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Stage-I small cell lung cancer: A new potential option for stereotactic ablative radiation therapy? A review of literature
Accepted Manuscript Title: Stage-I small cell lung cancer: A new potential option for sterotactic ablative radiation therapy? A review of literature Authors: Filippo Alongi, Stefano Arcangeli, Berardino De Bari, Niccol`o Giaj-Levra, Alba Fiorentino, Rosario Mazzola, Marco Trov`o PII: DOI: Reference:
S1040-8428(17)30078-1 http://dx.doi.org/doi:10.1016/j.critrevonc.2017.02.010 ONCH 2321
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
1-6-2016 15-1-2017 14-2-2017
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Title: Stage-I Small Cell Lung Cancer: a new potential option for Sterotactic Ablative Radiation Therapy? A review of Literature Filippo Alongi1, Stefano Arcangeli2, Berardino De Bari3, Niccolò Giaj-Levra1, Alba Fiorentino1, Rosario Mazzola1, Marco Trovò4. 1
Radiation Oncology Department, Sacro Cuore Don Calabria Cancer Care Center, Negrar-Verona, Italy .
2
Radiation Oncology, San Camillo and Forlanini Hospital, Rome, Italy.
3
Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
4
Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano, Italy.
Corresponding Author: Niccolò Giaj-Levra, MD Radiation Oncology Department Sacro Cuore Don Calabria Cancer Care Center Via Don A.Sempreboni 5, 37024 Negrar-Verona, Italy Phone: +390456104800 Fax: +390456014801 email: [email protected]
Abstract Small cell lung cancer (SCLC) is relative rare histology in lung cancer patients. The standard treatment, in patients with an intra-thoracic disease, is represented by the use of concurrent chemoradiotherapy; while patients with early SCLC stage, surgical resection could be recommended. Stereotactic body radiotherapy (SBRT) is a recently introduced technique allowing the delivery of very high radiation doses to limited target volumes and it is considered the standard approach in the treatment of not operable stage I Non Small-Cell Lung Cancer (NSCLC). The successful role option of SBRT in early NSCLC in terms of local control and toxicity profile opened the issue in the use of this approach in early stage small cell lung cancer (SCLC). Aim of this review is to discuss the current literature in the safety and efficacy of SBRT in the treatment of patients with stage I SCLC. Keywords: Small cell lung cancer, stereotactic ablative radiotherapy, outcomes, toxicity
1. Introduction Small cell lung cancer (SCLC) accounts for 20% of all lung cancer patients. Only one fourth of SCLC patients will be expected to have limited disease in the thorax, while the vast majority already has metastatic disease (Jemal A, et al. 2003). The standard of care for patients with limited disease and good performance status is thoracic radiation therapy (RT), up to a total dose of 60 Gy (1.8 – 2 Gy fraction), preferably associated with concurrent chemotherapy. As a matter of fact, surgery was abandoned after the publication of a trial conducted by the Medical Research Council in the 1960s , which showed better overall survival for RT compared to surgery (Fox W et al. 1973). The only possible exception in which surgical resection might be recommended is for the uncommon tumor presentation as solitary pulmonary nodule (stage I disease) (Jett JR et al. 2013, Higgins GA et al. 1975; Johnson BE et al. 2006). Stereotactic body radiotherapy (SBRT), also called stereotactic ablative radiation therapy (SABR), is a recently introduced technique that allows delivery of very high focused radiation doses to the tumor by using different kind of approaches (including multiple planar and non-coplanar beams, Intensity modulated RT, Volumetric modulated RT, Robotic-assisted delivery, etc), typically delivering the dose in 3 to 10 fractions. SBRT has been shown to be highly effective in the treatment of non operable stage I Non Small-Cell Lung Cancer (NSCLC), with reported local control rates of 80% to 95%, and it has become the standard of care for this group of patients (Bradley JD et al. 2010; Ricardi U et al. 2014; Franco P et al. 2014). The successful option of SBRT in achieving high local tumor control and low toxicity raises the question of whether SBRT can be a viable option in patients with stage I small cell lung cancer (SCLC), namely those who are medically inoperable. The role of SBRT in the clinical scenario of stage I SCLC is still not well defined, given the rarity of disease presentation as solitary nodule and the lack of prospective data. Aim of this review is to summarize and discuss the published data about safety and efficacy of SBRT in the treatment of patients with stage I SCLC.
2. Methods and materials 2.1 Literature search A detailed literature search strategy was developed a priori.
Key words and subject terms used in the search included: (("radiosurgery"[MeSH Terms] OR "radiosurgery"[All Fields] OR ("stereotactic"[All Fields] AND "body"[All Fields] AND "radiotherapy"[All Fields]) OR "stereotactic body radiotherapy"[All Fields]) AND ("small cell lung carcinoma"[MeSH Terms] OR ("small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "carcinoma"[All Fields]) OR "small cell lung carcinoma"[All Fields] OR ("small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "cancer"[All Fields]) OR "small cell lung cancer"[All
Fields]))
OR
(stereotactic[All
Fields]
AND
ablative[All
Fields]
AND
("radiotherapy"[Subheading] OR "radiotherapy"[All Fields] OR "radiotherapy"[MeSH Terms])). The search strategy was applied to Ovid MEDLINE (R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE (R) from January 1946 to April 2016. The grey literature was searched by applying a similar strategy to Google Scholar, PubMed and the Proquest Dissertation and Theses databases. Additional references were identified by a manual review of the reference lists of included articles. 2.2 Inclusion and exclusion criteria A study was included if (1) it reported on SBRT or SABR (2) it included patients with diagnosis of stage I-SCLC. A study was excluded if focusing on SBRT/SABR and different histology. Review articles and notEnglish speaking articles were excluded from the analysis.
2.3 Data extraction All the papers were scrutinized for the following: (1) study design (retrospective, prospective, casecontrol, cross-sectional and case series, case report); (2) number of patients and age (mean, range); (3) outcome in terms of efficacy and toxicity profile.
3 Clinical Outcomes and Toxicity Five available publications met the inclusion criteria of the current research. Findings by a total of 108 patients were here analyzed (Li C et al. 2014; Shioyama Y et al. 2013; Shioyama Y et al. 2015; Videtic GM et al. 2013; Duimering A et al. 2015). Among them, only one (Li C et al. 2014) represents a Prospective phase II trial, while all the other studies are basically case reports/series
(Table IA-B). In detail, Shioyama et al. (Shioyama Y et al. 2013) reported on a total of eight patients with biopsy-proven Stage I SCLC treated with SBRT. A schedule of 48 Gy in four fractions was applied. The majority of patients (6/8) received 3–4 cycles of chemotherapy using carboplatin (CBDCA) plus etoposide or cisplatin (CDDP) plus irinotecan (CPT-11). At a median follow-up of 32 months (range, 6–60 months), 6 patients (75%) were alive without evidence of relapse. Local control (LC), overall (OS) and disease-specific survival (DSS) rates at 3 years were 100%, 72% and 86%, respectively. No Grade 2 or higher treatment-related toxicities were observed. An update of this study was included in a multiinstitutional retrospective study of the Japan Radiation Oncology Study Group (JROSG) (Shioyama Y et al., 2015) which evaluated 64 patients – 2/3 of them deemed inoperable – who underwent SBRT for Stage I SCLC (IA: 83%; IB: 17%). The treatment was performed using non-coplanar multiple static beams or dynamic arcs. A total SBRT dose and fractions ranged from 35 Gy to 60 Gy in 3 to 19 fractions (median 48 Gy in 4 fractions). More than half (56%) received systemic chemotherapy, mainly consisting in CBDCA or CDDP plus etoposide regimen for a median of 4 cycles. With a median follow up of 26.4 months (range, 5–94 months) regional failures and distant metastases were found in 28.1% and 40.6% of the patients, respectively. LC, OS and DSS rates at two years were 89.3%, 76.3% and 79.1%, respectively. Two-year progression-free survival (PFS) was significantly higher when SBRT was combined with chemotherapy (66.7% versus 22.2%). No Grade 3 or higher SBRT-related toxicities were encountered. In another series, 6 patients with inoperable SCLC (Videtic GM et al. 2013) underwent chemotherapy and SBRTDespite the short follow-up (median 11.9 months), 1-year LC, OS and DSS rates were 100%, 63% and 75%, respectively, and a limited toxicity was reported (only one patient with grade 2 chest wall toxicity). Among the three patients who died, only one, who developed distant failure, died of disease. Li et al. (Li C et al. 2014) carried out a prospective phase II study of SBRT delivered concurrently with CDDP-based chemotherapy in patients with limited SCLC (I: 13.8%; II: 27.6%; III: 58.6%) having OS and progression-free survival (PFS) as primary end-points. The treatment schedule consisted in a dose of 40–45 Gy in 10 fractions given concurrently with 4–6 cycles of CDDP 75 mg/(m2/day) and etoposide 80 mg/(m2/day) at 3 weekly intervals. Twenty-nine patients were included and followed for a median duration of 19 months (range, 10–85 months). The crude LC rate was 82.5%. The estimated OS and PFS rates at 2 years were 47.7 % and 27%, respectively. Despite 86.2% of patients were stage II or III, regional recurrence rate was low (20.7%). No grade 4 treatment adverse events were observed. Grade 3 treatment related toxicities occurred in five (13.8 %) patients, and consisted in Grade 3 esophagitis (4 patients) and Grade 3 neutropenia (1 patient).
4 On-going trials Based on these results, a single prospective study is now ongoing at the Third Military Medical University (China) comparing SBRT Compared With IMRT Concurrently With Chemotherapy (ClinicalTrials.gov Identifier: NCT02738723) [14]. In this Phase II randomized trial, the investigators analyzed the progression free survival as primary endpoint. The standard arm consists in 45 Gy of accelerated twice-daily thoracic radiotherapy (1.5 Gy in 30 treatments over a period of three weeks), while the experimental one delivers 40 Gy in 10 fraction over a period on 2 weeks. In both the arms, a concomitant chemotherapy with Etoposide 75mg/m2/iv (days 1-4) and cisplatin 25mg/m2/iv (days 1-3), repeated every 3 weeks is delivered. The trial has been open in 01.2016 and is currently recruiting. Results are awaited for 01.2019.
5 Discussion While SBRT/SABR has been consistently shown to be superior to conventional RT for early-stage NSCLC, nearly doubling the 5-year OS (Grutters JP, et al. 2010; Shirvani SM, et al. 2014), this radiation modality is slow to be adopted in stage I SCLC simply because of the lack of available data. To date, no clinical trials have been conducted to compare the efficacy of surgery and SBRT/SABR in early stage SCLC. Analyzing the surgery database, two relevant experiences have been published from International Association for the Study of Lung Cancer (IASLC) and Surveillance, Epidemiology and End Results (SEER) (Vallières E et al. 2009; Yu JB et al. 2010). IASLC Lung Cancer Study Project reported over 8000 SCLC cases, including 349 patients in which primary tumor was resected. Sixty-eight patients were classified as pT1N0 (Stage IA) and 91 cases (Stage IB) were defined as pT2N0. Median survival time was 78 months in Stage IA and 31 months in Stage IB, while 1 year and 5 years OS were 90%, 53% and 78%, 44%, respectively. Comparable results have been published by Surveillance, Epidemiology and End Results (SEER) study of 247 patients with stage I SCLC who underwent resection, in which 205 did not receive an adjuvant radiation treatment. OS was 57.1% (95% CI 49.4 – 64.1%) and 49.1% (95% CI 41.2–56.6%) at 3 and 5 years, respectively. Several retrospective experiences have been published on this issue, employing resection as a primary treatment or after standard chemotherapy. Median survival time was in the range of 10.5 –
33 months, while
five-year survival rates were in the range of 27–38% (Friess GG et al. 1985;
Hara N et al. 1991; Badzio A et al. 2004; Rea F et al. 1998). Moreover, similar results have been published in prospective phase II studies with a median survival time range 15 – 36 months (Shepherd FA et al. 1991; Eberhardt W et al. 1999; Tsuchiya R et al. 2005), OS time at 5 years range of 25%-46% (Shepherd FA et al. 1991), and LC range between 57% - 100% (Shepherd FA et al. 1991; Eberhardt W et al. 1999; Tsuchiya R et al. 2005). Despite the presence of previously discussed data of surgery in stage I SCLC, and the existence of guidelines with specific surgery recommendations (available at http://www.nccn.org/professionals/ physician_gls/PDF/sclc.pdf), chemo-RT with conventionally fractionated schedules of dose (available at http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf) continues to be frequently proposed as treatment of choice in many centers. In the current Review of literature, we found five articles on the role of SBRT/SABR in the setting of stage I SCLC. Present research documented, in a cumulative population of 108 patients, that SBRT/SABR provided excellent outcomes in terms of LC (range, 82.5% - 100% at 3 years) and tolerability, which are comparable with the larger and more robust data reported for SBRT/SABR in early-stage NSCLC (Bradley JD et al. 2010; Ricardi U et al. 2014). The dominant pattern of failure is distant in all the reported studies, as well as for SBRT/SABR in early-stage NSCLC. This observation could support a potential omission of elective nodal irradiation in early-stage SCLC patients treated concomitantly with SBRT/SABR and chemotherapy. The hypothesis is that occult microscopic nodal disease might be sufficiently controlled by chemotherapy, while SBRT/SABR could be able to maximize LC of macroscopic disease. Assuming a presumptive equivalence in outcomes of SBRT/SABR for stage I SCLC to the NSCLC counterpart, a potential benefit in OS in patients with early stage SCLC as compared with conventional RT may be expected. Although in its infancy, there are plenty of hints to believe that SBRT/SABR has the potential to replace conventional RT for stage I SCLC, thus emerging as the standard of care in inoperable patients, similar to early-stage NSCLC, and likely even showing equipoise with surgery in operable patients. Given the paucity of evidence this hypothesis, as well as a therapeutic role of SBRT/SABR alone in this setting, needs to be evaluated prospectively. Considering our results, one of the major limitation of the current review is related to the poor data quality of the available case series/reports and their small population of study. In fact, of the five selected articles, one is a case report (Duimering A et al. 2015), another is published only as
abstract (Shioyama Y et al. 2015), and only one is a prospective designed trial (Li C et al. 2014). Moreover, the median follow-up in these studies is quite short ranging between 12 and 32 months (Table 2). Secondly, of the 108 evaluated patients, 29 were classified as stage II and III. Thus in the present review, this subgroup can dramatically affect the homogeneity of Stage I data, in regards to clinical outcomes and tolerability. Moreover, in the cumulative patient population of 108 cases, a series of 8 patients, was reported in the paper by Shioyama et al. in two subsequent analyses (Shioyama Y et al. 2013; Shioyama Y et al. 2015). Third, all the presented series, except one, reported the data on SBRT/SABR and chemotherapy. Therefore, the pure impact of SBRT/SABR in early stage SCLC remains to be determined. Interestingly, the multi-institutional Japanese trial assessed the outcome of 36 patients treated with SBRT/SABR combined 4 cycles of chemotherapy and 28 treated with SBRT/SABR alone. The 2years PFS was 66.7% for patients treated with SBRT/SABR associated with chemotherapy vs. 22% for those treated with SBRT/SABR alone. This observation would confirm the previously discussed rationale of adding chemotherapy in SCLC patients treated with SBRT/SABR, as reported in surgical series. The 5-year overall survival rates after surgery and chemotherapy is documented to be between 40% and 67%, which is comparable with the SBRT/SABR plus chemotherapy data showed in the present review (Table 1). One of the potential arguments against the adoption of SBRT in the treatment of SCLC is the potential risk of increasing the mediastinal nodal relapses. Available data do not support this argument. In the study by Shioyama et al., only 1/8 patients presented mediastinal nodal recurrence 12 months after treatment (Shioyama Y et al. 2013). Videtic et al reported no regional failures after a median follow-up of 19 months (Videtic GM et al. 2013). Fifteen months after the treatment, the patient presented by Duimering et al. did not show a nodal relapse, but a new lung nodule, considered suspect to be a NSCLC (Duimering A et al. 2015). In order to exclude nodal metastases, the we consider that a PET/CT should be always part of the initial staging of a SCLC, in particular if a SBRT is planned, because of its high sensitivity and specificity in identifying nodal and systemic metastases and, finally, in defining the treatment strategy in SCLC (Lu YY et al. 2014; Sohn BS et al. 2012; Xanthopoulos EP et al. 2013) 6 Conclusions In conclusion, the results of the present Review seem to suggest that SBRT/SABR for early stage SCLC may provide excellent outcomes in terms of LC and tolerability. Thus, SBRT/SABR could
deserve to be proposed in early stage SCLC when surgery is excluded and/or patient is eligible, taking also into account an appropriate technology and clinical expertise of the center. Nevertheless, given the paucity of evidence, the promising role of SBRT/SABR with or without combined chemotherapy needs to be further investigated. Fundings: No fundings to be declared
Conflict of interest: None to be declared.
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Biographies Alongi Filippo: He is Radiation Oncologist and clinical investigator, Associate Professor in Radiation Oncology professional qualification. He published more than 130 articles (indexed/ Peer reviewed Journals, including Lancet Oncology, JAMA oncology, JCO), 3 book chapters and more than 180 abstracts presented as oral presentation or posters at national and international scientific congress). His h-index is 21. Main topics of his activity are: SBRT, hypofractionation, IGRT, molecular imaging in Radiation Oncology, prostate cancer. From 2010 to 2014 he was assistant and then associate chief at Radiotherapy and Radiosurgery department Humanitas Cancer Center in Milan(Rozzano). From 2012 to 2014, he was the national coordinator of young group of AIRO (Italian society of Radiation Oncology) and he is in the board of AIRO prostate working group. From 2014 to 2016 was is member of AIRO National Scientific Committe and, to date, component of AIRO national Board. He was member of Editorial board of "Tumori" and "Technology in Cancer Research Treatment "and reviewer for several Journals. From 2014 , He is Chief of Radiation Oncology Department of Sacro Cuore-Don Calabria Hospital in Negrar (Verona). In 2015 he received patent for Associate Professor professional qualification in Radiation Oncology Stefano Arcangeli: Radiation oncologist and clinical researcher. He has published more than 50 articles (indexed/peer-reviewed journals) and several book chapters. Main topics of his activity are: radiation oncology and prostate cancer, SBRT. Peer-Reviewer for: Reports of Practical Oncology and Radiotherapy, Radio- therapy Oncology, Tumori and Editorial Board Member of the World Journal of Radiology. He’s an ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation Oncology) member. De Bari Berardino: Radiation Oncologist and clinical investigator. He published more than 60 articles (indexed/Peer reviewed Journals), one book chapter and more than 150 abstracts presented as oral presentations or posters at national and inter-national scientific congress. Main topics of his activity are: prostate cancer, GI cancer, imaging in radiotherapy, SBRT and IGRT. He is an ESTRO (European Society of Radiation Oncology) fellow and is co-coordinator of the live ESTRO contouring workshops in the context of the FALCON Project. He participated continuously with oral presentations and invited talks at national and international scientific congresses. Giaj-Levra Niccolò: Radiation Oncologist and PhD student at Sacro Cuore Hospital Negrar-Verona and University of Torino. He published more than 30 articles (indexed/Peer reviewed Journals), one book chapter and over 50 abstract presented as oral presentations or posters at national and international scientific congress. His favorite topics are: lung cancer, neuro-oncology, stereotactic ablative radiotherapy. He is an ESTRO and AIRO member and he is member of AIRO lung cancer working group. Fiorentino Alba: Radiation Oncologist and clinical investigator at Sacro Cuore Hospital Negrar, Verona (Italy). She published more than 40 articles (indexed/Peer reviewed Journals) and one book chapter. Main topics of her activity are: neuro-oncology, elderly patients with cancer, prostate cancer, and IGRT. She is an
ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation Oncology) member and she is on the board of AIRO neuro-oncology working group Mazzola Rosario: Resident in Radiation Oncology and clinical investigator. He published more than 20 articles (indexed/Peer reviewed Journals) and more than 50 abstracts presented as oral presentations or posters at national and international scientific congress. Main topics of his activity are: gynecologic cancer, head neck cancer and stereotactic body radiation therapy. He is member of ESTRO, AIRO (Italian Association Society of Radiation Oncology) and AIRO young group. Trovò Marco: Radiation Oncologist and clinical investigator at Centro di Riferimento Oncologico, CRO – Aviano (Italy). He published more than 30 articles (indexed/Peer reviewed Journals) and several book chapters. He is an ESTRO (European Society of Radiation Oncology), AIRO (Italian Society of Radiation Oncology) member and AIRB (Italian Society of Radiobiology). He is the chief of AIRO lung cancer working group. He is focused in lung cancer treatment and stereotactic ablative radiotherapy.
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Schedule Technique
[Gy/ No. Fractions]
13.8 % I Li et al. 2014
Shioyama et al.
29
55 (41-72)
83% M 17% F
74 (58-84)
75% M 25% F
8
Prospective phase II
Retrospective
2015
78 (56-96) 64
80% M 20% F
Retrospective
100% Concurrent *
N.A.
40–45/10
58.6% III
25% IA
2013
Shioyama et al.
27.6 % II
75% preSBRT**
25% IB
3D
50% IIA
25% post SBRT**
83% IA
56% ***
17% IB
3D
Target definition
GTV: on 3 respiratory phases
Adopted dose-constraints
Dmax to OAR₮: 50 Gy
PTV: 5 mm in axial plan and 10 mm in longitudinal
spinal cord:30 Gy
GTV: all 4D phases (ITV)
Lung volume: V20<20%
PTV: ITV + 5 mm
3D-RT and portal imaging
N.A
N.A.
3D - gamma-ray treatment system
48 Gy/4
48 Gy/4°
Videtic et al.
60/3 (3 patient) 68 6
80% M 20% F
100% Concurrent *
Retrospective
Novalis/ BrainLAB
2015
50/5 (2 patient)
N.A.
N.A.
N.A.
N.A.
30/1 (1 patient)
Duimering et al.
61
100% F
1
100% IA Case-report
100% preSBRT ****
2015
dynamic conformal arcs
48 Gy/4
GTV: gross target volume, ITV: internal target volume; PTV: planning target volume, N.A.: not available; 3D‐RT: conformal radiotherapy; ₮ OAR: organ at risk (main bronchi, esophagus, trachea, heart, and major blood vessels and spinal)
* 4-6 cycles of CDDP plus VP-16 ** 3-4 cycles of CBDCA plus VP-16 or CDDP plus CPT-11 *** 4 cycles of CBDCA or CDDP plus VP-16 **** 4 cycles of CDDP plus VP-16 Table IA: Patients' characteristics of selected studies
Table IB: Clinical outcomes reported by selected studies
Author publication year [reference]
Median Follow Up
Local Control
Overall Survival
Disease Free Survival
Treatment related (≥G3) Toxicity
(months)
(%)
(months)
(months)
(%)
19 (10–85)
82.5
27 (20.2–33.8)
12 (4.2–19.8)
Li et al. 2014
3.4 Neutropenia G3 3.4 Leucopenia G3 13.8 Esophagitis G3
Shioyama et al. 2013
32 (6–60)
100 at 3-y
72
86
0
26.4 (5-94)
89.3 at 2-y
76.3
79.1
0
Shioyama et al. 2015
Videtic et al. 2015
Duimering et al. 2015
Legend: NA = Not available.
11.9
100 at 1-y
63
75
0
Case report
100 at 3-y
72
NA
0
S1040-8428(17)30078-1 http://dx.doi.org/doi:10.1016/j.critrevonc.2017.02.010 ONCH 2321
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
1-6-2016 15-1-2017 14-2-2017
Please cite this article as: {http://dx.doi.org/ This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Stage-I Small Cell Lung Cancer: a new potential option for Sterotactic Ablative Radiation Therapy? A review of Literature Filippo Alongi1, Stefano Arcangeli2, Berardino De Bari3, Niccolò Giaj-Levra1, Alba Fiorentino1, Rosario Mazzola1, Marco Trovò4. 1
Radiation Oncology Department, Sacro Cuore Don Calabria Cancer Care Center, Negrar-Verona, Italy .
2
Radiation Oncology, San Camillo and Forlanini Hospital, Rome, Italy.
3
Radiation Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
4
Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano, Italy.
Corresponding Author: Niccolò Giaj-Levra, MD Radiation Oncology Department Sacro Cuore Don Calabria Cancer Care Center Via Don A.Sempreboni 5, 37024 Negrar-Verona, Italy Phone: +390456104800 Fax: +390456014801 email: [email protected]
Abstract Small cell lung cancer (SCLC) is relative rare histology in lung cancer patients. The standard treatment, in patients with an intra-thoracic disease, is represented by the use of concurrent chemoradiotherapy; while patients with early SCLC stage, surgical resection could be recommended. Stereotactic body radiotherapy (SBRT) is a recently introduced technique allowing the delivery of very high radiation doses to limited target volumes and it is considered the standard approach in the treatment of not operable stage I Non Small-Cell Lung Cancer (NSCLC). The successful role option of SBRT in early NSCLC in terms of local control and toxicity profile opened the issue in the use of this approach in early stage small cell lung cancer (SCLC). Aim of this review is to discuss the current literature in the safety and efficacy of SBRT in the treatment of patients with stage I SCLC. Keywords: Small cell lung cancer, stereotactic ablative radiotherapy, outcomes, toxicity
1. Introduction Small cell lung cancer (SCLC) accounts for 20% of all lung cancer patients. Only one fourth of SCLC patients will be expected to have limited disease in the thorax, while the vast majority already has metastatic disease (Jemal A, et al. 2003). The standard of care for patients with limited disease and good performance status is thoracic radiation therapy (RT), up to a total dose of 60 Gy (1.8 – 2 Gy fraction), preferably associated with concurrent chemotherapy. As a matter of fact, surgery was abandoned after the publication of a trial conducted by the Medical Research Council in the 1960s , which showed better overall survival for RT compared to surgery (Fox W et al. 1973). The only possible exception in which surgical resection might be recommended is for the uncommon tumor presentation as solitary pulmonary nodule (stage I disease) (Jett JR et al. 2013, Higgins GA et al. 1975; Johnson BE et al. 2006). Stereotactic body radiotherapy (SBRT), also called stereotactic ablative radiation therapy (SABR), is a recently introduced technique that allows delivery of very high focused radiation doses to the tumor by using different kind of approaches (including multiple planar and non-coplanar beams, Intensity modulated RT, Volumetric modulated RT, Robotic-assisted delivery, etc), typically delivering the dose in 3 to 10 fractions. SBRT has been shown to be highly effective in the treatment of non operable stage I Non Small-Cell Lung Cancer (NSCLC), with reported local control rates of 80% to 95%, and it has become the standard of care for this group of patients (Bradley JD et al. 2010; Ricardi U et al. 2014; Franco P et al. 2014). The successful option of SBRT in achieving high local tumor control and low toxicity raises the question of whether SBRT can be a viable option in patients with stage I small cell lung cancer (SCLC), namely those who are medically inoperable. The role of SBRT in the clinical scenario of stage I SCLC is still not well defined, given the rarity of disease presentation as solitary nodule and the lack of prospective data. Aim of this review is to summarize and discuss the published data about safety and efficacy of SBRT in the treatment of patients with stage I SCLC.
2. Methods and materials 2.1 Literature search A detailed literature search strategy was developed a priori.
Key words and subject terms used in the search included: (("radiosurgery"[MeSH Terms] OR "radiosurgery"[All Fields] OR ("stereotactic"[All Fields] AND "body"[All Fields] AND "radiotherapy"[All Fields]) OR "stereotactic body radiotherapy"[All Fields]) AND ("small cell lung carcinoma"[MeSH Terms] OR ("small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "carcinoma"[All Fields]) OR "small cell lung carcinoma"[All Fields] OR ("small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "cancer"[All Fields]) OR "small cell lung cancer"[All
Fields]))
OR
(stereotactic[All
Fields]
AND
ablative[All
Fields]
AND
("radiotherapy"[Subheading] OR "radiotherapy"[All Fields] OR "radiotherapy"[MeSH Terms])). The search strategy was applied to Ovid MEDLINE (R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE (R) from January 1946 to April 2016. The grey literature was searched by applying a similar strategy to Google Scholar, PubMed and the Proquest Dissertation and Theses databases. Additional references were identified by a manual review of the reference lists of included articles. 2.2 Inclusion and exclusion criteria A study was included if (1) it reported on SBRT or SABR (2) it included patients with diagnosis of stage I-SCLC. A study was excluded if focusing on SBRT/SABR and different histology. Review articles and notEnglish speaking articles were excluded from the analysis.
2.3 Data extraction All the papers were scrutinized for the following: (1) study design (retrospective, prospective, casecontrol, cross-sectional and case series, case report); (2) number of patients and age (mean, range); (3) outcome in terms of efficacy and toxicity profile.
3 Clinical Outcomes and Toxicity Five available publications met the inclusion criteria of the current research. Findings by a total of 108 patients were here analyzed (Li C et al. 2014; Shioyama Y et al. 2013; Shioyama Y et al. 2015; Videtic GM et al. 2013; Duimering A et al. 2015). Among them, only one (Li C et al. 2014) represents a Prospective phase II trial, while all the other studies are basically case reports/series
(Table IA-B). In detail, Shioyama et al. (Shioyama Y et al. 2013) reported on a total of eight patients with biopsy-proven Stage I SCLC treated with SBRT. A schedule of 48 Gy in four fractions was applied. The majority of patients (6/8) received 3–4 cycles of chemotherapy using carboplatin (CBDCA) plus etoposide or cisplatin (CDDP) plus irinotecan (CPT-11). At a median follow-up of 32 months (range, 6–60 months), 6 patients (75%) were alive without evidence of relapse. Local control (LC), overall (OS) and disease-specific survival (DSS) rates at 3 years were 100%, 72% and 86%, respectively. No Grade 2 or higher treatment-related toxicities were observed. An update of this study was included in a multiinstitutional retrospective study of the Japan Radiation Oncology Study Group (JROSG) (Shioyama Y et al., 2015) which evaluated 64 patients – 2/3 of them deemed inoperable – who underwent SBRT for Stage I SCLC (IA: 83%; IB: 17%). The treatment was performed using non-coplanar multiple static beams or dynamic arcs. A total SBRT dose and fractions ranged from 35 Gy to 60 Gy in 3 to 19 fractions (median 48 Gy in 4 fractions). More than half (56%) received systemic chemotherapy, mainly consisting in CBDCA or CDDP plus etoposide regimen for a median of 4 cycles. With a median follow up of 26.4 months (range, 5–94 months) regional failures and distant metastases were found in 28.1% and 40.6% of the patients, respectively. LC, OS and DSS rates at two years were 89.3%, 76.3% and 79.1%, respectively. Two-year progression-free survival (PFS) was significantly higher when SBRT was combined with chemotherapy (66.7% versus 22.2%). No Grade 3 or higher SBRT-related toxicities were encountered. In another series, 6 patients with inoperable SCLC (Videtic GM et al. 2013) underwent chemotherapy and SBRTDespite the short follow-up (median 11.9 months), 1-year LC, OS and DSS rates were 100%, 63% and 75%, respectively, and a limited toxicity was reported (only one patient with grade 2 chest wall toxicity). Among the three patients who died, only one, who developed distant failure, died of disease. Li et al. (Li C et al. 2014) carried out a prospective phase II study of SBRT delivered concurrently with CDDP-based chemotherapy in patients with limited SCLC (I: 13.8%; II: 27.6%; III: 58.6%) having OS and progression-free survival (PFS) as primary end-points. The treatment schedule consisted in a dose of 40–45 Gy in 10 fractions given concurrently with 4–6 cycles of CDDP 75 mg/(m2/day) and etoposide 80 mg/(m2/day) at 3 weekly intervals. Twenty-nine patients were included and followed for a median duration of 19 months (range, 10–85 months). The crude LC rate was 82.5%. The estimated OS and PFS rates at 2 years were 47.7 % and 27%, respectively. Despite 86.2% of patients were stage II or III, regional recurrence rate was low (20.7%). No grade 4 treatment adverse events were observed. Grade 3 treatment related toxicities occurred in five (13.8 %) patients, and consisted in Grade 3 esophagitis (4 patients) and Grade 3 neutropenia (1 patient).
4 On-going trials Based on these results, a single prospective study is now ongoing at the Third Military Medical University (China) comparing SBRT Compared With IMRT Concurrently With Chemotherapy (ClinicalTrials.gov Identifier: NCT02738723) [14]. In this Phase II randomized trial, the investigators analyzed the progression free survival as primary endpoint. The standard arm consists in 45 Gy of accelerated twice-daily thoracic radiotherapy (1.5 Gy in 30 treatments over a period of three weeks), while the experimental one delivers 40 Gy in 10 fraction over a period on 2 weeks. In both the arms, a concomitant chemotherapy with Etoposide 75mg/m2/iv (days 1-4) and cisplatin 25mg/m2/iv (days 1-3), repeated every 3 weeks is delivered. The trial has been open in 01.2016 and is currently recruiting. Results are awaited for 01.2019.
5 Discussion While SBRT/SABR has been consistently shown to be superior to conventional RT for early-stage NSCLC, nearly doubling the 5-year OS (Grutters JP, et al. 2010; Shirvani SM, et al. 2014), this radiation modality is slow to be adopted in stage I SCLC simply because of the lack of available data. To date, no clinical trials have been conducted to compare the efficacy of surgery and SBRT/SABR in early stage SCLC. Analyzing the surgery database, two relevant experiences have been published from International Association for the Study of Lung Cancer (IASLC) and Surveillance, Epidemiology and End Results (SEER) (Vallières E et al. 2009; Yu JB et al. 2010). IASLC Lung Cancer Study Project reported over 8000 SCLC cases, including 349 patients in which primary tumor was resected. Sixty-eight patients were classified as pT1N0 (Stage IA) and 91 cases (Stage IB) were defined as pT2N0. Median survival time was 78 months in Stage IA and 31 months in Stage IB, while 1 year and 5 years OS were 90%, 53% and 78%, 44%, respectively. Comparable results have been published by Surveillance, Epidemiology and End Results (SEER) study of 247 patients with stage I SCLC who underwent resection, in which 205 did not receive an adjuvant radiation treatment. OS was 57.1% (95% CI 49.4 – 64.1%) and 49.1% (95% CI 41.2–56.6%) at 3 and 5 years, respectively. Several retrospective experiences have been published on this issue, employing resection as a primary treatment or after standard chemotherapy. Median survival time was in the range of 10.5 –
33 months, while
five-year survival rates were in the range of 27–38% (Friess GG et al. 1985;
Hara N et al. 1991; Badzio A et al. 2004; Rea F et al. 1998). Moreover, similar results have been published in prospective phase II studies with a median survival time range 15 – 36 months (Shepherd FA et al. 1991; Eberhardt W et al. 1999; Tsuchiya R et al. 2005), OS time at 5 years range of 25%-46% (Shepherd FA et al. 1991), and LC range between 57% - 100% (Shepherd FA et al. 1991; Eberhardt W et al. 1999; Tsuchiya R et al. 2005). Despite the presence of previously discussed data of surgery in stage I SCLC, and the existence of guidelines with specific surgery recommendations (available at http://www.nccn.org/professionals/ physician_gls/PDF/sclc.pdf), chemo-RT with conventionally fractionated schedules of dose (available at http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf) continues to be frequently proposed as treatment of choice in many centers. In the current Review of literature, we found five articles on the role of SBRT/SABR in the setting of stage I SCLC. Present research documented, in a cumulative population of 108 patients, that SBRT/SABR provided excellent outcomes in terms of LC (range, 82.5% - 100% at 3 years) and tolerability, which are comparable with the larger and more robust data reported for SBRT/SABR in early-stage NSCLC (Bradley JD et al. 2010; Ricardi U et al. 2014). The dominant pattern of failure is distant in all the reported studies, as well as for SBRT/SABR in early-stage NSCLC. This observation could support a potential omission of elective nodal irradiation in early-stage SCLC patients treated concomitantly with SBRT/SABR and chemotherapy. The hypothesis is that occult microscopic nodal disease might be sufficiently controlled by chemotherapy, while SBRT/SABR could be able to maximize LC of macroscopic disease. Assuming a presumptive equivalence in outcomes of SBRT/SABR for stage I SCLC to the NSCLC counterpart, a potential benefit in OS in patients with early stage SCLC as compared with conventional RT may be expected. Although in its infancy, there are plenty of hints to believe that SBRT/SABR has the potential to replace conventional RT for stage I SCLC, thus emerging as the standard of care in inoperable patients, similar to early-stage NSCLC, and likely even showing equipoise with surgery in operable patients. Given the paucity of evidence this hypothesis, as well as a therapeutic role of SBRT/SABR alone in this setting, needs to be evaluated prospectively. Considering our results, one of the major limitation of the current review is related to the poor data quality of the available case series/reports and their small population of study. In fact, of the five selected articles, one is a case report (Duimering A et al. 2015), another is published only as
abstract (Shioyama Y et al. 2015), and only one is a prospective designed trial (Li C et al. 2014). Moreover, the median follow-up in these studies is quite short ranging between 12 and 32 months (Table 2). Secondly, of the 108 evaluated patients, 29 were classified as stage II and III. Thus in the present review, this subgroup can dramatically affect the homogeneity of Stage I data, in regards to clinical outcomes and tolerability. Moreover, in the cumulative patient population of 108 cases, a series of 8 patients, was reported in the paper by Shioyama et al. in two subsequent analyses (Shioyama Y et al. 2013; Shioyama Y et al. 2015). Third, all the presented series, except one, reported the data on SBRT/SABR and chemotherapy. Therefore, the pure impact of SBRT/SABR in early stage SCLC remains to be determined. Interestingly, the multi-institutional Japanese trial assessed the outcome of 36 patients treated with SBRT/SABR combined 4 cycles of chemotherapy and 28 treated with SBRT/SABR alone. The 2years PFS was 66.7% for patients treated with SBRT/SABR associated with chemotherapy vs. 22% for those treated with SBRT/SABR alone. This observation would confirm the previously discussed rationale of adding chemotherapy in SCLC patients treated with SBRT/SABR, as reported in surgical series. The 5-year overall survival rates after surgery and chemotherapy is documented to be between 40% and 67%, which is comparable with the SBRT/SABR plus chemotherapy data showed in the present review (Table 1). One of the potential arguments against the adoption of SBRT in the treatment of SCLC is the potential risk of increasing the mediastinal nodal relapses. Available data do not support this argument. In the study by Shioyama et al., only 1/8 patients presented mediastinal nodal recurrence 12 months after treatment (Shioyama Y et al. 2013). Videtic et al reported no regional failures after a median follow-up of 19 months (Videtic GM et al. 2013). Fifteen months after the treatment, the patient presented by Duimering et al. did not show a nodal relapse, but a new lung nodule, considered suspect to be a NSCLC (Duimering A et al. 2015). In order to exclude nodal metastases, the we consider that a PET/CT should be always part of the initial staging of a SCLC, in particular if a SBRT is planned, because of its high sensitivity and specificity in identifying nodal and systemic metastases and, finally, in defining the treatment strategy in SCLC (Lu YY et al. 2014; Sohn BS et al. 2012; Xanthopoulos EP et al. 2013) 6 Conclusions In conclusion, the results of the present Review seem to suggest that SBRT/SABR for early stage SCLC may provide excellent outcomes in terms of LC and tolerability. Thus, SBRT/SABR could
deserve to be proposed in early stage SCLC when surgery is excluded and/or patient is eligible, taking also into account an appropriate technology and clinical expertise of the center. Nevertheless, given the paucity of evidence, the promising role of SBRT/SABR with or without combined chemotherapy needs to be further investigated. Fundings: No fundings to be declared
Conflict of interest: None to be declared.
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Biographies Alongi Filippo: He is Radiation Oncologist and clinical investigator, Associate Professor in Radiation Oncology professional qualification. He published more than 130 articles (indexed/ Peer reviewed Journals, including Lancet Oncology, JAMA oncology, JCO), 3 book chapters and more than 180 abstracts presented as oral presentation or posters at national and international scientific congress). His h-index is 21. Main topics of his activity are: SBRT, hypofractionation, IGRT, molecular imaging in Radiation Oncology, prostate cancer. From 2010 to 2014 he was assistant and then associate chief at Radiotherapy and Radiosurgery department Humanitas Cancer Center in Milan(Rozzano). From 2012 to 2014, he was the national coordinator of young group of AIRO (Italian society of Radiation Oncology) and he is in the board of AIRO prostate working group. From 2014 to 2016 was is member of AIRO National Scientific Committe and, to date, component of AIRO national Board. He was member of Editorial board of "Tumori" and "Technology in Cancer Research Treatment "and reviewer for several Journals. From 2014 , He is Chief of Radiation Oncology Department of Sacro Cuore-Don Calabria Hospital in Negrar (Verona). In 2015 he received patent for Associate Professor professional qualification in Radiation Oncology Stefano Arcangeli: Radiation oncologist and clinical researcher. He has published more than 50 articles (indexed/peer-reviewed journals) and several book chapters. Main topics of his activity are: radiation oncology and prostate cancer, SBRT. Peer-Reviewer for: Reports of Practical Oncology and Radiotherapy, Radio- therapy Oncology, Tumori and Editorial Board Member of the World Journal of Radiology. He’s an ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation Oncology) member. De Bari Berardino: Radiation Oncologist and clinical investigator. He published more than 60 articles (indexed/Peer reviewed Journals), one book chapter and more than 150 abstracts presented as oral presentations or posters at national and inter-national scientific congress. Main topics of his activity are: prostate cancer, GI cancer, imaging in radiotherapy, SBRT and IGRT. He is an ESTRO (European Society of Radiation Oncology) fellow and is co-coordinator of the live ESTRO contouring workshops in the context of the FALCON Project. He participated continuously with oral presentations and invited talks at national and international scientific congresses. Giaj-Levra Niccolò: Radiation Oncologist and PhD student at Sacro Cuore Hospital Negrar-Verona and University of Torino. He published more than 30 articles (indexed/Peer reviewed Journals), one book chapter and over 50 abstract presented as oral presentations or posters at national and international scientific congress. His favorite topics are: lung cancer, neuro-oncology, stereotactic ablative radiotherapy. He is an ESTRO and AIRO member and he is member of AIRO lung cancer working group. Fiorentino Alba: Radiation Oncologist and clinical investigator at Sacro Cuore Hospital Negrar, Verona (Italy). She published more than 40 articles (indexed/Peer reviewed Journals) and one book chapter. Main topics of her activity are: neuro-oncology, elderly patients with cancer, prostate cancer, and IGRT. She is an
ESTRO (European Society of Radiation Oncology) and AIRO (Italian Society of Radiation Oncology) member and she is on the board of AIRO neuro-oncology working group Mazzola Rosario: Resident in Radiation Oncology and clinical investigator. He published more than 20 articles (indexed/Peer reviewed Journals) and more than 50 abstracts presented as oral presentations or posters at national and international scientific congress. Main topics of his activity are: gynecologic cancer, head neck cancer and stereotactic body radiation therapy. He is member of ESTRO, AIRO (Italian Association Society of Radiation Oncology) and AIRO young group. Trovò Marco: Radiation Oncologist and clinical investigator at Centro di Riferimento Oncologico, CRO – Aviano (Italy). He published more than 30 articles (indexed/Peer reviewed Journals) and several book chapters. He is an ESTRO (European Society of Radiation Oncology), AIRO (Italian Society of Radiation Oncology) member and AIRB (Italian Society of Radiobiology). He is the chief of AIRO lung cancer working group. He is focused in lung cancer treatment and stereotactic ablative radiotherapy.
Author publication year [reference]
Number of patients
Median
Gender
Age
Type of Study
T-stage
Systemic Chemotherapy
Schedule Technique
[Gy/ No. Fractions]
13.8 % I Li et al. 2014
Shioyama et al.
29
55 (41-72)
83% M 17% F
74 (58-84)
75% M 25% F
8
Prospective phase II
Retrospective
2015
78 (56-96) 64
80% M 20% F
Retrospective
100% Concurrent *
N.A.
40–45/10
58.6% III
25% IA
2013
Shioyama et al.
27.6 % II
75% preSBRT**
25% IB
3D
50% IIA
25% post SBRT**
83% IA
56% ***
17% IB
3D
Target definition
GTV: on 3 respiratory phases
Adopted dose-constraints
Dmax to OAR₮: 50 Gy
PTV: 5 mm in axial plan and 10 mm in longitudinal
spinal cord:30 Gy
GTV: all 4D phases (ITV)
Lung volume: V20<20%
PTV: ITV + 5 mm
3D-RT and portal imaging
N.A
N.A.
3D - gamma-ray treatment system
48 Gy/4
48 Gy/4°
Videtic et al.
60/3 (3 patient) 68 6
80% M 20% F
100% Concurrent *
Retrospective
Novalis/ BrainLAB
2015
50/5 (2 patient)
N.A.
N.A.
N.A.
N.A.
30/1 (1 patient)
Duimering et al.
61
100% F
1
100% IA Case-report
100% preSBRT ****
2015
dynamic conformal arcs
48 Gy/4
GTV: gross target volume, ITV: internal target volume; PTV: planning target volume, N.A.: not available; 3D‐RT: conformal radiotherapy; ₮ OAR: organ at risk (main bronchi, esophagus, trachea, heart, and major blood vessels and spinal)
* 4-6 cycles of CDDP plus VP-16 ** 3-4 cycles of CBDCA plus VP-16 or CDDP plus CPT-11 *** 4 cycles of CBDCA or CDDP plus VP-16 **** 4 cycles of CDDP plus VP-16 Table IA: Patients' characteristics of selected studies
Table IB: Clinical outcomes reported by selected studies
Author publication year [reference]
Median Follow Up
Local Control
Overall Survival
Disease Free Survival
Treatment related (≥G3) Toxicity
(months)
(%)
(months)
(months)
(%)
19 (10–85)
82.5
27 (20.2–33.8)
12 (4.2–19.8)
Li et al. 2014
3.4 Neutropenia G3 3.4 Leucopenia G3 13.8 Esophagitis G3
Shioyama et al. 2013
32 (6–60)
100 at 3-y
72
86
0
26.4 (5-94)
89.3 at 2-y
76.3
79.1
0
Shioyama et al. 2015
Videtic et al. 2015
Duimering et al. 2015
Legend: NA = Not available.
11.9
100 at 1-y
63
75
0
Case report
100 at 3-y
72
NA
0