Document Type : Original Article
Authors
1 Assistant Lecturer of Clinical Oncology Faculty of Medicine Al-Azhar University
2 Associate Professor of Clinical Oncology Al-Azhar Faculty of medicin
3 Therapeutic Radiology and Nuclear Medicine, Al-Azhar University
Abstract
Keywords
INTRODUCTION
Radiotherapy is the cornerstone of the therapy for locally advanced head and neck cancer (AHNC), because of its ability to preserve organs instead of surgical resection with function loss, in addition to that radiotherapy increase the tumor control rate with acceptable toxicity profile in comparison to the surgery that may cause long term sever morbidity. 1
Because of the high number of organs at risk in the small neck and head area, as well as the complexities of lymphatic drainage, as well as the high sensitivity of organs at risk to radiotherapy, which results in a high incidence of acute toxicity, intensity-modulated radiation therapy (IMRT) has become the primary strategy for such patients due to its ability to decrease dosages to organs at risk and cover different irregular targets with different dose gradients. 2
During the radiotherapy course that likely extend to 6-7 weeks the tumor as well as some organs at risk like parotid glands change in size and location, these changes not taken in account during the traditional radiotherapy course although this may lead to a lack of target coverage and/or higher dosage for the
organs at risk, because of this problem the idea of adaptive radiotherapy (ART) come to practice 3
Many trials have tracked adjustments in target and risk organs throughout radiotherapy treatment courses throughout different schedules of CT, ranging between daily to weekly imaging and found significant geometrical changes that mandate adoptive replanting during the radiotherapy course for at least one time. References required 4
If no adaptive replanning done routinely likely the coverage of the targeted will not be adequate along the treatment course, in addition to that organs at risk may receive radiation dose higher than what is seen in the primary plan and even exceed the predefined tolerance.5
The primary aim of this research is to assess the strategy of adaptive radiotherapy in advanced squamous cell carcinoma of the head and neck as regards dose to organ at risk (OAR) and dose to gross target volume (GTV), while the secondary aim is to assess the impact of tumor volume reduction rate (TVRR) on progression-free survival (PFS).
PATIENTS AND METHODS
Eligibility Criteria:
Age ≥ 18 years and ≤ 70 of both genders, Performance Status ≤ 2 ECOG scale, Histologically confirmed invasive Squamous cell carcinoma of the head and neck, Locally advanced tumors stage III and IVA (AJCC cancer staging system the 7th edition), Adequate laboratory investigations, Patients without any primary treatment for their current disease (surgical, chemotherapy, or radiotherapy); Informed consent.
Exclusion criteria:
Cellular subtypes other than squamous cell carcinoma, Pregnant women, Obese patients (> 120 kg); Sever skeletal deformity or any disease interfering with patient alignment and positioning of radiation therapy delivery.
Clinical examinations, ENT and dental evaluations, contrasted CT scans of the chest as well as upper abdomen, head and neck contrasted CT+MRI, and a series of laboratory investigations were performed on all patients to assess the degree of illness and the existence of comorbidity, if present.
Trial design:
Patients in this prospective study were given definitive IMRT (70 Gy/33 fractions) as well as weekly cisplatin 40 mg/m2 chemotherapy for seven weeks (weekly carboplatin AUC 2 allowed if impaired renal profile).
An IMRT treatment plan that covers 98% of the PTV with 95% of the treatment dosage while delivering 105% of the treatment dose to below 10%, and not delivering ≥ 110 of the treatment dose to the PTV.
Plans were generated concerning delivery using only 6-MV photons via linear accelerator (Varian Medical System). Quality assurance (QA) was done before starting treatment for every case; verification with an electronic portal image device (EPID) was done with the first three fractions, then weekly.
Adaptive design:
All patients at our study underwent to CT imaging for adaptive planning and radiological evaluation (off board) at the end of the 4th week (median dose 38.2 Gy). Adaptive replanning and new plan formation was done for all patients with comparing the clinical and dosimetric outcomes with original plan.
On the original CT scan, Plan 1 (P1) was defined as the original primary and boost plans (Original plan).
On rescan CT, Plan 2 (P2) was defined as the original primary and boost plans (new CT), with the calculation done without optimization to give us an accurate guide for dosimetric evaluation as regards the expected plan if the patient completed radiotherapy without adaptation.
On rescan CT, Plan 3 (P3) was defined as the original primary and adaptive boost (Adaptive plan).
Tumour Volume Reduction Rate (TVRR): has been calculated as ([pre-RT GTVt-rescan GTVt]/pre-RT GTVt), and the volume has been utilized to associate with survival differences (OS and PFS).
Follow up:
After finishing radiation course, radiological assessment was done after 6-8weeks with contrasted CT + MRI head and neck, endoscopy was done if required with/without biopsy upon need. Clinical and radiological evaluations were assessed based on Response assessment criteria (RECIST 1.1). Patients with PR, SD, and PD will be considered as locoregional failure. Patients with locoregional failure were evaluated for possible surgery for possibility for maximum locoregional control. If not candidate for surgery they received salvage chemotherapy.
Statistical methodology
The Statistical Package for Social Sciences (SPSS) versus 24 was used for data processing and analysis, with the mean, standard deviation, median, and range, Chi square, student t-test, linear correlation coefficient, and analysis of variance [ANOVA] tests. Survival analysis has been carried out utilizing the Kaplan-Meier method, and the P-value has been regarded as significant if it was less than 0.05.
Ethical Approval
Before the study began, the ethical committee of the faculty of medicine at Al-Azhar University granted approval.
RESULTS
The current prospective study involved 49 patients who fulfilled the eligibility criteria and had a pathologically confirmed locally advanced head and neck squamous cell carcinoma. Table (1) demonstrates the clinicopathological features of the patients.
The whole study group received IMRT radiation therapy with concurrent weekly cisplatin 40mg/m2, target volume coverage of original and boost plan on primary CT (P1), also doses to organs at risk (ipsilateral parotid, contralateral parotid, spinal cord as well as brain stem) are displayed in table (2)
The modified IMRT plan increased GTV and PTV2 median coverage by 0.25% and 0.1.27%, respectively; ipsilateral and contralateral parotid volumes were reduced by 13.26% and 17.68%, respectively. Table (3)
The median dose decrease to the ipsilateral parotid, contralateral parotid, spinal cord, and brain stem was 3.86%, 5.32%, 3.5%, and 5.28%, respectively, with adaptive replaning. The median coverage for GTV and PTV2 was improved by 0.25% and 0.1.27%, respectively, with the adapted IMRT plan. (Table 3)
Acute toxicities related to radiation therapy were assessed for all patients, grade III oral mucositis was developed in 36.7% of patients (5/49), grade III Xerostomia in 16.3% (8/49), grade III skin toxicity in 6.12% (3/49) and 34.6% of patients (17/49) developed grade III dysphagia (Table 4).
Response assessment was done after 8 weeks of finishing CCRTH. It was noticed that 65.3% of patients (32/49) had complete remission (CR), 24.48% (12/49) had partial response, 10.22% (5/49) had stationary disease (Table 5).
The mean pre-RT GTVt was 67.44 cm3 versus 45.78 cm3 for the adaptive GTVt. The calculated median Tumor volume reduction rate (TVRR) and relation with clinical outcomes are shown in table (6).
Based on the median change in TVRR, we looked at the impact of TVRR on DFS and OS, dividing patients into2 groups: TVRR <= 31.2 vs > 31.2 and results showed none statistically significant P-value (Table 7).
Variable |
Total (49) |
Percent (%) |
|
Age (years) |
Median:56.00 |
|
|
Range:(19-74) |
|
||
Gender |
Male |
35 |
71.4 |
Female |
14 |
28.6 |
|
Family history |
Positive |
1 |
2.04 |
Negative |
48 |
97.96 |
|
Smoking |
Smokers |
32 |
65.3 |
Non-Smokers |
17 |
34.7 |
|
Comorbidity |
DM |
14 |
28.6 |
HTN |
9 |
18.4 |
|
(IHD) |
3 |
6.1 |
|
(HCV) Positive |
3 |
6.1 |
|
PS (Performance Status) |
0-1 |
48 |
97.96 |
II |
1 |
2.04 |
|
Clinical presentation |
Hoarseness of voice |
22 |
44.9 |
Nasal obstruction |
10 |
20.4 |
|
Neck swelling |
9 |
18.4 |
|
Dysphagia |
5 |
10.2 |
|
Otalgia |
3 |
6.1 |
|
Tumor site |
Larynx |
26 |
53.1 |
Nasopharynx |
15 |
30.6 |
|
Oropharynx |
6 |
12.3 |
|
Hypopharynx |
1 |
2.04 |
|
External auditory canal |
1 |
2.04 |
|
Grade |
I |
4 |
8.2 |
II |
21 |
42.8 |
|
III |
24 |
49.00 |
|
T stage |
T2 |
6 |
12.3 |
T3 |
18 |
36.7 |
|
T4 |
25 |
51.0 |
|
N stage |
N0 |
17 |
34.7 |
N1 |
20 |
40.8 |
|
N2 |
5 |
10.2 |
|
N3 |
7 |
14.3 |
|
Stage |
III |
20 |
40.8 |
IVA |
29 |
59.2 |
Table 1: The clinicopathological characteristics of the study group.
|
Plan 1 (original Plan on original CT) |
|
No. = 49 |
||
GTV volume (cm3) |
Median (IQR) |
48.3 (26.8 – 74.1) |
Range |
4.7 – 232.2 |
|
Mean |
67.442 |
|
SD |
64.7738 |
|
GTV 100% |
Median (IQR) |
98.94 (98.45 – 99.36) |
Range |
98.14 – 99.95 |
|
PTV volume (cm3) |
Median (IQR) |
126.2 (75.8 – 224.5) |
Range |
19.4 – 855.9 |
|
PTV2 V95 (%) |
Median (IQR) |
95.84 (95.26 – 96.53) |
Range |
94.16 – 97.58 |
|
Ipsilateral Parotid Volume (cm3) |
Median (IQR) |
30 (23.5 – 37.3) |
Range |
17.7 – 49 |
|
Ipsilateral Parotid Mean (Gy) |
Median (IQR) |
24.2 (22.6 – 24.6) |
Range |
16 – 25.8 |
|
Contralateral Parotid volume (cm3) |
Median (IQR) |
30.9 (25.8 – 37.3) |
Range |
19.5 – 48.1 |
|
Contralateral Parotid Mean (Gy) |
Median (IQR) |
24.8 (23.1 – 25.2) |
Range |
16.6 – 25.63 |
|
Spinal Cord Max (Gy) |
Median (IQR) |
42.6 (38.02 – 44) |
Range |
28.1 – 49.7 |
|
Brain Stem Max (Gy) |
Median (IQR) |
41.4 (35.18 – 45.8) |
Range |
6.4 – 54.13 |
Table 2: Target volumes and organs at risk of P1 (original Plan).
|
Percentage change |
|
No. = 49 |
||
GTV volume (CC) |
Median (IQR) |
-31.26 (-45.52 – -26.15) |
Range |
-80.75 – 0 |
|
GTV 100% |
Median (IQR) |
0.25 (0 – 1.01) |
Range |
(-0.05 – 2.08) |
|
PTV volume (CC) |
Median (IQR) |
-22.81 (-36.21 – -8.11) |
Range |
(-91.75 – -38.66) |
|
PTV 2 V95 (%) |
Median (IQR) |
1.27 (0.57 – 2.09) |
Range |
(-0.05 – 5.1) |
|
Ipsilateral Parotid Volume (cc) |
Median (IQR) |
-13.62 (-21.72 – -9.81) |
Range |
(-35.11 – -3.75) |
|
Ipsilateral Parotid Mean (Gy) |
Median (IQR) |
-3.86 (-7.67 – 0) |
Range |
(-32.41 – -4.46) |
|
Contralateral Parotid volume (cc) |
Median (IQR) |
-17.68 (-22.41 – -8.41) |
Range |
-47.15 – -12.26 |
|
Contralateral Parotid Mean (Gy) |
Median (IQR) |
-5.32 (-14.59 – -1.56) |
Range |
(-33.59 – -0.35) |
|
Spinal Cord Max (Gy) |
Median (IQR) |
-3.5 (-6.56 – 0) |
Range |
(-33.25 – -1.89) |
|
Brain Stem Max (Gy) |
Median (IQR) |
-5.28 (-7.92 – -2.13) |
Range |
(-32.62 – -3.08) |
Table 3: Percentage of dose reduction for organ at risks after adaptation.
Toxicity |
GI |
GII |
GIII |
GIV |
GV |
Mucositis |
5(10.2%) |
16(32.6%) |
18(36.7%) |
0 |
0 |
Xerostomia |
7(14.28%) |
24(44.9%) |
8(16.3%) |
0 |
0 |
Acute laryngitis |
5(10.2%) |
22(44.9%) |
0 |
0 |
0 |
Acute skin toxicity |
18(36.7%) |
13(26.5%) |
3(6.12%) |
0 |
0 |
Dysphagia |
6(12.2%) |
22(44.9%) |
17(34.6%) |
0 |
0 |
Table 4: Radiotherapy related toxicities
Response |
No. (49) |
Percent (%) |
|
Response Rate |
-CR |
32 |
65.30 |
-PR |
12 |
24.48 |
|
-SD |
5 |
10.22 |
|
|
|
NO. (48) |
Percent (100%) |
Disease Control |
Local control (CR) |
32 |
65.30 |
Loco regional failure |
17 |
34.70 |
|
|
|
NO. (14/48) |
Percent (100%) |
Site of relapse |
Locoregional |
11 |
22.9 |
Distant (lung) |
2 |
4.16 |
|
Distant (Bone) |
1 |
2.08 |
Table 5: Response details
|
CR No. = 32 |
PR No. = 12 |
SD No. = 5 |
Test value |
P-value |
Sig. |
|
Tumor volume |
Median (IQR) |
32.25 (26.2 – 45.7) |
29.6 (9.65 – 51.05) |
31.2 (31.2 – 35.8) |
0.147 |
0.929 |
NS |
Range |
0.6 – 63.2 |
0 – 82.6 |
4.4 – 39.5 |
Table 6: Relations between TVRR and clinical outcomes
(PFS) |
Total |
N of |
Mean |
SE |
95% CI |
Surviving proportion at |
Test value |
P-value |
Sig. |
|||
Lower |
Upper |
1 year |
2 years |
|
|
|
||||||
|
Total |
49 |
14 |
30.522 |
1.704 |
27.182 |
33.862 |
89.7% |
70.2% |
- |
- |
- |
Tumor volume |
<= 31.2 |
26 |
9 |
26.089 |
1.863 |
22.438 |
29.739 |
84.4% |
66.2% |
0.996 |
0.318 |
NS |
> 31.2 |
23 |
5 |
32.496 |
2.215 |
28.156 |
36.837 |
95.7% |
74.4% |
||||
(OS) |
Total |
N of |
Mean |
SE |
95% CI |
Surviving proportion at |
Test value |
P-value |
Sig. |
|||
Lower |
Upper |
1 year |
2 years |
|||||||||
|
Total |
49 |
11 |
32.438 |
29.580 |
29.580 |
35.297 |
89.8% |
83.0% |
- |
- |
- |
Tumor volume |
<= 31.2 |
26 |
6 |
29.959 |
26.937 |
26.937 |
32.982 |
88.50% |
79.70% |
0.070 |
0.791 |
NS |
> 31.2 |
23 |
5 |
32.744 |
28.647 |
28.647 |
36.841 |
91.30% |
86.50% |
Table 7: Relations between TVRR and survivals.
Survival analysis
The median (PFS) and OS have not been reached. The cumulative one-year and two-year PFS were 89.7% and 70.2%, respectively, while the cumulative one-year and two-year Os were 89.8 % and 83.0 % respectively figures (1&2).
Fig. 1: progression free survival.
Fig. 2: Overall survival.
DISCUSSION
The majority of our patients had tumors in the Larynx (53.1%) which is matched with our national data,6 while data published at Loyola university medical center (USA) showed the most common tumor site was oropharynx (58.2%),5 which also matched with epidemiological data at USA that showed oropharynx is the commonest site for HNSCC.7
Many structures, most noticeably the primary tumor, have been demonstrated to change shape and size during radiation treatment for HNSCC. Changes in the shape and size of target structures and organs at danger during the radiation therapy process may effectively blur the dose distribution and may cause systematic uncertainties that alter the dose distribution relative to the target.8
According to Liu et al.9, tumor shrinkage can be detected as early as the first two weeks, with median revealed shrinkage rates varying from 3 to 16%, 9 Surcus et al.5 found that tumor size was reduced by the end of the fourth week, with median revealed shrinkage rates ranging from7 to 48%, 5 while Loo et al.10 discovered that the tumor size had shrunk by the end of the 7th week, with median disclosed shrinkage rates varying from 6 to 66%.10
In our study we found that median primary tumor volume changed from (48.3) cm3 to (31.26) cm3 with percentage reduction about (35.2%) at the end of 4th week.
Surcus et al.5 attempted to link TVRR to clinical outcomes in their study and were willing to show statistically significant differences in DFS (8.9 months vs 17.5%, respectively) and OS (14.2 months vs 21.4 respectively) for patients with TVRR 35.2 % and TVRR > 35.2 %. 5
Lee et al.11 examined the RT registers of 59 oropharyngeal cancer patients who underwent a mid-RT scan to create an adaptive plan and discovered that patients with TVRR > 35% had significantly better 3-year loco regional control than those with TVRR 35% (94.4% versus 72.4%, respectively).11
Yang et al.12 compared pre-RT GTV and interval GTV produced from rescan CT during the 4th week of therapy in 152 patients with oropharyngeal and hypopharyngeal cancer and discovered that TVRR was a statistically significant diagnostic predictor for local control.12
In our study, we found that the median range of tumor volume decrease rate (was 31.2 %) and by correlating TVRR with clinical outcomes our results showed no statistically significant differences for patients with TVRR 32.25% and TVRR >32.25% in two year DFS (66.2% vs 74.4%) respectively and two years OS (79.7% vs 86.5%) respectively.
When it comes to OARs, the parotid glands are especially important because their radio sensitivity is well defined, leading to a reduction in salivary output at a reduced dosage of radiation, as well as xerostomia and a lower quality of life.13
Eisbruch and colleagues found that even a low dosage of 26 Gy to the parotid glands could result in irreversible xerostomia. With the introduction of IMRT, therapy plans could be designed to avoid the parotid glands while still conforming to the target as well as providing sufficient coverage.14 Even so, not all patients with excellent parotid sparing on therapy planning have excellent xerostomia rates, as 38% of patients who received IMRT in PARSPORT I and 21% in PARSPORT II had grade 2 or larger xerostomia by month 12.15
According to Capelle et al.16, the average volume of the parotids shrieked during radiation therapy. The average volume of the parotids had decreased by as much as 14.7, 37, and 48% by the end of weeks 2, 4, and 7, implying that the given dosages could be much higher than anticipated by the original plan. 16
Surcus et al.5 discovered that the median dose reduction to the ipsilateral and contralateral parotids was 6.2% and 2.5%, respectively, in his study at Loyola University Medical Center.5
In our research, we discovered that the median mean ipsilateral parotid volume shrank during adaptation up to (13.62%) and the median dose reduced up to (3.86%). While the contralateral parotid volume shrank by up to (17.68%), the median dose was reduced by (5.32%).
The spinal cord is an important area of study because hot spots can form during radiation therapy. However, Capelle et al.16 do not report any significant increases in the maximum dose during radiation therapy and Wu et al.17 also noting no change in D max of spinal cord through the course radiotherapy. 16,17
According to Loo et al.10, the volume and position of the spinal cord have not been shown to change during radiation therapy, which might explain why changes in dosimetric in the spinal cord are not as coherent or profound.10
Even so, the dose variability in studies which do report extra dosages to the spinal cord could be quite high, with one finding a range of 0.2–15.4 Gy rise in the spinal cord peak dose (Hansen et al., 2006) and another finding 2.1–9.9 Gy, respectively. 18,19
Surcus et al.5 reported in their study that the median dose decrease to D max of the spinal cord was reduced by 4.5% in 51 patients with advanced neck and head cancers managed with simultaneous chemoradiation with adaptation at a median dosage of 37.8 Gy.5
In our study we found that the median reduction in D max of spinal cord through the course of radiotherapy was (3.5%).
The brain stem, like the spinal cord, is of interest because hot spots could be created during radiation therapy, exceeding traditional dosimetric restrictions that have been selected to keep brainstem necrosis rates low. When (D max dosage < 54 Gy) is exceeded during radiation therapy, Hansen et al.18 recommend re-planning.
Capelle et al.16 report no significant increases in the higher dosage over the course of radiation therapy, and Wu et al.17 also note no change in the D max of the brain stem through the course of radiotherapy. 16,17
Even so, in the studies which do disclose extra doses to the brain stem, the dosage variance could be quite high, with one study finding a range of 0.6–8.1 Gy increase in the brain stem max dose by Hansen et al.18, as well as 1.6–5.9 Gy by Chitapanarux et al.19 and (4.5%) in another. 5,18,19
In our study we found that the median reduction in D max of brain stem through the course of radiotherapy was (5.28%).
CONCLUSION
Adaptive radiation therapy helps in improving tumor coverage, decreasing dosages to organs in danger, and subsequently minimizing the expected toxicity.
REFERENCES