Lohia S, Rajapurkar M, Nguyen SA, Sharma AK, Gillespie MB, Day TA. A Comparison of Outcomes Using Intensity-Modulated Radiation Therapy and 3-Dimensional Conformal Radiation Therapy in Treatment of Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg. 2014;140(4):331-337. doi:10.1001/jamaoto.2013.6777
Approximately 50% of head and neck cancer survivors experience dysphagia and related morbidity. Intensity-modulated radiation therapy (IMRT) is increasingly used to treat oropharyngeal cancers with excellent oncologic outcomes, but few studies have compared it with conventional 3-dimensional conformal radiation therapy (3D-CRT) to determine whether it can decrease treatment-related toxic and adverse effects.
To determine whether IMRT improves percutaneous endoscopic gastrostomy (PEG) tube and treatment-related toxicity outcomes compared with 3D-CRT in patients with oropharyngeal squamous cell carcinoma.
Design, Setting, and Participants
Retrospective review of 159 patients with oropharyngeal primary tumors with no history of chemotherapy, radiation therapy, or surgery of the head and neck who underwent definitive treatment with radiotherapy for oropharyngeal squamous cell carcinoma at the Hollings Cancer Center outpatient clinic, Medical University of South Carolina, from 2000 to 2009.
Doses of 70 Gy in 35 daily fractions of radiotherapy delivered via IMRT or 3D-CRT.
Main Outcomes and Measures
Primary end points included PEG tube dependence 1 year after radiotherapy start, weight loss during treatment, and change in Eastern Cooperative Oncology Group performance status. Secondary end points included overall and disease-free survival, disease recurrence, and toxic effect profiles.
The IMRT group (n = 103) had a significantly lower rate of PEG tube dependence 1 year after treatment initiation than the 3D-CRT group (n = 56) for all patients (P = .02) and for those with advanced T stage (P = .01) and a shorter time to PEG tube removal (P < .001). Acute grade 3 or greater toxic effects to skin and mucous membranes occurred less frequently in the IMRT group (P = .02 and P < .001, respectively). The 2 groups did not differ significantly in weight loss, treatment failure (hazard ratio, 0.82 [95% CI, 0.47-1.41]), overall survival (P = .45), or disease-free survival (P = .26).
Conclusions and Relevance
The use of IMRT significantly improves PEG tube and toxicity-related outcomes compared with 3D-CRT in the treatment of oropharyngeal primary cancers. Given the association between mucosal toxic effects, PEG tube dependence, and dysphagia, these findings may be an indication of improved swallowing outcomes with IMRT.
Radiation therapy is an important treatment modality in the management of head and neck squamous cell carcinoma (SCC). Studies have shown that the addition of postoperative radiotherapy improves locoregional control and survival in patients with locally advanced head and neck cancer.1- 3 However, surgical resection of advanced oropharyngeal SCC often results in substantial impairment in speech and swallowing, which negatively affects quality of life, nutrition, and social functioning. Thus, radiotherapy with and without concurrent chemotherapy is being increasingly used as an organ preservation treatment modality.1 Unfortunately, the benefits of radiotherapy in the management of head and neck cancers are also often offset by the development of severe acute and late toxic effects such as dysphagia, aspiration, laryngeal edema, and xerostomia. Other adverse effects may manifest months to years after radiation therapy because of fibrosis and vascular and neural damage4,5 and result in substantial swallowing dysfunction.
Recently, numerous authors have identified the relationship between radiation dose and scatter to normal structures involved in swallowing and swallowing dysfunction after definitive treatment with radiation therapy.6,7 In addition, 2 recent studies revealed that radiation dose to the larynx and pharyngeal constrictors can predict increased risk of percutaneous endoscopic gastrostomy (PEG) tube dependence following treatment completion.8,9 Given the results of these investigations, intensity-modulated radiation therapy (IMRT) has received increasing attention as a new technique that may be able to decrease toxic effects by sparing normal tissue while maintaining locoregional control of malignant neoplasms through high-dose radiation exposure.
Studies have shown that IMRT can successfully decrease dysphagia and aspiration by sparing the pharyngeal constrictors and the glottic and supraglottic larynx, which are responsible for swallowing function.10- 12 Furthermore, patients who undergo treatment with IMRT vs conventional 3-dimensional conformal radiation therapy (3D-CRT) have significantly improved functional outcomes and quality-of-life scores.13,14
The use of IMRT treatment planning with concurrent chemotherapy in the treatment of oropharyngeal SCC decreases radiation dose to the suprahyoid muscles and pharyngeal constrictors, especially on the contralateral side, without compromising the therapeutic dose to the primary tumor. Thus, it is predicted that patients treated in this manner should have better functional outcomes in terms of swallowing. There is little literature comparing the swallowing outcomes after IMRT and 3D-CRT. Therefore, the objective of this study was to compare treatment-related outcomes in patients undergoing definitive treatment with IMRT vs 3D-CRT for oropharyngeal SCC. Specifically, we sought to assess the incidence of PEG tube reliance and treatment-related toxic effects between the 2 modalities.
Given the retrospective nature of this review, we obtained institutional review board approval at the Medical University of South Carolina to waive obtaining informed consent and to create a research database with study-specific patient, treatment, and outcome data measures. A review of patients with head and neck cancer who underwent definitive treatment with radiation therapy from September 2000 to September 2009 was conducted. Inclusion criteria for the present analysis included resectable or unresectable SCC originating in the oropharynx, and absence of distant metastatic disease at treatment initiation. Patients with SCC of the head and neck of any stage treated with primary radiotherapy alone or concurrent chemoradiotherapy were included in the present analysis. Patients were excluded from the study if they had a history of radiation exposure to the head and neck, history of treatment with chemotherapy, induction chemotherapy prior to concurrent chemoradiation, or surgery of the head and neck prior to concurrent chemoradiotherapy. The majority of patients underwent PEG tube placement prior to treatment initiation (within the first 2 weeks of treatment or earlier).
The 3D-CRT treatment consisted of initial lateral opposed 6-MV photon fields covering the primary tumor and at-risk regional lymph nodes to 40 to 44 Gy. This was followed by the use of customized posterior block shielding designed to protect the spinal cord and bring the anterior target dose to 50 Gy. The dose of posterior blocked nodal regions was increased to 50 Gy using supplemental electrons, and a boost of 20 Gy was delivered to the primary tumor and involved lymph nodes. All treatments were administered at 2 Gy per once daily fraction, 5 days per week. The IMRT technique involved a 7-field or 9-field plan that delivered 70 Gy to the primary tumor and involved lymph nodes and 56.0 to 58.1 Gy to at-risk lymph nodes using a simultaneous integrated boost technique. Sparing of the spinal cord (maximum dose, 45 Gy) and at least 1 parotid gland (mean dose, <26 Gy) was attempted when possible. All treatments were delivered at 2 Gy in 35 daily fractions, 5 days per week.
Treatment planning for both 3D-CRT and IMRT was performed using computed tomography with the patient in the supine position using a Bear Claw shoulder depression device (WFR Aquaplast Corp and Qfix Systems) and thermoplastic mask with bite block for immobilization and setup variability. Contrast medium was used to define target volume. The Pinnacle treatment planning software system (ADAC Laboratories) was used to create an individualized radiation therapy plan for each patient. Treatment plans for all patients were made using 3-dimensional image reconstruction and dosimetric verification.
For both 3D-CRT and IMRT, the gross tumor volume (GTV) was calculated using sites of disease as indicated by clinical examination or radiographic imaging and included involved or suspicious lymph nodes. The clinical target volume was calculated using the GTV with an expansion of 5 to 10 mm beyond the GTV and adjacent nodal regions at risk for spread of microscopic disease. For IMRT only, 1 planning treatment volume was designed for the GTV and clinical target volume and consisted of an expansion of 3 to 5 mm of the original volume to account for variations in daily setup. Concurrent chemotherapy generally consisted of cisplatin 100 mg/m2 once every 3 weeks or cisplatin 20 mg/m2 plus paclitaxel 30 mg/m2 once every week and was usually only offered to patients with locally advanced primary tumors (cT3-T4b) or with regional lymph node involvement (cN1-N3).
Radiation-induced adverse effects were recorded prospectively and scored according to the Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system at weekly intervals during the treatment period. In the event that a patient experienced RTOG grade 4 toxic effects or was hospitalized, treatment was either delayed or suspended. In patients with N3 or residual neck disease (clinical or radiologic), elective neck dissection was performed within 12 weeks of treatment completion. After the end of therapy, patients followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. Posttreatment follow-up included physical examination and fiber-optic nasolaryngoscopy, contrast-enhanced computed tomography within 4 to 6 weeks of treatment end (and when clinically indicated), and positron-emission tomography and computed tomography scan within 10 to 12 weeks of treatment completion. Chest imaging was performed if clinically indicated or at time of recurrence.
Primary end points for this study were the incidence of PEG tube dependence at 1 year after start of radiotherapy, weight loss during treatment, and change in Eastern Cooperative Oncology Group (ECOG) performance status. Secondary end points included overall survival, disease-free survival, disease recurrence, and toxicity profiles at treatment completion. Reliance on the PEG tube, type of diet, and decision to remove it were taken into account when assessing PEG tube status at 1 year after treatment start. Weight loss during treatment and change in ECOG performance status were measured from the date of treatment initiation to date of treatment end. Patient status at last follow-up was recorded as one of the following: alive with no evidence of disease, alive with disease, died of or with disease, died of treatment-associated toxic effects, died of other cause, or died of unknown cause. Treatment failure was measured from date of treatment start to earliest date of recurrence (as indicated by clinical or radiographic assessment) within 2 years of treatment end. The RTOG scores at the end of treatment were used to measure adverse effects of treatment.
All statistical analyses were performed with Sigma Stat software, version 3.5 (Aspire Software International), and SPSS software, version 20.0 (IBM). Participant information and demographic variables, such as age, ethnic group, and sex, were described with summary statistics. A normality distribution test (Kolmogorov-Smirnov) was performed for all continuous variables. Simple descriptive statistics such as frequency, mean, standard deviation, minimum, and maximum were calculated for all outcome variables. If these variables were not normally distributed, other descriptive measurements, such as median and interquartile range (IQR), were used.
Comparisons of baseline patient characteristics and clinical outcomes were performed using the χ2 or Fisher exact test (categorical variables) and the t test (continuous variables). Hazard ratio and the 2-year and 5-year locoregional control and survival probabilities were estimated using the Kaplan-Meier method. P ≤ .05 was considered to indicate a statistically significant difference for all statistical tests.
A total of 315 patients were identified in the Head and Neck database. Of these, 159 patients met eligibility criteria and were included in the current analysis. There were 133 men and 26 women, with a mean (range) age of 58.5 (33-82) years at the start of radiotherapy. Fifty-six patients were treated with 3D-CRT, 81 patients were treated with IMRT, and 22 patients with helical IMRT (tomotherapy). Baseline patient demographic and clinical characteristics are outlined in Table 1, and tumor characteristics are outlined in Table 2.
Overall, the patients were well matched between the 2 groups, without significant variations in baseline characteristics. Median (IQR) time to start of treatment following biopsy was 42 (31-57) days in the 3D-CRT group and 54 (40-70) days in the IMRT group. Median (IQR) duration of treatment was 49 (46-52) days in the 3D-CRT group and 49 (46-51) days in the IMRT group, and the majority of patients received more than 95% of their planned dose of radiation therapy (Table 3). Overall, median (IQR) follow-up was 34.8 (13.1-55.0) months in the IMRT group and 57.5 (19.1-102.2) months in the 3D-CRT group.
In the 3D-CRT group, 36 patients (64%) received weekly cisplatin and paclitaxel, 7 patients (12%) received cisplatin alone, 6 (11%) received cisplatin with fluorouracil, and 1 patient received cetuximab (2%). In the IMRT group, 23 patients (22%) received cisplatin and paclitaxel, 38 (37%) received cisplatin alone, 10 (10%) received carboplatin plus paclitaxel, 2 (2%) received carboplatin alone, 16 (16%) received cetuximab, 4 (4%) received cisplatin plus erlotinib hydrochloride, 1 (1%) received cisplatin plus cetuximab, and 1 (1%) received cisplatin, fluorouracil, and paclitaxel. Of the patients who underwent concurrent chemoradiotherapy in the 3D-CRT group, 45 (90%) completed their prescribed treatment and 5 (10%) required a decrease in dose. In the IMRT group, 74 patients (78%) completed their prescribed treatment and 21 (22%) required a decrease in dose.
Overall, PEG tubes were placed at the start of treatment (or within 2 weeks of radiation therapy start) for 79% of patients in the 3D-CRT group and 61% of patients in the IMRT group (P = .04) (Table 4). However, there was a higher proportion of PEG tube placement after therapy initiation in the IMRT group compared with the 3D-CRT group (P = .009). One year after radiation therapy start in our series, 14 patients in the 3D-CRT group (35%) and 7 patients in the IMRT group (13%) remained PEG tube dependent (P = .02). This finding was also statistically significant in a comparison of only the subset of patients with stage III and stage IV cancer (P = .01). Median (IQR) duration of PEG tube dependence was 259 (157-716) and 154 (102-240) days in the 3D-CRT group and IMRT group, respectively (P < .001).
The mean (SD) weight loss during treatment was 8.1 (6.4) kg in the IMRT group (n = 81) and 8.4 (17.1) kg in the 3D-CRT group (n = 49), with 36 patients (35%) and 19 patients (34%) losing more than 10% of total body weight during treatment in each group, respectively (Table 5). There was no significant difference between the 2 groups in total amount of weight lost (P = .86). There was also no significant correlation between the presence of a PEG tube and degree of weight loss in either the 3D-CRT group (P = .36) or the IMRT group (P = .26). In addition, the presence of a PEG tube during treatment did not influence the degree of weight loss within groups or between groups.
The 3D-CRT group demonstrated significantly more acute toxic effects compared with the IMRT group in our analysis. Acute grade 3 or greater toxic effects to the skin occurred in 9 of 39 patients in the 3D-CRT group (23%), compared with 7 of 97 patients in the IMRT group (7%) (P = .02). Acute grade 3 or greater toxic effects to the mucous membranes occurred in 37 of 49 patients in the 3D-CRT group (76%) and only 37 of 101 patients in the IMRT group (37%) (P < .001). There were no significant differences in RTOG toxicity scores for toxic effects to the salivary gland, pharynx, and larynx between groups.
In the IMRT group, 11 patients (11%) had a decline in ECOG performance status, 22 patients (21%) had no change, and 6 patients (6%) had an improvement in ECOG performance status score. In the 3D-CRT group, 6 patients had a decline in ECOG performance status and 6 patients had no change. There were no significant differences in change in ECOG performance status scores between groups (P = .42). During the treatment period, 2 patients in the IMRT group (2%) died as a result of treatment-related toxic effects, 20 patients (19%) required treatment-related hospitalization, and 6 patients (6%) required treatment delay because of toxic effects. In the 3D-CRT group, 17 patients (30%) were hospitalized as a result of treatment-related toxic effects and 6 patients (11%) required treatment delay; however, there were no significant differences in these outcomes between the 2 groups.
Disease-free median (IQR) survivor follow-up was 32.4 (11.4-51.8) and 46.9 (12.2-102.2) months in the IMRT and 3D-CRT groups, respectively (Table 6). At 24-month follow-up, 61 patients (59%) were alive without evidence of disease, 3 patients (3%) were alive with disease, and 17 patients (16%) had died of or with disease in the IMRT group. At 24-month follow-up, 37 patients (66%) were alive without evidence of disease, 3 patients (5%) were alive with disease, and 2 patients (4%) had died of or with disease in the 3D-CRT group. Disease recurrence rates did not significantly differ between the 2 groups (hazard ratio, 0.82 [95% CI, 0.47-1.41]).
The present study reports the treatment outcomes for patients with SCC of the oropharynx treated with definitive radiotherapy or chemoradiotherapy. Overall, we found that the majority of patients require PEG tube placement during radiation therapy (especially with concurrent chemoradiation therapy) for the maintenance of nutrition and prevention of dehydration. However, between the 2 radiation therapy techniques, IMRT was associated with a significantly lower rate of PEG tube dependence at the start of treatment compared with 3D-CRT. More importantly, IMRT was associated with a significantly lower rate of PEG tube dependence (or PEG tube presence) 1 year after radiotherapy completion than 3D-CRT and a shorter median duration of PEG tube use. This is particularly meaningful because previous studies have shown the substantial negative impact of the presence of PEG tubes on quality of life in these patients, likely related to both poor swallowing function and the presence of the PEG tube.16- 18
Although our findings cannot be directly linked to differences in swallowing function between the 2 groups, they are likely to be related. Previous investigations have identified the suprahyoid musculature that elevates the larynx and the pharyngeal constrictors as playing a key role in normal swallowing function and have linked the irradiation of these structures to posttherapy dysphagia and increased risk of PEG tube dependence.6- 9,19- 21 With the use of IMRT, it is possible to limit the radiation exposure to these sites, which is associated with improved swallowing outcomes.19
Similarly, in patients undergoing treatment with IMRT we were able to outline the pharyngeal constrictors, the larynx, and the muscles of mastication and make plans based on thresholds to spare these structures. Thus, it is possible that the decreased dependence on PEG tubes after radiation therapy may indicate improved swallowing function in patients who underwent treatment with IMRT compared with 3D-CRT. In addition, the data suggest that IMRT can also offer improved swallowing outcomes in cases of advanced oropharyngeal carcinoma. Therefore, the preservation of anatomic structures involved with swallowing, swallow therapy during and after radiation therapy, and performance of posttreatment swallow studies are likely to improve swallowing and PEG tube outcomes following therapy completion.
Interestingly, there was no significant difference in weight loss between the 2 patient groups. Given the lower incidence of PEG tube dependence in the patients treated with IMRT, we had also expected less weight loss in this group. However, the weight loss was likely due to dehydration and anorexia from concurrent chemotherapy rather than swallowing dysfunction.
In regards to toxic effects of treatment, our findings are in agreement with previous reports.22- 24 In our analysis, IMRT was associated with a significantly lower incidence of grade 3 or greater acute toxic effects to skin and mucous membranes than 3D-CRT. We were unable to find any differences in change in ECOG performance status between the 2 radiation therapy techniques and also attributed this to low power and inconsistent reporting of results. In addition, the 2 groups did not demonstrate appreciable differences in the number of treatment days missed, hospitalization related to toxic effects of treatment, or number of days hospitalized, indicating no significant differences in systemic toxic effects related to treatment.
Our analysis also did not demonstrate a significant difference in overall survival, disease-free survival, or locoregional control (treatment failure). These findings are in agreement with previous reports demonstrating comparable rates of cure and control with the use of either radiation therapy modality.25 However, in our study there was improved disease-free survival in the IMRT group, although this result was not statistically significant. There were also no specific factors that predicted improved survival (overall and disease-free survival). Given the limited power of our study, multivariate analysis was not performed to identify specific factors that predicted increased risk of PEG tube dependence, disease survival, and treatment failure. Last, data in the form of results of swallow studies, patient rating scales regarding dysphagia and swallowing function, and quality-of-life questionnaires are required to correlate our clinical outcomes with improvements in radiation therapy techniques.
In our experience, the use of IMRT for definitive treatment of early-stage and late-stage oropharyngeal SCC is associated with a decreased incidence of grade 3 or greater acute toxic effects to skin and mucous membranes and significantly lower rates of PEG tube dependence during and after therapy compared with 3D-CRT. In addition, IMRT offers locoregional control and disease-free survival rates comparable to those of 3D-CRT, lending additional support for its use in improving quality-of-life outcomes in patients undergoing treatment of SCC of the oropharynx.
Submitted for Publication: February 25, 2013; final revision received December 7, 2013; accepted December 27, 2013.
Corresponding Author: Shivangi Lohia, MD, Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Ave, MSC 550, Charleston, SC 29403 (firstname.lastname@example.org).
Published Online: February 20, 2014. doi:10.1001/jamaoto.2013.6777.
Author Contributions: Drs Sharma and Day had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lohia, Rajapurkar, Nguyen, Sharma, Day.
Acquisition of data: Lohia, Gillespie, Day.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Lohia, Nguyen, Day.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Lohia, Nguyen.
Administrative, technical, and material support: Gillespie.
Study supervision: Rajapurkar, Sharma, Gillespie, Day.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented at the American Head and Neck Society 2013 Annual Meeting; April 10, 2013; Orlando, Florida.