3.1 Non-small Cell Lung Cancer

Overview

Epidemiology: Non small-cell lung cancer (NSCLC) is most common non-cutaneous cancer in the world which is again the most common cause of cancer related death worldwide. Smoking (active/passive) is related with more than 90% of cases, which requires low-dose CT screening with strong smoking history [1].

Pathological and Biological Features: Adenocarcinoma (40%), squamous cell carcinoma (25%) and large cell carcinoma (10%) constitute the main pathological subtypes.

TTF-1 is only positive in adenocarcinomas of primary lung and thyroid, while napsin positivity is distinguishing as being 80% positive in lung and 10% in thyroid.

Former “bronchoalveolar carcinoma” is currently documented as “Adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIS)” with weak association with smoking.

Subtype analysis of NSCLC for all patients whose tumor contains an element of adenocarcinoma requires determination of presence or absence of a driver mutation as epidermal growth factor receptors (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene 1 (ROS1) mutations for not only being identifiable but their targeted treatment resulting in responses better than that with standard chemotherapy [2, 3].

Immunotherapy has recently been an effective option for those with a high level of programmed death ligand 1 (PD-L1) expression (membranous PD-L1 expression on at least 50 percent of tumor cells), regardless of the staining intensity [4].

Prognostic factors include stage, weight loss (>10% body weight over 6 months), performance status, pleural effusion [5, 6].

Definitive Therapy: Despite locally advanced (stage III) and disseminated (stage IV) disease, early stage I-II disease is often curable with aggressive definitive therapy. Eligible patients having adequate function pulmonary volume without serious medical comorbidity are surgical lobectomy candidates for patients with stage I or II NSCLC rather than radiation therapy; while stereotactic body radiation therapy (SBRT)/stereotactic ablative radiotherapy (SABR) is a viable alternative with growing evidence as definitive treatment in selected stage I patients. For patients with larger primary tumors who are not surgical candidates, standard-fractionation radiation therapy is applicable. Adjuvant chemotherapy is recommended after complete resection of stage IB NSCLC with high-risk features & stage II NSCLC with a cisplatin-based doublet. Postoperative radiotherapy is indicated for patients with positive surgical resection margins for stage I-II NSCLC.

Keywords: Non-small cell lung cancer, Radiotherapy

3.1.1 Case Presentation

60 years old male with 40 packet year smoking history and no significant past medical history admitted with dyspnea and hiccups. He had no dysphagia, odynophagia, or swallowing, and chewing problems. His physical exam was normal in general except right sided rhonchus in pulmonary auscultation. As he has been a heavy smoker, a chest CT was ordered revealing right hilar parenchymal tumor encasing the main bronchus with multiple stations of mediastinal nodal disease (starting at right level 2 upper mediastinum and continuing to level 10 & 11 ipsilaterally in addition to contralateral small nodes). PET CT (Fig. 3.1) confirmed the CT findings as major tumor bulk on right mediastinum and hilum, but low SUV on left sided small nodes. Endobronchial ultrasound guided biopsies revelaed squamous cell carcinoma both in primary and multiple stations. He was staged as T2N3M0, locoregionally advanced non-small cell lung cancer.

Fig. 3.1
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Axial PET-CT fusion images defining multiple stations of mediastinal disease

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3.1.2 Staging

Systemic physical examination is important depending on the high incidence of metastases.

Routine complete blood count as well as biochemistry including blood urea/creatinine, liver function tests etc.

Eligibility criteria for definitive concurrent chemoradiotherapy is generally considered as;

KPS ≥ 70, FEV-1 > 1 L, FVC ≥ 45%, Absolute neutrophil > 1500/μL, Trombosite > 100,000/μL, Serum creatinine < 1.5× normal.

Pathological examination is required by less likely using sputum, but mostly fine needle aspiration, endobronchial or CT-guided biopsy, or mediastinoscopy guided biopsy.

Radiological imaging includes CT of chest and abdomen, MRI brain, preferably PET/CT, radionuclide bone scan.

Smoking cessation is important.

At diagnosis, three groups reflecting the extent of the NSCLC and the treatment approach are detailed:

Surgically resectable disease (mainly stage I, stage II, and selected stage III tumors): the best prognostic cohort, eligible for curative surgery or eligible for curative radiotherapy with resectable but medical contraindicated to surgery. Resected stage II or stage IIIA NSCLC might benefit postoperative cisplatin-based combination chemotherapy.

Locally (T3–T4) and/or regionally (N2–N3) advanced disease: Require combined modalities. If unresectable or N2–N3, radiotherapy with chemotherapy is recommended. If resectable for selected T3 or N2, either preoperative or postoperative chemotherapy or chemoradiotherapy.

Distant metastatic disease: radiotherapy or platinum-based chemotherapy for palliation of symptoms of the primary tumor. Selected oligometastatic disease might be recommended definitive treatment based on response [7].

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer was adopted in 2010 by the AJCC and the Union Internationale Contre le Cancer [8, 9]. The 8th Edition of TNM in Lung Cancer (Table 3.1), has recently been changed to be the standard of non-small cell lung cancer staging since January 1st, 2018; issued by the IASLC (International Association for the Study of Lung Cancer) and replaces the TNM 7th edition [10,11,12,13].

Table 3.1 The 8th edition of TNM in lung cancer
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Changes in T Stage Are as Follows [14]

T1 into T1a (≤1 cm), T1b (>1 to ≤2 cm), and T1c (>2 to ≤3 cm);

T2 into T2a (>3 to ≤4 cm) and T2b (>4 to ≤5 cm); involvement of main bronchus regardless of distance from carina; partial and total atelectasis/pneumonitis;

T3 as greater than 5 to less than or equal to 7 cm;

T4 as greater than 7 cm; diaphragm invasion;

Mediastinal pleura invasion is not a T descriptor anymore.

3.1.3 Evidence Based Treatment Approaches

Stages I and II NSCLC: Lobectomy with systematic lymph node dissection over pneumonectomy is the recommended treatment modality for patients with stages I and II NSCLC [15,16,17]. SBRT/SABR is a viable alternative with growing evidence as definitive treatment in selected stage I patients [18,19,20,21,22,23,24,25].

As accurate mediastinal nodal staging is crucial for SABR eligibility of stage I & II NSCLC patients, PET/CT started to be replacing the need for mediastinoscopy in recent years. [26, 27]. Senthi et al. retrospectively evaluated their series of 676 medically inoperable PET staged early stage NSCLC patients, treated with SABR (54–60 Gy, three to eight once-daily fractions) between April 2003 and Dec 2011 [18], and documented an actuarial two-year regional recurrence rates of 7.8% while local and distant recurrence rates were 4.9% and 14.7%, respectively. Initially, patients bearing early stage NSCLC with high surgical risk and medical inoperability were the target population for SABR and were compared with surgical series [28,29,30,31,32,33]. Phase II RTOG 0236 trial prescribing SABR in stage I medically inoperable NSCLC patients enrolled a poor functional status cohort with a baseline hypoxemia and/or hypercapnia, a baseline FEV1 < 40% predicted, baseline severely reduced diffusion capacity, post-operative predicted FEV1 < 30% predicted, etc. [21] and Timmerman et al. reported encouraging median survival of 48 months win comparison to 13 months for an untreated T1 N0 M0 patient [23]. Onishi et al. retrospectively analyzed multiinstitutional data from 14 Japanese centers revealing 87 Stage I medically operable NSCLC patients who refused surgery [24], and stated cumulative local control rates of 92% for T1 and 73% for T2 at 5 years in addition to 72% and 62% overall survival for Stage IA and IB respectively at five years with a median follow-up of 55 months. Lagerward et al. presented outcomes of 177 potentially operable patients treated with SABR from their institutional prospective database and documented an exciting median overall survival of 61.5 months with 94.7% and 84.7% survival rates at 1 and 3 years respectively [34]. The Japan Clinical Oncology Group (JCOG) documented the SABR outcome of operable peripheral stage IA NSCLC patients in phase II JCOG 0403 trial with 76% overall survival and 69% locally progression-free survival rates at 3 years [35]. Retrospective series including clinical stage I NSCLC patients treated with surgery or SABR were studied by matched-pair analysis and propensity score comparisons [36,37,38]; defining SABR as a comparable definitive treatment choice with definitive surgery in early stage NSCLC patients matched for selection factors to reduce the bias due to confounding variables [36,37,38]. Solda et al. recently reported about 3771 patients treated with SABR for NSCLC recognized comparable survival outcome to surgery (2 year survival with SABR 70% versus 68% with surgery) regardless of co-morbidity [38]. Meta-analysis by Zheng et al. (4850 SABR and 7071 surgery) underlined no significant OS and disease free survival difference in stage I NSCLC between SABR and surgery [39]. Prospective phase III studies for operable early stage NSCLC patients comparing SABR versus surgery (optimal lobectomy with mediastinal dissection) were Dutch multicenter study (ROSEL) and international cooperative clinical trial (STARS) with very close inclusion criteria. Chang et al. combined two datasets and documented the first findings of two randomized phase III trials comparing the current standard of care of surgery and SABR for operable stage I NSCLC patients [40]. Despite fairly small—58 patients—sample size and limited follow up time, non-invasive SABR appeared to be non-inferior to lobectomy, perhaps better, with 95% (only one death) estimated overall survival at 3 years versus 79% (six deaths) with surgery; in addition to better recurrence-free survival at 3 years (SABR, 86% vs. Surgery, 80%) [40]; with better tolerance and no high-grade toxicity in this SABR cohort [40, 41]. There are continuing prospective efforts in stage I peripheral NSCLC patients such as United Kingdom SABRT TH study (NCT02629458) to compare SABR with lobectomy or sublobar resection in patients considered having higher surgical risk of complications; RTOG3502/POSTLIV study (NCT01753414) to compare radical resection versus SABR; and University of Texas Southwestern STABLE-MATES study (NCT02468024) to compare sublobar resection with SABR; Veterans Affairs VALOR study in both peripheral and central stage I NSCLC patients to compare lobectomy or segmentectomy with SABR [42]. A recent meta-analysis on survival outcome after SBRT and Surgery for early stage NSCLC, Yu et al. found more favorable outcomes with stage I NSCLC treated with SBRT where the surgery had no obvious advantages in this meta-analysis [43]. In contrary, another recent meta-analysis by Li et al. comparing SABR versus surgery for patients with T1-3 N0 M0 NSCLC concluded that surgery, both lobectomy and sublobectomy, might be superior to SBRT/SABR with regard to survival [44]. Videtic et al. has just released the executive Summary of The American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline on SBRT for early-stage NSCLC [25]; and concluded that SBRT has gained an significant role in particularly treating medically inoperable early-stage NSCLC patients with limited other treatment options (Figs. 3.2 and 3.3) [25].

Fig. 3.2
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Stereotactic ablative radiotherapy for an early stage NSCLC in four fractions, iGTV 60Gy and PTV 50 Gy in four fractions

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Fig. 3.3
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Stereotactic ablative radiotherapy for an early stage NSCLC in ten fractions, iGTV 80Gy and PTV 70 Gy in ten fractions

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Stage III NSCLC covers a very mixed group of patients due to extent and localization of primary and nodal disease, leading into a controversial management strategies, where common consensus guidelines are generally followed such as American Society for Radiation Oncology (ASTRO) and American Society of Clinical Oncology (ASCO) [45,46,47]. Mediastinal lymph nodes which are enlarged on CT or metabolically active on PET-CT requires pathologic confirmation of tumor involvement who are otherwise potentially resectable. If mediastinal lymph nodes are negative, then lobectomy with systematic lymph node dissection, similar to stage I and stage II disease, is next step; if pathologically involved by tumor, definitive chemoradiation, as well as bi- or tri-modality therapy for selected cases, is recommended. Preoperative pathologic evaluation of mediastinal lymph nodes for a peripheral T1a primary lesion, in case of no suspicious CT and/or PET-CT guided N1 or N2-3 lymph node involvement, is controversial. For potentially resectable central T2, T3, and T4 tumors, invasive mediastinal staging is indicated if there is enlarged hilar lymph nodes by CT and/or clinical N1 involvement by PET, even without prominent mediastinal nodal involvement [48, 49].

T3 N1 M0 NSCLC (stage IIIA): Patients are triaged with initial invasive mediastinal staging with systematic lymph node dissection followed by lobectomy, and finally consulted for adjuvant chemotherapy for those with completely resected disease. If surgery with clear margins is not technically possible, concurrent chemoradiotherapy is recommended.

T4 lesions were identified as unresectable and classified as stage IIIB, while resectable T4N0-1 lesions are rare, therefore the initial recommendation is definitive chemoradiotherapy.

Mediastinal nodal involvement in the final pathology is not surprising in approximately 20% of surgically treated cases based on careful preoperative evaluation (endobronchial ultrasound -EBUS and/or mediastinoscopy). In postoperative mediastinal nodal involvement, adjuvant chemotherapy with platinum-based doublet regimens and mostly adjuvant postoperative radiotherapy sequentially after chemotherapy are recommended [50]. Targeted therapy for those with or without driver mutations, the use of adjuvant targeted therapy including cetuximab, erlotinib, and crizotinib is not indicated.

Postoperative radiotherapy (PORT): indicated in positive surgical margins or pathologically N2 disease without much controversy [50,51,52]. Positive surgical margins increases local recurrences leading to decreased survival, so the general consensus is to recommend postoperative radiotherapy [53,54,55]. The unresolved controversy is related with close surgical margins and about the definition of adequate margins [56,57,58]. Therefore, clinical insight from surgeon is very important during evaluating the indication [59]. PORT seems to improve locoregional outcome specifically in N2 disease independent from chemotherapy effect, and N1 disease when no chemotherapy administered [52, 60,61,62,63,64]. PORT in N2 disease is being explored in phase 3 “The Lung Adjuvant Radiotherapy (LungART)” trial to provide prospective information [65,66,67].

Retrospective analysis of ANITA study, evaluating the adjuvant vinorelbine prospectively on 840 IB-IIIA patients, underlined the effectivity of PORT in N2 disease [52], and SEER data analysis involving more than 7000 patients confirmed the survival advantage of PORT in N2 patients [68]. The detrimental effect of PORT on survival documented by 1998 PORT metaanalysis, updated in 2013 including nine studies, is important to understand that the poor technology in older series and lack of conformal sparing the organs at risk can result in decrease outcome [69,70,71]. Modern radiotherapy techniques, focusing on critical threshold doses of organs at risk, might provide better outcome such as the meta-analysis defining the potential of 10% local control benefit by PORT in stage IIIA-N2 might turn into 13% survival benefit at 5 years [72]; as well as the survival benefit of PORT noted in 2015 “The National Cancer Data Base” analysis of PORT for N2 disease [73, 74]. Matsuguma et al. published that PORT is more effective in involvement of multiple N2 stations [75], besides another Japan series noted that inadequate nodal dissection which is less than 10 and/or 4 or more nodal involvement are poor prognostic factors on survival [76]. SEER data pointed out that survival benefit of PORT was more prominent in group with N2 disease having a ratio of positive nodes/dissected nodes ≥ 50% [77]. MD Anderson Cancer Center analysis on 1402 patients between 1998 & 2009, staged I-III (N0-N1) who did not receive PORT, revealed that recurrence was evident in 9% which decreased survival [78]; multivariate factors increasing local recurrence independently were surgical procedure (wedge + segmentectomy × lobectomy + bilobectomy + pneumonectomy), tumor size larger than 2.7 cm and visceral pleural invasion; multivariate factors increasing regional recurrence independently were N1, visceral pleural invasion (VPI), and lymphovascular invasion (LVI) [78]. Hui et all documented that PORT is more helpful in patients staged IIIA-N2 NSCLC if 3 or more factors are present among smoking index (daily cigarettes × years of smoking) ≤ 400, cN2, pT3, squamous cell cancer histology, and ≥ 4 positive nodes [79]. Therefore, there is common ground to recommend PORT in very close/positive surgical margins and/or pathologic N2 disease, and routine PORT is not recommended for N1 disease, while multidisciplinary tailoring is recommended for N1 disease based on number of nodes involved, LVI, VPI, and extracapsular extension [59, 78].

Stage III NSCLC with mediastinal involvement (N2, N3): require a multidisciplinary institutional approach including input from medical oncology, radiation oncology, and thoracic surgery, which has not been clearly defined. Crucial factors prompting the decision are the patient’s overall performance status, preferences of the patients’ and medical team, as well as the probability of R0 complete resection based on the extension of the primary and nodal disease. Concurrent chemoradiotherapy is the first treatment choice in most patients with clinically evident N2 disease, delivering full-dose radiation therapy with platinum-based chemotherapy; as induction/neoadjuvant chemotherapy or chemoradiotherapy followed by surgery might be also applicable decisions in a tailored group of patients [80,81,82]. Randomized prospective phase III (Intergroup 0139, EORTC 08941 and ESPATUE) trials have not showed any survival advantage for consolidative surgery following either neoadjuvant concurrent chemoradiotherapy or induction chemotherapy followed by radiotherapy [83,84,85,86,87,88]; while Intergroup 0139 defined a significant increase in the primary tumor control and an improvement in five-year progression-free survival (22% versus 11%).

N3 disease dictates concurrent chemoradiotherapy as the standard of care [89]. Concurrent chemoradiotherapy in highly selected medically fit septuagenarians with stage III might also be as effective as younger patients to improve survival outcomes, with a relatively acceptable toxicity profile [90]. Sequential chemoradiotherapy or radiotherapy alone are viable treatment preferences for any ineligible candidate for concurrent chemoradiotherapy.

Stage III NSCLC who completed concurrent chemoradiotherapy without any progression can be recommended immunotherapy with PD-L1 antibody durvalumab, where a phase III trial recently documented that, relative to placebo, durvalumab after at least two cycles of platinum-based chemoradiotherapy increased the median progression free survival (16.8 versus 5.6 months; HR for disease progression or death 0.52), and median time to death or distant metastasis (23.2 versus 14.6 months) [91].

3.1.4 Radiotherapy Planning

Lung function guided radiotherapy selection is given below in Table 3.2 [92]. Stage guided treatment selection is summarized in Table 3.3.

Table 3.2 Lung function guided radiotherapy selection
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Table 3.3 Stage guided treatment selection
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3.1.4.1 Immobilization and Simulation

Intravenous contrast is preferred during CT simulation to improve the visualization of the primary tumor and nodal disease, if patient’s renal functional status allows and if adequate measures for any possible anaphylactic reactions could be taken.

Generate CT topograms before the acquisition of the planning simulation scan to review and verify patient alignment and perform any relevant adjustments.

Planning CT is acquired using a slice-thickness of 1–3 mm covering from above the supraclavicular field to below diaphragm.

3.1.4.2 Utilization of Motion Awareness and Management

Target motion in correlation with respiratory cycle is a major challenge for ideal delivery of radiotherapy. The conventional approaches is to both plan and deliver radiotherapy in normal breathing pattern without any respiratory management, but to prescribe dose to a larger estimated volume with additional margin to compensate the unknown motion under treatment. The lung tumor motion and methods to cope with it have long been studied in order to consider this change in lung cancer treatment planning [93,94,95]. The American Association of Physicists in Medicine (AAPM) Task Group 76 guidelines summarized the adequate methods to account this obscure motion by different methods as motion encompassing (slow CT scanning; combination of inhale and exhale breath-hold CT; 4Dimensional-CT/respiration-correlated CT); respiratory gating (internal fiducial markers or external markers to signal respiration); breath hold (self or device controlled with or without respiratory monitoring); abdominal compression for shallow breathing; and real time tracking [96]. The most well accepted and user friendly method seems to be 4D-CT during normal breathing to obtain an average internal target volume (ITV) model to cover and compensate respiration-related tumor motion [95, 97,98,99]. The ITV approach provides individualization in prescription by designing patient and motion specific margins of incorporating the extent of tumor motion.

As the motion could be managed with 4DCT and ITV utilization, dose calculation was another concern in IMRT due to the fact that motion information and change in density based on movement was not included in calculation in conventional setting and especially breathing-related intra-fraction organ motion was an issue. However, the plans after 4DCT simulation are generally reconstructed on an average intensity projection dataset and dose calculations are performed with treatment planning software including modern dose algorithms based on heterogeneity correction such as Monte Carlo, collapsed-cone, convolution/superposition, anisotropic analytical algorithm, and Acuros® XB [100,101,102,103,104]. Additionally, Bortfeld et al. has shown that the effect of organ motion in IMRT does not cause systematic errors in dose delivery and is averaging the dose distribution without motion over the path of the tumor motion and this is actually not different from conventional beams [105]. The vital component in planning is 4D-CT simulation, which should be used if available; if it is not available, other alternative options to produce an average image of the tumor at all respiratory phases such as spiral CT or slow CT scanning need to be considered. Based on the complex extent of dose shaping and conformity requirement in IMRT than 3DCRT, it ought to be expressed that motion awareness and 4D planning support to identify the margins of the runaway target are more critical for IMRT than for conventional 3D-CRT. Therefore, the planned IMRT doses with motion awareness including 4DCT dataset and current heterogeneity correction algorithms most definitely represent the doses delivered.

3.1.4.3 Target Volume Delineation Guidelines

Although elective nodal irradiation is not recommended, surgical lymph node levels are important to evaluate per case; International Association for the Study of Lung Cancer has published lymph node contouring atlas revealing levels 1–9 corresponding to N2 nodes, and levels 10–14 to N1 nodes [106].

Volume Definition (Contouring for Involved Field Irradiation)

GTV: Contoured based on CT image.

Internal GTV (iGTV): contouring the GTV based on 4D CT (Respiratory data sets are “binned” by phase: 0–100% at 10% interval): Define the GTV contour using the maximum intensity projection (MIP) and modify based on visual verification of contours in individual respiratory phases. Pulmonary extent is contoured on lung windows (−600/1600 HU), spiculated part of lesion is recommended to be considered as GTV. PET-CT scan is used to differentiate between atelectasis and tumor in parenchyma. Mediastinal extent and lymph nodes (>1 cm in the shortest dimension on CT and PET-CT positive nones) are contoured on mediastinal windows (+20/400 HU).

If neoadjuvant chemotherapy received: GTV include post-chemotherapy lung extent in addition to pre-chemotherapy positive nodal stations, as well as ipsilateral hilum if positive mediastinal nodal disease initially; if complete response post-chemotherapy, pre-chemotherapy positive nodal station and positive lung parenchymal involvement is defined as CTV to receive at least 50 Gy.

CTV = Internal Target Volume (ITV); ITV is determined to be the iGTV plus a margin that accounts for microscopic disease, therefore:

ITV = iGTV plus 8 mm margin for all histologies [107].

Should not extend beyond anatomic boundaries (chest wall, vertebral body, vessels, mediastinal wall etc.) except evidence of invasion.

No elective node in theory, however lobe-specific extent of systematic lymph node dissection algorithm might be followed for CTV2 (the right mid lobe or right lower lobe, or left lingular, left lower lobe lesion require subcarinal nodal station; and left upper lobe lesion requires aorticopulmonary window nodal station if positive mediastinal nodal disease) [108].

PTV: Definitive treatment is recommended to use ITV generally or respiratory gating (end of expiration) very selectively [109].

ITV: iGTV +8 mm margin accounts for respiratory motion, but not patient motion on table, therefore image guidance is the determining factor for PTV margin.

PTV_SABR for early stage disease = iGTV +5 mm.

PTV=ITV + 5 mm-1 cm margin (if once-weekly port films).

PTV=ITV + 5 mm (if daily orthogonal kV).

PTV=ITV + 3 mm (if daily orthogonal kV daily and CBCT daily or 2–3 times/week).

Postoperative Volume Definition (Contouring)

GTV: gross/microscopic positive margins or gross residual disease as indicated by CT, PET, operative note, and pathological report.

CTV: iGTV+ 8 mm plus the surgical stump + positive mediastinal nodal stations (N2) as identified pathologically or radiologically + Ipsilateral hilum (N1) + if there is no mediastinal nodal dissection or adequate mapping, ipsilateral hilar (N1) and ipsilateral mediastinal nodes (N2) + high-risk areas due to surgeon input.

PTV: As defined.

3.1.4.4 Case Contouring

The patient with locally-advanced T2N3M0 squamous cell carcinoma treated with concurrent CRT (cisplatin & etoposide) utilizing image guided simultaneous integrated volumetric modulated arc treatment (SIB-VMAT) technique with iGTV = 66Gy (2.2Gy/fraction), CTV = 60Gy (2Gy/fraction), in 30 fractions and 6 weeks (Figs. 3.4 and 3.5).

Fig. 3.4
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Contouring for T2N3M0 NSCLC, iGTV 66Gy (skyblue), and CTV 60Gy (blue)

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Fig. 3.5
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Treatment plan for T2N3M0 NSCLC, iGTV 66Gy, and CTV 60Gy

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3.1.4.5 Treatment Planning

3.1.4.5.1 Prescription Dose

Stereotactic Ablative Radiotherapy

60 Gy in 3 fractions, 50 Gy in 4 fractions or 70 Gy in 10 fractions, depending on tumor location/size, using computed tomography-based heterogeneity corrections and a convolution superposition calculation algorithm [110, 111].

Locoregionally Advanced

The results of phase III comparison of 60 Gy versus 74 Gy conformal chemoradiotherapy with or without cetuximab for stage III NSCLC in RTOG 0617 demonstrated 60 Gy is superior to 74 Gy in terms of overall survival and local-regional control, and “RTOG standard dose” is documented to be minimum 60 Gy, while a moderate dose escalation is encouraged between 60–70 Gy for locoregionally advanced NSCLC [112]. Based on our 4DCT and IMRT approach with strict OAR criteria, high dose radiotherapy seems a feasible and appropriate practice.

Radiotherapy with concurrent chemotherapy:

  • 66 Gy (2.2 Gy/fraction/day) simultaneous integrated radiation boost to iGTV while prescribing 60 Gy (2 Gy/fraction/day) to the PTV in 30 fractions

  • 60–66 Gy (2 Gy/fraction/day) to the PTV in 30 fractions

Radiotherapy alone after sequential chemotherapy or consolidation/Palliation with radiotherapy alone:

  • 45 Gy (3 Gy/fraction/day) to the PTV in 15 fractions

  • 52.5 Gy (3.5 Gy/fraction/day) simultaneous integrated radiation boost to iGTV while prescribing 45 Gy (3 Gy/fraction/day) to the PTV in 15 fractions

  • 60 Gy (3 Gy/fraction/day) to the PTV in 20 fractions for selected small volume disease which is not involving critical organs at risk

  • 30 Gy (3 Gy/fraction/day) to the PTV in 10 fractions if life expectancy <6 months with poor KPS and/or with multiple visceral/brain metastasis

Postoperative Dose

Negative margins: 50 Gy (2 Gy/fraction/day) in 25 fractions.

Positive ECE: 54 Gy (2 Gy/fraction/day) in 27 fractions.

Microscopic positive margin: 60 Gy (2 Gy/fraction/day) in 30 fractions.

Gross residual disease: 66–70 Gy (2 Gy/fraction/day) in 33–35 frs.

Concurrent chemotherapy could be used in case of gross disease in postop setting.

Tailoring could be made such as simultaneous integrated boost to gross disease with 70 Gy (2Gy/fraction/day) while prescribing 63 Gy (1.8 Gy/fraction/day) to the remaining bed.

The recommended organs at risk doses are detailed in Tables 3.4 and 3.5 for SABR prescribed in 4 and 10 fractions.

Table 3.4 Normal tissue constraints for SABR [110, 111]
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Table 3.5 Normal tissue constraints for fractionated radiotherapy
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3.2 Small Cell Lung Cancer

Abstract

Epidemiology Small cell lung cancer (SCLC) accounts for 15–20% of lung cancer cases with decreasing incidence. Extensive stage disease constitutes almost 2/3 of patients at admission, while the remainder present with limited stage disease. In more 95% of cases, tobacco exposure is the main etiological factor. SCLC has a classic radiographic presentation with bulky hilar and mediastinal lymph node involvement.

Pathological and Biological Features SCLC is characterized by small cells with scant cytoplasm and nuclear features of fine, dispersed chromatin without distinct nucleoli. SCLC might be associated with paraneoplastic syndromes such as SIADH, ACTH production syndrome, and Eaton–Lambert syndrome. The vast majority of SCLCs express at least one neuroendocrine marker. Most important prognostic factors are stage and performance status.

Definitive Therapy SCLC was documented as highly sensitive to cytotoxic chemotherapy. Standard treatment for limited stage is systemic therapy and concurrent radiotherapy, however if very early staged small cell lung cancer as clinical T1-2N0M0 is evaluated, for N0 cases, mediastinal staging followed by lobectomy and mediastinal nodal dissection is not inappropriate to be recommended. For extensive stage patients, treatment starts with cisplatin/carboplatin based chemotherapy and thoracic ± metastatic site radiotherapy for selected patients. The median overall survival (OS) for patients with limited SCLC is median 20 months, metastatic SCLC receiving standard chemotherapy in range of 9–11 months over the past 20+ years, even in the most recent large randomized clinical trials. Prophylactic cranial radiotherapy (PCI) is recommended for all stages, as brain metastases incidence is 10–15% at presentation and 50–80% at 2-year after chemo-RT.

Keywords: Small cell lung cancer, Radiotherapy

3.2.1 Case Presentation

54 years old female with 50 packet year smoking history and no significant past medical history admitted with coughing and blood in sputum. Her physical exam was normal in general except right sided decreased breathing sounds and rhonchus in pulmonary auscultation. A chest CT was ordered revealing right hilar small tumor with conglomerated multiple stations of mediastinal nodal disease filling and expanding anterior mediastinum in addition to bilateral supraclavicular disease. PET CT confirmed the CT findings without distant metastases (Fig. 3.6). Endobronchial ultrasound guided biopsies revealed small cell carcinoma both in primary and mediastinum, as well as fine needle aspiration of CT guided biopsy confirmed contralateral supraclavicular nodes involvement. Her cranial MRI was normal without metastases. She was staged as limited stage small cell lung cancer.

Fig. 3.6
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Axial PET-CT fusion images defining multiple stations of mediastinal disease

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3.2.2 Staging

Two staging systems are commonly used. The Veterans’ Administration Lung Study Group (VALSG) presented a two-stage classification system in the 1950s [115]. Basically, this system categorizes SCLC as limited-stage (LS), in which the disease is limited to an area within the thorax that can be covered within a radiation port, and extensive-stage (ES), in which disease cannot be encompassed in a radiation field such as having malignant pleural or pericardial effusions or metastases consistent with hematogenous spread. The International Association for the Study of Lung Cancer (IASLC) also projected that the TNM lung cancer staging system be used in place of the VALSG system. Although the TNM system is in more details and could predict more precise the situation of the disease, the VALSG system is very practical staging system and widely used clinically.

Limited Stage (LS): disease fitting into a single radiation port, typically confined to one hemithorax and regional nodes.

Extensive Stage (ES): may include malignant pleural or pericardial effusions or metastases consistent with hematogenous spread.

3.2.3 Evidence Based Treatment Recommendation

For Limited stage disease, concurrent cisplatin and etoposide (4 cycles every 3 weeks) with early thoracic radiotherapy during cycle 1 or 2 (45 Gy for 1.5 Gy b.i.d. or 60–70 Gy for 1.8-2Gy QD). For <5% of patients with cT1-2N0 disease with negative mediastinoscopy (or endoscopic biopsy), lobectomy and mediastinal node dissection/sampling may be performed initially [116, 117]. If pN0, chemotherapy alone; if pN+, concurrent chemoradiation as above. Prophylactic cranial radiotherapy is recommended in all patients after completion of other treatments (25 Gy in 10 fractions).

For extensive disease, initial step is combination platinum-based chemotherapy. For patients with PR or CR to chemotherapy, prophylactic cranial RT (25 Gy in 10 fractions), consolidative thoracic/metastatic radiotherapy to primary and metastatic sites. If brain metastases present, whole brain radiotherapy (WBRT, 30–37.5 Gy in 10–15 fractions) is recommended.

Stage guided treatment selection is summarized in Table 3.6.

Table 3.6 Stage guided treatment selection
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3.2.3.1 Limited Stage SCLC

Approximately 30% of patients with SCLC present with early stage disease. The clinical presentation without clinical or pathologic evidence of mediastinal lymph node involvement is rare and N0 SCLC usually undergo surgical resection [116, 117]. There are no prospective studies evaluating the value of adjuvant chemotherapy for operated patients. The retrospective analyses of National Cancer Database including 1574 cases between 2003 and 2011, demonstrated that overall survival (OS) was improved with adjuvant chemotherapy with or without adjuvant radiation [118]. Also furthermore, platinum-based neoadjuvant or adjuvant therapy was shown to provide superior OS for surgically staged patients in a retrospective review from Johns Hopkins University compared to patients receiving non-platinum regimens [119]. Often, LS-SCLCs have mediastinal lymph node involvement at the time of diagnosis and the standard treatment for these cancers is concurrent chemotherapy and radiation [117]. In 1992, meta-analysis by Pignon consists 13 trials and 2140 patients with LS-SCLC treated with chemo ± thoracic radiotherapy with a median follow-up of 43 months [120,121,122]. Thoracic radiotherapy improved 3-year overall survival by 5.4% vs. chemotherapy alone (14.3 vs. 8.9%). The optimal timing of radiation for LS-SCLC remains controversial. Metaanalyses of randomized controlled trials, assessing LS-SCLC patients receiving chemo and early vs. late timing of thoracic radiotherapy revealed an improved survival for early concurrent combination of radiotherapy with platinum-based chemotherapy [123, 124]. In addition to this finding, the amount of time from start to completion of thoracic radiotherapy in LD-SCLC may also effect overall survival. The completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = 0.0003) [123].

Turrisi et al. randomized 417 patients to receive a total of 45 Gy radiotherapy, either once-daily (1.8 Gy in 25 fractions) or twice-daily (1.5 Gy in 30 fractions) with concurrent cisplatin and etoposide [125]; the median survival improved from 19 months by once-daily to 23 months by twice-daily radiotherapy, after a median follow up of almost 8 years, and though twice daily radiotherapy decreased local failure (36 vs. 52%), also increased grade 3 esophagitis (27 vs. 11%). Despite this benefit, the widely clinical implementation of twice daily radiotherapy was limited due to scheduling/accommodation problems and significant acute side effects. The dose escalation interest from once daily 45 Gy radiotherapy in 25 fractions to a 60–70 Gy of once-daily radiation schema with concurrent chemotherapy has been evaluated in randomized trials [126,127,128]. The ideal timing to initiate radiotherapy with the concurrent chemotherapy is within the first two cycles of chemotherapy [124, 129, 130]. Komaki et al. reported RTOG 0239 phase II trial using accelerated high-dose thoracic radiotherapy (61.2 Gy in 5 weeks with large field to 28.8 Gy/1.8 Gy QD, then 14.4 Gy/1.8 Gy b.i.d. in the evening) concurrent with etoposide/cisplatin [131]; revealing two-year overall survival of 37% and local control of 80%, aside from 18% acute severe esophagitis. CALGB 30610/RTOG 0538 ongoing trial has planned to compare standard fractionation (70 Gy/2 Gy daily) versus Turrisi regimen (45 Gy/1.5 Gy BID) versus RTOG 0239 dose escalation (61.2 Gy in 5 weeks) schemas, and has been revised with closure of accelerated high-dose thoracic radiotherapy arm at interim analysis after the publication of RTOG 0239.

Recently reported CONVERT trial by Faivre-Finn et al., with 45 months of median follow up, randomized 547 patients to 45 Gy (1.5 Gy BID over 15 weekdays, 3 weeks) vs. 66 Gy (2 Gy daily QD over 33 weekdays, 6.5 weeks), each with 4 to 6 cycles of concurrent cisplatin/etoposide, followed by PCI as indicated, in order to demonstrate superiority of the once-daily regimen [132]. After a median follow up of 45 months, no statistically significant difference was acknowledged in overall survival at 2 years (BID 56% × QD 51%) and median survival (BID 30 months × QD 25 months, hazard radio for death for QD regimen was 1.18, P = 0.14) The rate of grade 2 esophagitis, grade 3/4 esophagitis and grade 3/4 pneumonitis were 55% × 63%, 19% × 19%, 2.2% × 2.5%, respectively and found to be similar in both arms [132]. Due to the failure of CONVERT to define QD reqimen superior and lack of sufficient power to validate equivalence of the BID to QD regimens, BID 45 Gy is yet the gold standard, while QD 60–70 Gy is appealing easier in many practices be applicable in LS-SCLC. Hopefully, emerging evidence will be provided by ongoing CALGB 30610/RTOG 0538 study (NCT00632853; 45 Gy BID × 70 Gy QD).

3.2.3.2 Extensive Stage SCLC

Extensive stage SCLC is mostly not curable, therefore, except selected patients for definitive treatment approach, the general management is to increase quality of life as well as prolong disease free survival as much as possible. The first step is systemic therapy including platinum (cisplatin or carboplatin) combined with etoposide. As the first site progressing after initial chemotherapy is frequently the primary thoracic disease, the role of consolidative thoracic radiotherapy following chemotherapy was evaluated in ES-SCLC, principally in manageable extrathoracic disease burden [133,134,135,136]. Jeremic et al. randomized 109 patients already received three cycles of standard cisplatin/etoposide (PE) with complete or a partial response to either thoracic radiotherapy (54 Gy in BID 36 fractions over 18 week days, n = 55) in combination with chemotherapy followed by two cycles of PE or an additional four cycles of PE (n = 54) [136]; and documented significantly better survival rates with thoracic radiotherapy than those chemotherapy alone (median survival, 17 × 11 months; 5-year survival rate, 9.1% vs. 3.7%, respectively; P = 0.041). The phase 3 randomised controlled CREST Trial/NTR1527 enrolled 498 patients with ES-SCLC to receive thoracic radiotherapy of 30 Gy in 10 fractions or not after chemotherapy, while all patients were prescribed prophylactic radiotherapy (PCI) [133]; and Slotman et al. documented a significant survival advantage at 2 years with the use of thoracic radiotherapy (3% versus 13%, P = 0.004). The meta-analysis of the Jeremic trial and the CREST trials with a total of 604 patients (302 thoracic radiotherapy; 302 non-thoracic radiotherapy) underlined the consolidative thoracic radiotherapy to overall provide 20% improvement in overall survival and 25% improvement in progression-free survival [137]. Therefore, ES-SCLC patients with a partial/complete response to chemotherapy, are candidates to be evaluated for consolidative thoracic radiotherapy. Likewise, consolidative radiotherapy to multiple sites of metastasis with complete or partial response to chemotherapy has been evaluated in phase II RTOG 0937 trial enrolling 97 patients who all received PCI to consolidative radiotherapy to the thorax and up to four extracranial metastases or not [138]. Gore et al. documented that the overall survival at 1 year was not different between the groups (60.1% for PCI and 50.8% for PCI+ consolidation radiotherapy-PCI + cRT, p = 0.21), but time to progression favored consolidation radiotherapy as 3- and 12-month rates of progression were 53.3% versus 14.5% and 79.6% versus 75% for PCI versus PCI + cRT, respectively; with being more efficient in a subgroup having 1 metastasis compared to 2–4 metastases, as well as in partial response as opposed to a complete response after chemotherapy [138]. This indicates the requirement of individualization until future studies delineating the pathway for consolidative radiotherapy to metastatic sites in ES-SCLC.

3.2.3.3 PCI for Limited Stage

In case of a complete response, partial response or stable disease following chemoradiotherapy, subsequent prophylactic cranial irradiation (PCI) is commonly recommended. The meta-analysis analyzing seven trials involving 987 limited and extensive stage patients by Auperin et al. concluded that PCI in patients with a complete response after induction chemotherapy provided an improvement in 3-year overall survival of approximately 5.4% (15.3% in no PCI vs. 20.7% in PCI arm), as well as a reduction of the 3-year incidence of brain metastases (59 in no PCI vs. 33% in PCI arm) [139]. RTOG 0212/Intergroup trial by Le Pechoux et al. questioned the optimal dose for PCI in their cohort of 720 LS-SCLC patients having complete response to chemoradiotherapy by randomizing to standard dose (25 Gy/2.5 Gy QD) or to a higher dose (36 Gy/2 Gy QD or 36 Gy/1.5 Gy b.i.d.) of PCI [140]; and concluded that incidence of brains metastases were similar at 2 years, with a decreasing overall survival with higher dose at 2 years (37 vs. 42%). Consequently, 25 Gy is considered standard of care, aside from the discussion on the decline in both short-term quality of life and long-term cognitive functioning with PCI. Phase II multi-institutional RTOG 0933 trial is one of the studies exploring preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy [141].

3.2.3.4 PCI for Extensive Stage (ES-SCLC)

PCI is also often recommended in patients with ES-SCLC, based on EORTC 22993 trial in support of PCI in ES-SCLC, randomizing 286 patients with a response to 4–6 cycles of chemotherapy to PCI versus observation [142]. Slotman et al. revealed the decrement in risk of symptomatic brain metastases (HR 0.27, P < 0.001) and the increment in median overall survival (6.7 vs. 5.4 months, P = 0.003) with PCI [142]. The most criticized limitation of the study was the lack of proper brain imaging for staging or follow-up unless patients were symptomatic (only 29% with brain imaging). Recently, a multi-institutional Japanese trial by Takahashi et al. evaluated the same question of PCI in MR staging and follow up era, randomizing 224 patients with ES-SCLC, and concluded in the interim analysis that PCI has reduced the incidence of brain metastases but has not provided an improvement in survival (median overall survival of 11.6 months with PCI vs. 13.7 months with observation, HR 1.27, p = 0.094) [143]. This Japanese trial investigating PCI for patients with ES-SCLC was stopped early due to this interim analysis failing to confirm a survival benefit which might motivate the additional trials to rethink the role of PCI in ES-SCLC.

3.2.4 Radiotherapy Planning

3.2.4.1 Volume Definition (Contouring for Involved Field Irradiation)

Volume Definition (Contouring): Involved Field Irradiation as Defined in NSCLC

Allowing 1 or 2 cycles of chemotherapy before concurrent chemotherapy is acceptable if the volume is too large to start with concurrent chemoradiotherapy. Though traditional mediastinal fields covered ipsilateral hilum and bilateral mediastinum from thoracic inlet to subcarinal region, current practice is using involved field radiotherapy as in NSCLC. This approach is supported by Van Loon et al. with PET-based selective nodal irradiation for LD-SCLC resulting in a low rate of isolated nodal failures (3%), and with a low percentage of acute esophagitis [144]; as well as the retrospective data by Shirvani et al. confirming only 2% isolated nodal failure with same strategy [145].

3.2.4.2 Prescription Dose

Definitive thoracic radiotherapy with concurrent chemotherapy was prescribed with three options previously as compared in RTOG 0538, high-dose conventional radiotherapy of 70 Gy (2 Gy once daily over 7 weeks), or 61.2 Gy (1.8 Gy once daily for 16 days followed by 1.8 Gy twice daily for 9 days), or hyperfractionated 45 Gy (1.5 Gy twice daily over 3 weeks) in patients with limited-stage small cell lung cancer. Based on the results of RTOG 0239 [131], an interim analysis closed the arm 61.2 Gy based upon a comparison of treatment-related toxicity. Therefore the possible options for prescription are:

  • 45 Gy (1.5 Gy/fraction BID) to PTV in 30 fractions in 15 week days

  • 54 Gy (1.8 Gy/fraction BID) simultaneous integrated radiation boost to iGTV while prescribing 45 Gy (1.5 Gy/fraction BID) to the PTV in 30 fractions in 15 week days

  • 70 Gy (2 Gy/fraction/day) to PTV in 35 fractions in 35 week days

Evaluating patients for response and regression with cone beam CT after 1st week which might require plan adaptation as there is no cut off for any modification: mostly subjective per physician disposal based on V20 at first plan and response.

Radiotherapy for Consolidation in extensive stage patients following chemotherapy

  • 30 Gy–45 Gy (3 Gy/fraction/day, in 10–15 fractions) to the PTV

  • Or for a more definitive dose consider 52.5 Gy (3.5 Gy/fraction/day) simultaneous integrated radiation boost to iGTV while prescribing 45 Gy (3 Gy/fraction/day) to the PTV in 15 fractions

3.2.4.3 Case Contouring

The patient with limited stage small cell carcinoma treated with concurrent CRT utilizing image guided simultaneous integrated volumetric modulated arc treatment (SIB-VMAT) technique with iGTV = 54Gy (1.8Gy/fraction), CTV = 45Gy (1.5Gy/fraction), in 30 fractions, twice per day, and 3 weeks (Figs. 3.7 and 3.8).

Fig. 3.7
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Contouring for iGTV 54Gy (skyblue), and CTV 45Gy (blue)

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Fig. 3.8
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Treatment plan for limited stage small cell lung cancer, iGTV 54Gy, and CTV 45Gy

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Normal Tissue Constraints for fractionated radiotherapy is summarized in Table 3.7.

Table 3.7 Normal tissue constraints for fractionated radiotherapy
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3.2.5 Follow-Up Recommendations

Follow up for algorithm for NSCLC & SCLC is shown in Fig. 3.9.

Fig. 3.9
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Follow up for algorithm for NSCLC and SCLC

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