Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer.

BACKGROUND: Treatment intensification for resected, high-risk, head and neck squamous cell carcinoma (HNSCC) is an area of active investigation with novel adjuvant regimens under study. In this trial, the epidermal growth-factor receptor (EGFR) pathway was targeted using the IgG2 monoclonal antibody panitumumab in combination with cisplatin chemoradiotherapy (CRT) in high-risk, resected HNSCC. PATIENTS AND METHODS: Eligible patients included resected pathologic stage III or IVA squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or human-papillomavirus (HPV)-negative oropharynx, without gross residual tumor, featuring high-risk factors (margins <1 mm, extracapsular extension, perineural or angiolymphatic invasion, or ≥2 positive lymph nodes). Postoperative treatment consisted of standard RT (60-66 Gy over 6-7 weeks) concurrent with weekly cisplatin 30 mg/m2 and weekly panitumumab 2.5 mg/kg. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-six patients were accrued; 44 were evaluable and were analyzed. The median follow-up for patients without recurrence was 49 months (range 12-90 months). The probability of 2-year PFS was 70% (95% CI = 58%-85%), and the probability of 2-year OS was 72% (95% CI = 60%-87%). Fourteen patients developed recurrent disease, and 13 (30%) of them died. An additional five patients died from causes other than HNSCC. Severe (grade 3 or higher) toxicities occurred in 14 patients (32%). CONCLUSIONS: Intensification of adjuvant treatment adding panitumumab to cisplatin CRT is tolerable and demonstrates improved clinical outcome for high-risk, resected, HPV-negative HNSCC patients. Further targeted monoclonal antibody combinations are warranted. REGISTERED CLINICAL TRIAL NUMBER: NCT00798655.

Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer.

BACKGROUND: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS: Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS: Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS: RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

A single-port operator-controlled flexible endoscope system for endoscopic skull base surgery.

OBJECTIVE: In a human cadaver study, a single-port operator-controlled flexible endoscope (Flex® System), facilitated with a high-definition camera and two accessory channels was tested for skull base surgery. DESIGN: Skull base surgery was performed on human cadavers (n=4) using the Flex® System. A modified surgical midfacial approach, performed by rigid standard tools, was used for access to the sinus system, the skull base, and the middle cranial fossa. RESULTS: Endoscopic skull base visualization with the Flex® System is feasible. Surgical procedures performed included extended sinus surgery, anterior skull base approach, and visualization of the brain stem in the posterior cranial fossa. Important landmarks of the anterior skull base were visualized and manipulated by flexible compatible tools. CONCLUSION: The Flex® System allows for manipulation of the anterior skull base and visualization of the posterior cranial fossa in a preclinical setting. Further studies as well as development of supplemental tools are in progress.

Positive Predictive Value of Neck Imaging Reporting and Data System Categories 3 and 4 Posttreatment FDG-PET/CT in Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: The Neck Imaging Reporting and Data System is a standardized reporting system intended to risk stratify patients treated for head and neck squamous cell carcinoma. The purpose of this study is to investigate the positive predictive value of the Neck Imaging Reporting and Data System categories 3 and 4 on posttreatment PET/CT in patients treated definitively for head and neck squamous cell carcinoma. MATERIALS AND METHODS: We retrospectively identified patients treated definitively for head and neck squamous cell carcinoma between 2006 and 2018. Patients whose posttreatment PET/CT scans were interpreted as Neck Imaging Reporting and Data System 3 (suspicious) or 4 (definitive recurrence) at the primary site, regional nodes, or at distant sites were included. The reference standard was histopathology or unequivocal imaging or clinical evidence of treatment failure. The positive predictive values of Neck Imaging Reporting and Data System 3 and 4 posttreatment PET/CT were calculated. RESULTS: Seventy-two of 128 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 3 at the primary site, regional nodes, or distant sites were proved to have treatment failure at the suspicious sites, yielding an overall positive predictive value of 56% (95% CI, 48%-65%). The positive predictive values of Neck Imaging Reporting and Data System 3 by subsite were as follows: primary site, 56% (44/79); regional nodes, 65% (34/52); and distant sites, 79% (42/53). All 69 patients with posttreatment PET/CT interpreted as Neck Imaging Reporting and Data System 4 had true treatment failure, yielding a positive predictive value of 100% (95% CI, 96%-100%): primary site, 100% (28/28); regional nodes, 100% (32/32); and distant sites, 100% (29/29). CONCLUSIONS: The positive predictive value of Neck Imaging Reporting and Data System 3 on posttreatment PET/CT is relatively low. Thus, Neck Imaging Reporting and Data System 3 findings should be confirmed with tissue sampling before instituting new salvage treatment regimens to avoid unnecessary overtreatment and its associated toxicities. Neck Imaging Reporting and Data System 4 reliably indicates recurrent disease.

Quantitative T1rho magnetic resonance imaging of RIF-1 tumors in vivo: detection of early response to cyclophosphamide therapy.

This study compares two potential magnetic resonance imaging (MRI) indices for noninvasive early detection of tumor response to chemotherapy: the spin-lattice relaxation in the rotating frame (T1rho) and the transverse relaxation time (T2). Measurements of these relaxation parameters were performed on a s.c. murine radiation-induced fibrosarcoma (RIF-1) model before and after cyclophosphamide treatment. The number of pixels exhibiting T1rho values longer than controls in viable regions of the tumor increased significantly as early as 18 h after drug administration and remained elevated up to 36 h after treatment (P < 0.005). Although a trend of increasing T2s relative to controls was noted in viable regions of the tumor 36 h after treatment, the changes were not statistically significant. Histological examination indicated a decrease in mitotic index that paralleled the changes in T1rho. We conclude that T1rho measurements may be useful for noninvasive monitoring of early response of tumors to chemotherapy.

Oncologic outcomes and patient-reported quality of life in patients with oropharyngeal squamous cell carcinoma treated with definitive transoral robotic surgery versus definitive chemoradiation.

OBJECTIVE: It has been postulated that treatment outcomes are similar between transoral robotic surgery (TORS) and definitive chemoradiation (CRT) for oropharyngeal squamous cell carcinomas (OPSCC). We compared oncologic and quality of life (QOL) outcomes between definitive CRT and definitive TORS. MATERIALS AND METHODS: An observational comparison study was performed on 92 patients treated with TORS±adjuvant therapy and 46 patients treated with definitive CRT between July 2005 and January 2016. The Kaplan Meier method was used for survival analyses, and the Mann-Whitney test was used to compare QOL scores between groups. RESULTS: All patients had T0-T2 and N0-N2 disease, although CRT patients had higher clinical staging (p<0.001). HPV+ disease was present in 79% (n=73) of TORS patients and 91% (n=19) of tested CRT patients. Median follow-up was 22.1months (range: 0.33-83.4). There were no significant differences in locoregional control or overall survival between CRT and TORS groups. Definitive TORS resulted in better saliva-related QOL than definitive CRT at 1, 6, 12, and 24months (p<0.001, p=0.025, p=0.017, p=0.011). Among TORS patients, adjuvant therapy was associated with worse QOL in the saliva domain at 6, 12, and 24months (p<0.001, p<0.001, p=0.007), and taste domain at 6 and 12months (p=0.067, p=0.008). CONCLUSION: Definitive CRT and definitive TORS offer similar rates of locoregional control, overall survival, and disease-free survival in patients with early stage OPSCC. TORS resulted in significantly better short and long-term saliva-related QOL, whereas adjuvant therapy was associated with worse saliva and taste-related QOL compared to TORS alone.

Tumour-node-metastasis staging of human papillomavirus negative upper aerodigestive tract cancers: a critical appraisal.

OBJECTIVE: The tumour-node-metastasis staging system has a dynamic structure that is continuously being updated as scientific data develops. This review discusses some suggested revisions on tumour-node-metastasis staging of human papillomavirus negative upper aerodigestive tract cancers. METHODS: The seventh edition of The American Joint Committee on Cancer Staging Manual was reviewed and important issues that could be considered for revision were identified and discussed. RESULTS: According to our assessment of the oncological outcomes of previous studies, the following factors should be considered for revision: anterior commissure involvement and subglottic extension in laryngeal cancers; underlying bone involvement in hard palate and upper alveolar ridge cancers; tumour thickness in oral cancers; and extracapsular spread and carotid artery involvement in neck metastases. CONCLUSION: Sufficient data on the prognostic importance of these issues have been reported. Suggested revisions in line with current knowledge on the clinical behaviour of upper aerodigestive tract cancers would improve the relevancy of staging.

17O-decoupled (1)H spectroscopy and imaging with a surface coil: STEAM decoupling.

(17)O-decoupled (1)H spin-echo imaging has been reported as a means of indirect (17)O detection, with potential application to measurement of blood flow and metabolism. In its current form, (17)O decoupling requires large RF amplitudes and a 180 degrees refocusing pulse, complicating its application in volume and surface coils, respectively. To overcome this problem, we have developed an (17)O-decoupled proton stimulated echo sequence ("STEAM decoupling") to allow (17)O detection with a surface coil. A high B(1) amplitude is easily generated, allowing complete decoupling of (17)O and (1)H. Slice-selective, (17)O-decoupled (1)H imaging is readily performed and the sequence is easily adapted for localized spectroscopy. Intrinsic correction for variations in B(1) and further compensation for B(1) inhomogeneity are discussed.

T1rho imaging of murine brain tumors at 4 T.

RATIONALE AND OBJECTIVES: The goal of this study was to evaluate the utility of T1rho weighting in magnetic resonance imaging of murine brain tumors. MATERIALS AND METHODS: S91 Cloudman melanoma was implanted in mouse brains (n = 4). A T2-weighted spin-echo (SE) and a T1rho-weighted fast SE-based sequence were performed on a 4-T clinical imager. T2 and T1rho maps were computed. The tumor-to-normal-tissue contrast was compared between T2-weighted, T1rho-weighted, proton-density-weighted, and pre- and postcontrast T1-weighted SE images. RESULTS: The tumor-tissue contrast of the T1rho-weighted images was similar to that of the T2-weighted images but less than that of the postcontrast T1-weighted images. The T1rho-weighted images provided better definition of tumor boundaries than T2-weighted images. At spin-locking powers of 0.5 and 1.5 kHz, the T1rho of the tumor was 64.0 msec +/- 0.46 and 68.65 msec +/- 0.59, respectively. There was no significant inter- or intra-animal variation in T1rho for tumor or normal brain cortex. CONCLUSION: T1rho-weighted imaging performed at low spin-lock strengths qualitatively depicted tumor borders better than proton-density or T2-weighted imaging and could be useful in treatment planning when combined with other imaging sequences.

Negative predictive value of surveillance PET/CT in head and neck squamous cell cancer.

BACKGROUND AND PURPOSE: Optimizing the utilization of surveillance PET/CT in treated HNSCC is an area of ongoing research. Our aim was to determine the negative predictive value of PET/CT in patients with treated head and neck squamous cell cancer and to determine whether negative PET/CT reduces the need for further imaging surveillance. MATERIALS AND METHODS: We evaluated patients with treated HNSCC who underwent posttreatment surveillance PET/CT. During routine clinical readouts, scans were categorized as having negative, probably negative, probably malignant, or malignant findings. We followed patients clinically and radiographically for at least 12 months from their last PET/CT (mean, 26 months; median, 28 months; range, 12-89 months) to determine recurrence rates. All suspected recurrences underwent biopsy for confirmation. RESULTS: Five hundred twelve patients (1553 scans) were included in the study. Two hundred fourteen patients had at least 1 PET/CT with negative findings. Of the 214 patients with a scan with negative findings, 19 (9%) eventually experienced recurrence, resulting in a NPV of 91%. In addition, a subgroup of 114 patients with 2 consecutive PET/CT examinations with negative findings within a 6-month period was identified. Only 2 recurrences were found in this group, giving a NPV of 98%. CONCLUSIONS: In patients treated for HNSCC, a single PET/CT with negative findings carries a NPV of 91%, which is not adequate to defer further radiologic surveillance. Two consecutive PET/CT examinations with negative findings within a 6-month period, however, resulted in a NPV of 98%, which could obviate further radiologic imaging in the absence of clinical signs of recurrence.

T(1rho) relaxation can assess longitudinal proteoglycan loss from articular cartilage in vitro.

Objective To assess the correlation between changes in spin-lattice relaxation in the rotating frame (T(1rho)) and proteoglycan (PG) loss from bovine articular cartilage and to demonstrate the feasibility of performing T(1rho) MR imaging on a 1.5T clinical scanner. Design MR relaxation times (T(1rho), T(2) and T(1)) were measured from excised cartilage plugs (N=3) before and after two sequential digestions with trypsin on a 2T whole-body magnet. Proteoglycan and collagen loss induced by the trypsin digestion was measured using standard biochemical techniques. The correlation between changes in relaxation times and PG loss were tested with regression analysis. T(1rho) MRI was also performed on a clinical 1.5T MRI system to determine whether the spatial distribution of PG loss could be detected. The MRI results were compared with histology sections of native and PG-depleted tissue. Results Increase in T(1rho) relaxation times correlated with PG loss (R(2)=0.81). T(1rho) measurements alone were indicative of PG loss (R(2)=0.8), the addition of T1 and T2 data into the statistical model did not improve the correlation substantially (R(2)=0.83). T(1rho)-weighted imaging demonstrated a hyperintense lamina at the articular surface of the digested tissue, which was subjected to trypsin digestion that correlated with a superficial zone of PG loss observed on histological sections. Conclusion The results of this study demonstrate that T(1rho) relaxation changes are correlated with PG loss in vitro. Furthermore, T(1rho) measurements alone can be used to indicate PG loss data. T(1rho) MRI may thus be developed into a useful adjunct to existing techniques for the evaluation of cartilage disease.

Detection of residual quadrupolar interaction in the human breast in vivo using sodium-23 multiple quantum spectroscopy.

Sodium multiple quantum (MQ) spectroscopy of the human breast in vivo was performed. Double quantum (DQ) filtered spectra were used to demonstrate the existence of a non-vanishing (residual) quadrupolar interaction in the tissue. Triple quantum (TQ) filtered spectra were used to measure the two time constants associated with the biexponential transverse relaxation times of sodium in biological tissues. The two time constants were found to be 0.64 and 26.57 msec. The potential applications of this finding are discussed.

Magnetization transfer imaging of the brain: A quantitative comparison of results obtained at 1.5 and 4.0 T.

The preliminary results of magnetization transfer (MT) imaging on a whole body 4.0 T system are presented. Cooked egg phantoms and several volunteers were imaged on 1.5 and 4.0 T magnets interfaced to GE Signa scanners. The MT ratio (MTR), signal difference to noise ratio (SDNR), and contrast parameters were measured at both fields and compared. Furthermore, single-shot Z-spectroscopy was used to characterize the frequency dependence of the MT phenomenon. The results show that MT imaging can be safely performed at 4.0 T without exceeding limitations of radio frequency power. The MT effect is more pronounced at the higher field, leading to better quality images with higher contrast and SDNR. The Z-spectra are not markedly different at the higher field although the MTR is greater. The potential applications of this technique to study neurodegenerative diseases, as well as, perfusion imaging and angiography are discussed. J. Magn. Reson. Imaging 1999;10:527-532.

T1rho-relaxation in articular cartilage: effects of enzymatic degradation.

Spin-lattice relaxation in the rotating frame (T1rho) dispersion spectroscopy and imaging were used to study normal and enzymatically degraded bovine articular cartilage. Normal specimens demonstrate significant T1rho "dispersion" (approximately 60 to approximately 130 ms) in the 100 Hz to 9 kHz frequency range. Proteoglycan-degraded specimens have 33% greater T1rho values than collagen-degraded or normal samples. T1rho-weighted images reveal structure not found in conventional T1- or T2-weighted images. Our results suggest that T1rho measurements are selectively sensitive to proteoglycan content. The potential of this method in distinguishing the early degenerative changes in cartilage associated with osteoarthritis is discussed.

Sodium multiple quantum spectroscopy of articular cartilage: effects of mechanical compression.

The effects of mechanical compression on the multiple quantum coherences generated from sodium ions in articular cartilage were investigated. Cartilage samples obtained from bovine patellae were studied during compression at 0.7 MPa (100 psi) for 1 hour. The double quantum filtered spectra showed marked lineshape changes in the compressed samples. Compression did not seem to influence the lineshapes of the single quantum and triple quantum filtered spectra significantly. We found that the residual quadrupolar interaction was reduced in the compressed samples. Changes in the ordering of collagen fibers may be responsible for the observed effect.

Water magnetic relaxation dispersion in biological systems: the contribution of proton exchange and implications for the noninvasive detection of cartilage degradation.

Magnetic relaxation has been used extensively to study and characterize biological tissues. In particular, spin-lattice relaxation in the rotating frame (T(1rho)) of water in protein solutions has been demonstrated to be sensitive to macromolecular weight and composition. However, the nature of the contribution from low frequency processes to water relaxation remains unclear. We have examined this problem by studying the water T(1rho) dispersion in peptide solutions ((14)N- and (15)N-labeled), glycosaminoglycan solutions, and samples of bovine articular cartilage before and after proteoglycan degradation. We find in model systems and tissue that hydrogen exchange from NH and OH groups to water dominates the low frequency water T(1rho) dispersion, in the context of the model used to interpret the relaxation data. Further, low frequency dispersion changes are correlated with loss of proteoglycan from the extra-cellular matrix of articular cartilage. This finding has significance for the noninvasive detection of matrix degradation.

Human knee: in vivo T1(rho)-weighted MR imaging at 1.5 T--preliminary experience.

A fast spin-echo sequence weighted with a time constant that defines the magnetic relaxation of spins under the influence of a radio-frequency field (T1(rho)) was used in six subjects to measure magnetic resonance (MR) relaxation times in the knee joint with a 1.5-T MR imager. A quantitative comparison of T2- and T1(rho)-weighted MR images was also performed. Substantial T1(rho) dispersion was demonstrated in human articular cartilage, but muscle did not demonstrate much dispersion. T1(rho)-weighted images depicted a chondral lesion with 25% better signal-difference-to-noise ratios than comparable T2-weighted images. This technique may depict cartilage and muscular abnormalities.