Evaluation of Adaptive Radiation Therapy in Treatment of Locally Advanced Head and Neck cancers

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).

Table 1: The clinicopathological characteristics of the study group.

Table 2: Target volumes and organs at risk of P1 (original Plan).

     Table 3: Percentage of dose reduction for organ at risks after adaptation.

Table 4: Radiotherapy related toxicities

Table 5: Response details

Table 6: Relations between TVRR and clinical outcomes

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.