Quantitative pretreatment CT volumetry: Association with oncologic outcomes in patients with T4a squamous carcinoma of the larynx.

BACKGROUND: The purpose of this study was to determine the impact of CT-determined pretreatment primary tumor volume on survival and disease control in T4a laryngeal squamous cell carcinoma (SCC). METHODS: We retrospectively reviewed 124 patients with T4a laryngeal cancer from 2000-2011. Tumor volume measurements were collected and correlated with outcomes. RESULTS: Five-year overall survival (OS) for patients with tumor volume ≥21 cm3 treated with larynx preservation (n = 26 of 41) was significantly inferior compared to <21 cm3 (42% vs 64%, respectively; P = .003). Five-year OS for patients with tumor volumes ≥21 cm3 in the cohort treated with total laryngectomy followed by radiotherapy (RT; n = 42 of 83) was not statistically significant when compared to <21 cm3 (50% vs 63%, respectively; P = .058). On multivariate analysis, tumor volume ≥21 cm3 was a significant independent correlate of worse disease-specific survival (DSS; P = .004), event-free survival (P = .005), recurrence-free survival (RFS; P = .04), noncancer cause-specific survival (P = .02), and OS (P = .0002). CONCLUSION: Pretreatment CT-based tumor volume is an independent prognostic factor of outcomes in T4a laryngeal cancer.

Long-term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches.

BACKGROUND: The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers. METHODS: We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011. RESULTS: The 10-year overall survival (OS) was 35%; disease-specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status <2, node-negative status, and glottic subsite were associated with improved survival (all p < .03). Larynx preservation with induction and/or concurrent chemoradiotherapy (LP-CRT) had better laryngectomy-free survival than RT alone (LP-RT; hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.47-0.81; p = .0005); 10-year laryngectomy-free survival rates of the LP-CRT cohort (37%) were higher than those of the LP-RT cohort (18%). The 5-year DSS and OS rates of the LP-CRT cohort (79% and 67%) were better after total laryngectomy with postoperative RT (TL-PORT; 61% and 50%) and LP-RT (64% and 46%; p < .006 for all). CONCLUSION: In patients with T3 laryngeal cancers, LP-CRT provides better functional, oncologic, and survival outcomes than historical TL-PORT or LP-RT does. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1739-1751, 2016.

Long-term outcomes after surgical or nonsurgical initial therapy for patients with T4 squamous cell carcinoma of the larynx: A 3-decade survey.

BACKGROUND: The current study was conducted to evaluate long-term disease control, survival, and functional outcomes after surgical and nonsurgical initial treatment for patients with T4 larynx cancer. METHODS: Demographics, disease stage, and treatment characteristics were reviewed for 221 sequential patients treated for T4 laryngeal squamous cell cancer at a single institution between 1983 and 2011. Survival and disease control outcomes were calculated. RESULTS: The median follow-up time was 47 months (71 months for patients still alive at the time of analysis). The overall 5-year and 10-year overall survival rates were 52% and 29%, respectively, and the corresponding disease-free survival rates were 57% and 48%, respectively. Overall 5-year and 10-year locoregional control rates were 78% and 67%, respectively, and the corresponding rates for freedom from distant metastasis were 76% and 74%, respectively. On both univariate and multivariate analyses, lymph node-positive disease at the time of presentation was associated with overall mortality (P<.0001). Patients treated with laryngectomy followed by postlaryngectomy radiotherapy (161 patients) achieved better initial locoregional control than patients treated with a laryngeal preservation (LP) approach (60 patients) throughout the follow-up period (log-rank P<.007) yet the median overall survival times were equal for both groups (64 months; 95% confidence interval 47-87 months and 38-87 months, respectively [P =.7]). Patients treated with an LP approach had a tracheostomy rate of 45% and an any-event aspiration rate of 23%. Rates of high-grade dysphagia at the time of last follow-up were worse for patients treated with an LP approach (P<.01). CONCLUSIONS: Surgery and postoperative radiotherapy can produce substantial long-term cancer control and survival rates for patients with T4 larynx cancer. Caution should be taken when selecting patients for initial nonsurgical treatment because of significant rates of functional impairment despite survival equivalence.

Clinical practice guidance for radiotherapy planning after induction chemotherapy in locoregionally advanced head-and-neck cancer.

PURPOSE: The use of induction chemotherapy (IC) for locoregionally advanced head-and-neck cancer is increasing. The response to IC often causes significant alterations in tumor volume and location and shifts in normal anatomy. Proper determination of the radiotherapy (RT) targets after IC becomes challenging, especially with the use of conformal and precision RT techniques. Therefore, a consensus conference was convened to discuss issues related to RT planning and coordination of care for patients receiving IC. METHODS AND MATERIALS: Ten participants with special expertise in the various aspects of integration of IC and RT for the treatment of locoregionally advanced head-and-neck cancer, including radiation oncologists, medical oncologists, and a medical physicist, participated. The individual members were assigned topics for focused, didactic presentations. Discussion was encouraged after each presentation, and recommendations were formulated. RESULTS: Recommendations and guidelines emerged that emphasize up-front evaluation by all members of the head-and-neck management team, high-quality baseline and postinduction planning scans with the patient in the treatment position, the use of preinduction target volumes, and the use of full-dose RT, even in the face of a complete response. CONCLUSION: A multidisciplinary approach is strongly encouraged. Although these recommendations were provided primarily for patients treated with IC, many of these same principles apply to concurrent chemoradiotherapy without IC. A rapid response during RT is quite common, requiring the development of two or more plans in a sizeable fraction of patients, and suggesting the need for similar guidance in the rapidly evolving area of adaptive RT.

Dose escalation of gemcitabine is possible with concurrent chest three-dimensional rather than two-dimensional radiotherapy: a phase I trial in patients with stage III non-small-cell lung cancer.

PURPOSE: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. METHODS AND MATERIALS: Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m(2)/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m(2)/wk and cisplatin 60 mg/m(2). RESULTS: In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m(2)/wk cohort and 2 of 3 patients in the 125-mg/m(2)/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m(2)/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. CONCLUSIONS: We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m(2)/wk when using 3D planning. The Phase II dose is 150 mg/m(2)/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.

IMRT reirradiation of head and neck cancer-disease control and morbidity outcomes.

PURPOSE: Institutional and cooperative group experience has demonstrated the feasibility of reirradiation for head and neck cancer. Limited data are available regarding the use of intensity-modulated radiotherapy (IMRT) for this indication. We reviewed our initial experience using IMRT for previously irradiated head and neck cancer patients. METHODS AND MATERIALS: Records of 78 consecutive patients reirradiated with IMRT for head and neck cancer between 1999 and 2004 were reviewed; 74 cases were analyzed. Reirradiation was defined as any overlap between original and new radiation treatment volumes regardless of the time interval between initial and subsequent treatment. Severe reirradiation-related toxicity was defined as toxic events resulting in hospitalization, corrective surgery, or patient death. Longitudinal estimates of survival were calculated by Kaplan-Meier technique. RESULTS: Twenty (27%) patients underwent salvage surgical resection and 36 (49%) patients received chemotherapy. Median follow-up from reirradiation was 25 months. Median time interval between initial radiation and reirradiation was 46 months. Median reirradiation dose was 60 Gy. Median lifetime radiation dose was 116.1 Gy. The 2-year overall survival and locoregional control rates were 58% and 64%, respectively. Severe reirradiation related toxicity occurred in 15 patients (20%); one treatment-related death was observed. CONCLUSIONS: The use of IMRT for reirradiation of recurrent or second primary head and neck cancers resulted in encouraging local control and survival. Reirradiation-related morbidity was significant, but may be less severe than previously published reports using conventional techniques.

Surgical management of locally advanced adenoid cystic carcinoma of the lacrimal gland.

PURPOSE: To review our experience with multidisciplinary surgical management of locally advanced adenoid cystic carcinoma of the lacrimal gland. METHODS: We present a case series of 7 patients with lacrimal gland adenoid cystic carcinoma treated at our institution between June 2001 and October 2003. Clinical records, histologic sections, and radiographic images were reviewed. RESULTS: The study included 3 men and 4 women (mean age at diagnosis, 44 years). All 7 patients underwent an orbital exenteration with bone removal. Five patients had an orbitectomy through a craniotomy approach and 2 patients had an exenteration through a fronto-orbito-zygomatic approach, all with removal of the bone of the superior and lateral wall. Six patients underwent reconstruction of the socket through the use of a vascularized flap. The surgical approach involved a neurosurgeon, an oculoplastic or head and neck surgeon, and a plastic surgeon. Six patients received postoperative radiation therapy. One patient with a recurrent tumor had already received radiation therapy, which precluded additional radiation therapy after surgical resection. The radiation field included the orbit and the skull base because all patients had evidence of perineural invasion. As of this writing, there have been no local recurrences. Five patients had development of distant metastases and died of disease, at follow-up times from 12 to 32 months after surgery. Two patients are alive without evidence of disease, both at 24 months' follow-up. CONCLUSIONS: Orbitectomy with bone removal may be indicated for achieving local and regional control in advanced cases of adenoid cystic carcinoma of the lacrimal gland. This surgery does not decrease the risk of distant metastasis. The cases in our series highlight the locally invasive and metastatic behavior of this cancer.

Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma.

The farnesyl transferase inhibitor (FTI) SCH66336 has been shown to have antitumor activities in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. However, its mechanism of action has not been well defined. Here, we report that the insulin-like growth factor (IGF) binding protein (IGFBP)-3 mediates antitumor activities of SCH66336 in HNSCC by inhibiting angiogenesis. SCH66336 significantly suppressed HNSCC tumor growth and angiogenesis via mechanisms that are independent of H-Ras and RhoB. By inducing IGFBP-3 secretion from HNSCC cells, this compound suppresses angiogenic activities of endothelial cells, including vessel formation in chorioallantoic membranes of chick, endothelial cell sprouting from chick aorta, and capillary tube formation of human umbilical vascular endothelial cells (HUVEC). Knockdown of IGFBP-3 expression in HNSCC cells by RNA interference or depletion of IGFBP-3 in HUVECs by neutralizing antibody effectively blocked the effects of IGFBP-3 secreted from SCH66336-treated HNSCC cells on HUVECs. These findings suggest that IGFBP-3 could be a primary target for antitumor activities of FTIs and that IGFBP-3 is an effective therapeutic approach against angiogenesis in HNSCC.

Gene expression screening of salivary gland neoplasms: molecular markers of potential histogenetic and clinical significance.

Salivary gland neoplasms comprise phenotypically and biologically diverse lesions of uncertain histogenesis. The molecular events associated with their development and clinicopathological heterogeneity remain unknown. To reveal these events, we performed microarray expression analysis using a nylon-filter membrane platform on 18 primary lesions representing the most common benign and malignant types. Our study identified a small set of genes that are differentially altered between normal salivary gland tissues and benign and malignant tumors. Of the 5000 genes arrayed, 136 genes were differentially expressed by normal tissue, benign tumors, and various malignant neoplasms. Hierarchical clustering analysis differentiated between adenoid cystic carcinomas (ACCs) and other malignant subtypes. Non-ACC specimens manifested overlapping patterns of gene expression within and between tumors. Most of the differentially expressed genes share functional similarities with members of the adhesion, proliferation, and signal transduction pathways. Our study identified: 1) a set of genes that differentiate normal tissue from tumor specimens, 2) genes that differentiate pleomorphic adenoma and ACCs from other malignant salivary gland neoplasms, and 3) different patterns of expression between ACCs arising from major and minor salivary gland sites. The differentially expressed genes provide new information on potential genetic events of biological significance in future studies of salivary gland tumorigenesis.

Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease.

The purpose of this study was to evaluate the feasibility, efficacy, safety, and pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to study the relationship between results from the two methods for determining levels of Her2 overexpression. Chemonaive patients were eligible if they had stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least 15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21 patients enrolled, 8 (38%) patients had a partial response. The 1-year survival rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic studies revealed no interaction between trastuzumab and gemcitabine plus cisplatin. In patients screened for this study, Her2 expression was zero in 283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients (5%). Serum Her2 shed antigen was >15 ng/ml in 27/ 288 (9%) patients. Of patients who had both Her2 assays, 24% (4/17) with ELISA scores >15 ng/ml had IHC scores of 3+, compared with only 2% (3/145) of the patients <15 ng/ml and 4% (7/162) of all patients. The addition of trastuzumab to cisplatin and gemcitabine was well tolerated, but further study will be required to determine whether this combination is superior to chemotherapy alone. This may be demonstrated if only those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen >15 ng/ml would greatly increase the efficiency of IHC screening though at the cost of excluding nearly half the patients with Her2 scores of 3+ on IHC analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC analysis is implemented, it may make a trastuzumab trial feasible but should ultimately be supplanted by another screening system if trastuzumab is shown to be beneficial to some patients with IHC Her2 scores of 3+.