Sue S. Yom

Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522

PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). PATIENTS AND METHODS Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. RESULTS Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v. 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v. 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v. 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v. 2.0%, respectively; P = .81), 3-year PFS (61.2% v. 58.9%, respectively; P = .76), 3-year OS (72.9% v. 75.8%, respectively; P = .32), locoregional failure (19.9% v. 25.9%, respectively; P = .97), or distant metastasis (13.0% v. 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v. 49.2%, respectively; P < .001) and OS (85.6% v. 60.1%, respectively; P < .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome. CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

Long-term follow-up of the RTOG 9501/intergroup phase III trial: Postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck

PURPOSE Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. METHODS AND MATERIALS A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m(2)i.v. on days 1, 22, and 43 (RT + CT). RESULTS At 10 years, the local-regional failure rates were 28.8% vs 22.3% (P=.10), disease-free survival was 19.1% vs 20.1% (P=.25), and overall survival was 27.0% vs 29.1% (P=.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs 21.0% (P=.02), disease-free survival was 12.3% vs 18.4% (P=.05), and overall survival was 19.6% vs 27.1% (P=.07), respectively. CONCLUSION At a median follow-up of 9.4 years for surviving patients, no significant differences in outcome were observed in the analysis of all randomized eligible patients. However, analysis of the subgroup of patients who had either microscopically involved resection margins and/or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy. The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT.

Head and neck cancers, version 1.2015 featured updates to the NCCN guidelines

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Intensity-modulated chemoradiation for treatment of stage III and IV oropharyngeal carcinoma: the University of California-San Francisco experience.

Treatment outcomes for stage III and IV oropharyngeal carcinoma treated with intensity‐modulated radiotherapy (IMRT) and concurrent chemotherapy without prior surgical resection were reviewed.

Dose-volume thresholds and smoking status for the risk of treatment-related pneumonitis in inoperable non-small cell lung cancer treated with definitive radiotherapy.

PURPOSE To identify clinical risk factors and dose-volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade > or = 3 TRP calculated from start of radiotherapy. Clinical factors and dose-volume parameters were analyzed for their association with risk of TRP. RESULTS Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan-Meier estimate of the incidence of grade > or = 3 TRP at 12 months was 22%. An analysis of dose-volume parameters identified a threshold dose-volume histogram (DVH) curve defined by V(20) < or = 25%, V(25) < or = 20%, V(35) < or = 15%, and V(50) < or = 10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade > or = 3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors. CONCLUSIONS The risk of TRP varied significantly, depending on radiation dose-volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP.

ACR appropriateness criteria retreatment of recurrent head and neck cancer after prior definitive radiation expert panel on radiation oncology-head and neck cancer.

Recurrent and second primary head-and-neck squamous cell carcinomas arising within or in close proximity to previously irradiated fields are a common clinical challenge. Whereas surgical salvage therapy is recommended for resectable disease, randomized data support the role of postoperative reirradiation in high-risk patients. Definitive reirradiation is an established approach for patients with recurrent disease who are medically or technically inoperable or decline radical surgery. The American College of Radiology Expert Panel on Head and Neck Cancer reviewed the relevant literature addressing re-treatment after prior definitive radiation and developed appropriateness criteria for representative clinical scenarios. Examples of unresectable recurrent disease and microscopic residual disease after salvage surgery were addressed. The panel evaluated the appropriateness of reirradiation, the integration of concurrent chemotherapy, radiation technique, treatment volume, dose, and fractionation. The panel emphasized the importance of patient selection and recommended evaluation and treatment at tertiary-care centers with a head-and-neck oncology team equipped with the resources and experience to manage the complexities and toxicities of re-treatment.

Dosimetric Evaluation of Automatic Segmentation for Adaptive IMRT for Head-and-Neck Cancer

PURPOSE Adaptive planning to accommodate anatomic changes during treatment requires repeat segmentation. This study uses dosimetric endpoints to assess automatically deformed contours. METHODS AND MATERIALS Sixteen patients with head-and-neck cancer had adaptive plans because of anatomic change during radiotherapy. Contours from the initial planning computed tomography (CT) were deformed to the mid-treatment CT using an intensity-based free-form registration algorithm then compared with the manually drawn contours for the same CT using the Dice similarity coefficient and an overlap index. The automatic contours were used to create new adaptive plans. The original and automatic adaptive plans were compared based on dosimetric outcomes of the manual contours and on plan conformality. RESULTS Volumes from the manual and automatic segmentation were similar; only the gross tumor volume (GTV) was significantly different. Automatic plans achieved lower mean coverage for the GTV: V95: 98.6 +/- 1.9% vs. 89.9 +/- 10.1% (p = 0.004) and clinical target volume: V95: 98.4 +/- 0.8% vs. 89.8 +/- 6.2% (p < 0.001) and a higher mean maximum dose to 1 cm(3) of the spinal cord 39.9 +/- 3.7 Gy vs. 42.8 +/- 5.4 Gy (p = 0.034), but no difference for the remaining structures. CONCLUSIONS Automatic segmentation is not robust enough to substitute for physician-drawn volumes, particularly for the GTV. However, it generates normal structure contours of sufficient accuracy when assessed by dosimetric end points.

Survival impact of planned restaging and early surgical salvage following definitive chemoradiation for locally advanced squamous cell carcinomas of the oropharynx and hypopharynx

Objectives:Patients who have received definitive radiation therapy (RT) for a nonlaryngeal T3/4 head and neck squamous cell carcinoma have a limited opportunity for post-RT surgical salvage. The authors reviewed the practice of planned post-RT restaging to determine its impact on the success of early surgical salvage. Methods:A retrospective review was performed for patients with resectable T3/4 cancers of the oropharynx and hypopharynx treated with RT ± chemotherapy who underwent planned restaging clinically, radiographically (CT or MRI), and by direct laryngoscopy with biopsy at 4 to 8 weeks post-RT. Chemotherapy was given as induction, concurrently, or both. Neck dissection was performed at time of restaging in patients with primary tumor control and initial N2/N3 neck disease or persistent lymphadenopathy. Results:A total of 54 patients had a median follow-up of 34.7 months (range, 7.6–97.8 months). Forty-two patients (78.8%) achieved a complete response (CR) at the primary site immediately after RT. Six developed late local failure at 9 to 61 months, of whom 2 were successfully salvaged. The ultimate 2-year local control among patients with initial CR was 94.8%. The 2-year organ preservation, disease-free survival, and overall survival (OS) rates were was 92.5%, 87%, and 90%, respectively. Twelve patients did not achieve initial CR. Two patients with bulky stage IV disease had unresectable cancers. Ten underwent immediate surgical salvage and 7 achieved local control (1 of whom developed distant metastases) whereas 3 had continued local failure. For patients without initial CR, the 2-year ultimate local control rate was 46.7% and OS was 46.8%. For all patients, overall 2-year local control, organ preservation, and OS rates were 85.6%, 75.6%, and 81.8% respectively. The rate of local failure-free organ preservation was 71.5%. Conclusion:For patients with T3/4 resectable nonlaryngeal head and neck cancers, planned clinical, radiographic, and pathologic restaging at 1 to 2 months after definitive RT provides the opportunity for early surgical salvage in those who fail at the primary site. This practice produces improved overall local control and survival rates compared with the literature reports for delayed attempted salvage with timing based on the findings of routine postradiation clinical surveillance. Future efforts may focus on the improved selection of patients who would be most likely to require early surgical intervention.

Patterns of Regional Recurrence After Definitive Radiotherapy for Cervical Cancer

PURPOSE To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer. METHODS AND MATERIALS The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined. RESULTS The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months). CONCLUSIONS Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

Genetic analysis of sinonasal adenocarcinoma phenotypes: distinct alterations of histogenetic significance

Sinonasal adenocarcinomas, a relatively rare entity, are composed of distinctly different morphologic subtypes with variable biological behavior. To investigate the genetic events associated with their development and clinicopathologic features, we analyzed the alterations in K-ras, APC, β-catenin, hMLH1 and hMSH2 and p53 genes expression in a cohort of 15 primary tumors comprising the two main sinonasal adenocarcinoma subtypes (enteric and seromucinous). The patients consisted of 13 men and two women, who ranged in age from 50 to 87 years. Tumors were predominantly located in the ethmoid sinus. Eight tumors were Enteric-type, and seven were seromucinous type. Nine patients were smokers and four were nonsmokers; and no information was available on two patients. Two of the eight enteric-type, had K-ras mutation at codons 12A and 12B, and one showed microsatellite instability at BAT-25. Two patients with enteric-type tumors had a history of wood-dust exposure, and one had a K-ras mutation at 12A codon as well as p53 overexpression. No patients with the seromucinous type had any genetic abnormalities, except for overexpression of p53 in two tumors. Our results show that (1) a subset of enteric-type sinonasal adenocarcinoma shares certain genetic alterations with colonic adenocarcinomas, (2) the seromucinous-type sinonasal adenocarcinoma lacks alterations and may develop through a different pathway, (3) high p53 expression is associated with aggressive tumor features in both subtypes and (4) the enteric-type runs a more malignant course than the seromucinous counterpart.