Timothy E. Sawyer

Analysis of outcome in patients reirradiated for brain metastases

PURPOSE Patients with newly diagnosed brain metastases generally benefit from whole brain radiation therapy (WBRT). However, the role of reirradiation for patients who develop progressive brain metastases has been controversial. This retrospective study examines our experience with reirradiation of patients for progressive brain metastases after an initial+ course of WBRT. METHODS AND MATERIALS From 1975-1993, 2658 patients received WBRT for brain metastases at our institution. Eighty-six patients were subsequently reirradiated for progressive brain metastases. The median age of these patients was 58 (range: 31-81). The most common primary sites were breast and lung. Fifty patients had metastatic disease at other sites. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (40 patients) or 3 (38 patients). The median dose of the first course of irradiation was 30 Gy (range: 1.5-50.6 Gy). The median dose of the second course of irradiation was 20 Gy (range: 8.0-30.6 Gy). RESULTS Twenty-three patients (27%) had resolution of neurologic symptoms, 37 patients (43%) had partial improvement of neurologic symptoms, and 25 patients (29%) had either no change or worsened after reirradiation. The median survival following reirradiation was 4 months (range: 0.25-72 months). The majority of patients had no significant toxicity secondary to reirradiation. Five patients had radiographic abnormalities of their brain consistent with radiation-related changes. One patient had symptoms of dementia that was thought to be caused by radiotherapy. Various potential prognostic factors were evaluated for possible associations with survival, including age, sex, primary site, ECOG performance status, RTOG neurologic functional class, absence of extracranial metastases, and dose of irradiation. Absence of extracranial metastasis, solitary brain metastasis, and retreatment dose > 20 Gy were associated with improved survival in univariate analysis (p=0.025, 0.033, and 0.061, respectively). The absence of extracranial disease was the only significant factor in multivariate analysis (p=0.05). CONCLUSION The majority of patients in our series had favorable symptomatic responses. Clinically significant complications were minimal. Reirradiation should be offered to patients who develop progressive brain metastases.

Effectiveness of Postoperative Irradiation in Stage IIIA Non–Small Cell Lung Cancer According to Regression Tree Analyses of Recurrence Risks

BACKGROUND In the setting of grossly resected stage IIIA (N2 involvement) non-small cell lung carcinoma, the role of adjuvant postoperative thoracic radiation therapy (TRT) remains controversial. This study was initiated to subcategorize these patients into high-, intermediate-, and low-risk groups with respect to local recurrence and survival rates, and to determine whether there were certain subgroups of patients who were particularly likely or unlikely to benefit from postoperative TRT. METHODS Two hundred twenty-four patients were studied. A regression tree analysis was used to separate patients who had undergone operation alone into groups that had a high, intermediate, or low risk of local recurrence and death. The effect of adjuvant postoperative TRT then was examined in each of these groups. RESULTS The use of adjuvant postoperative TRT (compared with operation alone) was associated with an improvement in freedom from local recurrence and survival for patients who had an intermediate or high risk of local recurrence and death. However, the greatest level of improvement in freedom from local recurrence (p < 0.0001) and survival (p = 0.0002) associated with the use of adjuvant postoperative TRT was in the high-risk group. Similarly, but of lesser magnitude, the intermediate-risk group had improved freedom from local recurrence and survival rates with the use of adjuvant post-operative TRT (p = 0.002 and p = 0.01, respectively). For the low-risk group, the freedom from local recurrence and survival rates were not statistically different between the patients who received adjuvant postoperative TRT and those who underwent observation. CONCLUSIONS Patients with non-small cell lung carcinoma involving ipsilateral mediastinal lymph nodes (stage IIIA) who undergo gross resection and who are at either high or intermediate risk for local recurrence and death are likely to benefit from adjuvant postoperative irradiation. The role of radiation therapy in low-risk patients is unclear. Prospective confirmation of these observations is warranted.

Factors predicting patterns of recurrence after resection of N1 non-small cell lung carcinoma

BACKGROUND Although irradiation and chemotherapy are unproved adjuvant treatments for completely resected N1 non-small cell lung carcinoma, previous studies may have been diluted by the inclusion of low-risk patients. Risk factors in this situation, however, are not yet well defined. METHODS One hundred seven consecutive patients with complete resection of N1 disease who received no other therapy were studied to identify factors independently predicting the risk of freedom from local recurrence (FFLR), freedom from distant metastasis (FFDM), and overall survival (OS). RESULTS Twelve factors were assessed for a potential prognostic relationship with FFLR, FFDM, and OS. Regression analyses revealed that the factors independently associated with an improved outcome were positive bronchoscopic findings (FFLR, p = 0.005), a greater number of dissected N1 nodes (FFDM, p = 0.02), and a lesser T stage (OS, p = 0.01). Classification and regression tree analyses were then used to separate the patients into risk groups. CONCLUSIONS Although these results require corroboration in further studies, they may aid the design of trials examining therapies used to decrease rates of local recurrence or distant metastasis.

Patients with stage I non-small cell lung carcinoma at postoperative risk for local recurrence, distant metastasis, and death: implications related to the design of clinical trials

PURPOSE Patients with pathologically staged American Joint Committee on Cancer stage I (T1 N0 or T2 N0) non-small cell lung cancer have a favorable prognosis after complete surgical resection compared with patients with more advanced stages. Benefits of adjuvant therapy in this setting are unproved. However, there may be subgroups of patients with stage I disease at high enough risk for local recurrence to prompt consideration of adjuvant or neoadjuvant radiation therapy. Likewise, there may be subgroups of patients at high enough risk for distant metastasis to justify the evaluation of chemotherapy. METHODS AND MATERIALS From 1987 through 1990, 370 patients undergoing gross total resection of non-small cell lung cancer had stage I disease and received no chemotherapy or radiation therapy as part of their primary treatment. These patients were the subject of a retrospective review to separate patients into high-, intermediate-, and low-risk groups with respect to freedom from local recurrence (FFLR), freedom from distant metastasis (FFDM), and overall survival by using a regression tree analysis. RESULTS The 5-year rates of FFLR, FFDM, and survival were 85%, 83%, and 66%, respectively. Regression analyses revealed that the factors independently predicting for a poorer FFLR rate included fewer than 15 lymph nodes dissected and pathologically evaluated (p = 0.002) and the presence of a T2 tumor (p = 0.04). Factors independently predicting for a poorer FFDM rate included a maximal dimension greater than 5 cm (p = 0.02) and nonsquamous histology (p = 0.03). Factors independently predicting for a poorer survival rate included fewer than 15 lymph nodes dissected and pathologically evaluated p = 0.001) and a maximal dimension greater than 3 cm (p = 0.003). Regression tree analyses were used to separate patients into risk groups. CONCLUSION Incorporating the aforementioned factors into regression tree analyses, three risk groups were identified with respect to FFLR. Two each were identified for FFDM and for survival. For each of these three end-points, the differences in outcomes for each risk group were found to be both statistically and clinically significant. These risk groups may be useful in the future design of phase III trials evaluating the use of adjuvant chemotherapy and radiation therapy in the stage I setting.

Predictors of subclinical nodal involvement in clinical stages I and II non-small cell lung cancer: implications in the inoperable and three-dimensional dose-escalation settings

PURPOSE When mediastinal lymph nodes are clinically uninvolved in the setting of inoperable non-small cell lung cancer, whether conventional radiation techniques or three-dimensional dose-escalation techniques are used, the benefit of elective nodal irradiation is unclear. Inclusion of the clinically negative mediastinum in the radiation portals increases the risk of lung toxicity and limits the ability to escalate dose. This analysis represents an attempt to use clinical characteristics to estimate the risk of subclinical nodal involvement, which may help determine which patients are most likely to benefit from elective nodal irradiation. METHODS From 1987 to 1990, 346 patients undergoing complete resection of non-small cell lung cancer underwent a preoperative computed tomographic scan revealing no clinical evidence of N2/N3 involvement. Multivariate regression and regression tree analyses attempted to define which patients were at highest risk for subclinical mediastinal involvement (N2) and which patients were at highest risk for subclinical N1 and/or N2 involvement (N1/N2). Immunohistochemical data suggest that the conventional histopathologic techniques used during this study somewhat underestimate the true degree of lymph node involvement; therefore, a third end point was also evaluated: N1 involvement and/or N2 involvement and/or local-regional recurrence (N1/N2/LRR). RESULTS Regression analyses revealed that the following factors were independently associated with a high risk of more advanced disease: positive preoperative bronchoscopy (N2, p = 0.02; N1/N2, p < 0.0001; N1/N2/LRR, p < 0.001) and tumor grade 3/4 (N1/N2/LRR, p < 0.01). A regression tree analysis was then used to separate patients into risk groups with respect to N1/N2/LRR. CONCLUSION In inoperable non-small cell lung cancer, the patients for whom mediastinal radiation therapy may most likely be indicated are those with a positive preoperative bronchoscopy, especially with large (> 3 cm) primary tumors.

Patterns of failure and overall survival in patients with completely resected T3 N0 M0 non-small cell lung cancer

BACKGROUND Previous studies of patients with surgically resected non-small cell lung cancer and chest wall invasion have shown conflicting results with respect to prognosis. Whether high-risk subsets of the T3 N0 M0 population exist with respect to patterns of failure and overall survival has been difficult to ascertain, owing to small numbers of patients in most series. METHODS AND MATERIALS A retrospective review was performed to determine patterns of failure and overall survival for patients with completely resected T3 N0 M0 non-small cell lung cancer. From 1979 to 1993, 92 evaluable patients underwent complete resection for T3 N0 M0 non-small cell lung cancer. The following potential prognostic factors were recorded from the history: tumor size, location, grade, histology, patient age, use of adjuvant radiation therapy (18 of 92 patients), and type of surgical procedure (chest wall or extrapleural resection). RESULTS The actuarial 2- and 4-year overall survival rates for the entire cohort were 48% and 35%, respectively. The actuarial local control at 4 years was 94%. Neither the type of surgical procedure performed nor the addition of thoracic radiation therapy impacted local control or overall survival. CONCLUSION Patients with completely resected T3 N0 M0 non-small cell lung cancer have similar local control and overall survival irrespective of primary location, type of surgery performed, or use of adjuvant radiation therapy. Additionally, the tumor recurrence rate and overall survival found in this study support the placement of this group of patients in Stage IIB of the 1997 AJCC lung staging classification.