David J. Adelstein

An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer

PURPOSE The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer. PATIENTS AND METHODS Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test. RESULTS Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant). CONCLUSION The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.

Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma

BACKGROUND Patients with clinically localized, intermediate- or high-grade non-Hodgkins lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients. METHODS We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone. RESULTS Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02). CONCLUSIONS Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkins lymphoma.

Esophageal Carcinoma: Depth of Tumor Invasion Is Predictive of Regional Lymph Node Status

BACKGROUND The depth of tumor invasion (T) and regional lymph node status (N) are two factors that define the stage of an esophageal carcinoma. However, the arrangement of staging groups assumes that these factors are independent variables. A retrospective review of 359 consecutive patients undergoing esophageal resection was conducted to define the relationship between T and N and to determine whether T is a significant predictor of regional lymph node metastasis (N1). METHODS Primary treatment was operation without preoperative therapy. There were 295 (82%) adenocarcinomas, 55 (15%) squamous cell carcinomas, and 9 (3%) adenosquamous carcinomas. T status was Tis in 29 (8%) patients, T1 in 65 (18%), T2 in 37 (10%), T3 in 219 (61%), and T4 in 9 (3%). N status was N0 in 161 (45%) patients and N1 in 198 (55%). M status was M0 in 327 (91%) patients and M1 in 32 (9%). Stage was 0 in 29 (8%) patients, I in 58 (16%), IIA in 70 (20%), IIB in 22 (6%), III in 148 (41%), and IV in 32 (9%). RESULTS The likelihood of N1 disease occurring with increasing T was tested using the trend test. The percentage of patients with N1 disease is 0% for Tis, 11% for T1, 43% for T2, 77% for T3, and 67% for T4 (p < 0.001). This relationship existed for both adenocarcinoma and squamous cell carcinoma. Multivariable analysis identified increasing T, adenocarcinoma, and lack of well-differentiated histologic features as significant predictors of N1 disease. Compared with a T1 patient, a T2 patient is 6 times more likely to have N1 disease, a T3 patient 23 times, and a T4 patient 35 times. CONCLUSIONS We conclude that for patients with esophageal carcinoma, T is an important predictor of N and this association should be included with other established factors used in clinical staging and treatment decisions.

A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and iv squamous cell head and neck cancer: Preliminary results

A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous‐course radiotherapy was performed at the Cleveland Clinic Foundation.

Who merits a neck dissection after definitive chemoradiotherapy for N2–N3 squamous cell head and neck cancer?

The role of neck dissection (ND) after definitive chemoradiotherapy for squamous cell head and neck cancer is incompletely defined. We retrospectively reviewed 109 patients with N2–N3 disease treated with chemoradiotherapy to identify predictors of a clinical complete response in the neck (CCR‐neck), pathologic complete response after ND (PCR‐neck), and regional failure.

Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer.

OBJECTIVE:Endoscopic ultrasound (EUS) provides important information in the initial staging of patients with esophageal cancer. With recent modifications in chemoradiotherapy protocols, a significant number of patients have no residual tumor at esophagectomy. The high surgical morbidity and mortality might be avoided if complete response to chemoradiotherapy could be predicted. Previously published clinical trials, with relatively small patient numbers, have suggested that EUS may accurately stage esophageal cancer after chemoradiotherapy. The aim of this study was to verify the accuracy of EUS in staging esophageal cancer after effective chemoradiotherapy.METHODS:EUS staging was performed before and after concurrent cisplatin, 5-fluorouracil, and hyperfractionated radiotherapy in 59 patients with newly diagnosed esophageal cancer. All patients underwent subsequent esophagectomy and pathological staging. The accuracy of preoperative, postchemoradiotherapy EUS was evaluated in a retrospective fashion by comparison to pathological staging.RESULTS:After chemoradiotherapy, 18 patients (31%) had no residual disease at pathological staging (T0N0). However, EUS correctly predicted complete response to chemoradiotherapy (T0N0) in only three patients (17%). The accuracy of postchemoradiotherapy EUS for pathological T stage was only 37%, and its sensitivity for N1 disease was only 38%. EUS was unable to distinguish postradiation fibrosis and inflammation from residual tumor.CONCLUSION:When aggressive preoperative chemoradiotherapy is provided to patients with esophageal cancer, the predictive value of postchemoradiotherapy EUS is inadequate for use in clinical decision making.

Head and neck squamous cell cancer and the human papillomavirus: Summary of a National Cancer Institute State of the Science Meeting, November 9–10, 2008, Washington, D.C.

Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio. E-mail: adelstd@ccf.org Fox Chase Cancer Center, Philadelphia, Pennsylvania Ohio State University Comprehensive Cancer Center, Columbus, Ohio National Cancer Institute, Bethesda, Maryland 5 Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 6 Johns Hopkins University School of Medicine, Baltimore, Maryland Yale University School of Medicine, New Haven, Connecticut University of Southern California, Los Angeles, California University of Washington, Seattle, Washington H. Lee Moffitt Cancer Center, Tampa, Florida

Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer.

Treating the neck after organ‐preservation treatment with radiotherapy or chemoradiotherapy can be 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.

Risk factors for hypopharyngeal/upper esophageal stricture formation after concurrent chemoradiation

Concurrent chemoradiation therapy has been demonstrated to be effective as an organ‐sparing treatment for select advanced head and neck squamous cell carcinoma (HNSCC). However, this treatment modality is not without side effects. One side effect is the formation of upper esophageal strictures. As concurrent chemoradiation treatment is used more frequently, it is important to identify risk factors associated with stricture formation.