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34
Factors Associated with Severe Late
Toxicity After Concurrent Chemoradiation
for Locally Advanced Head and Neck
Cancer: An RTOG Analysis
Purpose
Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck
(SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that
are associated with and might predict severe late toxicity after CCRT.
Methods
Patients were analyzed from a subset of three previously reported RTOG trials of concurrent
chemoradiotherapy for locally advanced SCCHN (RTOG 91-11; 97-03; and 99-14). Severe late
toxicity was defined in this secondary analysis as chronic Grade 3-4 pharyngeal/laryngeal toxicity
(RTOG/EORTC late toxicity scoring system) and/or requirement for a feeding tube ≥2 years after
registration and/or potential treatment-related death (e.g. pneumonia) within 3 years. Case-control
analysis was performed, with a multivariable logistic regression model that included pre-treatment
and treatment potential factors.
Results
A total of 230 patients were evaluable for this analysis, 99 cases (patients with severe late toxicities)
and 131 controls; thus 43% of evaluable patients had a severe late toxicity. On multivariable analysis,
significant variables correlated with the development of severe late toxicity were older age (odds ratio
1.05 per year; p = 0.001); advanced T-stage (odds ratio 3.07; p=0.0036); larynx/hypopharynx primary
site (odds ratio 4.17; p=0.0041); and neck dissection after chemo-RT (odds ratio 2.39; p=0.018).
Conclusions
Severe late toxicity following CCRT is common. Older age, advanced T-stage, and larynx/
hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was
associated with an increased risk of these complications.
Background/Introduction
Concurrent chemoradiotherapy (CCRT) is a standard treatment for patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) treated non-surgically. Meta-analyses
show an improved 5-year survival by approximately 8% when CCRT is compared to radiotherapy
alone
1, 2
. The advantage of this approach with respect to disease free survival and local-regional
control is greater than 8%
3-6, 7-10
.
While there are undisputed advantages to CCRT for local-regional control, it increases toxicity
when compared to radiotherapy alone
11
. Many studies have focused on acute toxicity, particularly
mucositis, as summarized in a meta-analysis
by Trotti et al.
12
. Comprehensive data on late
toxicity from randomized trials of RT +/-
chemotherapy, however, are sparse. Late toxicity
may include long-term severe dysphagia and
its related effects, including dependence upon
a feeding tube, and have a profound effect on
quality of life. The increased incidence of these
serious, potentially permanent effects after
CCRT is concerning, leading some to question
as to whether chemoradiotherapy is truly a
major improvement in the therapeutic ratio
over radiotherapy alone.
13
Starting approximately 15 years ago, the RTOG
conducted a series of prospective clinical trials
using CCRT for locally advanced SCCHN.
General data on efficacy and early and subacute
toxicity have been reported
14-16
. It is likely,
however, that each individual study is
underpowered for a thorough analysis of late
effects, given sample size and patient attrition
due to mortality and other causes. Consequently,
we performed a secondary analysis of severe late
toxicities from these several trials, specifically
focusing on late toxicities and mortality related
to pharyngolaryngeal dysfunction. An analysis
of potential factors associated with severe late
toxicities was undertaken.
Materials/Methods
As noted above, the three prospective trials
analyzed for this paper have been previ-
ously reported. All three studies required an
acceptable performance status (60-100% by
Karnofsky scale); non-metastatic stage III/IV
SCCHN; and good hematologic, renal, hepatic
and cardiovascular function.
Briefly, the three studies are:
RTOG 91-11
14
: A phase III trial of larynx-
preserving radiotherapy or chemoradiotherapy
for selected Stage III/IV larynx cancer. For
this analysis, only the concurrent chemo-
radiotherapy arm was studied; this treatment
in this arm consisted of 70 Gy in convention-
ally fractionated radiotherapy (XRT) – 2 Gy
once daily –
plus three cycles of high dose
Mitchell Machtay, MD
1
, Jennifer Moughan, MS
2
, Andrew Trotti, MD
3
,
Adam S. Garden, MD
4
, Randal S. Weber, MD
5
, Jay S. Cooper, MD
6
,
Arlene Forastiere, MD
7
, K. Kian Ang, MD
4
1
Jefferson Medical College and Kimmel Cancer Center of Thomas Jefferson University,
Philadelphia;
2
RTOG Headquarters and Statistical Center and the American College of
Radiology, Philadelphia;
3
Moffitt Cancer Center of University of South Florida, Tampa;
Departments of
4
Radiation Oncology and
5
Head and Neck Surgery at MD Anderson Cancer
Center, Houston;
6
Maimonides Medical Center, New York; and
7
Johns Hopkins University
Medical Center, Baltimore.
The following article is Reprinted with permission.(c) American Society of Clinical Oncology.
All rights reserved. Machtay, M. et al: J. Clin. Oncol. 26 (21), 2008:3582-3589.
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RTOG Analysis
cisplatin (100 mg/m2, Weeks 1, 4, and 7). There were 172 patients in
this arm from RTOG 91-11; 88 patients were evaluable for this analysis
of late toxicity.
RTOG 97-03
17
: A Phase IIR trial of several novel regimens of concur-
rent chemoradiotherapy for stage III/IV head and neck cancer (excluding
patients who were eligibile for RTOG 91-11). This study included three
arms. Arms 1 and 3 utilized conventionally fractionated XRT as per 91-
11. Arm 1 chemotherapy was infusional 5-FU and cisplatin, both given
daily during the last two weeks of XRT. Arm 3 chemotherapy was once
weekly cisplatin (20 mg/m2/week) and paclitaxel (30 mg/m2/week).
Arm 2 chemoradiotherapy was modeled upon the prospective phase
II trials performed by the University of Chicago. In Arm 2, although
the total XRT dose remained 70 Gy in 2 Gy fractions, it was delivered
over 13 weeks (week-on, week-off technique); chemotherapy in Arm 2
consisted of concurrent infusional 5-FU and hydroxyurea. There were
231 patients in RTOG 97-03; 102 patients were evaluable for this analysis
of late toxicity.
RTOG 99-14
16
: A Phase II trial of accelerated radiotherapy with
concurrent chemotherapy for stage III/IV head and neck cancer. This
single arm phase II study consisted of accelerated concomitant boost
radiotherapy to 72 Gy over 6 weeks (as per the concomitant boost arm of
RTOG 90-03), with two cycles of high dose cisplatin (100 mg/m2 weeks 1
and 4). There were 76 patients in RTOG 99-14; 40 patients were evaluable
for this analysis of late toxicity.
All of these studies used conventional radiotherapy techniques, mostly
2-dimensional planning and delivery. No patient received intensity
modulated radiation therapy (IMRT). For this report, a severe late
toxicity was defined as any or all of the following events:
• Grade 3 or greater toxicity (RTOG/EORTC Late Toxicity Criteria)
present > 180 days after the start of XRT and clearly related to
dysfunction of the larynx and/or pharynx (e.g. dysphagia)
• Requirement for a feeding tube/gastrostomy 2 years or longer after the
start of XRT.
• Death without cancer progression and from an uncertain cause in
which laryngeal dysfunction is suspected to be a contributing factor
(e.g. pneumonia) ≤ 3 years from the date of randomization. Patients
who died of unknown causes were included in this category. Review
of these deaths was performed by one of the study authors (MM) in
a manner blinded to any of the patient’s clinical pre-treatment and/or
treatment related characteristics.
Patients who suffered one or more qualifying severe late toxicity events
were only considered to be one “case.”
Patients with severe laryngopharynx dysfunction due to cancer, prior to
the start of treatment, were excluded because of the potential confounding
nature of tumor destruction of critical normal tissues (See Table 1). In
RTOG 91-11, the determination of severe pre-treatment laryngopharynx
dysfunction was based on patients’ on-study data collection form, which
scored airway obstruction and dysphagia on a 4-point scale (none, mild,
moderate, severe/life-threatening); patients with severe/life-threatening
airway obstruction and/or dysphagia based on this form were excluded.
In RTOG 91-11, data on pre-treatment use of feeding tubes were not
collected. In RTOG 97-03 and RTOG 99-14, pre-treatment feeding tube
data were collected, and this was used as the primary means of defining
patients with pre-treatment severe laryngopharynx dysfunction.
Patients with missing/inevaluable data or early death from acute toxicity
were also excluded.
Statistical Analysis
Frequency tables with counts and percentages were used to describe
pretreatment and treatment characteristics for each group. Univariate
and multivariable logistic regression models were used to identify
associations of pretreatment and treatment-related factors with severe
late toxicity. All models were stratified by the 5 treatment arms described
above. The following factors were studied: age (continuous variable);
gender; race (non-black vs. black); KPS (60-80 vs. 90-100); hemoglobin
(continuous variable); weight loss pre-treatment (continuous variable);
T-stage (T1/2 vs. T3/4); N Stage (Nx/0/1 vs. N2 vs. N3); Tumor site
(oral cavity/oropharynx vs. larynx/hypopharynx); radiotherapy dose
received as assessed by late effects BED model (total RT dose multiplied
by (1+ [dose/fraction size] ÷ 3): continuous variable); chemotherapy
dose received (<85% of planned dose vs. > 85% of planned dose); and
post-RT neck dissection (yes vs. no). Variables’ levels were grouped in
order to avoid small cell counts. A stepwise selection procedure was
used to build the multivariable logistic regression model using the above
pretreatment/treatment variables. Entry criterion was set at p < 0.05.
The odds ratios (OR) for each variable in the final model along with
their 95% confidence intervals and p-values are reported. The odds
ratios estimate how much more (less) likely it is to be in the case group
versus the control group among patients with the specific variable level’s
characteristic compared to those patients in the reference level (RL), after
stratifying for treatment arm. The cumulative incidence method was
used to estimate time to severe late toxicity and levels for pre-treatment/
treatment-related variables were compared using the Gray’s test
18, 19
.
Table 1. Summary of Patients Excluded from this Analysis
RTOG 91-11
(Original
N=172)
RTOG 97-03
(Original
N=231)
RTOG 99-14
(Original
N=76)
Total
(Original
N=479)
Reason for Exclusion
Severe Pre-treatment 15 — — 15
Airway Obstruction
Severe Pre-treatment 5 — — 5
Dysphagia
Pre-treatment Feeding — 62 18 80
Tube Dependence
Total Excluded due to 20 62 18 100
Severe pre-treatment
laryngopharynx
dysfunction
Death from Acute 2 3 1 6
toxicity
Tumor Recurrence/ 52 62 16 130
death < 3 yrs followup.
Missing Data 10 2 1 13
Grand Total Excluded 84 129 36 249
Total Analyzable 88 102 40 230
for this study
Abbreviations as in Table 4.
Reference level: GTV ≤45 cm
3
, dose 90.3 Gy.
*Chi-square test using Cox proportional hazards model.
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36
Results
The original, potential patient population from these three studies was
479. However, there were 130 patients excluded because of local-regional
failure or death due to cancer, 100 patients excluded because of severe
pre-treatment laryngopharynx dysfunction due to tumor, 13 patients
excluded because of missing data, and 6 patients excluded because of
early death due to acute toxicity (see Table 1);. Thus, the overall evaluable
sample size for this report was 230 patients. The median followup for the
patient population is 2.96 years.
Of these 230 patients, 99 patients (cases) had severe late toxicity and
131 patients (controls) did not have severe late toxicity. This results in
a crude rate of late toxicity of 43%. It should be noted that if the entire
population of patients (N=479) from all three studies are analyzed (as is
often performed for studies of late effects) the crude rate would appear
to be 21%., considerably lower than the data reported here. An actuarial
plot of “Time to Severe Late Toxicity” for all 230 evaluable patients is
shown in Figure 1.
for Case
230 174
143 81
36 17
Pts. at Risk
11
0
25
50
75
100
0122436486072
Months From Randomization
% Failed
Figure 1. Time to Severe Late Toxicity Events – All Evaluable Patients.
Table 2. Summary of patients with severe late toxicities (cases)
and patients without severe late toxicities (controls)
Case Group
(n=99)
Control Group
(n=131)
Age
Median 60 56
Range 33-78 26-78
Age ≤ 70 85 (86%) 118 (90%)
Age > 70 14 (14%) 13 (10%)
Gender
Male 78 (79%) 99 (76%)
. Female 21 (21%) 32 (24%)
Race
Non-Black 90 (91%) 120 (92%)
Black 9 ( 9%) 11 ( 8%)
KPS
60-80 24 (24%) 20 (15%)
90-100 75 (76%) 111 (85%)
Hemoglobin
Median 14.3 14.2
Range 7.1-18.2 9.9-18.2
Hgb ≤ 13.5 gm/dl 28 (28%) 43 (33%)
Hgb > 13.5 gm/dl 71 (72%) 88 (67%)
Weight Loss in Previous 6 months (kg)
Mean 3.9 2.8
≤ 5 kg 78 (79%) 112 (86%)
> 5 kg 21 (21%) 19 (14%)
T Stage
T1/T2 18 (18%) 39 (30%)
T3/T4 81 (82%) 92 (70%)
N Stage
NX/N0/N1 47 (47%) 63 (48%)
N2 42 (42%) 58 (44%)
N3 10 (10%) 10 ( 8%)
Tumor Site
Oral cavity/oropharynx 42 (42%) 71 (54%)
Oral Cavity 7 (7%) 5 (4%)
Oropharynx 35 (35%) 66 (50%)
Larynx/hypopharynx 57 (58%) 60 (46%)
Larynx 41 (41%) 51 (39%)
Hypopharynx 16 (16%) 9 (7%)
Radiotherapy Dose-Intensity
delivered (BED)
Mean 115 Gy 116 Gy
Median 117 Gy 117 Gy
Range 67-117 Gy 111-126 Gy
Neck Dissection after RT
Yes 26 (26%)* 21 (16%)
No 73 (74%) 110 (84%)
Chemotherapy dose-intensity
delivered
< 85% 22 (22%) 29 (22%)
≥ 85% 77 (78%) 102 (78%)
*Two of these patients had their neck dissection after experiencing a severe late toxicity
Table 3. Types of late toxicity events seen by trial
91-11
97-03 99-14
Total
Feeding Tube Dependence —* 29* 29
> 2 yrs. Post RT
Grade 3+ Pharyngeal 16 28 19 63
Dysfunction (RTOG late
toxicity criteria)
Grade 3+ Laryngeal 22 6 0 28
Dysfunction (RTOG late
toxicity criteria)
Death 11 9 2 22
Other (e.g. infection, fistula) 3 0 1 4
Any 38** 40** 21** 99**
No Severe late toxicity 50 62 19 13
event (controls)
* Feeding tube data were not collected at all in RTOG 91-11.
** Numbers do not always add up along columns, due to some patients having more than one
toxicity event.