Abstract
Objective:
To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy.
Methods:
Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated.
Results:
With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of −4.5%, −3.0%, −6.2%, and −2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate ≤35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control.
Conclusion:
Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival.
Keywords: adaptive radiotherapy, head and neck cancer, IGRT, tumor volume reduction rate, intensity modulated radiotherapy
Introduction
In current practice for head and neck cancer (HNC) radiotherapy (RT), many centers carry out the original treatment plan to completion without accounting for anatomical changes that can occur due to weight loss, tumor shrinkage, edema, inflammation, and normal tissue volume alterations.1,2 In the past decade, significant progress in image-guided RT has revealed that significant volumetric changes to organs at risk (OARs) and target volumes can occur on a daily basis during a typical course of intensity-modulated radiation therapy (IMRT) for HNC treatment.3,4 Furthermore, these volumetric changes can have profound impact on delivered doses to the tumor and normal tissues as planned from the original pretreatment plan.
For IMRT-delivered HNC treatment plans, these anatomical alterations have a more critical impact than for conventional RT due to the sharp dose gradient between the edges of target volumes and critical OARs. Thus, these changes could potentially lead to overdosing of normal tissues and underdosing or marginal geographical misses of target volumes during a course of treatment based on a single planning data set. A possible solution to account for these changes is adaptive radiotherapy (ART), which involves repeat imaging and replanning during a course of radiation treatment.
Based on previous studies, approximately 21% to 65% of all patients undergoing HNC RT treatment may benefit dosimetrically from ART.5,6 Furthermore, the use of ART can improve local control for patients with HNC, while providing critical insight into tumor volume reduction rates (TVRRs), which can ultimately help to “tailor” therapy and management during an RT course.2 Hence, the purpose of this study is to verify the potential impact of ART on final dosimetric, clinical, and toxicity outcomes for HNC IMRT. The study also examines the use of ART to calculate TVRR and its potential correlation with clinical outcomes.
Materials and Methods
Radiotherapy Planning
Fifty-one patients with advanced squamous cell carcinoma of the head and neck treated with definitive IMRT and concurrent chemotherapy between January 2009 and July 2014 were retrospectively analyzed per institutional review board–approved protocol. Patients had pretreatment computed tomography (CT; Big Bore; Phillips Medical Systems, Andover, Massachusetts) simulation in our department and were immobilized using custom-fitted thermoplastic head-and-shoulder mask. Contrast-enhanced CT scan was performed with 3-mm interval slices, and data were transferred to XIO (Elekta, Maryland Heights, Missouri) planning software (2009 to July 2012) or Eclipse (Varian Medical Systems, Palo Alto, California; August 2012 to present). Radiation therapy was delivered using megavoltage Varian linear accelerators with 6 MV photons using static IMRT or RapidARC (Varian Medical Systems) techniques.
All patients had bilateral neck radiation. See Table 1 for target volume delineation. Low-risk planning target volume (PTV1) received a median dose of 48.6 Gy and PTV2 received an additional 21.6 Gy for a total of 70.2 Gy in 1.8 Gy per fraction. Positron emission tomography/CT, when available, was fused to planning CT to aid in gross tumor volume (GTV) delineation. All patients had daily kV imaging to align to bones for daily setup verification. In addition, all patients underwent weekly cone beam CT (CBCT) to monitor for anatomical changes.
Table 1.
Treatment Volume Delineation.
| Target Volume | Description | Dose Prescribed (Gy) |
|---|---|---|
| GTVt | Total primary and gross nodal volume | 70.2 |
| CTV2 | High-risk clinical target volume = GTVt + 5 mm margin | 70.2 |
| PTV2 | High-risk planning treatment volume = CTV2 + 3 mm margin | 70.2 |
| CTV1 | Low-risk clinical target volume = CTV2 + bilateral neck nodes + 5 mm margin | 48.60 |
| PTV1 | Low-risk planning treatment volume = CTV1 + 3 mm margin | 48.60 |
Abbreviations: CTV, clinical target volume; GTVt, total gross tumor volume; PTV, planning treatment volume.
Chemotherapy Details
Patients were treated with daily RT and concurrent chemotherapy. The majority of patients (28 of 34, 82.3%) received 100 mg/m2 cisplatin given every 3 weeks, whereas 3 (8.8%) of 34 received weekly cetuximab chemotherapy. Three (8.8%) of the 34 patients received weekly 30 mg/m2 cisplatin due to poor performance status or decreased kidney function. At our institution, all patients undergoing concurrent HNC chemoradiotherapy (CRT) have percutaneous gastrostomy tube placed prior to starting treatment.
Adaptive Radiotherapy
Repeat CT scan (without contrast) was performed at a median dose of 37.8 Gy, which correlated with approximately the end of week 4 of treatment. There was no set protocol in place to identify patients for ART prior to starting treatment. Instead, the decision to rescan was based on the treating physician’s discretion and generally was due to a combination of factors, including assessment of weight loss (>15% from baseline), changes in clinical/palpable tumor volume, assessing anatomical changes from weekly CBCT, ill-fitting mask, or prolonged treatment breaks. The original radiation plan was fused onto the rescan CT after careful matching to bony and soft tissue anatomy. The primary and nodal GTVs and OARs were recontoured on the rescan CT. All 51 patients underwent repeat CT scan, but only 34 were replanned and their data were fully analyzed in this study.
Patient Characteristics
Table 2 highlights the patient and tumor characteristics of the 34 patients who were analyzed in this study. Of note, the median age was 60 years (range, 41-76 years). The majority of patients had tumors in the oropharynx (58.2%). The base of tongue (65%) was the most common site of oropharyngeal disease. The group stage distributions were as following: II (9), III (20), IVA (4), and IVB (1).
Table 2.
Patient and Tumor Characteristics.
| Characteristics | No. of Patients |
|---|---|
| Age | |
| <60 | 15 |
| >60 | 19 |
| Gender | |
| Male | 30 |
| Female | 4 |
| KPS | |
| 50 | 1 |
| 60 | 1 |
| 70 | 5 |
| 80 | 3 |
| 90 | 24 |
| HPV | |
| Positive | 18 |
| Negative | 7 |
| Unknown | 9 |
| Site | |
| Nasopharynx | 5 |
| Oropharynx | 20 |
| Oral cavity | 6 |
| Hypopharynx | 3 |
| Tumor growth pattern | |
| Endophytic | 21 |
| Exophytic | 13 |
| Chemotherapy | |
| High-dose cisplatin | 28 |
| Cetuximab | 3 |
| Low-dose cisplatin | 3 |
| T Stage | |
| cT1 | 3 |
| cT2 | 14 |
| cT3 | 7 |
| cT4a | 8 |
| cT4b | 2 |
| N Stage | |
| cN0 | 1 |
| cN1 | 6 |
| cN2 | 27 |
Abbreviations: HPV, human papilloma virus; KPS, Karnofsky Performance Status.
Dosimetric Analysis
Doses to OARs (spinal cord, brain stem, ipsilateral, and contralateral parotid) and target volume coverage of original primary and boost plans on the original CT (P1), original primary and boost plans superimposed on the rescan CT (P2), and original primary with adaptive boost plan on rescan CT (P3) were recorded. The dosimetric effects were quantified by comparing dose–volume histograms of P1, P2, and P3. The target coverage in these plans was clinically assessed using GTV V100 and PTV V95 (volume receiving 100% and 95% of the prescription dose, respectively). The planning goal was to cover 100% of the GTV with 100% of the prescription dose and to cover 95% of the PTV with at least 95% of the prescription dose.
Clinical Outcomes
All patients were evaluated for treatment response and adverse effects starting at 4 to 6 weeks post-CRT completion. Patients underwent follow-up at 3-month intervals during the first year, then every 4 to 6 months for years 2 to 4, and then every 6 months thereafter. The follow-up visits included a thorough physical examination with fiber optic nasolaryngoscope. Further imaging was performed at the treating physicians’ discretion.
Local control was defined as no evidence of disease at the pretreatment gross tumor site (primary or nodal), whereas local failure was defined either as residual disease (within 6-8 weeks post-CRT) or recurrent disease, verified by biopsy or salvage surgery. When a patient achieved local control, but had evidence of disease in the neck nodes, then this was identified as regional failure. Lastly, distant failure was defined as the development of distant metastasis. Assessment of tumor response was based on the physical examination and/or CT scan of the head and neck. Patient follow-up was reported to the date last seen in clinic or to the date of death. All events were measured from the last day of RT.
Toxicity
Acute and late tissue effects were graded according to Common Terminology Criteria for Adverse Events (CTCAE V4.03)7. Acute and late dermatitis, esophagitis, mucositis, and xerostomia toxicities as well as rate of percutaneous gastrostomy tube dependence and incidence of esophageal stricture were recorded.
Tumor Volume Reduction Rate
Total gross tumor volume (GTVt) changes between the original and rescan CT were analyzed. Pre-RT GTVt and rescan GTVt values were used to calculate TVRR, which was defined as: ([pre-RT GTVt − rescan GTVt]/pre-RT GTVt).8 The TVRR was used to correlate differences in overall survival (OS), disease-free survival (DFS), and locoregional control rates.
Statistical Analysis
Student t test was used to assess statistical significance of changes, and Fisher exact test was used to assess significance of the effect of TVRR on clinical outcomes. The P value <.05 was considered a statically significant difference.
Results
Tumor Response
With a median follow-up time of 17.6 months (range, 0.5-57.5 months), the median DFS was 14.8 months (range, 0.9-57.5 months) and the median OS was 21.1 months (range, 4.5-61.4 months). After completion of CRT, 4 (11.8%) of the 34 patients had residual disease; all underwent salvage surgery. Overall, 20 (64.7%) of the 34 patients achieved locoregional control, and 8 (23.5%) of the 34 developed metastatic disease after CRT. There were 4 deaths in the metastatic group, and all died due to cancer-related complications.
Dosimetric Analysis
With adaptive replanning, the median dose reduction to spinal cord, brain stem, ipsilateral, and contralateral parotid was −4.5%, −3.0%, −6.2%, and −2.5%, respectively. The adapted IMRT plan improved the median coverage for GTV and PTV2 by 0.8% and 0.5%, respectively. Table 3 highlights the reduction in dose to OARs with adapted P3 plan. Table 4 highlights the relative dosimetric benefits in coverage and dose to OARs when comparing P1, P2, and P3.
Table 3.
Median and Maximum Dose Reduction of Organs at Risk and Increase From Original Plan on Rescan CT (P2) to Adapted IMRT Plan (P3).a
| Median, Dose Reduction (%) | Maximum Dose Reduction (%) | Maximum Dose Increase (%) | |
|---|---|---|---|
| Spinal cord (max) | −4.5 | −45.9 | 4.6 |
| Brainstem (max) | −3.0 | −34.6 | 19.9 |
| Ipsilateral parotid (mean) | −6.2 | −46.2 | 6.9 |
| Contralateral parotid (mean) | −2.5 | −48.5 | 28.4 |
Abbreviations: CT, computed tomography; max, maximum.
aDifferences were reported as (P3 − P2)/P2.
Table 4.
Dosimetric Effects of Anatomical Changes During Treatment (P1 Versus P2) and the Result of the Adaptive Planning (P2 Versus P3).a
| Original Plan on Original CT (P1) | Change From P1 to P2 | Original Plan on Rescan CT (P2) | Change From P2 to P3 | Adapted Plan on Rescan CT (P3) | |
|---|---|---|---|---|---|
| GTV V100 (%) | 99.3 (2.4) | b↘ | 97.5 (5.3) | b↗ | 99.4 (2.9) |
| PTV2 V95 (%) | 98.5 (4.5) | b↘ | 97.1 (6.1) | b↗ | 99.2 (2.6) |
| Ipsilateral parotid (mean, Gy) | 42.0 (12.4) | c↗ | 41.9 (13.1) | b↘ | 39.1 (11.9) |
| Contralateral parotid (mean, Gy) | 23.0 (7.9) | ↗ | 23.2 (10.6) | b↘ | 22.4 (8.8) |
| Cord (max, Gy) | 47.6 (4.1) | b↗ | 48.9 (6.1) | b↘ | 46.0 (4.0) |
| Brainstem (max, Gy) | 44.2 (8.7) | c↗ | 44.9 (11.8) | b↘ | 42.2 (10.2) |
Abbreviations: CT, computed tomography; GTV, gross tumor volume; max, maximum; OAR, organs at risk; PTV2, high-risk planning target volume.
aMedian values of target coverage and OAR doses for all 34 patients (standard deviation) were presented, with arrows demonstrating the changes.
b P < .01.
c P < .05.
Toxicity
Patients tolerated concurrent CRT relatively well. Five of the 28 patients in the standard group did not receive the last cycle, whereas 1 patient in each of the low-dose cisplatin and cetuximab discontinued chemotherapy due to increased toxicity. The incidence of grade 3 acute and late toxicities are highlighted in Table 5. The incidence of esophageal stricture was 8.8% (3 of the 34), and only 1 patient required esophageal dilation. The median time to percutaneous endoscopic gastrostomy (PEG) tube removal was 3.1 months (range, 1.3-15.1 months). The incidence of PEG tube dependence at 1 year was 11.7%.
Table 5.
Acute and Late Grade 3 Toxicities.
| Acute, No. of Patients (%) | Late, No. of Patients (%) | |
|---|---|---|
| Dermatitis | 5 (14.7) | NA |
| Dysphagia | 14 (41.2) | 6 (20.0) |
| Mucositis | 12 (35.3) | NA |
| Xerostomia | NA | 1 (3.3) |
Abbreviation: NA, not applicable.
Tumor Volume Reduction Rate
The mean pre-RT GTVt was 82.6 cm3 compared to mean rescan GTVt of 53.8 cm3. The calculated median TVRR was 35.2% (range, −18.8% to 79.6%). Three patients’ tumor volumes were larger on the rescan CT. We analyzed the effect of TVRR to DFS and control rates by dividing patients into 2 groups: TVRR ≤35.2% versus TVRR >35.2%. Table 6 highlights the differences in DFS, OS, and tumor control rates between the 2 groups. Furthermore, patients with grade 3 tumor were more likely to be in the TVRR >35.2% group (12 of 17 vs 7 of 17 patients in TVRR ≤35.2%). Of 20 patients with oropharyngeal cancer, 13 of them were in TVRR >35.2% group. There was no difference in the number of human papillomavirus (HPV)-positive patients in both TVRR groups (assessed only for 25 of the 34 patients who had HPV results).
Table 6.
Tumor Volume Regression Rate and Clinical Outcomes.
| TVRR ≤35.2% | TVRR >35.2% | P | |
|---|---|---|---|
| Median DFS (months) | 8.9 | 17.5 | .045a |
| Median OS from CRT (months) | 14.2 | 21.4 | .003a |
| Local failure | 1/17 | 0/17 | 1b |
| Locoregional failure | 0/17 | 1/17 | 1b |
| Distant failure | 5/17 | 3/17 | .688b |
| Residual disease | 2/17 | 2/17 | 1b |
Abbreviations: CRT, chemoradiotherapy; DFS, disease-free survival; OS, overall survival; TVRR, tumor volume regression rate.
aStudent t test.
bFisher exact test.
Discussion
Our results demonstrated that adaptive replanning resulted in a decreased dose to normal tissues, while improving target volume coverage for patients undergoing repeat CT during the course of head and neck RT. Without replanning, the dose to some OARs would have exceeded their respective tolerance threshold. For instance, the maximum dose to spinal cord for one patient was 50.5 Gy in the original plan, and then it went up to 57.1 Gy when the original plan was calculated on the midtreatment rescan CT. This would have exceeded the spinal cord tolerance, and with replanning, the maximum spinal cord dose was reduced to 50.9 Gy. Several studies have reported on the dosimetric advantages of adaptive replanning for patients with HNC.9,10 Hansen et al performed midcourse repeat CT imaging and subsequent replanning of 13 patients with HNC. Their study noted increased dose to normal structures and decreased target volume coverage if the original plan was continued without adapting to the midtreatment anatomical changes.11 Schwartz et al conducted a prospective trial of ART in 22 patients with HNC and noted decrease in the ipsilateral and contralateral parotid mean dose.12
Furthermore, in this study, we attempted to correlate TVRR with clinical outcomes and we were able to show statistically significant differences in DFS and OS for patients with TVRR ≤35.2% and TVRR >35.2%. Previously, Lee et al reviewed RT records of 59 patients with oropharyngeal cancer who underwent a mid-RT scan to generate an adaptive plan and noted that patients who achieved TVRR >35% had significantly superior 3-year locoregional control than the TVRR <35% group (94.4% vs 72.4%, respectively; P = .018).13 Yang and colleagues measured TVRR in 152 patients with oropharyngeal and hypopharyngeal cancer by comparing pre-RT GTV and interval GTV generated from rescan CT during the fourth or fifth week of treatment. The authors noted TVRR was a statistically significant prognostic indicator for local control.8 Thus, by identifying patients with low TVRR with the use of ART, physicians can potentially consider change in therapeutic strategy for this group of patients.
There are several factors to consider when comparing results of this study to other ART studies. In our study, the median dose at rescan in our study was 37.8 Gy, which correlates with fraction #21 or the start of the fifth week of treatment. There are conflicting data on the optimal time to rescan patients during RT. Bhide et al investigated the use of weekly CT scans in patients having HNC treated with CRT. The study found the most significant volumetric changes in tumor and OARs occurred at week 2.3 However, several studies report significant volumetric changes occurring between weeks 4 and 5 of a typical 7-week course of HNC IMRT.1,14
Furthermore, in our study, we acquired a single CT scan to assess the internal anatomical changes and used rigid registration to fuse rescan CT with original planning CT. Unfortunately, there is no set standard on the frequency of repeat imaging, optimal number of replans, manual versus automated contouring, and rigid versus deformable registration.15–17 Hence, comparing results between studies is difficult due to the above-mentioned technique differences.
Despite all the benefits highlighted in our study, several studies have found minimal or no benefit to ART. Wu and colleagues monitored patients with weekly helical CT scans and noted regression in tumor and normal tissues during treatment; however, these anatomical changes were not associated with significant dosimetric differences.18 Ho et al concluded that despite weight loss and parotid volume reduction, there was no significant excess dose to OARs and no replanning was necessary.4 Furthermore, implementing ART for routine use is a time- and resource-intensive process.9 The cost of an adaptive IMRT plan can be 30% to 40% more expensive than a standard IMRT plan.19 Hence, a more judicious use of ART would be to identify patients pretreatment who are more likely to experience significant tumor regression during RT course. In a previous publication, it was demonstrated that the use of decision trees predicting for high tumor volume reduction can accurately identify these patients based on the pretreatment clinical and pathological factors.20
This study has identified numerous benefits to ART for patients with HNC, including improvement in tumor coverage, decrease in dose to OARs, and measurement of tumor volume regression rate to potentially tailor therapy for individual patients. Future prospective trials with adequate number of participants will help determine optimal criteria for repeat imaging and adaptive replanning for patients with HNC.
Abbreviations
- ART
adaptive radiotherapy
- CBCT
cone beam computed tomography
- CRT
chemoradiotherapy
- CT
computed tomography
- DFS
disease-free survival
- GTV
gross tumor volume
- HNC
head and neck cancer
- HPV
human papilloma virus
- IMRT
intensity-modulated radiotherapy
- OARs
organs at risk
- OS
overall survival
- PTV
planning target volume
- TVRR
tumor volume reduction rate.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
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