Carol R. Bradford

EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer

PURPOSE To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer. PATIENTS AND METHODS Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status. RESULTS EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS (rho(EGFR) = 0.008; rho(HPV) = 0.03) and DSS (rho(EGFR) = 0.01; rho(HPV) = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002). CONCLUSION Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer: Response and Survival Positively Associated With HPV16 Copy Number

PURPOSE To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome. PATIENTS AND METHODS Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV. RESULTS Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008). CONCLUSION Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase

In accord with the cancer stem cell (CSC) theory, only a small subset of cancer cells are capable of forming tumors. We previously reported that CD44 isolates tumorigenic cells from head and neck squamous cell cancer (HNSCC). Recent studies indicate that aldehyde dehydrogenase (ALDH) activity may represent a more specific marker of CSCs.

Merkel Cell Carcinoma: Critical Review With Guidelines for Multidisciplinary Management

Merkel cell carcinoma (MCC) is a relatively rare cutaneous malignancy that occurs predominantly in the older white population. The incidence of MCC appears to have tripled during the past 20 years; an increase that is likely to continue because of the growing number of older Americans. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenetic role. Many questions currently remain unanswered regarding the biologic behavior and optimal treatment of MCC. Large, prospective, randomized studies are not available and are unlikely to be performed because of the rarity of the disease. The objective of this review was to provide a comprehensive reference for MCC based on a critical evaluation of the current data. The authors investigated the importance of sentinel lymph node biopsy as a staging tool for MCC to assess the status of the regional lymph node basin and to determine the need for additional therapy to the lymph node basin. In an attempt to standardize prospective data collection with the intention to define prognostic indicators, the authors also present histopathologic profiles for primary MCC and sentinel lymph nodes. The controversies regarding the appropriate surgical approach to primary MCC, the use of adjuvant radiation therapy, and the effectiveness of adjuvant chemotherapy were examined critically. Finally, the authors have provided treatment guidelines based on the available evidence and their multidisciplinary experience. Cancer 2007.

Intensity-Modulated Chemoradiotherapy Aiming to Reduce Dysphagia in Patients With Oropharyngeal Cancer: Clinical and Functional Results

PURPOSE To assess clinical and functional results of chemoradiotherapy for oropharyngeal cancer (OPC), utilizing intensity-modulated radiotherapy (IMRT) to spare the important swallowing structures to reduce post-therapy dysphagia. PATIENTS AND METHODS This was a prospective study of weekly chemotherapy (carboplatin dosed at one times the area under the curve [AUC, AUC 1] and paclitaxel 30 mg/m(2)) concurrent with IMRT aiming to spare noninvolved parts of the swallowing structures: pharyngeal constrictors, glottic and supraglottic larynx, and esophagus as well as the oral cavity and major salivary glands. Swallowing was assessed by patient-reported Swallowing and Eating Domain scores, observer-rated scores, and videofluoroscopy (VF) before therapy and periodically after therapy through 2 years. RESULTS Overall, 73 patients with stages III to IV OPC participated. At a median follow-up of 36 months, 3-year disease-free and locoregional recurrence-free survivals were 88% and 96%, respectively. All measures of dysphagia worsened soon after therapy; observer-rated and patient-reported scores recovered over time, but VF scores did not. At 1 year after therapy, observer-rated dysphagia was absent or minimal (scores 0 to 1) in all patients except four: one who was feeding-tube dependent and three who required soft diet. From pretherapy to 12 months post-therapy, the Swallowing and Eating Domain scores worsened on average (+/- standard deviation) by 10 +/- 21 and 13 +/- 19, respectively (on scales of 0 to 100), and VF scores (on scale of 1 to 7) worsened from 2.9 +/- 1.5 (mild dysphagia) to 4.1 +/- 0.9 (mild/moderate dysphagia). CONCLUSION Chemoradiotherapy with IMRT aiming to reduce dysphagia can be performed safely for OPC and has high locoregional tumor control rates. On average, long-term patient-reported, observer-rated, and objective measures of swallowing were only slightly worse than pretherapy measures, representing potential improvement compared with previous studies.

Tobacco Use in Human Papillomavirus–Positive Advanced Oropharynx Cancer Patients Related to Increased Risk of Distant Metastases and Tumor Recurrence

Purpose: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)–positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. Experimental Design: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. Results: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). Conclusions: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users. Clin Cancer Res; 16(4); 1226–35

Parotid gland sparing in patients undergoing bilateral head and neck irradiation: Techniques and early results.

PURPOSE To minimize xerostomia in patients receiving bilateral head and neck irradiation (RT) by using conformal RT planning to spare a significant volume of one parotid gland from radiation. METHODS AND MATERIALS The study involved 15 patients with head and neck tumors in whom bilateral neck radiation was indicated. The major salivary glands and the targets (tumor, surgical bed, metastases to lymph nodes, and the locations of lymph nodes at risk for metastases) were outlined on axial computed tomography images. Beams-eye view (BEV) displays were used to construct conformal beams that delivered the prescribed doses to the targets while sparing from direct radiation most of one parotid gland. The gland that was planned to be spared resided in the neck side that was judged in each patient to be at a lesser risk of metastatic disease. Major salivary gland flow rates and the responses to a subjective xerostomia questionnaire were assessed before, during, and after radiation. RESULTS Radiation planning for patients with central oropharyngeal tumors required the generation of multiple axial nonopposed beams. The resulting isodoses encompassed the targets, including the retropharyngeal nodes and the jugular nodes up to the base of skull bilaterally, while limiting the dose to the oral cavity, spinal cord, and one parotid gland. For patients with lateralized tumors, the ipsilateral neck side was treated up to the base of the skull; in the contralateral neck side, the treatment included the subdigastric nodes but excluded the jugular nodes at the base of the skull and most of the parotid gland. This was accomplished by a moderate gantry angle that was chosen using the BEV displays. Three months following the completion of radiation, the spared parotid glands retained on average 50% of their unstimulated and stimulated flows. In contrast, no saliva flow was measured from the unspared glands in any of the patients. Subjective xerostomia was absent, mild, or not different from that reported before radiation in 10 of 15 patients (67%). CONCLUSION Partial parotid gland sparing is feasible by using three-dimensional planning in patients undergoing bilateral head and neck radiation. Approximately 50% of the saliva flow from the spared glands may be retained, and most patients thus treated have no or mild xerostomia in the early period after the completion of radiation. Whether tumor control and late complications are comparable to standard radiation will be assessed as more experience is gained.

Single-Cycle Induction Chemotherapy Selects Patients With Advanced Laryngeal Cancer for Combined Chemoradiation: A New Treatment Paradigm

PURPOSE Primary chemoradiotherapy in patients with advanced laryngeal cancer can achieve high rates of organ preservation without sacrificing survival compared with radiation alone or conventional laryngectomy. Appropriate selection of patients for organ preservation approaches could enhance overall treatment outcome and quality of life. We conducted a phase II organ preservation trial for patients with stage III and IV larynx cancer to determine whether late salvage surgery rates could be decreased and survival improved by selecting patients for organ preservation based on response to a single cycle of induction chemotherapy. PATIENTS AND METHODS The chemotherapy was cisplatin 100 mg/m2 on day 1 and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who achieved less than 50% response had immediate laryngectomy. Patients who achieved more than 50% response went on to concurrent chemoradiotherapy. Histologic complete responders after chemoradiotherapy received two more cycles of chemotherapy. Patients with residual disease after chemoradiotherapy had planned salvage surgery. RESULTS Of 97 eligible patients, 73 (75%) achieved more than 50% response and received chemoradiotherapy. A total of 29 patients (30%) had salvage surgery; 19 patients (20%) had early salvage surgery after the single cycle of induction chemotherapy, three patients (3%) had late salvage surgery after chemoradiotherapy, six patients (6%) eventually had salvage surgery for recurrence, and one patient had laryngectomy for chondroradionecrosis. The median follow-up time was 41.9 months. The overall survival rate at 3 years is 85%. The cause-specific survival rate was 87%. Larynx preservation was achieved in 69 patients (70%). CONCLUSION These results confirm excellent larynx preservation and improved overall survival rates compared with historical results.

Pain, Quality of Life, and Spinal Accessory Nerve Status After Neck Dissection

Objective To assess quality of life (QOL) in patients with head and neck cancer who underwent neck dissection and to compare QOL scores for patients in whom the spinal accessory nerve (CN XI) was resected or preserved.

Salivary Gland Sparing and Improved Target Irradiation by Conformal and Intensity Modulated Irradiation of Head and Neck Cancer

The goals of this study were to facilitate sparing of the major salivary glands while adequately treating tumor targets in patients requiring comprehensive bilateral neck irradiation (RT), and to assess the potential for improved xerostomia. Since 1994 techniques of target irradiation and locoregional tumor control with conformal and intensity modulated radiation therapy (IMRT) have been developed. In patients treated with these modalities, the salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands’ dose volume histograms (DVHs). In addition, subjective xerostomia questionnaires have been developed and validated. The pattern of locoregional recurrence has been examined from computed tomography (CT) scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans, and regenerating the dose distributions at the recurrence sites. Treatment plans for target coverage and dose homogeneity using static, multisegmental IMRT were found to be significantly better than standard RT plans. In addition, significant parotid gland sparing was achieved in the conformal plans. The relationships among dose, irradiated volume, and the residual saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean radiation dose of 26 Gy was found to be the threshold for preserved stimulated saliva flow. Xerostomia questionnaire scores suggested that xerostomia was significantly reduced in patients irradiated with bilateral neck, parotid-sparing RT, compared to patients with similar tumors treated with standard RT. Examination of locoregional tumor recurrence patterns revealed that the large majority of recurrences occurred inside targets, in areas that had been judged to be at high risk and that had received RT doses according to the perceived risk. Tangible gains in salivary gland sparing and target coverage are being achieved, and an improvement in some measures of quality of life is suggested by our findings. Additional reduction of xerostomia may be achieved by further sparing of the salivary glands and the non-involved oral cavity. A mean parotid gland dose of ≤ 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to areas judged to be at highest risk may improve tumor control.