Robert J.J. van Es

Treatment failure and margin status in head and neck cancer. A critical view on the potential value of molecular pathology

Molecular pathology may demonstrate tumour cells not detected by histology. The idea has emerged that these cells influence the prognosis negatively and that their detection will lead to more appropriate treatment and improved patient survival. We theorized that tumour cells at surgical margins overlooked by the pathologist should demonstrate their clinical significance by causing recurrences at the primary site in the patients reported to have tumour-free margins by histology. To assess this assumption, we investigated the prognostic influence of the histologically determined status of the surgical margins. The material that formed the basis of this study consisted of 394 patients that underwent resection for their primary tumour during the years 1990-1995. In 207 patients, initial treatment was complete as assessed by conventional histopathological examination of the surgical specimen. In 187 patients, initial treatment was incomplete, defined as tumour in or close to the margin, or mild, moderate or severe dysplasia or in situ cancer at the margin. Causes for treatment failure were recorded for both groups separately. In the group with tumour-free margins, 16.9% had a second primary head and neck cancer, 8.2% had a second tumour in the lung, 10.6% had recurrent disease in the neck, 2.9% had distant metastasis, and 3.9% had local recurrence at the same site as the primary cancer. For the group without tumour-free margins, these figures were the following: second primary in the head and neck area: 17.1%, second primary in the lung: 7.0%, recurrent disease in the neck: 11.8%, distant metastasis: 8.0% and local recurrence at the primary site: 21.9%. Local recurrences were rare in patients in which the pathologist reported the resection to be complete. Although there may be tumour cells in surgical margins that evade histological detection, their clinical impact appears to be almost negligible.

Osteosarcoma of the jaw bones. Long-term follow-up of 48 cases

To evaluate the incidence and treatment results of osteosarcoma of the jaw (OSJ) in the Netherlands, data from 48 patients with a histologically proven diagnosis of osteogenic sarcoma of the maxilla or mandible were retrospectively analysed. Patient files, covering the period from 1964 to 1992, were obtained from all university hospitals in the Netherlands and the Netherlands Cancer Institute. The incidence of OSJ in the Netherlands is estimated to be at least 0.14 per 1,000,000. The overall 10-year survival was 59%. Distant metastasis occurred in 21% and local recurrences in 31% of the cases. Survival was significantly better in case of radical surgery and small tumours. Long-term survival after treatment of OSJ was good if complete surgical excision was achieved. Radiotherapy should only be considered to prevent local recurrence if surgery is not complete. The possible benefit of current chemotherapy in preventing metastatic disease is still questionable. Since other malignant neoplasms associated with OSJ occurred in 17% of the cases, lifelong follow up is mandatory for the detection of these second primary malignancies.

Nonvascularized Bone Grafts for Segmental Reconstruction of the Mandible—A Reappraisal

PURPOSE To evaluate the success rate and complications of segmental mandibular reconstructions with autogenous nonvascularized iliac crest bone grafts, and to refine treatment strategies. PATIENTS AND METHODS Seventy-four patients with segmental mandibular defects were included. Malignant lesion, immediate reconstruction, smoking habit, radiotherapy, site of the defect, surgical approach, and method of graft fixation were analyzed as factors of influence on success. Success was defined as maintenance of bone continuity and stability, and absence of infection 1 year after reconstruction upon clinical and radiographic examination. Complications were divided into recipient and donor-site complications and classified as minor or major. The reconstruction was considered functionally complete if prosthetic rehabilitation was accomplished or if there was a sufficient remaining dentition for mastication. RESULTS In 56 (76%) patients, the initial reconstruction was successful. Multivariate analyses showed that symphyseal involvement (SI) and intraoral approach (IA) were significantly associated with failure (P(SI) = .022, P(IA) = .038) and major recipient-site complications (P(SI) = .022, P(IA) = .038). Thirty-two (43%) patients showed complications in the first postoperative year: 27 recipient-site complications and 6 donor-site complications. Nineteen (70%) recipient-site complications were classified as major. The reconstruction was functionally complete in 48 (86%) of the 56 patients with a successful initial reconstruction. CONCLUSIONS Nonvascularized iliac crest bone grafts for segmental reconstruction of the mandible is the method of choice on the condition that the defect is truly lateral and only an extraoral approach is used. In these cases, microvascular tissue transfer is not necessary.

Free Vascularized Flaps for Reconstruction of the Mandible: Complications, Success, and Dental Rehabilitation

PURPOSE To evaluate complications and success of mandibular reconstruction with free fibula flaps, iliac crest flaps, and forearm flaps with reconstruction plates and to evaluate dental rehabilitation after these reconstructions. PATIENTS AND METHODS Eighty-three patients with segmental mandibular defects were included. Correlation analyses were used to determine the relationship between reconstruction type and clinical parameters with recipient-site complications and success. The dental rehabilitation was evaluated in successfully reconstructed survivors. RESULTS Multivariate analyses showed significant correlations between flap type and success (P < .0001). Of the patients, 51 (61%) were alive 2 years after the reconstruction. Mandibular reconstruction with a free forearm flap and reconstruction plate was associated with higher complication rates at the recipient site and higher failure rates compared with reconstruction with free vascularized bone flaps. Of the 32 successfully reconstructed survivors, 14 (44%) had a complete dental rehabilitation, of which 10 had dental implants and 4 did not. Only 6 (29%) of the edentulous survivors ultimately had an implant-supported prosthesis. CONCLUSIONS Reconstruction of the mandible with a free vascularized bone flap is superior to reconstruction with a free forearm flap with a reconstruction plate. Complete dental rehabilitation was reached in fewer than half of the surviving patients.

Sentinel lymph node biopsy in clinically N0 T1-T2 staged oral cancer: the Dutch multicenter trial

OBJECTIVES Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer. PATIENTS AND METHODS Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology. Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS). RESULTS Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5 months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p=0.916, OS: p=0.134, DSS: p=0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%. CONCLUSION SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck.

Validation of a Gene Expression Signature for Assessment of Lymph Node Metastasis in Oral Squamous Cell Carcinoma

PURPOSE Current assessment of lymph node metastasis in patients with head and neck squamous cell carcinoma is not accurate enough to prevent overtreatment. The aim of this study was validation of a gene expression signature for distinguishing metastasizing (N+) from nonmetastasizing (N0) squamous cell carcinoma of the oral cavity (OSCC) and oropharynx (OPSCC) in a large multicenter cohort, using a diagnostic DNA microarray in a Clinical Laboratory Improvement Amendments/International Organization for Standardization-approved laboratory. METHODS A multigene signature, previously reported as predictive for the presence of lymph node metastases in OSCC and OPSCC, was first re-evaluated and trained on 94 samples using generic, whole-genome, DNA microarrays. Signature genes were then transferred to a dedicated diagnostic microarray using the same technology platform. Additional samples (n=222) were collected from all head and neck oncologic centers in the Netherlands and analyzed with the diagnostic microarray. Human papillomavirus status was determined by real-time quantitative polymerase chain reaction. RESULTS The negative predictive value (NPV) of the diagnostic signature on the entire validation cohort (n=222) was 72%. The signature performed well on the most relevant subset of early-stage (cT1-T2N0) OSCC (n=101), with an NPV of 89%. CONCLUSION Combining current clinical assessment with the expression signature would decrease the rate of undetected nodal metastases from 28% to 11% in early-stage OSCC. This should be sufficient to enable clinicians to refrain from elective neck treatment. A new clinical decision model that incorporates the expression signature is therefore proposed for testing in a prospective study, which could substantially improve treatment for this group of patients.

Novel diagnostic modalities for assessment of the clinically node-negative neck in oral squamous-cell carcinoma

Oral squamous-cell carcinomas arise in mucosal linings of the oral cavity and frequently metastasise to regional lymph nodes in the neck. The presence of nodal metastases is a determinant of prognosis and clinical management. The neck is staged by palpation and imaging, but accuracy of these techniques to detect small metastases is low. In general, 30-40% of patients will have occult nodal disease and will develop clinically detectable lymph-node metastases when the neck is left untreated. The choice at present is either elective treatment or careful observation followed by treatment of the neck in patients who develop manifest metastases. These unsatisfying therapeutic options have been the subject of debate for decades. Recent developments in staging of the neck, including expression profiling and sentinel lymph-node biopsy, will allow more personalised management of the neck.

Oral Function After Oncological Intervention in the Oral Cavity: A Retrospective Study

PURPOSE To assess self-perceived oral function of patients with oral cavity cancer at different stages of treatment, ie, before oncologic intervention, 5 weeks after intervention, and 5 years after intervention. PATIENTS AND METHODS A cohort of 158 patients with malignancy in the oral cavity treated by surgery in 1999 or 2000 was included. From this cohort we interviewed 69 patients by telephone in 2005 and collected data on dental status, disorders of chewing and swallowing, xerostomia, preference of food consistency, tube nutrition, weight loss, and speech for different stages of treatment. RESULTS For patients treated in the maxilla region we observed a significant (P < .05) recovery of perceived chewing ability after 5 years to the level experienced before oncologic intervention. Patients treated in the mandible region reported a deteriorated dental state, chewing ability, lip competence, and xerostomia after 5 years. Patients treated in the tongue and mouth-floor region experienced deterioration for dental state, chewing ability, and xerostomia after 5 years compared with the level before the oncologic intervention. CONCLUSIONS Our telephone interview on oral function provided supplementary information on how patients experienced their problems with oral function during various phases of oncologic treatment. A retrospective interview may thus help to add information to incomplete retrospective data.

Resection of early oral squamous cell carcinoma with positive or close margins: Relevance of adjuvant treatment in relation to local recurrence: Margins of 3 mm as safe as 5 mm

OBJECTIVES The treatment strategy of early stage oral squamous cell carcinomas (OSCC) resected with close or involved margins is a returning point of discussion. In this study we reviewed the consequences of re-resection (RR), postoperative radiotherapy (PORT) or watchful waiting (WW). PATIENTS AND METHODS Two-hundred patients with a primary resected Stage 1-2 OSCC of the tongue, floor of the mouth and cheek were included and retrospectively analysed. Local recurrence ratio was related to margin status, unfavourable histological parameters (spidery infiltrative, peri-neural and vascular-invasive growth) and postoperative treatment modality. 3-year overall survival (OS) and disease-specific survival (DSS) was calculated in relation to margin status. RESULTS Twenty-two of 200 (11%) patients had pathological positive margins (PM), 126 (63%) close margins (CM), and 52 (26%) free margins (FM). OS and DSS were not significantly different between these groups. Nine of 200 (4.5%) patients developed local recurrent disease. Two (9.1%) had a PM, five (4.0%) a CM and two (3.8%) a FM. Of the nine recurrences, five patients had undergone PORT, one a RR, and three follow-up. Watchful waiting for CM ⩾3 mm with ⩽2 unfavourable histological parameters showed, besides margin status no significant differences with the FM group. CONCLUSION With this treatment strategy, the local recurrence rate was 4.5%. No evidence was found for local adjuvant treatment in case of close margins ⩾3 mm with ⩽2 unfavourable histological parameters. Current data do not support the use of one treatment modality above any other.

FGFR1 is a potential prognostic biomarker and therapeutic target in head and neck squamous cell carcinoma

Purpose: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study, we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms. Experimental Design: IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis. Results: FGFR1 protein overexpression occurred in 82% (36/44) of human papillomavirus (HPV)–positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC [HR, 3.07; 95% confidence interval (CI), 1.74–6.90; P = 0.001 and HR, 1.53; 95% CI, 1.04–2.39; P = 0.033]. Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1-expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited the proliferation of resistant cell lines. Conclusions: Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, we provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor–resistant HNSCC patients. Clin Cancer Res; 22(15); 3884–93. ©2016 AACR.