Definitive intensity modulated radiotherapy in locally advanced hypopharygeal and laryngeal squamous cell carcinoma: mature treatment results and patterns of locoregional failure

Patient selection

Patients with locally advanced HL-SCC [American Joint Committee on Cancer (AJCC) stage III or IV] treated with curative IMRT treatment between January 2007 and December 2010 at the Department of Radiation Oncology, Inselspital, Bern University Hospital were retrospectively assessed. Ineligibility criteria included patients older than 85 years, initial Karnofsky Performance Status (KPS) less than 60%, history of another malignancy within 5 years of diagnosis, prior RT to the head and neck, histology other than squamous cell carcinoma and distant metastatic disease. Patients who underwent radical surgical procedures to the primary tumor were excluded, but functional tumor debulking and/or primary neck dissections (ND) were allowed. Patients who did not reach the prescribed RT dose or did not finish treatment within 60 days since delivery of the first RT fraction were excluded. Living patients with documented follow-up of less than one year were also excluded from analysis. This study was approved by the local research ethics committee and the Swiss Federal Office of Public Health (FOPH) (035.0001-90).

Treatment

All cases were presented at the weekly institutional interdisciplinary head-and-neck tumour board. After completion of staging examinations and final TNM staging (AJCC), selection of treatment modalities and treatment sequencing were defined. Pre-treatment staging involved laryngoscopy, measurement of the tumour, and high-resolution computed tomographic (CT) scanning of the primary tumour and the neck with or without magnetic resonance imaging (MRI). Prior to 2008, imaging for systemic staging was performed as clinically indicated; and from 2008 onwards positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) was regularly used in the staging of locally advanced cases to rule out distant metastasis, synchronous malignancies, and gain additional information on lymph node metastasis, especially on retropharyngeal (RP) node status. All patients were referred to dental evaluation before start of RT. Prophylactic feeding tube insertion via gastrostomy was recommended to most of the patients.

Radiotherapy

For treatment planning a dedicated high-resolution CT scan with 3 mm slices and intravenous contrast was used. Patients were immobilized in the supine position using a thermoplastic mask covering head and shoulders. No bite bock was used to facilitate dorsal hyperflexion of the cervical spine. Patients were additionally instructed to keep the tongue extended during treatment if possible. All visible surgical scars were marked with flexible wires if a neck dissection had been performed. All target volumes and organs at risk were contoured on the planning CT scan. Image fusion of diagnostic MRI and/or PET-CT with the planning CT was performed if cervical spine flexion was similar resulting in an acceptable matching distortion. Gross tumor volume (GTV) consisted of the primary tumor (or residual tumor after debulking in two patients) and pathologic lymph nodes as clinically diagnosed and visualized on all available imaging. High-risk CTV72 was derived from the GTV with an additional isotropic margin of 5 – 12 mm. Only in patients with prior ND, a high-risk CTV66 was defined as the levels of the original gross involved nodes harbouring extracapsular extension (ECE), as reconstructed from the preoperative imaging, with an additional isotropic margin of 5 – 15 mm. In nodal stages pN2a and pN3 we generally assumed presence of ECE even if not explicitly stated in the histopathologic report. In cases of reported intraoperative lymph node spillage the complete area of neck dissection was included in the CTV66.

In patients with ND and nodal stages pN1, pN2b, pN2c without ECE, the standard risk CTV54 included all dissected neck levels and the surgically manipulated area as proposed by Gregoire et al. [12] and all non-dissected elective lymph node levels bilaterally. In patients without ND, CTV54 included all elective lymph node levels bilaterally. The definition of elective nodal target volumes in respect to size and location of the primary tumor followed the recommendations proposed by Eisbruch et al. [13] and consensus guidelines [14] with minor adjustments. In clinical or pathological nodal stages N1, N2a and N2b, we did not include the cranial half of contralateral level II to spare contralateral parotid gland neither caudal half of contralateral level IV. When present, the area of tracheostomy was fully included in the CTV54. In cases of ipsilateral level II involvement, CTV54 extended cranially to the base of skull on the ipsilateral side including the retro-styloid space [11]. If ipsilateral level II was not involved in nodal stage N1, N2a, N2b, we also considered sparing the cranial half of ipsilateral level II. In the absence of metastatic RP nodes after diagnostic imaging with MRI and PET-CT, elective coverage of RP were limited to 3-4 cm cranially to the GTV.

All prescribed CTV margins were manually adapted to account for anatomical barriers such as thyroid and cricoid cartilages, hyoid, mandibular or vertebral bones, skin and air. The resulting CTVs were finally expanded to planning target volumes (PTVs) by adding a symmetric 3 mm margin for setup error compensation. In a final adjustment PTVs were set back from the skin surface 3 mm to allow for dose build-up except where the skin was deemed to be at risk of microscopic disease. Instead of using a skin flap in these cases we tried to optimize dose build-up by putting more weight on tangential beam directions accepting minor under-dosage. Prescribed doses to PTV72, PTV66 and PTV54 were 72 Gy, 66 Gy and 54 Gy, respectively. All PTVs were treated sequentially in a “shrinking-volume” technique with a fractionation of 5 times per week, 2Gy per fraction, resulting in two or three treatment plans per patient. All PTVs were comprehensively covered in one IMRT plan without field junctions. The total dose was prescribed to the median dose (D50%) of the PTV in accordance with the ICRU report 83. Pre-treatment setup imaging was performed daily. All treatment plans were contoured and calculated using Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA).

Concomitant systemic therapy

The standard concomitant therapy consisted of cisplatin 100mg/m2 day 1 in three-week intervals for all patients. In few cases of induction chemotherapy, cisplatin, docetaxel and 5-fluorouracil were used. Patients not deemed medically fit for cisplatin chemotherapy because of pre-existing co-morbidities were evaluated for weekly treatment with monoclonal antibody cetuximab [15] or carboplatin three weekly. Patients who did not tolerate the toxicity of cisplatin treatment were switched to either carboplatin as described or to low dose carboplatin weekly or to cetuximab at the discretion of the medical oncologist.

Assessments and evaluations

After treatment all patients underwent follow-up visits on a regular basis. These visits were scheduled every 3 months for the first 2 years, twice a year until the 5th year and yearly thereafter. For this study the follow-up information closeout date was December 2011 to guarantee a minimum follow-up of one year. A post-therapy baseline CT or MRI was performed eight to twelve weeks after the end of treatment. Time-to-event endpoints were calculated from end of IMRT until the date of event. Patients not experiencing an event were censored at the date of the last follow-up visit.

Toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for adverse events (CTCAE) version 3.0. The symptoms of pain, dermatitis, mucositis, dysphagia, xerostomia and osteonecrosis were assessed. Acute and late toxicity were defined as post-treatment-related complications during and/or within 3 months after chemo-RT, and after 3 months, respectively. Baseline pre-treatment assessments using the same criteria were also performed.

Analysis of locoregional failures

The earliest diagnostic imaging showing any LRF was matched to the planning CT and the treatment plan. All recurrent and/or persistent local or regional macroscopic tumor volumes (RTV) were then delineated on the planning CT and a quantitative comparison of the volume congruency was used to categorize the LRF as “in-volume”, if >95% of the RTV was included in the corresponding CTV54, CTV66 or CTV72; “marginal”, if 20–95%, and “out-volume”, if <20% of the RTV was included within the corresponding CTV, as previously described [16]. The relation of the RTVs to all CTVs was assessed sequentially. We decided to quantitatively compare RTVs to CTVs as opposed to treatment plan isodose lines [17] to better evaluate the accuracy of our target volume delineation and dose prescription.

Statistical considerations

The primary endpoint was locoregional control (LRC). Secondary endpoints included local (LC) and regional (RC) controls, distant metastasis-free survival (DMFS), laryngectomy-free survival (LFS), overall survival (OS), acute and late toxicities. Late toxicity at last follow-up visit was also assessed to determine whether the late toxicity persisted or was transient. Time-to-event endpoints were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards models. Known prognostic variables were analyzed in the multivariate analysis and a stepwise backward selection method (criterion for removal: p ≥0.05) was applied. Variables were summarized using absolute and relative frequencies. P-values were two-sided, not adjusted for multiple testing, and considered significant if < 0.05. The data were analyzed in SPSS (SPSS Inc., Chicago, IL, version 21.0).