy (1.8 Gy, 25 fractions). Since then, the radiotherapy doses used in standard fractionation have increased to ∼60–66 Gy and a direct comparison between the higher dose standard-fractionation and the twice-daily schedule was missing. The potential inconvenience of twice-daily administration and the significantly increased rates of transient grade 3 esophagitis were the main concerns that explain why the twice-daily regimen was not universally adopted (table 1) [30, 31]. The recent CONVERT phase III trial did not demonstrate superiority of once daily radiotherapy with 66 Gy when compared to the aforementioned twice-daily regimen, with both regimens having very similar toxicity rates [29]. Today, twice-daily radiotherapy remains a standard treatment for fit patients, but both regimens may be considered and the patients’ preference should be accommodated. The decision may also be influenced by pragmatic factors such as availability of transportation. An important finding of the CONVERT trial was the relatively favourable 3-year survival rate of ∼40% in both arms, which was probably a result of modern radiation techniques using selective instead of elective nodal irradiation. While Bogart et al. [32] concluded that 70 Gy in 35 daily fractions concurrent with EP has similar outcomes when compared with the trial carried out by Turrisi et al. [26], we have no direct comparison between these two regimes, to date. An ongoing study is comparing concurrent twice-daily radiotherapy with 70 Gy in daily fractions (ClinicalTrials.gov identifier: NCT00632853).

Table 1

Selected trials with hyper-fractionated regimes

Author, year [ref.]	Design	Patients n	Chemotherapy	Radiation dose/fractionation	Results		Oesophagitis grade 3–4
						p-value#		p-value#
Turrisi, 1999 [26]	Phase III	417	EP	45 Gy/1.5 Gy twice daily	Median OS 23 months, 5-year OS 26%	0.04	27%	<0.001
				45 Gy/1.8 Gy once daily	Median OS 19 months, 5-year OS 16%		11%
Schild, 2004 [22]	Phase III	261	EP	50.4 Gy/1.8 Gy once daily	Median OS 20.6 months, 5-year OS 21%	0.68	5%	0.05
				48 Gy/1.5 Gy twice daily (with a 2.5 week break inbetween)	Median OS 20.6 months, 5-year OS 22%		12%
Komaki, 2012 [27]	Phase II	71	EP	39.6 Gy/1.8 Gy once daily followed by 21.6 Gy/1.8 Gy	Median OS 19 months, 2-year OS 36.6%	N/A	18%	N/A
Gronberg, 2016 [28]	Phase II	157	EP	42 Gy/2.8 Gy once daily	Median OS 18.8 months	0.61	31%	0.80
				45 Gy/1.5 Gy twice daily	Median OS 25.1 months		33%
Faivre-Finn, 2016 [29]	Phase III	547	EP	66 Gy/2 Gy once daily	Median OS 25 months, 2-year OS 51%	0.15	19%	No statistical difference
				45 Gy/1.5 Gy twice daily	Median OS 30 months, 2-year OS 56%		19%

EP: etoposide and cisplatin-based chemotherapy; OS: overall survival. #: statistical significance p≤0.05.

Radiotherapy target volume

The treatment volume covers the primary tumour and the involved lymph nodes (figures 1 and 2). Whether only areas around malignant lymph nodes (involved field irradiation (IFI)) or elective regions (elective nodal irradiation (ENI)) should be included is still a matter of debate [33, 34], but the trend is moving away from elective volumes, aided by modern imaging such as positron emission tomography/computed tomography (CT) [33, 35–38]. With the smaller volumes of IFI versus ENI toxic side-effects, such as oesophagitis and pneumonitis can be reduced [39], while maintaining a low rate of isolated nodal failures (3%) [38]. The first step in contouring is to define the gross tumour volume (GTV), which represents the macroscopic tumour, and an iGTV, which represents gross disease taking breathing motion into account. This is performed on modern planning CT scanners capable of obtaining four-dimensional CT scans, which are three-dimensional CT datasets that are correlated with breathing phases. Microscopic tumour extension is addressed by the clinical target volume (CTV), which is typically expanded by adding 5–10 mm to the GTV in all directions (except where natural barriers would be expected, e.g. bone or pleura). Due to positioning and calculation inaccuracies, a further margin is added to create the final planning target volume (PTV) [40].

Figure 1

Radiotherapy target volumes. Blue line: macroscopic disease (GTV); green line: GTV with motion (iGTV); light green: microscopic extension (CTV); red line: the final target volume (PTV).

Figure 2

Sample radiation plan. The red line indicates the PTV; red coloured areas are the areas receiving the prescribed radiation dose; green and blue coloured areas receive a lower radiation dose.

Prophylactic cranial irradiation

SCLC is characterised by early metastases and the brain is their most common site with a cumulative incidence of over 50% at 2 years [41]. With prophylactic cranial irradiation (PCI) (figure 3) the risk of brain metastases can be reduced from 59% to 33% at 3 years and is accompanied by a survival benefit (21% versus 15%) [42-44]. PCI should be considered part of standard treatment in patients with LD-SCLC with partial or complete response to initial treatment. Restaging with magnetic resonance imaging (MRI) immediately before PCI can be considered, as patients with overt brain metastases would not qualify for PCI and might require higher dose palliative whole-brain radiotherapy instead [45].

Figure 3

Prophylactic cranial irradiation. a) Stretching a heated mask over the patient; when the mask gets cold it becomes rigid. b) Radiation plan for whole-brain radiotherapy, the radiation field encompassing at least 95% of the prescribed radiation dose is shown in green.

The use of PCI in very early stage SCLC after surgery has not been investigated sufficiently. As the incidence of brain metastases after completely resected stage I SCLC is low (below 11%), PCI may not to be necessary. In the case of higher pathological stages PCI should be individually discussed, as the incidence of developing brain metastases is up to 30% [46-50].

Neurocognitive deterioration is a potential side-effect of PCI and can be observed in 30–60% of patients [43, 51–53]. An important region for neurocognitive function is located in the hippocampus [54]. Hippocampal sparing cranial irradiation is being investigated (e.g. ClinicalTrials.gov identifier: NCT02058056), but is not widely established in routine clinical practice.

An estimated short overall survival (potentially due to comorbidities) might be a contraindication for PCI, it is important to discuss the prognosis of each individual patient. If PCI is omitted, close follow-up with cranial MRI and active treatment of emergent brain metastases might be considered [55].

The standard dose for PCI is 25 Gy in 10 fractions. Higher doses do not improve outcome, but increase mortality [53] and chronic neurotoxicity [43].

Post-operative radiation therapy for LD-SCLC

Besides radiochemotherapy [29], in localised disease (T1/2 N0 M0) surgery may be a treatment option, with reported 5-year survival rates in the order of 50% [56]. Of note, based on published data small peripheral lesions can be occasionally misdiagnosed as SCLC (e.g. typical or atypical carcinoid); however, only 5% of patients with SCLC have true stage I SCLC [57]. Surgery alone is not sufficient due to the high risk of recurrence [47]. Even in R0 resected patients without lymph node involvement adjuvant chemotherapy is recommended [58].

In the case of positive mediastinal lymph nodes, post-operative mediastinal radiation therapy (PORT) should be discussed. Data for PORT in this setting are rare and the decision should be made thoughtfully considering performance status, age, lung function and comorbidities. In addition, it is important to differentiate between pN0, pN1 (no or intrapulmonary/hilar lymph nodes) and pN2 (ipsilateral mediastinal lymph nodes) [56, 59]. In completely resected patients with pN0 or pN1 status evidence for PORT is lacking; however, even in this setting the indication may be discussed. PORT was associated with longer survival in pN+ in a retrospective review of the National Cancer Database [60]. For pN2 LD-SCLC patients the median overall survival significantly improved from 16 to 22 months with PORT in a SEER (Surveillance, Epidemiology, and End Results) analysis [56]. Wong et al. [59] reported a 5-year overall survival of 29% with PORT versus 18.6% without, but prospective trials are missing. The dose is also unclear due to scarce data, but the largest study to date used radiation doses up to 54 Gy in 2 Gy per fraction [59]. In case of R1 resection adjuvant radiotherapy is recommended [61].

Radiation therapy for ED-SCLC

Standard of care

Patients with ED-SCLC have a poor prognosis with a median overall survival of 8–13 months [62-64]. Palliative chemotherapy with EP for four to six cycles is the standard treatment [61, 65–67], and has remained unchanged in recent decades. Several trials have assessed whether the addition of thoracic radiotherapy (TRT) might improve outcomes [68-72].

Consolidative thoracic radiation therapy

Jeremic et al. [68] found a slight, but statistically significant, benefit in terms of overall survival by adding TRT to patients with complete response after chemotherapy, and these results were later confirmed [69, 70]. The most recent randomised trial is the CREST study by Slotman et al. [73]. TRT with 30 Gy (10×3 Gy) in patients with any response after 4–6 cycles of chemotherapy led to a 2-year survival rate of 13% compared with 3% without TRT, although the primary end-point (1-year overall survival) was not met (1-year overall survival of 33% versus 28%). A meta-analysis of the two randomised trials concluded that TRT improves overall survival and progression-free survival in patients with extensive stage SCLC [74]. The timing of TRT is not as critical as in the curative setting and can accommodate recovery from side-effects of chemotherapy [75].

Role of PCI for ED-SCLC

In an older randomised trial [76], PCI significantly reduced symptomatic brain metastases in ED-SCLC (14.6% versus 40.4%) and increased overall survival at 1 year (27.1% versus 13.3%). A limitation of this study was that no brain imaging was required before PCI. Recently, a Japanese randomised phase III trial in the same setting showed a detrimental effect of PCI on median overall survival (11.6 months versus 13.7 months) when rigid brain imaging is applied [77]. Presumably, previous trials showed a benefit for PCI because undetected manifest brain metastases were treated. In light of these findings, MRI monitoring for brain metastases is a reasonable option for these patients if accessible.

Other indications for radiation therapy in the management of SCLC

Radiotherapy is an important pillar in palliative lung cancer therapy [40]. Symptoms due to tumour obstruction of the bronchial tree or large vessels such as the vena cava superior are also indications for radiotherapy, especially if active systemic therapy is not available. Radiotherapy is effective at palliating pain due to cancerous lesions (e.g. of the pleura, bones or soft tissues). Haemoptysis is another severe and potentially dangerous complication of lung tumours, especially in the case of diffuse slow bleeding or bleeding from locations not accessible using endoscopic interventions, and radiotherapy can be an effective treatment option [40].

Radiotherapy for brain metastases

For patients diagnosed with synchronous brain metastases therapeutic whole brain radiation therapy (10×3 Gy or 5×4 Gy) is recommended in current guidelines [61]. Stereotactic radiotherapy/radiosurgery is typically not a first choice due to the high rate with which further brain metastases can be expected in SCLC. For brain metastases after failed whole-brain radiotherapy, stereotactic radiotherapy is an option [78-82]. The delivery of highly focused radiation can potentially reduce neurotoxicity and make re-irradiation feasible [83], especially for patients with controlled systemic disease [84].

Summary

Radiotherapy plays an important role in the treatment of every stage of SCLC (table 2). Concurrent chemotherapy is typically platinum-etoposide therapy. Whenever possible, radiochemotherapy with early radiotherapy is preferred in LD-SCLC. PCI is recommended in patients with a response to radiochemotherapy in LD-SCLC. For ED-SCLC the standard treatment is a combination of platinum and etoposide. TRT after chemotherapy and PCI for ED-SCLC are options which should be discussed critically. Intrathoracic symptoms such as obstruction due to tumour mass, pain or haemoptysis can often be treated with radiotherapy in the palliative setting. Symptoms caused by extrathoracic metastases can also be treated with radiotherapy. Interdisciplinary collaboration is essential to facilitate adequate treatment considering all aspects of care.

Table 2

Indications for radiotherapy in SCLC

Stage	Indications to be discussed
Very early	Primary curative radiochemotherapyPost-operative mediastinal radiotherapy (for N+ or R1)Prophylactic cranial irradiation
Locally advanced	Primary curative radiochemotherapyProphylactic cranial irradiation
Extensive disease (metastatic)	Prophylactic cranial irradiationConsolidative mediastinal radiotherapyPalliative radiotherapy (including whole brain radiotherapy)