Abstract
Objectives:
The aim of this retrospective study was to assess outcomes of SABR for metachronous isolated lung oligometastases from HNSCC.
Methods:
For patients who developed isolated, 1 or 2 lungs lesions (<5cm) consistent with metastases from HNSCC, the indication of SABR was validated in a multidisciplinary tumor board. All patients were monitored by CT or PET CT after SABR (Stereotactic Ablative Body Radiation) for HNSCC.
Results:
Between November 2007 and February 2018, 52 patients were treated with SABR for metachronous lung metastases. The median time from the treatment of the primary HNSCC to the development of lung metastases was 18 months (3-93). The cohort’s median age was 65.5 years old (50-83). The vast majority (94.2%) received 60 Gy in three fractions. Forty-one patients (78.5%) presented a solitary lung metastasis, while 11 patients (21.5%) had two lung metastases. With a median follow-up of 45.3 months, crude local and metastatic control rates were 74 and 38%, respectively. 1 year and 2 year Overall Survival (OS) were 85.8 and 65.9%, respectively. The median OS was 46.8 months. About one-fourth of patients were retreated by SABR for distant pulmonary recurrence. The treatment was well tolerated with only one patient who reported ≥ grade 3 toxicity (1.9%).
Conclusion:
In selected metastatic HNSCC patients, early detection and treatment of lung metastases with SABR is effective and safe. Prospective studies are required to validate this potential shift.
Advances in knowledge:
Patients with oligometastases and controlled primary HNSCC seem to benefit from metastasis directed therapies.
Introduction
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide, with 450 000 new cases per year. Even although locoregional failure remains the most common pattern, 15% of patients will develop distant metastases mainly to the lungs. Factors associated with distant metastasis are stage grouping and regional node positivity, extranodal extension, locoregional residual disease, and human papillomavirus (HPV) negative status in oropharyngeal squamous cell carcinoma. 1
The current standard for care for patients with HNSCC and distant metastases is systemic therapy consisting of chemotherapy and immunotherapy, irrespective of the number of metastatic lesions. However, outcomes of patients with a limited burden of metastatic disease may be slightly better. Hellman and Weichselbaum proposed the concept of oligometastases in 1995 based on the multistep nature of cancer progression and where the oligometastatic state represents an intermediate state between purely localized disease and widely disseminated disease. 2 In the literature, the most consensual definition is based on the number of metastases: 1 to 5. For such patients, not only do local therapies improve overall survival but they could also be potentially curative. Historically, the setting of liver-limited metastases from colorectal cancer has been one of the few examples of curative metastasectomy in oncology. Even before the development of effective systemic therapy, surgical resection of limited hepatic metastases was associated with prolonged survival and cures. 3
Other local therapies such as Stereotactic Ablative Radiation Therapy (SABR) are increasingly being administered for non-surgical candidates in the oligometastatic setting. SABR is particularly attractive since it is a non-invasive treatment modality that results in minimal morbidity and provides high local control rates in medically inoperable stage I non-small-cell lung cancer(NSCLC). 4 SABR represents the current standard of care for these patients. There has been data to support SABR in the oligometastatic setting, but no level I evidence. 5 SABR-COMET was a Phase 2, open-label trial which randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group) or standard of care plus SABR to all metastatic lesions (SABR group) in oligometastatic patients. Median overall survival was 28 months in the control group versus 41 months (26-not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30–1·10; p = 0·090). 6 One of the main caveats of this study was that the SABR arm included more patients with prostate/breast cancers known for their favorable prognosis, while lung/colon cancers were more prevalent in the control group. Moreover, more patients in the SABR arm presented single metastatic lesions. The primary was unknown in 14 patients, and no HNSCC tumors were included in the study. Some reports suggest the potential benefit of SABR for delaying systemic therapies. 7–10
The efficacy of SABR for lung metastases from HNSCC patients has not been well characterized. We aimed to assess outcomes of SABR in patients with HNCSCC and lung oligometastases.
Methods and materials
Patients inclusion
This retrospective study enrolled patients with lung oligometastases (≤2) from primary HNSCC treated with Cyberknife® from our two institutions between November 2007 and February 2018 and was approved by the Institutional Review Board of both centers. Inclusion criteria were: primary HNSCC with histology proof and local control achieved, 1–2 metachronous lung metastases and each lesion size <5 cm, and absence of extrapulmonary metastases. Eligible lung metastases (1–2 and <5 cm) were screened by CT or PET- CT. The histological proof was not mandatory. A multidisciplinary tumor board was required to validate the indication of curative intent SABR in all cases. HPV status was not analyzed as these data were incomplete.
Treatment technique
Cyberknife® is a device combining a compact 6 MV linear accelerator mounted on a robotic manipulator with an integrated image guidance system. Millimetric accuracy of patient position is achieved thanks to a dual kV X-ray imaging system and a robotic couch. Three tracking methods were available. Synchrony® is a tracking method using fiducial markers within or near the lesion. Xsight® lung is based on the identification of the tumor itself on X-ray images. Xsight® spine used the spine as a marker.
Treatment planning
CT was acquired with free-breathing for both Synchrony® and Xsight® Lung tracking system, whereas the Internal Target Volume (ITV) was generated from 3 CT acquisitions (deep inspiration, deep expiration, and free-breathing) for the Xsight® spine system. The GTV (gross tumor volume) was acquired from a one mm-sized slice CT scan, and the delineation was performed in the pulmonary window. The CTV was defined as follows: GTV = CTV (clinical target volume), and for 3 CT step acquisitions, ITV = CTV. The PTV was defined with a 5 mm margin around the CTV. For peripheral lesions, 60 Gy in three fractions was used. For central lesions (those located within 2 cm from trachea, main and lobar bronchi), different fractionations were possible depending on the dose constraints to the organs at risk: 60 Gy in three fractions, 45 Gy in three fractions, and 60 Gy in eight fractions. Prescription isodose was 80–95%.
Follow-up
Patients were monitored with clinical examination and CT every three months for two years and every six months thereafter. The posttreatment response was assessed using RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1. In case of any doubt, PET CT and/or biopsy were performed. Local failure was considered for lesions recurring within the PTV, while all other lesions were considered distant. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0. Acute toxicities are those which occur during or within six months following radiation. Late toxicities are those which occur after six months.
Statistical analyses
Time-to-event endpoints were estimated between the end date of SABR and the last follow-up using Kaplan-Meir methods. Crude local control and distant control rates, the cumulative incidence of local recurrence and metastatic recurrence rates, progression-free survival (PFS) and overall survival (OS) were assessed. Progression was defined as the time interval from the end of SABR until progression (local or distant) and/or death. Overall survival was defined as the time interval from the end date of SABR to death (from all causes) or the date of the last follow-up. Patients alive were censored at the last follow-up. Statistical differences between cohorts were tested by the two-tailed log-rank test. In order to assess the accuracy of the obtained estimates, hazard ratios and 95% confidence intervals (CIs) were assessed from the Cox proportional hazards models. Cox analyses were used to identify significant predictors of progression (local or metastatic) or death by assessing the following variables: age, sex, center, GTV, PTV, chemotherapy, the timing of metastases, and the number of metastases (1 vs 2). The optimal cut-off for each continuous variable was determined using a receiver operating characteristic (ROC) curve. Factors with p < 0.25 on univariate analysis were included in the multivariate analysis. The median follow-up was estimated by the Schemper and Smith method. 11 Statistical significance was defined as p < 0.05. All analyses were performed using R software version 3.5.1 (R project, Vienna, Austria)
Results
Patient demographics and tumor characteristics
We identified 52 patients with HNSCC and 63 treated lung metastases (Figure 1). Forty-two patients and ten patients were included from our two institutions. Table 1 described patients' characteristics. The median age was 66.5 (range 50–83). Most (86.5%) of subjects were male. CT alone and PET CT alone were performed for lung metastases diagnosis in 12 (23%) patients and 37 (71%) patients, respectively. Histological documentation was available in 3 patients (6%). Sixteen patients (31%), 32 patients (61%) and 4 (8%) patients had an ECOG performance status 0, 1 and 2, respectively. Forty-one patients (79%) presented a solitary lung metastasis, while 11 patients (21%) had two lung metastases.
Figure 1.
Trial flow chart
Table 1.
Characteristics of patients
| Number | Percentage | |
|---|---|---|
| Age | ||
| ≥71 | 17 | 33% |
| <71 | 35 | 67% |
| Sex | ||
| Male | 45 | 87% |
| Female | 7 | 13% |
| Peformance status | ||
| 0 | 16 | 31% |
| 1 | 32 | 61% |
| 2 | 4 | 8% |
| Treatment of the primary tumor | ||
| Surgery | 4 | 8% |
| RT | 23 | 44% |
| Surgery +RT | 25 | 48% |
| Number of metastases | ||
| 1 | 41 | 79% |
| 2 | 11 | 21% |
| Diagnosis of metastases | ||
| CT | 12 | 23% |
| PET-CT | 37 | 61% |
| Biopsy | 3 | 6% |
| Institution | ||
| Tours Hospital | 42 | 81% |
| Center Antoine Lacassagne | 10 | 19% |
CT, Computed Tomography; PET-CT, Positron Emission Tomography- Computed Tomography; RT, Radiation Therapy.
Treatment
Eleven patients (21.1%) received systemic therapy within two months (prior to or after SABR). The most used protocols were Carboplatin-Paclitaxel, the EXTREME regimen, Carboplatin-Cetuximab, or Cetuximab monotherapy. About one-fourth of patients (14/52 = 26.9%) were retreated by SABR for subsequent lung metastases. The median time from the treatment of the primary HNSCC to the development of initial lung metastases was 18 months (3–93). The median GTV was 6.5 cc (1–41.4), and the median PTV was 15.05 cc (1.5–83). Sixty Gy in three fractions was the most used fractionation (47/52 = 90%).
Toxicities
Acute Grade one toxicities were the most prevalent: fatigue (9 patients: 17.3%), cough (4 patients: 8%), dyspnea (4 patients: 8%), respiratory distress (5 patients: 10%). Acute Grade two fatigue was reported in one patient (2%). Late Grade three brachial plexopathy was reported in one patient (2%) with an apical lung lesion where brachial plexus was not contoured, and no dose was reported.
Outcomes
The median follow-up was 45.3 months. Efficacy outcomes were assessable in 50 patients. Crude local control and metastatic control rates were 74% (37/50) and 38% (19/50), respectively, at the end of the follow-up. The cumulative incidence of local recurrence was 13% at 1 year and 33% at 2 years. The cumulative incidence of metastases was 48.4% at 1 year and 69.7% at 2 years. All distant recurrences were in the lungs, with a couple of patients also presenting extrapulmonary lesions. Median progression-free survival (PFS) was 12 months. One-year and 2 year PFS were 49.4 and 27.7%, respectively (Figure 2). The median overall survival (OS) was 46.8 months. One-year and 2 year OS were 85.8 and 65.9%, respectively (Figure 2). To investigate the presence of potential predictive factors for progression or death, univariate and multivariate analyses were performed (Table 2). In univariate analysis, a larger GTV was associated with the poorest outcome in terms of the p-value (1.78 (0.84–3.79), 95% CI (0.84–3.79), p = 0.13). No factor remained significantly correlated with progression or death in the multivariate analysis.
Figure 2.
Overall survival and progression-free survival
Table 2.
Univariate and multivariate analysis for progression-free survival
| Number | Median PFS | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|---|
| HR 95% CI | p value | p value | ||||
| Age | ||||||
| ≥71 | 17 | 21 | 0.88 (0.43–1.8) | 0.73 | ||
| <71 | 35 | 12 | ||||
| Gender | ||||||
| Males | 45 | 12 | 2.1 (0.71–5.74) | 0.19 | 1.86 (0.63–5.53) | 0.26 |
| Females | 7 | 24 | ||||
| GTV | ||||||
| ≥16.6 | 12 | 9 | 1.78 (0.84–3.79) | 0.13 | 1.48 (0.68–3.19) | 0.32 |
| <16.6 | 40 | 17 | ||||
| PTV | ||||||
| ≥15.6 | 21 | 12 | 1.15 (0.59–2.24) | 0.67 | ||
| <15.6 | 27 | 17 | ||||
| Timing of metastasesa | ||||||
| ≥9 months | 39 | 12 | 1.12 (0.49–2.56) | 0.79 | ||
| <9 months | 13 | 6 | ||||
| Number of metastases | ||||||
| 2 | 11 | 12 | 1.66 (0.8–3.4) | 0.17 | 1.49 (0.66–3.33) | 0.33 |
| 1 | 41 | 12.2 | ||||
| Chemotherapy | ||||||
| Yes | 11 | 12 | 1.65 (0.81–3.339) | 0.17 | 1.33 (0.61–2.93) | 0.47 |
| No | 41 | 12.2 | ||||
| Center | ||||||
| Tours hospital | 42 | 12 | 1.1 (0.51–2.49) | 0.76 | ||
| Center Antoine Lacassagne | 10 | 16.5 | ||||
GTV, Gross tumor Volume; PTV, Planning Target Volume.
Time between the end of local treatment for primary tumor and development of lung metastases.
Discussion
The current standard of care for patients with metastatic HNSCC is systemic therapy regardless of the number of metastatic lesions. The choice of treatment is based on the patient’s performance status, previous systemic therapy, PD-L1 expression, and evolution of the disease, which can range from standard platinum-based chemotherapy to EXTREME regimen or immune-checkpoint inhibitors, resulting in a median OS of 7 to 13 months. 12,13 Metastasis-directed therapies for oligometastatic diseases might offer prolonged survival up to 47 months and are of great interest for investigation. 14–17
Even though the lung is the most common site of metastasis from HNSCC, the metachronous limited number of pulmonary lesions is quite rare. Studies evaluating local treatments for metastatic lung lesions from HNSCC are encouraging but sparse. 18–22 Our study included 52 patients and 63 lesions and represented one of the largest cohorts interested in the efficacy of SABR in metachronous pulmonary oligometastatic HNSCC. The favorable outcomes in our study are comparable to recent reports from other institutions and are summarized in Table 3. Interestingly, the median OS in these studies ranged from 23 to 47 months, obviously superior to the 13 month survivals obtained from the most successful systemic treatment to date with Pembrolizumab in the KEYNOTE 048 trial. 13 Patients with a single metastasis have been hypothesized to be the most likely to exhibit favorable metastatic biology, which may explain superior survival compared to patients with heterogeneous multisite of metastases. 2 Our study included a majority of patients with single lung metastasis, pleading for the excellent OS of 46.8 months.
Table 3.
Studies involving SABR for lung metastases from HNSCC primary
| First author | Year | Number of patients |
Median age |
Number of irradiated lung lesions | Synchronous vs metachronous |
Number of metastases | Extrapulmonary metastases |
SABR fractionation | Median follow up (months) | Local control | Disease /progression free survival |
Overall survival |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bates (17) | 2019 | 27 | 65(20-76) | 44 | 5 (18.5%)
vs
22 (81.5%) |
1: 12
(44..4%) 2–3: 12 (44..4%) >3: 3 (11..1%) |
Yes :16
(27%) No: 44 (73%) |
50 Gy in five fr | 19.2 | Per
lesion: 1 year: 75% 2 year: 57% |
DFS: 1 year: 27% 2 year: 14% |
1 year:
78% 2 year: 43% median: 22..8 months |
|
Benomo
(18) |
2019 | 27 | 67(37-85) | 28 | 28 | No: 27 (100%) | 54 Gy in three
fr 55 Gy in five fr 50 Gy in five fr |
22 | Per
patient: 81.25% (crude rate) |
TTP: 1 year: 56.2% 2 year: 35% median: 10 months |
Median: 47 months |
|
|
Pasalic
(19) |
2020 | 55 | 65(26-93) | 68 | 6 (9%) vs 62 (91%) | 1–3 :54
(79%) >4 :14 (21%) |
70 Gy in 10
fr 50 Gy in four fr |
19.3 | Per lesion
: 1 year : 96.6% 2 year : 91.1% |
1 year :
67% 2 year : 54.7% |
||
| Present study | 2020 | 52 | 66.5 (50–83) | 63 | 0 (0%)
vs
52 (100%) |
1: 41
(79%) 2: 11 (21%) |
No: 52 (100%) | 60 Gy in three fr | 45.3 | Per patient
: 1 year:87% 2 year:67% |
PFS: 1 year: 49.4% 2 year: 27.7% median: 12 months |
1 year:
85.8% 2 year: 65.9% median: 46.8 months |
DFS, Disease Free Survival; PFS, Progression Free Survival; TTP, Time To Progression.
A major advantage of metastasis-directed SABR in the setting of oligometastatic disease is toxicity profiles compared to those of systemic treatments. Toxicities of grade ≥3 were as high as 82–85% in the EXTREME and the KEYNOTE 048 trials. 12,13 Patients in the current study were all treated homogeneously by the Cyberknife® system with well-known dosimetric advantages on organs at risk. Toxicities reported were uncommon, with only one case of Grade three brachial plexopathy. No additional toxicities were reported in one-fifth of patients receiving concurrent systemic treatment. Furthermore, one-fourth of well-selected patients were re-irradiated for oligoprogressive lesions with no excessive adverse side effects. The possibility of further directed therapy to subsequent lesions may postpone more the (re)introduction of systemic treatment and, on the other hand, may explain the discrepancy between the short PFS (12 months) and the prolonged OS (46.8 months) in this study.
The local control rates (LCR) of irradiated lesions were 87% at 1 year and 67% at 2 years, which were comparable to the LCR of 81.25% reported by Bonomo et al, 21 and were better than the 1y-LCR of 75% and 2y-LCR of 57% from Bates et al.’s study. 20 These results were lower than those obtained with same-size primary lung cancers with excellent LCR of more than 90% at 2 years or more. 4,23 This observation is quite surprising since HNSCC is considered radiosensible among solid tumors. Some possible explanations include the heterogeneity of cancers and the primary radio(chemo)therapy previously administered could help to select and expand the radioresistant clones to metastatic sites, the acquirement of radioresistant genomic alterations during the metastatic process such as overexpression of EGFR and TP53 mutations, which enhance radiation-induced DNA damages repair. 24–26
Another concern of metastasis-directed therapy is the high rates of further distant relapse, which appeared in more than half of patients at 1 year. 20,21 Therefore, the role of systemic treatment in metastatic diseases remains important. The questions are the moment to incorporate this treatment and to which populations of patients so that we can achieve the highest synergistic potential of these two modalities. Several approaches using biomolecular and/or radiomics methods are under investigation and might help clinicians better discriminate between those who can benefit from SABR alone and those who need associated systemic treatment. 27–29
Our study has several limitations. Selection bias and the retrospective nature of data do not allow for generalization of the results of this study for all metastatic patients: the use of such approaches must be individualized and managed within a multidisciplinary team of dedicated specialists. HPV status and the primary tumor localization, which represent major prognostic factors, were also lacking. Moreover, histological confirmation was only available in a small proportion of patients (6%), knowing the fact that the majority of our patients had a solitary lung lesion which may have corresponded to a secondary HNSCC or primary lung cancer given the high prevalence of smoking in our cohort. Parameters on lung CT such as speculated margin, subsolid density, etc., can help to discriminate of primary lung cancer from solitary lung metastasis, 30 which was rigorously evaluated by a trained radiologist and validated by the local multidisciplinary tumor board. Finally, the benefit and the safety of systemic therapies were not assessed since most patients were referred from other institutions for SABR.
Conclusion
Our study suggests that HNSCC patients with controlled primary and oligometastatic phenotype benefit from metastatic directed local therapy and is associated with an extremely low toxicity rate. However, these results need to be interpreted with caution given the retrospective nature of the study and the risk of underreporting of toxicities.
Footnotes
Acknowledgements: Our patients, Fatima AZZOUNE DEBBI.
Contributor Information
Kamel Debbi, Email: kamel.debbi@aphp.fr, Oncology-Radiotherapy Department, Henry-S.-Kaplan Cancer Center, CHRU de Tours, Tours, France ; University François-Rabelais, Tours, France ; Radiation Oncology Department, Henri Mondor University Hospital, APHP, UPEC, Créteil, France .
Gokoulakrichenane Loganadane, Email: gokoulakrichenane.loganadane@aphp.fr, Radiation Oncology Department, Henri Mondor University Hospital, APHP, UPEC, Créteil, France .
Nhu Hanh To, Email: nhuhanh.to@aphp.fr, Radiation Oncology Department, Henri Mondor University Hospital, APHP, UPEC, Créteil, France .
Remy Kinj, Email: remykinj@gmail.com, Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice, France .
Zain A Husain, Email: zain.husain@gmail.com, Department of Radiation Oncology, Odette Cancer Center, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada .
Sophie Chapet, Email: S.CHAPET@chu-tours.fr, Oncology-Radiotherapy Department, Henry-S.-Kaplan Cancer Center, CHRU de Tours, Tours, France .
Nam P Nguyen, Email: npnguyen@towson.edu, Department of Radiation Oncology, Howard University, Washington, DC, USA .
Isabelle Barillot, Email: I.BARILLOT@chu-tours.fr, Oncology-Radiotherapy Department, Henry-S.-Kaplan Cancer Center, CHRU de Tours, Tours, France ; University François-Rabelais, Tours, France .
Karen Benezery, Email: karen.benezery@nice-unicancer.fr, Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice, France .
Yazid Belkacemi, Email: yazid.belkacemi@aphp.fr, Radiation Oncology Department, Henri Mondor University Hospital, APHP, UPEC, Créteil, France .
Gilles Calais, Email: gilles.calais@univ-tours.fr, Oncology-Radiotherapy Department, Henry-S.-Kaplan Cancer Center, CHRU de Tours, Tours, France ; University François-Rabelais, Tours, France .
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