Abstract
Objectives
We aim to report oncologic outcomes after conventional radiotherapy (ConRT) using opposed lateral beams and intensity modulated radiation therapy (IMRT) for T1N0 glottic squamous cell carcinoma.
Study design
Retrospective case-control study.
Methods
We retrospectively reviewed demographic, disease, and treatment characteristics for patients treated at our institution during 2000–2013.
Results
One hundred fifty-three patients (71%) were treated using ConRT and 62 (29%) using IMRT. The median follow-up for all patients was 68 months. There was no statistically significant difference in 5-year local control between patients with T1a vs. T1b disease (94% vs. 89%, respectively p=0.5). 3-year locoregional control for patients treated with ConRT was 94% compared to 97% with IMRT (p=0.4). 3-year overall survival (OS) for patients treated with ConRT was 92.5% compared with 100% with IMRT (p=0.1). Twelve of 14 patients with local recurrence underwent salvage surgery with 5-year ultimate locoregional control of 98.5% and 97.1% in the ConRT and IMRT cohorts, respectively (p=0.7). Multivariate analysis showed age< 60 years (p<0.0001) and pre-treatment ECOG performance status <2 (p=0.0022) to be independent correlates of improved OS. Post-radiation cerebrovascular events were in four patients in the ConRT cohort (3%) while no patients in the IMRT cohort suffered any events.
Conclusions
As the oncologic outcomes for patients treated with IMRT were excellent, and IMRT allows for carotid sparing, we have transitioned to IMRT as our standard for most patients with T1 glottic cancer.
Keywords: IMRT, radiation therapy, T1 glottic squamous cell carcinoma, larynx cancer, oncologic outcomes
INTRODUCTION
Patients treated with radiation therapy (RT) for T1 glottic squamous cell carcinoma have excellent disease control rates, with a general local control probability >90% for T1a disease, and ranging from 64% to 93% for T1b(1–16). The conventional radiation therapy (ConRT) technique uses opposed lateral radiation fields that give full or greater dose to the adjacent carotid arteries.(17–20) It is believed that patients who receive RT to the neck have an increased risk for cerebrovascular events (CVE) such as ischemic strokes or transient ischemic attacks (TIA), likely due to radiation to the carotid vessels.(21–25)
While most patients treated with RT for head and neck cancer have nodal risk requiring elective or therapeutic nodal irradiation, the risk for neck nodal metastases for patients with T1 glottic cancers is negligible. (26) This creates the opportunity to tailor RT delivery exclusively to the glottic target while avoiding the adjacent carotid arteries. Radiation techniques such as intensity modulated radiation therapy (IMRT/VMAT) allow for this dosimetric distinction.
Our group reported a preliminary experience using IMRT for early glottic cancers in an effort to reduce radiation dose to the bilateral carotid arteries, describing dosimetric and early clinical results.(20) While some groups subsequently also adopted IMRT for early stage glottic tumors(7, 27), others have raised the concern that more conformal techniques such as IMRT might increase the risk for geographic miss and subsequent local persistence/recurrence because of organ motion and/or uncertainties in target delineation (18, 28).
To this end, we herein update our growing experience with IMRT for T1 glottic cancer during our transition from conventional opposed lateral technique to IMRT. The aim of the current study is to determine the oncologic and survival outcomes for patients irradiated for T1 glottic larynx cancer in the modern era (i.e. since IMRT for T1 glottic cancer was initiated at our facility in 2006) compared with patients treated with conventional opposed lateral beams.
MATERIALS AND METHODS
Patient and Treatment Characteristics
The study was conducted under an approved Institutional Review Board (IRB) protocol. The electronic records of all patients treated between 2000 – 2013, whose disease met the staging criteria for T1N0M0 squamous cell cancer of the glottis (per the 7th [2010] edition of the American Joint Committee on Cancer [AJCC] staging manual), were reviewed. Patient demographics, Eastern Cooperative Oncology Group (ECOG) performance status scores, tumor data (pathologic grade and extent of involvement) were collected. All extracted information was recorded in a database (SPSS, IBM Inc., Chicago, IL), including radiotherapy dose, fractionation, technique, beam energy, and delivery technique. Biologically equivalent dose (BED) was calculated using the simple BED equation without correction for repopulation.(29) Disease recurrence was coded as local recurrence (i.e., occurring in the treated primary site), locoregional recurrence (i.e., occurring in the treated primary site or untreated lymph nodes), or distant metastases (i.e., squamous cell carcinomas occurring outside the treated head and neck). Cause of death was manually coded; patients with active cancer at the time of death were coded as having “cancer-related death,” whereas patients without active disease at last follow-up were coded as having “non-cancer death.”
Radiotherapy
All patients treated before 2006 received conventional radiation technique using opposed lateral beams. IMRT was first introduced to patients with T1 glottic cancer at 2006 in attempt to minimize the carotid dose. We initially used static field IMRT with 5–7 beams technique. Then, the volumetric modulated arc therapy (VMAT) was introduced 2010 using two-arc technique in order to improve treatment efficiency by reducing the time of treatment delivery. The CTV encompassed the entire thyroid and cricoid cartilages with the anterior margin covering the thyroid cartilage with up to a 5-mm margin and the posterior margin covering the posterior limit of the thyroid and cricoid cartilages. Organs at risk included the spinal cord with maximum dose < 20 Gy, the parotid gland with mean dose < 26 Gy, the submandibular gland with mean dose < 40 Gy, the mandible with maximum dose < 60 Gy, as well as the right and left carotid arteries. We tried to push the dose to carotids as low as possible but with no specific constraints because of the lack of well-defined dose thresholds associated with carotid toxicity. Daily kV imaging was used to assure that the setup is accurate, and the laryngeal cartilages was used as the setup markers. Dose prescription ranged from 63–65.25 Gy in 28–29 fractions using 2.25 Gy daily fractions or 66–70 Gy in 33–35 fractions using 2 Gy daily fractions. Higher doses were prescribed to more bulky tumors. Bolus was used when necessary to ensure adequate dose build-up. IMRT was delivered using Varian (Varian Medical Systems, Palo Alto CA) linear accelerators delivering 6-MV photons.
Survival Endpoints
Survival and local control outcomes were calculated. Patient- and treatment-related factors were evaluated for association with disease control and survival endpoints. Outcome measures included: overall survival (OS; defined as death from any cause as an event, all others censored), local control (LC; defined as time without local recurrence, with local recurrence or cancer in the larynx coded as an event and all others censored), locoregional control (LRC; defined as time without local or cervical nodal recurrence, with local or nodal recurrence coded as an event and all others censored) and freedom from distant metastasis (FDM; defined as time without distant metastasis, with any distant disease outside the coded as an event and all others censored).
Post-therapy Functional Endpoints
Patient dependence on PEG or Dobhoff tube at six months post-treatment, 12 months post-treatment, as well as at the time of most recent follow-up was recorded. Post-treatment aspiration events were recorded based on any evidence or indication in follow-up or speech pathology notes. Any pre and/or post-treatment cerebrovascular events were also recorded including: strokes, TIAs and carotid-embolic events.
Statistical Analysis
Chi-square testing (with Fisher’s exact technique with bins <5 patients) was used for proportional assessment; non-parametric Wilcoxon rank sum test was used for continuous variable comparison between cohorts. For actuarial comparisons of product limit curves, the log-rank test was used. We used Cox proportional hazards modeling to determine whether patient- and/or treatment-related factors were associated with outcomes. Hazard ratios (HR) and 95% confidence intervals (CI) were presented. Patients were categorized into two therapy cohorts for Kaplan Meier analysis: intensity modulated radiotherapy (IMRT) and conventional radiotherapy. Data were analyzed using JMP 12 Pro statistical software (SAS Institute, Cary, NC), and statistical significance was determined using a specified non–Bonferroni-corrected α of 0.05. The Kaplan-Meier product limit method was used to calculate survival and disease outcome rates at 3- and 5-year endpoints. The 3-year endpoints were used when we stratified by radiation technique due to relatively shorter median follow-up in the IMRT cohort as compared with the ConRT cohort. The date of diagnosis was used for time zero. The log-rank test was used for actuarial comparisons of endpoints between treatment methods.
RESULTS
Patient and Treatment Characteristics
A total of 215 patients with previously untreated T1 glottic SCC were irradiated at our facility during the study period. The patients’ median age at diagnosis was 63 years (range 23–93), and 186 patients (87%) were men. One hundred fifty-four patients (72%) had T1a disease while 61 patients (28%) had T1b. One hundred fifty-three patients (71%) were treated with ConRT using opposed lateral beams while 62 patients (29%) were treated with IMRT (static field n=49, and VMAT n=13). The majority of patients (51%) were treated using a total dose of 63 Gy in 28 fractions (i.e. 2.25 Gy per fraction). The second most common dose delivered was 66 Gy in 33 fractions (i.e. 2 Gy per fraction) in 32% of patients. Patient demographics, disease and treatment characteristics are summarized in Table 1 for both treatment cohorts.
Table 1:
Patients, disease and treatment characteristics.
| Characteristic | ConRT (n=153) (%) | IMRT (n=62) (%) | Significance |
|---|---|---|---|
| Sex | |||
| Female | 24 (16) | 5 (8) | p = 0.1 |
| Male | 129 (84) | 57 (92) | |
| Ethnicity | |||
| Black/African-American | 13 (8) | 5 (8) | p = 0.3 |
| Hispanic/Latino | 27 (18) | 7 (11) | |
| White | 108 (71) | 45 (73) | |
| Other/unspecified | 5 (3) | 5 (8) | |
| Age | |||
| <60 years | 53 (35) | 27 (44) | p = 0.2 |
| >60 years | 100 (65) | 35 (56) | |
| Pathologic grade | |||
| Well differentiated | 37 (24) | 12 (19) | p = 0.8 |
| Moderately differentiated | 69 (45) | 33 (53) | |
| Poorly differentiated | 8 (5) | 3 (5) | |
| Unknown/unspecified | 39 (26) | 14 (23) | |
| Smoking history at diagnosis | |||
| None | 22 (14) | 19 (31) | p = 0.01 |
| Positive | 131 (86) | 43 (69) | |
| T stage | |||
| T1a | 107 (70) | 47 (76) | p= 0.4 |
| T1b | 46 (30) | 15 (24) | |
| Radiation beam energy | |||
| 6 MV | 66 (43) | 62 (100) | p < .0001 |
| 60Co | 87 (57) | 0 (0) | |
| Mean ± SD total radiation dose (Gy) | 64.1 ± 3.4 | 64.3 ± 2.1 | p = 0.4 |
| Mean ± SD no. of fractions received | 30.2 ± 3.0 | 29.7 ± 2.4 | p = 0.3 |
| Mean ± SD BED (2GyE) | 77.9 ± 3.9 | 78.4 ± 2.1 | p = 0.9 |
Outcomes
The median follow-up for all patients was 68 months (range 3–172). The median follow up for the ConRT cohort was 81.5 months (range 3–172) while median follow up for the IMRT cohort was 39.0 months (range 9–103).
Fourteen patients (6.5%) had locoregional recurrence; 11 patients had local recurrence alone, and three patients had both local and regional recurrence. The actuarial 3- and 5-year LC for the entire cohort were 94.9% and 92.8%, respectively. There was no statistically significant difference in 3- and 5-year LC between T1a versus T1b patients (95% vs. 94% and 94% vs. 89%, respectively p=0.5).
When stratified by RT treatment technique; 12 patients (8%) in the ConRT cohort had locoregional recurrence (i.e. 9 of the 12 recurrences occurred in the first 3-years post-RT) compared with 2 patients (3%) in the IMRT cohort (i.e. all in the first 3-years post-IMRT). The 3-year LC was 96.5% in the IMRT cohort, compared to 93.6% for the cohort treated with conventional radiation. (HR= 0.5, 95% CI= 0.1–2, p=0.4, Figure 1).
Figure 1:
Kaplan Meier Curves showing the Local Control for Conventional vs. IMRT Cohorts through 84 months. Shaded areas denote 95% confidence intervals.
Ten of the 12 (86%) patients with recurrences in the ConRT cohort underwent salvage therapy. Five had total laryngectomies, 3 had partial laryngectomies, and 2 had cordectomies. Six patients who underwent laryngectomy, including all 5 who had total laryngectomies also had neck dissections. Of the two patients in the IMRT cohort who experienced a recurrence, one received salvage treatment with total laryngectomy followed by chemotherapy while the other patient had salvage treatment with a partial laryngectomy, followed by subsequent resection of the false cord. Sixty-seven percent of the cohort who received salvage therapy had no further evidence of tumor progression after salvage treatment. The actuarial 5-year ultimate locoregional control (uLRC) was 98.5% and 97.1% in the ConRT and IMRT cohorts, respectively (p=0.7).
Two patients (one in each treatment cohort) developed distant metastases subsequent to local failure. No patient ever developed an isolated event of distant metastases in this study. The actuarial 3-year FDM was 99.2% and 97.1% in the ConRT and IMRT cohorts, respectively (p=0.4).
An exceedingly small number of patients in this study experienced disease-related death; only three patients could be identified who died with active disease at the time of death. Two of these had distant metastases and one had an unsalvageable regional recurrence. Overall, this translates to only 1.4% of patients succumbing to a disease-related cause of death, as patients are much more likely to die from non-oncologic causes than cancer-attributable demise. Our data showed uniformly excellent survival outcomes regardless of whether patients had T1a or T1b disease and whether they were treated with ConRT or IMRT (Table 2). The actuarial 3- and 5-year overall survival (OS) for the entire cohort was 94.4% and 85.9%, respectively. The 3-year OS were numerically superior in the IMRT compared to the ConRT cohort, but the difference did not reach statistical significance (100% vs. 92.5%, respectively, HR= 0.4, 95%CI= 0.1–1.2, p=0.1, Figure 2).
Table 2:
5-Year Survival and Control Rates by Treatment Cohort and T1 subcategory.
| Endpoint | Combined (n=215) | ConRT (n=153) | IMRT (n=62) | |||
|---|---|---|---|---|---|---|
| T1a (n=154) | T1b (n=61) | T1a (n=107) | T1b (n=46) | T1a (n=47) | T1b (n=15) | |
| 5-Year LC (%) | 94 | 89 | 94 | 87 | 95 | 100 |
| 5-Year LRC (%) | 94 | 89 | 94 | 87 | 95 | 100 |
| 5-Year FDM (%) | 99 | 98 | 100 | 98 | 96 | 100 |
| 5-Year OS (%) | 84 | 92 | 82 | 90 | 90 | 100 |
LC: local control; LRC: Locoregional control; FDM: freedom from distant disease; OS: overall survival.
Figure 2:
Kaplan Meier Curves showing the Overall Survival for Conventional vs. IMRT Cohorts through 84 months.
Univariate and Multivariate analysis
In uni- and multi-variate analysis of LC, total dose, sex, age < 60 years at diagnosis, smoking status, T1a/T1b disease status, IMRT/conventional cohort, tumor extent, beam energy, fractionation schedule, total treatment duration or pre-treatment ECOG <2 was not associated with improved LC (all p>0.1).
Univariate analysis for OS showed age < 60 years at diagnosis (p<0.0001) and pre-treatment ECOG <2 (p=0.01) to be associated with improved OS. Multivariate analysis also showed age < 60 years at diagnosis (p<0.0001) and pre-treatment ECOG <2 (p=0.0022) to be independent correlates of improved OS.
Late sequelae
PEG/DHT tube was present in 4 patients in the ConRT cohort (3%) vs. no patients in the IMRT cohort at 6 months (p=0.5). An aspiration event was recorded in 10 patients in the ConRT cohort (7%) and 3 patients in the IMRT cohort (5%) (p=0.4). Post-RT cerebrovascular events occurred in 4 patients in the ConRT cohort (3%) (two within 3-years post-RT and two late after 5-years) while none of the patients in the IMRT cohort suffered any post-RT cerebrovascular events (p=0.7). Two patients experienced a TIA with no residual effects, one patient experienced an embolic stroke which was treated with a carotid endarterectomy and resulted in no residual effects, and one patient was reported to have experienced a CVE with subsequent hemiparesis.
DISCUSSION
Our expanded series of patients with T1 glottic cancer treated with IMRT demonstrate excellent rates of oncologic control and survival. These results mirror the local control and survival results reported in modern radiotherapy series (Table 3 and 4), yet patients treated with IMRT received substantially less dose to the carotid arteries. This may reduce risk for stroke, and maintain future radiation therapy options in case patients develop second head and neck cancers requiring RT. Our larger and maturing data set now provides clear evidence that carotid sparing in our experience did not compromise oncologic outcomes.
Table 3:
Clinical reports for outcomes of radiation therapy in glottic cancer.
| Reference | Author | Year | N* | T Stage | Modality | Results |
|---|---|---|---|---|---|---|
| (7) | Zumsteg et al. | 2015 | 330 | Tis (n=16), T1 (n=244) T2 (n=70 | ConRT (n=282) and IMRT (n=48) | 3-year LC of 91% for T1 tumors. 3-year LC rates of 88% and 89% for IMRT and ConRT, respectively (p=0.938). |
| (1) | Lim et al. | 2015 | 222 | T1 (n=155), T2 (n=67) | ConRT | 5-year LRFS and ultimate LRFS 87.8% and 90.3%, respectively (HR 2.30; 95% CI 1.08 to 4.94). |
| (2) | Chera et al. | 2010 | 585 | T1 (n=325), T2 (n=260) | ConRT | 5-year OS: T1a 82%, T1b 83%. 5-year LC: T1a 94%, T1b 93%. 5-year CSS: T1a 97%, T1b 99%. Overall treatment time >41 days (p=0.001) and poorly differentiate histology (p=0.016) adversely affected LC. |
| (3) | Khan et al. | 2012 | 141 | T1 (n=86), T2 (n=54) | ConRT | 5-year LC: T1a 94%, T1b 83%. 10-year LC: T1a 89%, T1b 83%. T-stage, heavy alcohol consumption during treatment, and use of weighted fields were predictive for poor outcome (p < 0.05). |
| (5) | Kim et al. | 2012 | 157 | T1 (n=125), T2 (n=32) | ConRT | Overall 5 year DFS and DSS 84.7% and 94.8%. DFS in group B (67.5 Gy in 30 fractions) was better in T1 cohort (94.6% vs. 83.4%, p=0.025). Univariate analysis showed tumor extent, cord mobility, T-stage, and dose schedule had significant influence on disease-free survival, and multivariate analysis showed tumor extent and dose schedule were associated with DFS. |
| (6) | Mourad et al. | 2013 | 253 | T1 (n=195), T2 (n=58) | ConRT | LRC T1 99.5%, T2 91%. 5-year overall CSS was 100%.LRC: 99.5% |
| (8) | Manzo et al. | 2010 | 98 | T1 | ConRT | 5-year LC: 84%, 10-year LC: 82% 5-year DFS: 96%, 10-year DFS: 96%, 5-year OS:85.8%. 10-year OS: 69.4% |
| (9) | Cacicedo et al. | 2013 | 117 | T1 | ConRT | 5/10/15-year LC: 84%/80.2%/80.2% 5/10/15-year OS: 81.2%/66.1%/48.3% 5/10/15-year CSS: 90.6%/90.6%/90.6%. 19/20 recurrences salvaged with laryngectomy, UC of 90.6 %. Age ≥65 years had a statistically significant effect on Os (but not in CSS), with a hazard ratio of 2.45 (95 % confidence interval 1.29–4.66; p = 0.006). |
| (10) | Laskar et al. | 2012 | 652 | T1 | ConRT | 10-year LC: 84%, 10-year OS: 86.1%. Response to radiation had significant effect LC with univariate analysis (p=0.001). |
| (11) | Gultekin et al. | 2012 | 183 | T1 | ConRT | 5-year OS: 89%, 5-year LC: 81%, 5-year CSS: 90%. Overall treatment time >38 days and age ≥60 years were significant prognostic factors for OS on MVA. |
| (12) | Dinapoli et al. | 2010 | 143 | T1 | ConRT (n=70) and Surgery (n=73) | OS & DFS non-different; Better scores for each category in the VHI were found for patients receiving radiotherapy compared to surgery (physical: p = 0.0023; functional: p < 0.0001; environmental: p < 0.001). |
| (13) | Hong et al. | 2013 | 1413 | T1 and T2 | ConRT (n=1055) and Surgery (n=358) | 10-year risk of CVD was 56.5% (95% CI 51.5%–61.5%) for the RT cohort (n=1055) versus 48.7% (41.1%–56.3%) in the surgery cohort (n=358; P=.27). UVA showed an increased association of CVD with more recent diagnosis (p=.001) and increasing age (p=.001). |
| (14) | Onimaru et al. | 2011 | 201 | T1 | ConRT | 5-year OS: 90.8%, 5-year LC: 89.8%. For overall treatment time ≥ 47 days, LC was 82.6 ± 6.0% at both 3 and 5 years. For overall treatment time ≤ 46 days, LC was 94.6 ± 1.9% at 3 years and 91.8 ± 2.4% at 5 years (p = 0.0349). |
| (15) | Ermis et al. | 2015 | 132 | T1 (n=68), T2 (n=64) | ConRT | 5-year LC: T1a 91.8%, T1b 81.6%. 5-year ULC: T1a 100%, T1b 93.8%. |
| (16) | Jones et al. | 2010 | 118 | T1 (n=77), T (n=41) | ConRT | 5-year LC: T1a 91%, T1b 95%. 5-year OS: T1a 73%, T1b 78%. 5-year CSS: T1a 96%, T1b 100%. Eight (7%) of the 118 patients developed a local recurrence. There were no isolated regional or distant recurrences. |
Table 4:
Dosimetric reports for outcomes of radiation therapy in glottic cancer.
| Reference | Author | Year | N* | T stage | Modality | Results |
|---|---|---|---|---|---|---|
| (20) | Rosenthal et al. | 2015 | 6 | T1 and T2 | ConRT and IMRT | IMRT reduced radiation dose to carotid arteries (p < 0.05). ConRT, median carotid V35, V50, and V60 were 100%, 100%, and 69.0%, respectively. IMRT decreased these to 2%, 0% and 0%, respectively (p<0.01) |
| (18) | Chera et al. | 2010 | 5 | T1 | ConRT and IMRT | Carotid dose lowest with IMRT. With bilateral vocal cord target, median carotid dose was 10Gy with IMRT, 25 Gy with 3DConRT, and 38 Gy with LATS (p < 0.05). With unilateral target, median carotid dose was 4 Gy with IMRT, 19 Gy with 3DConRT, and 39 Gy with LATS (p < 0.05). |
| (35) | Osman et al. | 2012 | 10 | T1 | ConRT and IMRT | ConRT and IMRT population-averaged mean dose ± standard deviation to the planning target volume was 67 ± 1 Gy. Contralateral vocal cord dose reduced from 66 ± 1 Gy in the conventional plans to 39 ± 8 Gy and 36 ± 6 Gy in the coplanar and non-coplanar IMRT plans, respectively. |
| (37) | Sert et al. | 2012 | 5 | T1 | ConRT and IMRT | IMRT planning provided the best carotid-sparing doses. Mean carotid V35, V50, and V63 values including OLBF, 3DConRT, and IMRT were 70%, 47%, 35%; 55%, 15%, 5% and 28%, 6%, 0%, respectively. The statistical comparison of V35, V50 and V63 revealed significant values for OLBF and IMRT. |
| (38) | Garcez et al. | 2014 | 10 | T1 | ConRT | The average dose carotids with anterior oblique technique was 21 Gy compared with 37 Gy using lateral parallel opposed pair arrangement (p < 0.0001). |
The rates of late radiation sequelae were very low in both cohorts. Given the overall low rate of cerebrovascular events and the relatively higher prevalence of smokers in the ConRT cohort, it is difficult to make any determinative statements regarding long-term probability of reduction of such toxicity and we will continue to follow these patients as survivorship continues. In addition, IMRT showed numerically lower rates of late dysphagia, aspiration, and feeding tube dependence.
However, our study is limited because of the retrospective nature and relatively shorter duration of follow-up for patients in the IMRT cohort compared to those in the ConRT cohort. While extended long-term data on cerebrovascular outcomes for all patients in this series is currently unavailable, we are continuously monitoring our data set, and thus far have had four post-treatment cerebrovascular events in the ConRT cohort while no events encountered in IMRT cohort. In addition, the study is also limited by the lack of formal assessment of voice quality after treatment. Another limitation is the lack of HPV status testing in our cohort, given that recent data suggest that HPV status may have a prognostic impact in early stage laryngeal tumors.(30–32)
Nonetheless, this data set represents, to our knowledge, the largest currently definitive series for benchmarking of local control and survival probability for IMRT for T1 glottic cancer. Our results are comparable to others published experience with IMRT. Especially notable is a recent study reporting the next largest T1 larynx dataset domestically, by Zumsteg et al., who report outcomes for T1–2 larynx cancers in an overlapping interval at a similar tertiary U.S. cancer center, detailing 32 IMRT and 212 ConRT T1 cases treated from 1989–2011, and showing 91% local control at 3-years for T1 tumors. We limited our series to the current era (e.g. after IMRT availability) to assure that staging /imaging techniques/technology were comparable across cohorts, and have included outcomes out to 5-years post-therapy, but in concert with Zumsteg et al., these data show concordant equivalence of IMRT and ConRT outcomes(7).
We previously reported that small volume IMRT for T1 glottic cancer requires rigorous patient evaluation, radiation planning, delivery, monitoring, and quality assurance.(20) This includes laryngoscopic examination, multidisciplinary surgical/radiotherapist evaluation of tumor extent, high resolution angled axial CT examination for evaluation of occult extension, carful target delineation, evaluation of glottic motion, rigorous clinical and physics quality assurance, and in-treatment image guidance.(20, 33, 34)
Future efforts are underway to continue our dose-reduction strategies for normal tissue dose reduction. For instance, Al-Mamgani et al. have defined a cohort of patients feasibly treated with unilateral single-vocal-cord radiotherapy.(17, 35) We have proposed a longitudinal protocol investigating vocal quality metrics following (unilateral or bilateral) vocal cord radiation. As Aaltonen et al. have suggested in randomized trial, current approaches with RT can result in comparably better vocal outcomes than laser micro-resection, though global voice quality is excellent regardless; conceivably, it may be that vocal cord sparing RT detectably improves on these already outstanding functional outcomes.(36) Nonetheless, given the paucity of observed events (either oncologic or cerebrovascular complications) such trials will likely take decades to accrue, even at a high-volume center such as ours. In the interim, we recommend that IMRT for T1 glottic cancers be carefully considered as standard of care in the setting of rigorous quality assurance as an alternative to opposed lateral conventional radiotherapy.
CONCLUSIONS
Excellent locoregional control and survival was achieved in all patients presented in this study. Treatment was safe with rare late sequelae in both ConRT and IMRT cohorts. The results of patients treated using IMRT were comparable to ConRT. Due to excellent local control and the reduced radiation dose delivered to the carotid arteries with the consequential potential for a reduced long-term toxicity profile, our standard is now IMRT for patients with T1 glottic SCC. However, ConRT remains a standard treatment approach, given the excellent outcomes as well as the low rates of long-term toxicity in patients treated with such radiation technique. Additional experience, larger cohorts, and longer follow-up will be necessary to demonstrate outcomes for carotid artery effects in both treatment cohorts.
Grant or financial support/disclosures
Drs. Mohamed, Lai, Hutcheson, and Fuller receive(d) funding support from the National Institutes of Health (NIH)/National Institute for Dental and Craniofacial Research (1R01DE025248–01/R56DE025248–01) and NIH/NCI Early Phase Clinical Trials in Imaging and Image-Guided Interventions Program (1R01CA218148–01). Dr. Fuller received/receives federal grant and/or salary support from: the NIH/National Cancer Institute (NCI) Head and Neck Specialized Programs of Research Excellence (SPORE) Developmental Research Program Award (P50CA097007–10) and Pau l Calabresi Clinical Oncology Program Award (K12 CA088084–06); a National Science Foundation (NSF), Division of Mathematical Sciences, Joint NIH/NSF Initiative on Quantitative Approaches to Biomedical Big Data (QuBBD) Grant (NSF 1557679); the NIH Big Data to Knowledge (BD2K) Program of the National Cancer Institute (NCI) Early Stage Development of Technologies in Biomedical Computing, Informatics, and Big Data Science Award (1R01CA214825–01); and the Cancer center Support Grant Radiation Oncology/Cancer Imaging Program Seed Grant (5P30CA016672). Dr. Fuller receives(d) industry grant support and speaker travel funding from Elekta AB. Dr. Fuller is a Sabin Family Foundation Fellow. Dr. Rosenthal receives grants from: NIH/NCI (5R0CA148707–03) and (5R01CA160880–03). These listed funders/supporters played no role in the study design, collection, analysis, and interpretation of data, manuscript writing, or decision to submit the report for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflict of interest of the listed funding with the content of this work.
REFERENCES
- 1.Lim YJ, Wu HG, Kwon TK, et al. Long-Term Outcome of Definitive Radiotherapy for Early Glottic Cancer: Prognostic Factors and Patterns of Local Failure. Cancer Res Treat 2015;47(4):862–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Chera BS, Amdur RJ, Morris CG, Kirwan JM, Mendenhall WM. T1N0 to T2N0 squamous cell carcinoma of the glottic larynx treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2010;78(2):461–6. [DOI] [PubMed] [Google Scholar]
- 3.Khan MK, Koyfman SA, Hunter GK, Reddy CA, Saxton JP. Definitive radiotherapy for early (T1-T2) glottic squamous cell carcinoma: a 20 year Cleveland Clinic experience. Radiat Oncol 2012;7:193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tong CC, Au KH, Ngan RK, et al. Definitive radiotherapy for early stage glottic cancer by 6 MV photons. Head Neck Oncol 2012;4:23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kim TG, Ahn YC, Nam HR, et al. Definitive radiation therapy for early glottic cancer: experience of two fractionation schedules. Clin Exp Otorhinolaryngol 2012;5(2):94–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mourad WF, Hu KS, Shourbaji RA, Woode R, Harrison LB. Long-term follow-up and pattern of failure for T1-T2 glottic cancer after definitive radiation therapy. Am J Clin Oncol 2013;36(6):580–3. [DOI] [PubMed] [Google Scholar]
- 7.Zumsteg ZS, Riaz N, Jaffery S, et al. Carotid sparing intensity-modulated radiation therapy achieves comparable locoregional control to conventional radiotherapy in T1–2N0 laryngeal carcinoma. Oral Oncol 2015;51(7):716–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Manzo R, Ravo V, Murino P, et al. Outcomes of radiation therapy for T1 glottic carcinoma from an Italian regional series with doses ranging from 60 to 66 Gy. Tumori 2010;96(4):577–81. [DOI] [PubMed] [Google Scholar]
- 9.Cacicedo J, Casquero F, del Hoyo O, et al. Definitive radiotherapy for T1 glottic squamous cell carcinoma: a 15-year Cruces University Hospital experience. Clin Transl Oncol 2013;15(11):925–31. [DOI] [PubMed] [Google Scholar]
- 10.Laskar SG, Baijal G, Murthy V, et al. Hypofractionated radiotherapy for T1N0M0 glottic cancer: retrospective analysis of two different cohorts of dose-fractionation schedules from a single institution. Clin Oncol (R Coll Radiol) 2012;24(10):e180–6. [DOI] [PubMed] [Google Scholar]
- 11.Gultekin M, Ozyar E, Cengiz M, et al. High daily fraction dose external radiotherapy for T1 glottic carcinoma: treatment results and prognostic factors. Head Neck 2012;34(7):1009–14. [DOI] [PubMed] [Google Scholar]
- 12.Dinapoli N, Parrilla C, Galli J, et al. Multidisciplinary approach in the treatment of T1 glottic cancer. The role of patient preference in a homogenous patient population. Strahlenther Onkol 2010;186(11):607–13. [DOI] [PubMed] [Google Scholar]
- 13.Hong JC, Kruser TJ, Gondi V, et al. Risk of cerebrovascular events in elderly patients after radiation therapy versus surgery for early-stage glottic cancer. Int J Radiat Oncol Biol Phys 2013;87(2):290–6. [DOI] [PubMed] [Google Scholar]
- 14.Onimaru R, Hasegawa M, Yasuda K, et al. Radiotherapy for glottic T1N0 carcinoma with slight hypofractionation and standard overall treatment time: importance of overall treatment time. Jpn J Clin Oncol 2011;41(1):103–9. [DOI] [PubMed] [Google Scholar]
- 15.Ermis E, Teo M, Dyker KE, Fosker C, Sen M, Prestwich RJ. Definitive hypofractionated radiotherapy for early glottic carcinoma: experience of 55Gy in 20 fractions. Radiat Oncol 2015;10:203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Jones DA, Mendenhall CM, Kirwan J, et al. Radiation therapy for management of t1-t2 glottic cancer at a private practice. Am J Clin Oncol 2010;33(6):587–90. [DOI] [PubMed] [Google Scholar]
- 17.Al-Mamgani A, van Rooij P, Fransen D, Levendag P. Unilateral neck irradiation for well-lateralized oropharyngeal cancer. Radiother Oncol 2013;106(1):69–73. [DOI] [PubMed] [Google Scholar]
- 18.Chera BS, Amdur RJ, Morris CG, Mendenhall WM. Carotid-sparing intensity-modulated radiotherapy for early-stage squamous cell carcinoma of the true vocal cord. Int J Radiat Oncol Biol Phys 2010;77(5):1380–5. [DOI] [PubMed] [Google Scholar]
- 19.Gomez D, Cahlon O, Mechalakos J, Lee N. An investigation of intensity-modulated radiation therapy versus conventional two-dimensional and 3D-conformal radiation therapy for early stage larynx cancer. Radiat Oncol 2010;5:74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Rosenthal DI, Fuller CD, Barker JL Jr., et al. Simple carotid-sparing intensity-modulated radiotherapy technique and preliminary experience for T1–2 glottic cancer. Int J Radiat Oncol Biol Phys 2010;77(2):455–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Arthurs E, Hanna TP, Zaza K, Peng Y, Hall SF. Stroke After Radiation Therapy for Head and Neck Cancer: What Is the Risk? Int J Radiat Oncol Biol Phys 2016;96(3):589–96. [DOI] [PubMed] [Google Scholar]
- 22.Brown PD, Foote RL, McLaughlin MP, et al. A historical prospective cohort study of carotid artery stenosis after radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys 2005;63(5):1361–7. [DOI] [PubMed] [Google Scholar]
- 23.Smith GL, Smith BD, Buchholz TA, et al. Cerebrovascular disease risk in older head and neck cancer patients after radiotherapy. J Clin Oncol 2008;26(31):5119–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Dorresteijn LDA, Kappelle AC, Boogerd W, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. Journal of Clinical Oncology 2002;20(1):282–288. [DOI] [PubMed] [Google Scholar]
- 25.Haynes JC, Machtay M, Weber RS, Weinstein GS, Chalian AA, Rosenthal DI. Relative risk of stroke in head and neck carcinoma patients treated with external cervical irradiation. Laryngoscope 2002;112(10):1883–1887. [DOI] [PubMed] [Google Scholar]
- 26.Waldfahrer F, Hauptmann B, Iro H. [Lymph node metastasis of glottic laryngeal carcinoma]. Laryngorhinootologie 2005;84(2):96–100. [DOI] [PubMed] [Google Scholar]
- 27.Choi HS, Jeong BK, Jeong H, et al. Carotid sparing intensity modulated radiotherapy on early glottic cancer: preliminary study. Radiation Oncology Journal 2016;34(1):26–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Feigenberg SJ, Lango M, Nicolaou N, Ridge JA. Intensity-Modulated Radiotherapy for Early Larynx Cancer: Is There a Role? International Journal of Radiation Oncology*Biology*Physics 2007;68(1):2–3. [DOI] [PubMed] [Google Scholar]
- 29.Fowler JF. 21 years of biologically effective dose. Br J Radiol 2010;83(991):554–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Baumann JL, Cohen S, Evjen AN, et al. Human papillomavirus in early laryngeal carcinoma. Laryngoscope 2009;119(8):1531–7. [DOI] [PubMed] [Google Scholar]
- 31.Torrente MC, Rodrigo JP, Haigentz M Jr., et al. Human papillomavirus infections in laryngeal cancer. Head Neck 2011;33(4):581–6. [DOI] [PubMed] [Google Scholar]
- 32.Sanchez Barrueco A, Gonzalez Galan F, Lora Pablos D, et al. HPV in Larynx Squamous Cell Carcinoma: New Serotypes and Survival Study within 10-Year Follow-up. Otolaryngol Head Neck Surg 2017;156(4):677–682. [DOI] [PubMed] [Google Scholar]
- 33.Baron CA, Awan MJ, Mohamed ASR, et al. Estimation of daily interfractional larynx residual setup error after isocentric alignment for head and neck radiotherapy: quality assurance implications for target volume and organs-at-risk margination using daily CT on-rails imaging. Journal of Applied Clinical Medical Physics 2015;16(1):159–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Cardenas CE, Mohamed ASR, Tao R, et al. Prospective Qualitative and Quantitative Analysis of Real-Time Peer Review Quality Assurance Rounds Incorporating Direct Physical Examination for Head and Neck Cancer Radiation Therapy. International Journal of Radiation Oncology*Biology*Physics 2017;98(3):532–540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Osman SO, Astreinidou E, de Boer HC, et al. IMRT for image-guided single vocal cord irradiation. Int J Radiat Oncol Biol Phys 2012;82(2):989–97. [DOI] [PubMed] [Google Scholar]
- 36.Aaltonen LM, Rautiainen N, Sellman J, et al. Voice quality after treatment of early vocal cord cancer: a randomized trial comparing laser surgery with radiation therapy. Int J Radiat Oncol Biol Phys 2014;90(2):255–60. [DOI] [PubMed] [Google Scholar]
- 37.Sert F, Karakoyun-Celik O, Esassolak MA. Can carotid-sparing radiotherapy approaches replace with conventional techniques for the patients with T1 glottic larynx cancer? Kulak Burun Bogaz Ihtis Derg 2012;22(5):267–74. [DOI] [PubMed] [Google Scholar]
- 38.Garcez K, Lim CC, Whitehurst P, et al. Carotid dosimetry for T1 glottic cancer radiotherapy. Br J Radiol 2014;87(1038):20130754. [DOI] [PMC free article] [PubMed] [Google Scholar]