Ability of positron emission tomography to detect residual neck node disease in patients with head and neck squamous cell carcinoma after definitive chemoradiotherapy.

OBJECTIVE: To report our experience using the neck examination, computed tomography (CT), and positron emission tomography (PET) to clinically evaluate node-positive patients with head and neck squamous cell cancer for residual neck node disease after definitive chemoradiotherapy. DESIGN: Retrospective review of all Cleveland Clinic patients with head and neck squamous cell cancer and N2 or N3 neck node involvement at presentation who were treated with definitive concurrent chemoradiotherapy and who underwent clinical restaging after treatment using the neck examination, CT, and PET. SETTING: Tertiary care referral institution. PATIENTS: Forty-eight patients with 72 positive necks at diagnosis were followed up for a median of 20 months. MAIN OUTCOME MEASURES: Palpable nodes on examination, nodes larger than 1 cm, nodes with central necrosis on CT, or any hypermetabolic lymph nodes on PET were considered clinical evidence of residual nodal disease. The true rate of pathologic involvement was determined by histologic examination after planned neck dissection or if regional recurrence developed. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for all 3 clinical assessment tools. RESULTS: Planned neck dissection was performed in 33 necks and was positive for residual neck node disease in 5 necks. A delayed neck dissection was performed in 5 necks and was positive in 3 necks. The positive predictive value was low for all 3 clinical assessment tools. The addition of PET did not significantly improve the negative predictive value or positive predictive value of CT and the clinical examination. CONCLUSIONS: Residual neck node disease after definitive chemoradiotherapy was infrequent and was not well predicted by PET. A positive PET finding in this setting is of little utility. Although a negative PET finding was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck examination and CT.

Split-Course Accelerated Hypofractionated Radiotherapy (SCAHRT): A Safe and Effective Option for Head and Neck Cancer in the Elderly or Infirm.

BACKGROUND: Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients. PATIENTS AND METHODS: The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis. RESULTS: Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively. CONCLUSION: In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches.

Maximizing local control and organ preservation in stage IV squamous cell head and neck cancer With hyperfractionated radiation and concurrent chemotherapy.

PURPOSE: Results are reported from an aggressive chemoradiotherapy protocol for advanced squamous cell head and neck cancer. PATIENTS AND METHODS: Patients with advanced squamous cell head and neck cancer were treated with hyperfractionated radiation therapy (72 Gy at 1.2 Gy twice per day) and two courses of concurrent chemotherapy with fluorouracil (1,000 mg/m(2)/d) and cisplatin (20 mg/m(2)/d), both given as 96-hour continuous intravenous infusions during weeks 1 and 4 of radiation therapy. Primary-site resection was reserved for residual or recurrent primary-site disease after chemoradiotherapy. Neck dissection was considered for N2 or greater disease, irrespective of clinical response, and for residual or recurrent neck disease after nonoperative treatment. RESULTS: Forty-one patients with stage IV disease were treated. Toxicity was significant, with grade 3 to 4 mucositis in 98%, dysphagia in 88%, and skin reaction in 85%. Neutropenic fever requiring hospitalization occurred in 51%. Despite feeding tube placement in 35 patients (85%), the mean weight loss during chemoradiotherapy was 13.3% of initial body weight. One patient died during treatment as a result of a pulmonary embolus. At a median follow-up period of 30 months, the 3-year Kaplan-Meier projected overall survival was 59%, disease-specific survival 69%, likelihood of local control without surgical resection 91%, and local control with surgical resection 97%. The likelihood of distant disease control at 3 years was 74%, and distant metastases were present in eight of 13 patients who died. CONCLUSION: This chemoradiotherapy schedule produces considerable but manageable toxicity. Survival and organ preservation are excellent for this poor-prognosis patient cohort. Distant metastases are the most common cause of treatment failure.

Randomized phase III study of 2 cisplatin-based chemoradiation regimens in locally advanced head and neck squamous cell carcinoma: impact of changing disease epidemiology on contemporary trial design.

BACKGROUND: Chemoradiotherapy results in excellent outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). This trial compared 2 chemoradiotherapy regimens. METHODS: Patients with locally advanced HNSCC were treated with radiation (70-74.4 Gy), and randomized to arm A: cisplatin 100 mg/m(2) on radiotherapy (RT) days 1, 22, and 43, or arm B: cisplatin (20 mg/m(2) /day) and 5-fluorouracil (5-FU; 1000 mg/m(2) /day) continuous 96-hour infusions on RT weeks 1 and 4. The primary endpoint was relapse-free survival (RFS). RESULTS: Between February 2008 and October 2011, 69 patients were enrolled in this study. The study prematurely closed when a scheduled interim analysis showed superior outcomes in both arms and futility of continuation. Eighty-three percent of patients had oropharyngeal cancer, of these, 86% were human papillomavirus (HPV)/p16+. The 3-year Kaplan-Meier outcome estimates (median follow-up, 41 months) for arms A and B were: RFS 87% versus 80% (p = .24), overall survival 97% versus 85% (p = .013), locoregional control 96% versus 94% (p = .52), and distant metastatic control 91% versus 87% (p = .9). CONCLUSION: Multiagent was not superior to single-agent chemoradiotherapy. Overrepresentation of HPV/p16+ patients resulted in better than expected outcomes.

Factors associated with improved survival in patients with brain metastases from esophageal cancer: a retrospective review.

There are over 200,000 cases of brain metastases (BrM) every year, but very few are from esophageal cancer primaries. In order to determine predictors for outcome of these patients, the authors conducted a retrospective review of twenty-seven patients with BrM from esophageal carcinoma diagnosed at the Cleveland Clinic Foundation between 1991 and 2001. For the entire cohort, median follow-up and median survival was 3.6 months and 3.6 months, respectively. On univariate analysis, patients with Karnofsky Performance Status (KPS) >/= 70, low recursive partitioning analysis score, single BrM, no systemic disease, and aggressive treatment [surgery, stereotactic radiosurgery (SRS) + whole brain radiation (WBRT), SRS + surgery + WBRT, surgery + WBRT)] had a significantly improved survival. In a multivariate model, patients with higher KPS and aggressive treatment had improved survival. The 1-year survival for the WBRT alone group and the aggressive treatment group was 6%, and 36% respectively. We conclude that based on the data presented here, patients with BrM from esophageal cancer have poor outcome. Aggressive treatment and favorable KPS are associated with longer survival for selected patients. We recommend esophageal cancer patients with BrM be enrolled in clinical trials to better delineate the role of treatment and potentially improve results.

A phase II trial of induction epirubicin, oxaliplatin, and fluorouracil, followed by surgery and postoperative concurrent cisplatin and fluorouracil chemoradiotherapy in patients with locoregionally advanced adenocarcinoma of the esophagus and gastroesophageal junction.

INTRODUCTION: Preoperative chemoradiotherapy improves local control in patients with locoregionally advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This phase II study investigated the addition of induction chemotherapy to surgery and adjuvant chemoradiotherapy. METHODS: Patients with cT3-4 or N1 or M1a (American Joint Committee on Cancer 6th edition) adenocarcinoma of the esophagus and GEJ were eligible. Induction chemotherapy, with epirubicin 50 mg/m/d, oxaliplatin 130 mg/m/d, and fluorouracil 200 mg/m/d continuous infusion for 3 weeks, was given every 21 days for three courses, followed by surgery. Adjuvant chemoradiotherapy consisted of 50 to 55 Gy at 1.8 to 2.0 Gy/d and two courses of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) during weeks 1 and 4 of radiotherapy. RESULTS: Between February 2008 and January 2012, 60 evaluable patients enrolled. Resection was accomplished in 54 patients (90%) and adjuvant chemoradiotherapy in 48 (80%) patients. Toxicity included unplanned hospitalization in 18% of patients during induction chemotherapy and 19% of patients during adjuvant chemoradiotherapy. There was one chemotherapy-related and two postoperative deaths. With a median follow-up of 43 months, the projected 3-year locoregional control is 88%, distant metastatic control 46%, relapse-free survival 41%, and overall survival 47%. Symptomatic response to chemotherapy and the percentage of remaining viable tumor at surgery proved the strongest predictors of survival and distant control. CONCLUSIONS: Chemotherapy, surgery, and adjuvant chemoradiotherapy are feasible and produce outcomes similar to other multimodality treatment schedules in locoregionally advanced adenocarcinoma of the esophagus and GEJ. Symptomatic response and less residual tumor at surgery were associated with improved outcomes.

Oropharyngeal squamous cell carcinoma with known human papillomavirus status treated with definitive chemoradiotherapy: patterns of failure and toxicity outcomes.

BACKGROUND: Tumor human papillomavirus (HPV) status has emerged as one of the most powerful prognostic factors for disease control and survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). We reviewed our experience in patients with OPSCC and known tumor HPV status treated with definitive chemoradiotherapy (CRT). METHODS: Patients with stage III-IVb OPSCC and known tumor HPV status treated with CRT between 2006 and 2011 were identified from an IRB approved registry for this retrospective review. Outcomes were estimated using the Kaplan-Meier method and compared between HPV-positive and negative patients using the log-rank test. RESULTS: Of the 121 pts (89% male, 93% Caucasian) included in this study, median age was 57 (range: 40-73) and median follow-up was 21 months (range: 6-63). Ninety-seven (80%) patients were HPV-positive and 24 (20%) were HPV-negative. Primary site was base of tongue (55%), tonsil (44%), and oropharyngeal wall (2%). Two year rates of locoregional recurrence (3% vs. 26%; p = 0.002), disease free survival (93% vs. 64%; p = 0.001) and overall survival (94% vs 73%; p = 0.002) were superior in HPV-positive patients, while rates of distant recurrence were similar (3% vs. 5%; p = 0.98). While acute toxicities were similar between both groups, patients with HPV-positive disease were more likely to resume a normal diet (90% vs. 65%; p = 0.017) at last follow up. Also, no HPV-positive patient required a feeding tube beyond 6 months after treatment, compared with 24% of HPV-negative patients. CONCLUSIONS: Definitive CRT produces excellent rates of disease control with minimal late toxicity for patients with HPV-positive OPSCC. Studies of OPSCC should account for tumor HPV status when identifying factors prognostic for outcome.

Definitive radiotherapy for early (T1-T2) glottic squamous cell carcinoma: a 20 year Cleveland Clinic experience.

PURPOSE: To report our 20 yr experience of definitive radiotherapy for early glottic squamous cell carcinoma (SCC). METHODS AND MATERIALS: Radiation records of 141 patients were retrospectively evaluated for patient, tumor, and treatment characteristics. Cox proportional hazard models were used to perform univariate (UVA) and multivariate analyses (MVA). Cause specific survival (CSS) and overall survival (OS) were plotted using cumulative incidence and Kaplan-Meir curves, respectively. RESULTS: Of the 91% patients that presented with impaired voice, 73% noted significant improvement. Chronic laryngeal edema and dysphagia were noted in 18% and 7%, respectively. The five year LC was 94% (T1a), 83% (T1b), 87% (T2a), 65% (T2b); the ten year LC was 89% (T1a), 83% (T1b), 87% (T2a), and 53% (T2b). The cumulative incidence of death due to larynx cancer at 10 yrs was 5.5%, respectively. On MVA, T-stage, heavy alcohol consumption during treatment, and used of weighted fields were predictive for poor outcome (p < 0.05). The five year CSS and OS was 95.9% and 76.8%, respectively. CONCLUSIONS: Definitive radiotherapy provides excellent LC and CSS for early glottis carcinoma, with excellent voice preservation and minimal long term toxicity. Alternative management strategies should be pursued for T2b glottis carcinomas.

Single-arm phase II study of multiagent concurrent chemoradiotherapy and gefitinib in locoregionally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: This phase II study tested the addition of the oral epidermal growth factor receptor gefitinib to multiagent concurrent chemoradiotherapy regimen in head and neck squamous cell cancer (HNSCC). METHODS: Patients with stage III-IV HNSCC received hyperfractionated radiation (72-74.4 Gy at 120 cGy twice daily), with concurrent 96-hour infusions of cisplatin 20 mg/m(2) /day and fluorouracil 1000 mg/m(2) /day given during weeks 1 and 4. Daily gefitinib 250 mg was started on day 1 of radiation and continued for 2 years. Results were retrospectively compared with our previous study using identical chemoradiotherapy without gefitinib. RESULTS: Sixty patients were enrolled in the study; 80% had stage IV disease and 68% had oropharyngeal primary tumors. The full course of gefitinib was not tolerated by 42%; there were 5 treatment-related deaths (8%). With a median follow-up of 54 months, 2- and 3-year overall survival estimates were 80% and 71%, respectively. Projected distant metastatic control at 2 and 3 years was 88%. When compared with our historical cohort, acute toxicities including renal dysfunction and unplanned rehospitalization were worse in the study patients. Projected outcome estimates did not differ between the 2 cohorts. CONCLUSIONS: Addition of gefitinib to concurrent chemoradiotherapy was difficult to complete, did not improve outcomes, and increased toxicity.

Multi-agent concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer in the elderly.

BACKGROUND: The reported decreasing benefit with increasing age from concurrent chemoradiotherapy in head and neck cancer patients prompted this retrospective review. METHODS: Two courses of cisplatin-based concurrent chemoradiotherapy were given to fit patients ≥70 years with locoregionally advanced cancers. Clinical characteristics, treatment, and outcomes were compared with those for an identically treated cohort <70 years. RESULTS: There were 44 patients ≥70 and 137 patients <70 years. Clinical characteristics, treatment and toxicities were similar except that the elderly were less likely to receive both chemotherapy courses, experienced more myelosuppression, required more unplanned hospitalization, and were feeding-tube dependent longer. Projected 5-year disease-specific survival (71% vs 74%) and freedom from recurrence (69% v. 71%) were nearly identical. CONCLUSIONS: Although these selected elderly patients experienced greater myelosuppression and supportive care requirements, outcomes were the same as in younger patients. Age alone should not be considered a contraindication to aggressive chemoradiotherapy for this disease.

Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma.

BACKGROUND: The management of initially bulky nodal disease after primary nonsurgical treatment for stage IV head and neck squamous cell carcinoma (HNSCC) continues to be a subject of debate. METHODS: A retrospective chart review of neck management in patients after chemoradiation was performed. RESULTS: Of the initially positive necks analyzed, 210/329 (65%) had a complete clinical response to treatment and 161 necks underwent neck surgery. Patients were pathologically positive 13.8% and 39.6% of the time after clinical complete or partial response, respectively. Regional recurrence was more frequent in necks with partial clinical (p = .04) or pathologic responses (p < .01) and with primary site recurrences (p < .01). CONCLUSIONS: It is still safest at our institution to perform selective neck dissection on patients with > or = N2 neck disease when initially observed to prevent unsalvageable regional recurrence until more accurate interval assessment tools are confirmed.

A phase II study of perioperative concurrent chemotherapy, gefitinib, and hyperfractionated radiation followed by maintenance gefitinib in locoregionally advanced esophagus and gastroesophageal junction cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) for locoregionally advanced esophageal or gastroesophageal junction cancer produces high locoregional control rates but suboptimal distant metastatic control (DMC) and overall survival. This phase II study added gefitinib (G) to our previously tested CCRT regimen in an effort to improve these outcomes. METHODS: Eligibility required T3, N1, or M1a esophageal or gastroesophageal junction squamous cell or adenocarcinoma staged by esophageal ultrasound and positron emission tomography/computed tomography. Four-day continuous intravenous infusions of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) began on day 1 of preoperative radiation (30 Gy and 1.5 Gy bid). Surgery followed in 4 to 6 weeks, and an identical course of CCRT 6 to 10 weeks postoperatively. G 250 mg/d was given with preoperative CCRT for 4 weeks and restarted with postoperative therapy for 2 years. Results were retrospectively compared with our historical series of 93 patients given CCRT without G. RESULTS: Between April 2003 and July 2006, 80 patients were enrolled. Patient and tumor characteristics were similar to our historical series. G did not increase toxicity except for development of rash in 42 (53%) and diarrhea in 44 (55%) 3-year Kaplan-Meier estimates (G versus non-G treated patients) included: overall survival (42% versus 28%, p = 0.06), DMC (40% versus 32%, p = 0.33), and locoregional control (76% versus 77%, p = 0.74). Intolerance for G maintenance occurred in 48% of patients. Patients who experienced G related diarrhea appeared to have improved outcomes. CONCLUSIONS: Although G did not worsen CCRT toxicity, maintenance therapy proved difficult. This contemporary cohort of patients enjoyed superior survival, which does not solely reflect a decrease in DMC and merits further investigation.

Mature results from a phase II trial of postoperative concurrent chemoradiotherapy for poor prognosis cancer of the esophagus and gastroesophageal junction.

INTRODUCTION: Mature results are presented from a phase II trial of postoperative concurrent chemoradiotherapy in patients with poor-prognosis cancer of the esophagus and gastroesophageal junction after primary surgical resection. METHODS: Resected patients with a pathologic stage of T3, N1, or M1a were eligible for this trial. Concurrent chemoradiotherapy was begun between 6 and 10 weeks after surgery and consisted of radiotherapy (1.8 Gy/d to a planned dose of 50.4-59.4 Gy), concurrent with two cycles of 5-fluorouracil (1000 mg/m/d) and cisplatin (20 mg/m/d), both given as 4-day continuous intravenous infusions during the first and fourth weeks of the radiation. RESULTS: Between 1995 and 2006, 50 patients were enrolled. The median age was 59 (range, 33-76) years, and most patients were male (86%), Caucasian (96%), and had undergone a transthoracic esophagogastrectomy (74%) for what proved to be a node positive (86%) adenocarcinoma (86%). Postoperative concurrent chemoradiotherapy was accompanied by neutropenia requiring hospitalization for fever in only four patients (8%) and no toxic deaths. With a median follow-up of 47 (range, 36-124) months, the Kaplan-Meier 4-year projected overall survival is 51%, freedom from recurrence 50%, distant metastatic control 56%, and locoregional control 86%. An earlier pathologic stage was the only predictor for a better outcome. CONCLUSIONS: This schedule of postoperative concurrent chemoradiotherapy has acceptable toxicity for patients with poor-prognosis esophageal and gastroesophageal junction cancer after surgery. Outcomes are better than historical results after surgery alone and justify further investigation of this approach.

Choice of radiotherapy planning modality influences toxicity in the treatment of locally advanced esophageal cancer.

PURPOSE: Three-dimensional computed tomography-based radiotherapy planning (3DCTP) is increasingly employed in the treatment of esophageal cancer. It is unknown whether a 3DCTP approach influences outcomes compared to two-dimensional planning (2DP). This study compares clinical outcomes for homogeneously treated patient cohorts stratified by planning modality. METHODS AND MATERIALS: A retrospective chart review was conducted on patients with T3/4 and/or node-positive esophageal carcinoma treated at the Cleveland Clinic between July 1, 2003 and May 31, 2006 who were managed with an institutional regimen consisting of preoperative radiotherapy, whether 3DCTP or 2DP [30 Gy/20 fractions/1.5 Gy twice daily over 2 weeks], with concurrent cisplatin and 5-fluorouracil the first week. Following definitive resection, an identical postoperative course of concurrent chemoradiotherapy (CRT) was delivered. RESULTS: One hundred and forty-one patients completed preoperative CRT and were available for review. The median follow-up of living patients is 21.7 months. Fifty-five percent underwent 3DCTP and 45% had 2DP. The treatment groups were similar, with the exception of clinical stage group, with 2DP having more stage II and fewer stage III patients than 3DCTP (p = 0.02). 3DCTP plans had significantly smaller field sizes by area (p < 0.0001). Pathologic response, locoregional control, distant control, and overall survival were equivalent between the two planning modalities. Esophagitis was significantly less common with a 3D approach compared to 2D planning (49% vs. 71%, p = 0.0096), with other toxicities equivalent between the groups. CONCLUSIONS: 3DCTP reduces acute esophagitis in patients receiving multimodality therapy for esophageal cancer without compromising clinical outcomes.

Utility of positron emission tomography compared with mediastinoscopy for delineating involved lymph nodes in stage III lung cancer: insights for radiotherapy planning from a surgical cohort.

PURPOSE: Mediastinoscopy is routinely carried out on the majority of nonmetastatic, non-small-cell lung cancer (NSCLC) patients in our institution. We used the results of mediastinoscopy from a Stage III NSCLC cohort to assess the reliability of positron emission tomography (PET) scans at identifying involved mediastinal lymph nodes (MLN) when used during radiotherapy planning. METHODS AND MATERIALS: Mediastinoscopy was the gold standard. Characteristics of PET were calculated for nodal sensitivity. To compare the impact on contouring, theoretical nodal targets (NTs) containing involved MLNs were generated using PET and mediastinoscopy. We determined whether the NT derived from PET (NT-P) was equivalent to, greater than, or less than that seen with the mediastinoscopy (NT-M). RESULTS: Data for 122 patients with Stage III NSCLC, treated between 2000 and 2004, were analyzed. After exclusions, 87 patients with Stage III disease by mediastinoscopy were analyzed. Overall PET sensitivity was 61% and positive predictive value was 94%. Of the 87 patients, 33 (38%) had no abnormal MLN findings by PET. Of 36 Stage IIIA cancer patients, 18 (50%) had NT-P equivalent to NT-M, 10 (28%) had smaller NT-Ps, and 8 (22%) had larger NT-Ps compared with NT-Ms. Of 18 Stage IIIB cancer patients, NTs were equivalent in 6 (34%); in 1 patient (5%) NT-P was larger than the corresponding NT-M, and in 11 (61%) smaller than the corresponding NT-M. CONCLUSIONS: In this study PET had modest sensitivity to detect MLN involvement and underestimated the extent of involved nodes for target definition. The role of PET in mediastinal contouring needs to be evaluated prospectively and ideally correlated with a pathology standard.

Clinical predictors of larynx preservation after multiagent concurrent chemoradiotherapy.

BACKGROUND: Determining which patients benefit from larynx preservation strategies remains problematic. We reviewed our experience using multiagent concurrent chemoradiotherapy to identify clinical predictors for success. METHODS: Cisplatin and fluorouracil were given during weeks 1 and 4 of radiation to 115 patients with locoregionally advanced larynx or hypopharynx squamous cell cancer without cartilage invasion or laryngeal destruction. Laryngectomy was reserved for local failure. RESULTS: The 5-year Kaplan-Meier projected overall survival was 58%, survival with larynx preservation 52%, local control without surgery 82%, local control (including surgical salvage) 94%, and survival with functional larynx 49%. Local control without surgery was superior in patients with T1-2 versus T3-4 tumors (97% vs 77%, p = .032). No other clinical parameters proved predictive of local control. CONCLUSION: Larynx preservation was successful in all subsets of appropriately selected patients. Although local failure was more likely in patients with T3-4 tumors, it was infrequent and surgical salvage was effective.

A phase II trial of accelerated multimodality therapy for locoregionally advanced cancer of the esophagus and gastroesophageal junction: the impact of clinical heterogeneity.

OBJECTIVES: This is a report of mature results from a phase II trial of an accelerated multimodality treatment program for locoregionally advanced cancer of the esophagus and gastroesophageal junction with a focus on the impact of clinical heterogeneity on outcomes. A split course of pre- and postoperative hyperfractionated radiation therapy and concurrent chemotherapy was used in an effort to limit perioperative mortality. METHODS: Eligibility required a diagnosis of esophageal or gastroesophageal junction cancer and an esophageal ultrasound stage of at least T3, N1, or M1A. Patients received a 12-day induction course of radiation (1.5 Gy twice a dose to a dose of 30 Gy) concurrent with 4-day continuous intravenous infusions of cisplatin (20 mg/m2 per day) and 5-fluorouracil (1000 mg/m2 per day) beginning on day 1. Surgery followed in 4 to 6 weeks followed 6 to 10 weeks later by a second, identical course of chemoradiotherapy. RESULTS: From October 1999 through March 2003, 93 patients were enrolled; 96% were white, 86% male, and 83% had adenocarcinoma. Resection was possible in 83 patients (89%) with 4 (5%) perioperative deaths. With a median follow up of 50 months (range, 34-72 months), the 3-year projected overall survival rate is 27.9%, freedom from recurrence 30.5%, and distant metastatic control 32.4%. Locoregional control in resected patients is 86%. Freedom from recurrence and distant control were significantly better in patients with 1) earlier pretreatment clinical stage, 2) earlier postinduction pathologic stage, 3) squamous cell cancer, and 4) a pathologic response. CONCLUSIONS: This accelerated multimodality treatment program is feasible and perioperative mortality proved acceptable. Despite excellent locoregional control, freedom from recurrence, and overall survival proved disappointing reflecting the frequency of distant metastases. Heterogeneity in patient populations makes comparisons with similar nonrandomized experiences problematic.

Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution.

PURPOSE: A retrospective review with long-term follow-up is reported from the Cleveland Clinic Foundation studying radiation and concurrent multiagent chemotherapy in patients with locoregionally advanced squamous cell head and neck cancer. PATIENTS AND METHODS: Between 1989 and 2002, 222 patients were treated with 4-day continuous infusions of fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d) during weeks 1 and 4 of either once daily or twice daily radiation therapy. Primary site resection was reserved for patients with residual or recurrent primary site disease after chemoradiotherapy. Neck dissection was considered for patients with N2 or greater disease, irrespective of clinical response, and for patients with residual or recurrent neck disease. RESULTS: With a median follow-up of 73 months, the Kaplan-Meier 5-year projected overall survival rate is 65.7%, freedom from recurrence rate is 74.0%, local control without the need for surgical resection rate is 86.7%, and overall survival rate with organ preservation is 62.2%. Including patients undergoing primary site resection as salvage therapy, the overall local control rate is 92.4%. Regional control rate at 5 years is 92.4%. Among patients with N2-3 disease, regional control was significantly better if a planned neck dissection was performed. Distant control at 5 years was achieved in 85.4% of patients and was significantly worse in patients with hypopharyngeal primary sites and patients with poorly differentiated tumors. CONCLUSION: Concurrent multiagent chemoradiotherapy can result in organ preservation and cure in the majority of appropriately selected patients with locoregionally advanced, nonmetastatic, squamous cell head and neck cancer. Distant metastatic disease was the most common cause of treatment failure. Late functional outcomes will require further investigation.

Phase III Trial of an emulsion containing trolamine for the prevention of radiation dermatitis in patients with advanced squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Trial 99-13.

PURPOSE: This multicentered phase III trial was designed to compare an emulsion containing trolamine against the usual supportive care within each participating institution for patients with head and neck cancer undergoing radiation therapy. PATIENTS AND METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to one of the following treatments: prophylactic trolamine emulsion, interventional trolamine emulsion, or declared institutional preference. The primary outcome was the reduction in grade 2 or higher skin toxicity, as per National Cancer Institute Common Toxicity Criteria version 2.0. Secondary outcomes included patient-reported quality of life (QOL). RESULTS: From October 2000 to April 2002, 547 patients from 51 institutions were entered onto the trial. The average age was 59 years. Patients were predominately male (79%) and most continued to use tobacco products (52%). The rates of grade 2 or higher radiation dermatitis were 79%, 77%, and 79% in the prophylactic, interventional, and institutional preference arms of the study, respectively. No significant differences in QOL were found. CONCLUSION: The results of this trial demonstrate no advantage for the use of trolamine in reducing the incidence of grade 2 or higher radiation dermatitis or improving patient-reported QOL. The use of 15 different local standards of care highlights the need to continue research that will result in evidence-based recommendations to reduce the burden of radiation dermatitis.

Use of the Radiation Therapy Oncology Group recursive partitioning analysis classification system and predictors of survival in 19 women with brain metastases from ovarian carcinoma.

BACKGROUND: Brain metastases are an uncommon complication in women with primary ovarian carcinoma; thus, little is known about whether the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) prognostic classification system is valid in this patient population. METHODS: From September 1985 to June 2002, 19 patients with brain metastases resulting from primary ovarian carcinoma underwent treatment at the Cleveland Clinic Foundation. The medical records of these patients were retrospectively reviewed. RESULTS: At the time of data analysis, all 19 women had died. The median age at diagnosis of primary ovarian carcinoma and brain metastasis was 51 and 54 years of age, respectively. Fifteen patients presented with a Karnofsky performance status (KPS) of 70 or higher. Seven patients had a single brain lesion and 12 had multiple lesions. All RTOG RPA prognostic classes were represented, with median survivals of 24.7, 8.9, and 2.6 months for Classes I, II, and III, respectively (P = 0.31). Patients who underwent surgical resection survived longer than those who did not (33.7 vs. 7.4 mos). The presence of multiple lesions was adversely related to survival on multivariate analysis (P = 0.03). Primary control was an important predictor of survival on multivariate analysis as well (P = 0.01) and was achieved in 15 of the 19 women. CONCLUSIONS: This is the first study to support the prognostic usefulness of the RTOG RPA classification for ovarian carcinoma patients with metastasis to the brain. The number of metastatic intracranial lesions should be included when determining the prognosis.