cancers

Review
Role of Adjuvant Radiotherapy in Non-Small Cell Lung
Cancer—A Review
Krisztian Süveg 1, *, Ludwig Plasswilm 1,2 , Thomas Iseli 1 , Pawel Leskow 3 , Galina Farina Fischer 4
and Paul Martin Putora 1,2

1 Department of Radiation Oncology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland;
[email protected] (L.P.); [email protected] (T.I.); [email protected] (P.M.P.)
2 Department of Radiation Oncology, University of Bern, 3010 Bern, Switzerland
3 Department of Thoracic Surgery, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland;
[email protected]
4 Department of Radiation Oncology, Kantonsspital Winterthur, 8401 Winterthur, Switzerland;
[email protected]
* Correspondence: [email protected]; Tel.: +41-71-494-6517

Simple Summary: The role of postoperative radiotherapy (PORT) in completely resected non-small
cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2) is controversial.
The aim of our review was to study the literature relating to PORT for completely resected NSCLC
patients with pN2 involvement. The Lung ART and PORT-C trials indicate better locoregional
control with PORT, but this has not yet translated into survival benefits. Given the conflicting results,
guidelines do not recommend the use of PORT routinely. Future research should focus on identifying
subgroups of patients who might benefit from PORT.

Abstract: Background: For patients with completely resected non-small cell lung cancer (NSCLC)



with ipsilateral mediastinal lymph node involvement (pN2), the administration of adjuvant chemother-


apy is the standard of care. The role of postoperative radiation therapy (PORT) is controversial.
Citation: Süveg, K.; Plasswilm, L.;
Iseli, T.; Leskow, P.; Fischer, G.F.;
Methods: We describe the current literature focusing on the role of PORT in completely resected
Putora, P.M. Role of Adjuvant NSCLC patients with pN2 involvement and reflect on its role in current guidelines. Results: Based
Radiotherapy in Non-Small Cell on the results of the recent Lung ART and PORT-C trials, the authors conclude that PORT cannot
Lung Cancer—A Review. Cancers be generally recommended for all resected pN2 NSCLC patients. A substantial decrease in the
2022, 14, 1617. https://doi.org/ locoregional relapse rate without translating into a survival benefit suggests that some patients with
10.3390/cancers14071617 risk factors might benefit from PORT. This must be balanced against the risk of cardiopulmonary
Academic Editor: Arya Amini
toxicity with potentially associated mortality. Lung ART has already changed the decision making
for the use of PORT in daily practice for many European lung cancer experts, with lower rates of rec-
Received: 13 February 2022 ommendations for PORT overall. Conclusions: PORT is still used, albeit decreasingly, for completely
Accepted: 19 March 2022
resected NSCLC with pN2 involvement. High-level evidence for its routine use is lacking. Further
Published: 23 March 2022
analyses are required to identify patients who would potentially benefit from PORT.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in Keywords: NSCLC; PORT; radiation therapy; resection; risk factors
published maps and institutional affil-
iations.

1. Introduction
Multimodal therapy is the standard of care for patients with locally advanced (LA)
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
non-small cell lung cancer (NSCLC) (stage IIIA-C) [1–4]. Patients with stage III N2 NSCLC
This article is an open access article
with primarily unresectable disease (IIIA4, IIIB) receive concurrent or sequential chemora-
distributed under the terms and diotherapy (CRT) followed by immunotherapy in some cases [5]. Alternatively, a surgical
conditions of the Creative Commons approach (bi- or trimodal) can be offered to patients with potentially resectable stage III
Attribution (CC BY) license (https:// NSCLC (IIIA3) [6,7]. Two meta-analyses confirmed that definitive CRT and a bimodal
creativecommons.org/licenses/by/ treatment including surgery and chemotherapy, were comparable options for treating N2
4.0/). disease [6,7]. Feasible treatment options should be discussed by a multidisciplinary team.

Cancers 2022, 14, 1617. https://doi.org/10.3390/cancers14071617 https://www.mdpi.com/journal/cancers

Cancers 2022, 14, 1617 2 of 15

In a setting with multiple treatment options, patient preference should play a prominent
role in the decision making [8].
After surgical resection, a large proportion of patients develop local recurrence (LR)
and distant metastasis [9]. The poor prognosis after surgery has led to the implementation
of perioperative treatments. The benefits of chemotherapy in patients with completely
resected NSCLC have been demonstrated in many phase 3 studies and a meta-analysis, with
an absolute survival benefit of 5% at 5 years [10]. Neoadjuvant or adjuvant chemotherapy
is recommended for patients with stage IIB to IIIA and can be considered for patients with
stage IIA with a resected primary tumor of >4 cm [1,2,11]. Nodal positive patients have
a significant risk of locoregional recurrence even after R0 resection and neoadjuvant or
adjuvant chemotherapy [9,12].
First data show that neoadjuvant immune checkpoint inhibitors (ICIs) (e.g., nivolumab)
plus chemotherapy increase the rate of pathological complete response compared with
chemotherapy alone (Checkmate 816 [13]). Likewise, in the same setting, adjuvant ICIs
with anti-PD-L1 agents (e.g., atezolizumab or pembrolizumab) lead to increased disease-
free survival (DFS) versus best supportive care for patients with PD-L1-positive tumors
(IMpower010 [14], PEARLS [15]). The role of (neo)adjuvant immunotherapy in stage IB–
IIIA NSCLC is rapidly developing and several large randomized phase 3 clinical trials are
underway [11,13,15]. Osimertinib is indicated for the adjuvant treatment after complete
resection with stage IB–IIIA EGFR-mutated NSCLC patients [11,16].
Postoperative radiation therapy (PORT) is often recommended in stage III N2 NSCLC
patients, but its role has historically been controversial.
This review focuses on the role of PORT in the multimodal treatment of LA-NSCLC.
We discuss how recent results may impact our current treatment approach [5].

2. PORT after Complete Resection

The International Association for the Study of Lung Cancer (IASLC) staging committee
defined complete resection as follows: microscopically free resection margins (R0), sys-
tematic nodal dissection or lobe-specific systematic nodal dissection, lack of extracapsular
nodal extension (ENE) and negativity for tumor infestation at the highest mediastinal
node removed [17–19].
Between 2017 and 2020, three different studies confirmed the prognostic value of the
IASLC definition [17–19].

2.1. pN0
A randomized trial from 1980 with 175 completely resected pN0 NSCLC patients
showed that PORT was clearly detrimental [20]. The same team highlighted a decade later
the potential benefit of modern treatment techniques, although the oncological results were
not superior to those of the control group [21]. A more recent randomized trial using linear
accelerators was similarly performed for 104 completely resected stage I patients. The
5-year overall survival (OS) showed a positive trend in the treated group (PORT group:
67% vs. non-PORT group: 58%, p = 0.048) [22].
PORT meta-analyses have shown a detrimental effect of PORT for completely resected
NSCLC with pN0 and pN1 disease [23–26].
The ANITA trial was a randomized trial of adjuvant chemotherapy vs. observation
in completely resected stage IB to IIIA NSCLC patients, revealing a significant 5-year OS
benefit of 8.6% for the chemotherapy group [27]. The post hoc analysis of the ANITA trial
study also showed a negative effect of PORT for pN0-1 patients [26].
Based on these data, PORT is not recommended for completely resected pN0 and pN1
NSCLC patients.
Cancers 2022, 14, 1617 3 of 15

2.2. pN+
PORT was evaluated in several trials performed in the 1980s–1990s. An older retro-
spective study from the Mayo clinic, including 224 pN2 patients resected between 1987 and
1993, found that PORT may improve local control (4-year LR 60% in the non-PORT group vs.
17% in the PORT group, p < 0.0001) and survival (4-year OS 22% in the non-PORT group vs.
43% in the PORT group, p = 0.005) [28]. The largest randomized trial, including 728 stage
I-III NSCLC patients, demonstrated that PORT had a detrimental effect on survival without
a significant effect on LR [29].
The PORT meta-analyses have shown a deleterious effect of PORT for completely
resected stage I–III NSCLC [23–25]. In patients with pN2 disease, PORT did not improve
survival but did reduce the risk of local recurrence by 24%. Due to these negative results in
the whole patient cohort, fewer patients were treated with PORT, even those in pN2 stage.
The meta-analyses were criticized due to the use of obsolete two-dimensional (2D) radiation
techniques (cobalt-60, not CT planned), suboptimal and outdated radiotherapy volumes
and fractionation schemes often using daily fractions of >2 Gy, which might have potentially
led to additional toxicities [30–32]. A comparison of RT plans used in older vs. current
trials showed poor target coverage and excessive heart and lung doses leading to high
toxicity with older techniques [33]. The included older studies were performed without
18 FDG PET-CT staging or brain MRI imaging. Finally, chemotherapy was not used [34,35].

Since the PORT meta-analysis in 1998, several retrospective population-based cohort

studies, database analyses and meta-analyses have found significantly improved OS for
PORT in patients with completely resected NSCLC with pN2 involvement (Table 1).
A larger cohort study of the Surveillance, Epidemiology, and End Results (SEER)
database with 7465 resected NSCLC patients suggested that PORT in pN2 patients was
associated with an increase in cancer-specific survival and 5-year OS [36].
In the randomized ANITA trial, PORT was recommended for pN+ disease but was
not randomized or mandatory [27]. A retrospective post hoc subgroup analysis demon-
strated that PORT led to improved OS in patients with resected pN2 NSCLC both in the
chemotherapy arm and observation arm [26] (Table 1). This trial was initiated in the era of
adjuvant chemotherapy.
The meta-analysis of Billiet et al. [37] (2387 patients) based on phase 3 randomized
controlled trials (RCTs), compared the effect of PORT in patients treated on linear accel-
erators or cobalt machines. PORT significantly decreased LR from 30% to 10% for pN2
patients independently of the radiotherapy machine used. Better OS was only achieved
when PORT was delivered with a linear accelerator. Most of the patients in the studies
were treated with 2D radiotherapy, which is no longer used in daily practice [37].
Another meta-analysis of 16 trials with 3278 patients indicated that PORT delivered
with modern techniques, significantly improved locoregional recurrence-free survival, DFS
and OS in patients with stage III N2 NSCLC [38].
A recent meta-analysis by Zhang et al. [12] summarized all studies (three RCTs [39–41]
with 237 patients and eight retrospective studies with 7748 patients) regarding the effect of
PORT on OS and DFS in stage III pN2 NSCLC. The results revealed that the use of PORT
tends to prolong OS and significantly improves DFS. The effect of PORT on OS did not
differ significantly between RCTs or retrospective studies [12].
A retrospective single center study by Wei et al. [42] with 183 patients from the Hunan
Cancer Hospital in China demonstrated a significant improvement in LR-free survival and
OS in the postoperative chemoradiotherapy (CRT) versus the postoperative chemotherapy
group in stage III pN2 NSCLC, especially in the multiple-station pN2 patients and patients
with single-station pN2 combined with multiple-station pN1.
A recently published retrospective study by Wang et al. [43] with 142 pN2 NSCLC
patients found that PORT can increase the OS of patients (5-year OS 32% vs. 27%) as well
as the local control rate of tumors.
Cancers 2022, 14, 1617 4 of 15

Table 1. Studies evaluating PORT in stage I–III pN0–pN2 NSCLC patients.

Year of Patient Inclusion Resection Technique

Trial Disease Stage Study Design Chemotherapy Dose (Gy) OS PORT Non-PORT
Publication Number Period Status PORT
Van Houtte 1980 pN0–pN2 RCT 224 NA NA No Cobalt 60 5 Y (n.s.) 24% 43%
LCSG 773 1986 pN1–pN2 RCT 230 NA NA No Cobalt, Linac 50 n.s. NA NA
Debevec 1996 pN2 RCT 74 1988–1992 R0 No Linac 30 n.s. NA NA
Lafitte 1996 pN0 RCT 163 1985–1991 NA No Cobalt, Linac 45–60 5 Y (n.s.) NA NA
Stephens 1996 pN1–pN2 RCT 308 1986–1993 NA No Cobalt, Linac 40 n.s. NA NA
Dautzenberg 1999 pN0–pN2 RCT 728 NA NA No Cobalt, Linac 60 5 Y (s.) 30% 43%
Feng 2000 pN1–pN2 RCT 366 1982–1995 NA No Cobalt, Linac 60 5 Y (n.s.) 43% 41%
Trodella 2002 pN0 RCT 104 1989–1997 NA No Linac 50 5 Y (n.s.) 67% 58%
Lally 2006 pN2 R 1987 1988–2002 R0–1–2 NA Linac NA 5 Y (s.) 27% 20%
Mayer 2006 pN2 RCT 155 NA R0 No Linac, 3D 50–56 2 Y (n.s.) 46% 41%
Perry 2007 pN2 RCT 37 1998–2000 R0 adj (100%) NA 50 1 Y (n.s.) 74% 72%
Douillard
2008 pN2 post hoc R 224 NA R0 adj (48.4%) Linac 45–60 5Y 47% 34%
(ANITA)
Shen 2013 pN2 RCT 135 2004–2009 R0 adj NA 50 5 Y (n.s.) 38% 28%
Linac (3D
Corso 2014 pN2 R 6979 1998–2006 R0 neo and or adj (34%) 54 (median) 5 Y (s.) 34% 28%
or IMRT)
Robinson 2015 pN2 R, multicenter 4483 2006–2010 R0 adj (100%) Linac, 3D 45–83 5 Y (s.) 39% 35%
Feng 2015 pN2 R 357 2005–2012 R0 adj Linac, 3D 50 (median) 5 Y (s.) 57% 35%
Billiet 2016 pN2 R 150 1998–2012 R0–1–2 neo (100%) Linac, 3D 50–66 5 Y (n.s.) 32% 42%
Park 2016 pN2 R 240 2006–2012 R0–1 adj Linac, 3D 50 (median) 5 Y (n.s.) NA NA
Herskovic 2017 pN2 R, multicenter 2691 2004–2013 R0 adj NA 50 (median) median OS 53 mo 45 mo
Sun 2017 pN2 RCT 101 2009–2014 adj NA 50 n.s. 74 mo 84 mo
Wei 2020 pN2 R, single center 183 2013–2016 R0 adj Linac, IMRT 50 (median) 2 Y (s.) 78% 62%
Wang 2021 pN2 R 142 2014–2015 R0 adj Linac, 3D 45–54 5 Y (s.) 32% 27%
Van Zandwijk not published,
pN1-pN2 RCT 106 NA NA NA Linac 56 NA NA NA
EORTC only abstract
Linac,
Le Pechoux
2021 pN2 RCT 501 2007–2018 R0 adj (96%) 3D (89%), 54 3 Y (n.s.) 67% 69%
Lung ART
IMRT (11%)
Linac, 3D
Hui PORT-C 2021 pN2 RCT 364 2009–2017 R0 adj (100%) (11%) or 50 3 Y (n.s.) 78% 83%
IMRT (89%)
NA: information not available, RCT: randomized controlled trial, R: retrospective study, neo: neoadjuvant chemotherapy. adj: adjuvant chemotherapy, linac: linear accelerator, IMRT:
intensity-modulated radiation therapy, OS: overall survival, Y: year, s.: significant, n.s.: not significant, mo: months.
Cancers 2022, 14, 1617 5 of 15

Retrospective studies, large database analyses and meta-analyses on PORT for pN2
completely resected NSCLC patients from the last 20 years (Table 1) show controversial
results. Our understanding of the use of PORT in the modern setting with a better selection
of patients with 18 FDG PET-CT and brain MRIs, improved radiotherapy and thoracic
surgery techniques is limited. In the daily routine, PORT was mostly based on the risk of
locoregional relapse for each individual patient. Two phase 3 randomized trials, Lung ART
and PORT-C [44,45], were published in 2021 and brought more insight to this debate.
The Lung ART trial compared mediastinal PORT with no PORT in a superiority design
in patients with completely resected NSCLC with pN2 involvement with modern surgery
and 3D conformal radiotherapy [45]. In total, 91% of the patients were staged preoperatively
with 18 FDG PET-CT in this trial, and 96% of the patients received neoadjuvant or adjuvant
chemotherapy. Five hundred and one patients were enrolled and randomized after resection
or adjuvant chemotherapy: 252 in the PORT group and 249 in the control arm (no PORT).
Only patients who had undergone a complete resection were included. The advisory
surgical quality assurance committee reclassified resections based on the IASLC definition
into R0, an uncertain resection, or R1 (because of ENE). The trial did not meet the primary
endpoint of significantly improved 3-year DFS (47.1% in the PORT arm vs. 43.8% in
the control arm, p = 0.18). Three-year OS was 66.5% in the PORT arm vs. 68.5% in
the control arm. Twenty-five percent of the PORT patients and 46% of the non-PORT
patients had mediastinal relapse at 3 years; this is a reduction of approximately 50%
in the risk of locoregional relapse using PORT compared with the control group. Most
patients died of recurrence: 85% in the non-PORT group and 69% in the PORT group.
Cardiopulmonary toxicity and related death was significantly higher in the PORT group
(16 patients, 16%) than in the control group (2 patients, 2%). The Lung ART authors
concluded that 3D conformal PORT cannot generally be recommended for all stage III pN2
patients after a (considered) complete resection, although PORT could significantly reduce
the risk for mediastinal relapse. In the PORT group there were more toxicities (especially
cardiopulmonary) without a statistically significant effect in terms of OS. Further analyses
are needed to determine if certain patients could benefit from PORT. It may be noted that
the initial target accrual was 700 patients, yet the trial closed with 501 patients. However,
it is unlikely that the results would have been significantly different with the initially
planned accrual [46].
Two other RCTs comparing PORT versus no PORT were published between 2014 and
2020. One study closed early because of poor accrual [40]. The study of Sun et al. [41]
recruited only patients with unsuspected N2 disease.
The Chinese RCT (PORT-C, n = 394) showed no significant difference in 3-year OS
(78.3% in the PORT arm vs. 82.8% in the non-PORT arm) for completely resected NSCLC
patients with pN2 involvement. The 3-year LR-only rate was significantly lower in the
PORT arm (9.5% vs. 18.3%). The authors stated that the low toxic effects in this trial were
due to the use of a modern RT technique (89% IMRT) and to the markedly tighter dose
restrictions to the organs at risk. Nevertheless, IMRT did not improve OS, with similar
death rates in the PORT and non-PORT arms [44].
However, further analysis is needed to identify cohorts that may potentially ben-
efit from PORT without increasing the cardiopulmonary toxicities and potentially re-
lated deaths.
Based on all these data, guidelines do not recommend PORT routinely. The NCCN
guidelines recommend PORT alone or with chemotherapy for selected pN2 patients only [2].
The updated ESMO Clinical Practice Guidelines see no benefit of PORT for patients with
completely resected stage III N2 NSCLC and recommend PORT only in the setting of
residual microscopic or macroscopic disease [11]. The recently published ASCO guidelines
do not recommend PORT for patients with completely resected NSCLC with mediastinal N2
involvement without extracapsular extension who have received neoadjuvant or adjuvant
platinum-based chemotherapy [47].
Cancers 2022, 14, 1617 6 of 15

2.3. Importance of Surgery and Preoperative Staging from the Perspective of Modern PORT
In the last decade there has been major progress in terms of preoperative staging.
Patients undergoing multimodality treatments are better selected based on modern staging
with 18 FDG PET-CT and brain MRI. 18 FDG PET-CT is highly sensitive and specific in
detecting mediastinal nodal and extracranial metastases. In total, 91% of the patients in the
Lung ART trial had undergone 18 FDG PET-CT scans. The ESMO guidelines recommend
a locoregional lymph node staging with 18 FDG PET-CT and, in the case of PET-positive
lymph nodes or central or >3 cm tumors, an invasive staging with EBUS/EUS (endoscopic
bronchial ultrasound) or VAM (video-assisted mediastinoscopy) [11].
The European Society of Thoracic Surgeons (ESTS) defined adequate intraoperative
lymph node staging as: a systematic nodal examination including at least three intrapul-
monary and hilar nodes and at least three mediastinal nodal stations depending on the
location of the primary tumor [48]. Handa et al. [49] advocate for lobe-specific mediastinal
lymph node dissection. One of the most important findings of the study is that nearly 6%
of patients in the lobe-specific dissection group might have had their metastatic lymph
nodes missed by not sampling stations outside of the lobe-specific stations.

2.4. Sequence of Postoperative Treatment

Sequential chemotherapy and PORT were associated with superior survival compared
with concomitant postoperative CRT in two National Cancer Database (NCDB) registry
analyses for pN2 NSCLC patients [50,51].
In the randomized trial of the Eastern Cooperative Oncology Group, PORT (50.4 Gy)
alone was compared to postoperative CRT (with cisplatin and etoposide). The 3-year OS
rates were similar in both groups [52].
In the RTOG 9705 trial, 86 patients with completely resected NSCLC underwent PORT
(50.4 Gy) and chemotherapy (paclitaxel plus carboplatin) concomitantly. This trial evaluated
the efficacy of combining chemotherapy and radiation therapy postoperatively. The trial
suggested improved 3-year progression-free and OS rates (50% and 61%, respectively),
compared with previously reported trials [53].
ESMO guidelines recommend administering chemotherapy first when both postoper-
ative chemotherapy and PORT have been used [1].

2.5. Risk Factors

Stage III pN2 NSCLC is a very heterogeneous group with different clinicopathologic
features, such as lymph node (LN) extent (number of stations or zones involved), LN
volume (bulky, non-bulky), primary tumor size and histological subtype.
The volume and extent of N2 disease correlates with the LR rate and prognosis [30,42,54,55].
The recent meta-analysis by Liu et al. [30] showed improved OS for PORT in patients with
high LN extent (multiple N2 LN metastases or multiple N2 station involvement) but not
for patients with single-station N2 involvement. Lymph node ratio (LNR) (the number
of pathologically positive LNs divided by the number of LNs examined) seems to be an
important prognostic factor [55,56]. Furthermore, in two analyses, PORT showed a survival
benefit only in pN2 patients with an LNR of 50% or more [55,56]. In a retrospective study
by Wei et al. [42], PORT reduced LR and improved OS for patients in stage III NSCLC with
multi-station pN2, single-station pN2 + multi-station pN1, patients with a high positive
LNR > 1/3 and tumors with poor histological differentiation.
In the PORT-C trial, a preplanned exploratory analysis found a significant DFS im-
provement with PORT in patients with four or more LNs compared to patients with less
than four LNs involved [44].
In several studies, the predictive value of absolute tumor size or pT stage in pN2
NSCLC regarding PORT was investigated, mostly with conflicting results [26,57–59]. The
meta-analysis of Liu et al. [30] showed no significant differences in OS between the PORT
and non-PORT groups for either patients with tumors >3.0 cm or those with tumors 3 cm
or less.
Cancers 2022, 14, 1617 7 of 15

There is also increasing evidence that there might be a benefit for PORT in persistent
pN2 disease (ypN2) after induction chemotherapy (ICT). The phase 2 trial of Betticher
et al. [60] found worse OS for patients with persistent N2 compared to patients with a
downstaging to N0 or N1 after ICT, suggesting a possible benefit of PORT for persistent
disease. Randomized trials evaluating PORT for persistent N2 disease after ICT are lacking.
The role of PORT in subjects with and without pathologic complete response after ICT
remains unclear [35].
The ADAURA trial found a significantly improved DFS for osimertinib in patients
with EGFR-mutated completely resected stage IB to III NSCLC [16]. The benefit of PORT
may be lower in patients with actionable mutations [61].
These findings indicate that treatments for stage III pN2 NSCLC should be individual-
ized. In routine clinical practice, many criteria influence the decision-making process [62].
The aim of a recently published decision-making analysis was to identify disease charac-
teristics in current clinical practice among European lung cancer experts for stage III pN+
NSCLC and how they impact decision making in the clinical routine regarding the use
of PORT before and after the first results of the Lung ART trial presented at ESMO 2020.
The most common risk factors used for decision making in the analysis were ENE and/or
capsular rupture of LNs, incomplete mediastinal lymphadenectomy, multi-station LNs,
high nodal tumor load and poor response to ICT [63].
The definition of complete resection has evolved over time, with findings of ENE/capsular
rupture of LNs automatically being classified as incomplete resections (Rami-Porta et al. [17]).
However, in clinical practice, ENE is often considered separately from otherwise completely
resected tumors (otherwise R0), as has been shown among European radiation oncology
experts [63]. Overall, there is ambiguity in differentiating incomplete resections from other
risk factors such as ENE.

3. PORT after Incomplete Resection

Incomplete resection is defined by Rami-Porta et al. [17] as the presence of positive
margins (R1: microscopic residual tumor, R2: macroscopic residual tumor), ENE of the
tumor in the nodes removed separately or those at the margin of the main lung speci-
men or positive nodes left in the operative field. The definition of uncertain resection
(R(uncertain)) was also created by Rami-Porta et al. [17]: no evidence of remnant tumor, but
intraoperative nodal evaluation not meeting the requirements of systematic nodal dissec-
tion or lobe-specific systematic nodal dissection or involvement of the highest mediastinal
node removed [17].
The justification for the presence of an ENE leading to the definition of an incomplete
resection is a matter of debate. A recent analysis on the IASLC database was not able to
determine the impact of ENEs on survival rates. The relevance of ENEs remains unclear,
as does the interplay between ENEs and PORT. The authors concluded that analyses of a
greater number of ENE cases are required to understand the prognostic impact [64].
A retrospective NCDB-based analysis of 3395 patients showed an improved OS across
all nodal stages with PORT in patients with incompletely resected (R1/2) stage II-III
NSCLC [65]. OS improvement was most pronounced in pN0 disease, with a 5-year OS of
41% vs. 26% with and without PORT, respectively. In another analysis of the same database
with 1446 incompletely resected (R1 or R2) patients, there was only a trend in favor of
sequential vs. concomitant postoperative CRT [66]. Both studies should be interpreted with
caution due to the limitations and biases of registries.
A recent analysis of the NCDB registry found no significant difference in the cohort
of 277 incompletely resected patients (R1: 94%, R2: 6%) between those who received
chemotherapy followed by PORT alone and those who received concomitant CRT postop-
eratively. Most patients in this cohort had microscopic positive margins rather than gross
residual disease, and it is patients in the latter group who, hypothetically, might derive the
most benefit from postoperative concomitant CRT [50].
Cancers 2022, 14, 1617 8 of 15

There is growing recognition that the uncertain resection status (inadequate intra-
operative lymph node dissection, positivity of the highest LN, involved LNs removed
in fragments, ENE) is associated with worse prognosis than R0 resection. These features
might be considered as risk factors for an increased rate of local recurrence and could be
potentially improved with PORT [67].
Controversial data are available for an ENE being used as a predictive marker for
PORT [68]. The retrospective analysis of Moretti et al. [69] involving 83 bulky pN2 patients
showed a significantly lower OS in pN2 patients with an ENE but a higher OS rate in
patients without an ENE who were treated with PORT.
In the Lung ART trial, after a review of the surgical and pathological reports in
accordance with IASLC, 33% of the reports did not contain any information about the
ENE of the resected LNs. All patients were reclassified into R0, uncertain and R1 resection.
Patients with an ENE were considered as R1 because of the insufficient description of the
ENE and whether these nodes were removed separately or not. A total of 149 patients
(74/250 in the PORT group, 75/243 in the control group) were reclassified as R1 (because
of the ENE). The authors of the Lung ART trial are expected to report on the effect of
the quality of surgery and the certainty of resection margins on the efficacy of PORT in
the future.
The NCCN guidelines recommend postoperative CRT (either sequential or concur-
rent) for R1 resection and concurrent CRT postoperatively for R2. Depending on the
stage of disease and site of R+-resection, re-excision may be considered [1,2,35,70]. The
ESMO guidelines recommend PORT and adjuvant chemotherapy in patients with R1 re-
section. In case both chemotherapy and PORT are administered, RT may be administered
before chemotherapy [11].

4. PORT Toxicity
Toxicity (mostly cardiopulmonary) is an important concern related to PORT, particu-
larly as several studies could not demonstrate a clear oncologic benefit. Excessive volumes
of RT, suboptimal radiation techniques, large doses and fraction sizes and non-CT-based RT
planning can probably explain the excess toxicity with non-cancer-related deaths observed
in previous trials with PORT.
Several retrospective databases and reviews have examined the hypothesis that more
modern radiation techniques do not lead to increased deaths. They found a similar risk of
intercurrent death between NSCLC patients with and without PORT [32,34,71].
An analysis of the SEER database investigated the cardiac toxicity and related mortality
in 6148 patients treated with or without PORT. PORT was associated with a significantly
increased number of deaths from heart disease in patients diagnosed with NSCLC between
1983 and 1988 but not in the latter cohorts [72].
The meta-analysis of the oldest trials using linear accelerators showed that the evolu-
tion from conventional 2D to 3D-RT has clearly alleviated radiation toxicity [35,37].
Subsequently, the improvements in RT technologies such as 3D conformal radiation
therapy (3D-CRT), intensity-modulated radiotherapy (IMRT) or volumetric modulated arc
therapy (VMAT) could have potential benefits [12,32,71,73,74].
A comparison of the dosimetric PORT plans of ten pN2 NSCLC patients using 3D-
CRT, IMRT and VMAT was unable to reveal that any technique had absolute dosimetry
advantages for all patients [75]. The selection of the technique should be individualized,
balancing target coverage and protection of the organs at risk. The use of protons may
be another step towards reducing RT-induced toxicity. Small retrospective series showed
there were significantly lower RT doses to surrounding organs at risk (heart, lungs) with
proton-based PORT [76–79]. In the monocentric retrospective review of Boyce-Fappiano
et al. [78], the improved sparing of the heart and lung with the use of proton beam PORT
was associated with improved OS. Multicenter studies randomizing patients to PORT with
proton therapy versus photon therapy, including a cardiopulmonary toxicity endpoint,
would be a good approach to understanding the potential benefits of proton therapy.
Cancers 2022, 14, 1617 9 of 15

Unfortunately, patients in the Lung ART trial were mainly treated with 3D-CRT (89%),
and only 11% of the patients in the study received IMRT, because when accrual started
for the study, IMRT was not standard. IMRT has now become a standard RT technique
with better dose conformity and organ at risk avoidance such as heart or lungs. In the
Lung ART trial, cardiopulmonary toxicity and related death was significantly higher in the
PORT group (16 patients, 16%) than in the control group (2 patients, 2%). Eleven percent of
the PORT patients and 5% of the non-PORT patients had late grade 3–4 cardiopulmonary
toxicities; the most common event was pneumonitis (6% in the PORT group, <1% in the
control group). Further analysis will be needed to explore which patient groups might
benefit most from PORT with lower toxicity [45].

5. Dose and Fractionation

The total RT dose, fractionation and the treated volume (including organs at risk)
should also be taken into consideration in decision making.
The randomized trial by Dautzenberg et al. [30] showed a higher risk for late toxicity
and intercurrent deaths using fraction sizes >2 Gy. There was a correlation between
fractionation size and morbidity. The risk for non-cancer-related death was 7% in the
control group (no PORT), 16–18% among patients treated with PORT with daily fractions
<2 Gy and 26% among patients who had >2 Gy doses per fraction [30].
In terms of RT dose, Corso et al. [80] showed a significantly improved OS in completely
resected NSCLC patients who received 45 to 54 Gy compared with patients without PORT.
With RT doses of over 54 Gy, the survival was equivalent to patients treated without PORT,
suggesting that these higher doses were detrimental.

6. Target Volume Delineation

PORT clinical target volume (CTV) must account for the lymph nodes involved ac-
cording to the surgery and pathology report and should consider preoperative imaging.
In cases of neoadjuvant chemotherapy, initially involved lymph node stations should be
included, even in cases of downstaging.
Spoelstra et al. [81] summarized which lymph node regions should be included
postoperatively for different positive lymph stations [81].
Several studies have investigated the pattern of locoregional relapse according to the
tumor location. Billiet et al. [82] showed the greatest LR at LN stations 7 (18%), 4R (16%)
and 10R (16%). Among left-sided tumors, LR occurred mostly bilaterally, whereas among
right-sided tumors, LR was more unilateral [82].
ESTRO/ACROP guidelines suggested that CTV should include the pathologically
involved and resected mediastinal lymph node stations, bronchial stump, ipsilateral hilum
and ipsilateral nodal stations 4 and 7. The definition of CTV depends on the lung lobe
where the tumor was located, but the bronchial stump, ipsilateral hilum, positive lymph
node regions and LN stations 4 and 7 must always be included in the CTV due to their
high risk of relapse [83] (Figure 1).
Cancers 2022, 14, 1617 10 of 15

Figure 1. Illustration of RT planning of PORT for a completely resected NSCLC patient with histologi-
cally proven lymph nodes (2/9) in stations 7 and 10R in (a) coronal and (b) sagittal views. Delineation
based on the Lung ART protocol of rCTV (orange): bronchial stump, ipsilateral hilar node region
(10R) and lymph node station 7. CTV (pink): rCTV+1 cm. In this case, 4R, 7 and 10R had a maximal
upper limit to the top of the aortic arc and a maximal lower limit 5 cm below the carina. PTV (red);
(c) color wash of dose distribution ranging from 20 Gy to 57.7 Gy (prescribed dose: 54 Gy). rCTV:
resected clinical tumor volume, CTV: clinical tumor volume, PTV: planning target volume.

7. Conclusions
The role of PORT in patients with completely resected NSCLC with pN2 involvement
remained unclear, based mostly on data from non-randomized studies and large database
analyses, until the publication of the Lung ART and PORT-C trials. The older studies
suggested for this patient cohort that PORT after adjuvant chemotherapy could improve
overall survival providing that a conformal RT technique such as 3D or IMRT would be
related with less cardiopulmonary toxicity.
The Lung ART and PORT-C trials represent robust evidence that 3D conformal PORT
should not be generally recommended in patients with resected stage III pN2 NSCLC
patients. Data indicate a significantly lower locoregional relapse rate with PORT without
translating into a survival benefit. It is a matter of ongoing debate as to whether PORT
might be beneficial for selected patients with high risk features, such as more than or equal
to four LN metastases, multiple-station N2 or persistent N2 disease after ICT [61,67]. It is
unclear whether PORT could improve the outcome for patients with ENE. The optimal RT
technique for PORT, such as IMRT or intensity-modulated proton therapy, and the role for
Cancers 2022, 14, 1617 11 of 15

PORT in selected high-risk patients should be evaluated. Future research should focus on
defining the profile of optimal candidates who might benefit from PORT.

Author Contributions: The concept for this review was developed by K.S. with help from P.M.P. The
manuscript was written by K.S. with help from P.M.P., T.I., G.F.F., P.L. and L.P. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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