The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.

Clinical biology of small cell carcinoma: relationship to surgical therapy.

No prognostic factors could be identified that influence survival in patients with small cell carcinoma undergoing traditional therapy. These findings identified small cell carcinoma (1) as a distinct disease entity with reference to non-small cell carcinoma, (2) as a nonsurgical disease, and (3) as a disease demanding systemic treatment.

Comparison of surgery and radiation therapy for non-small cell carcinoma of the lung with mediastinal metastasis.

Interest in the potential role of induction chemotherapy for patients with marginally operable non-small cell carcinoma of the lung (NSCCL) led to a retrospective study of surgical resection and radiation therapy, alone or combined with each other and/or chemotherapy. All 169 patients seen at The University of Texas M. D. Anderson Cancer Center from 1980 through 1985 with evidence of NSCCL metastatic to ipsilateral mediastinal lymph nodes but without extrathoracic spread were evaluated (NSM0). All patients had histologic or cytologic confirmation of NSCCL and clinical or pathologic evidence of mediastinal involvement. Nine patients received CHM alone and were excluded. The male:female ratio was 3:1, and 50% were less than 60 years old. Squamous cell carcinoma was reported in 42%, adenocarcinoma in 45%, large-cell carcinoma in 9%, and unclassified carcinoma in 4%. Radiation therapy (RT) was selected for 81 patients (+ CHM in 56%), in 85% because of the extent of tumor involvement and in 15 for medical reasons. Of RT patients, 31% had a Karnofsky performance status (KPS) of less than or equal to 80, 30% had greater than 5% weight loss, and 9% had Stage IIIB disease. Surgical resection (SX) was used in 41 patients (+CHM in 41%), of whom 10% had KPS less than or equal to 80, 17% had greater than 5% weight loss, and 2% had Stage IIIB disease. SX + RT was the treatment for 38 patients (+ CHM in 36%), of whom 13% had KPS less than or equal to 80, 13% had greater than 5% weight loss, and 13% had Stage IIIB disease. The proportions of patients with KPS less than or equal to 80 and weight loss greater than 5% were significantly greater (p less than .01 and p less than .05, respectively) in the RT group than in the other treatment groups. Actuarial survival rates at 2 and 5 years were 24% and 9%, respectively, for RT, 32% and 17% for SX, and 46% and 25% for SX + RT. Overall survival rates for all 160 patients were 30% at 2 years and 14% at 5 years. Prognostic factors that were found to be important were KPS (p = .027) and weight loss (p = .001); age, sex, histology, and Stage IIIa versus IIIB disease were not significantly related to outcome. The results of treatment with SX + RT were significantly better than with RT alone (p = .03); the difference between RT alone and SX alone was not significant (p = .39).(ABSTRACT TRUNCATED AT 400 WORDS)

Apoptosis and mitosis as prognostic factors in pathologically staged N1 nonsmall cell lung cancer.

PURPOSE: This study aimed to established whether spontaneous apoptosis or mitosis has prognostic value among patients with pathologically staged N1 nonsmall cell lung carcinoma (NSCLC) treated with surgical resection with or without adjuvant therapy. METHODS AND MATERIALS: Material from 173 patients who had resections between 1970 and 1988 was analyzed for apoptosis and mitosis. There were 128 men and 45 women, with a median age of 61 years. There were 86 squamous cell carcinomas (SQ), 73 adenocarcinomas (AC), 3 large-cell carcinomas (LC), 6 SQ-AC, and 5 unclassified. Patients were observed from 2 to 209 months (median 27). Actuarial methods were used to assess survival and freedom from distant metastasis. RESULTS: In NSCLC, apoptosis was found to range from 0.2% to 2.8% (median 1.0%) and mitosis from 0 to 1.8% (median 0.4%). Tumors having higher levels of apoptosis also had higher levels of mitosis (p = 0.001). The values of neither apoptosis nor mitosis depended on size, location, differentiation of tumors, age, performance status, or weight loss of patients. However, the values of apoptosis depended on tumor histology in that high values (greater than or equal to the median) were more frequent in SQ (49%) than in AC/LC (29%) (p = 0.01). The overall survival for NSCLC patients, which was 33% at 5 years, did not depend on the level of either apoptosis or mitosis. The 5-year survival of patients having SQ was higher (43%) than that of patients having AC/LC (21%) (p = 0.03). Patients with high apoptosis showed significantly better 5-year overall (p = 0.008) and DMF (p = 0.0012) survivals in the SQ group compared to the AC/LC group. High mitosis compared to low mitosis was a significantly better predictor for 5-year survival (62% vs. 29%, respectively) (p = 0.035) in the SQ. However, high mitosis was a significantly worse 5-year DMF survival predictor compared to low mitosis: 13% vs. 56%, respectively (p = 0.05) in AC/LC. In the multivariate models for AC/LC, mitosis remained a significant predictor of 5-year distant metastasis (p = 0.025) controlling for treatment groups (p = 0.042), whereas apoptosis was an independently significant predictor of 5-year distant metastasis (p = 0.010). CONCLUSION: Squamous cell histology predicted significantly better 5-year overall and DMF survivals compared to AC/LC. Apoptosis was correlated with mitosis. Although apoptosis or mitosis did not predict survival or DM, high apoptosis or mitosis predicted significantly better survival in SQ and significantly worse survival in AC/LC with regard to overall and DMF survivals. In the multivariate models for AC/LC, apoptosis alone or mitosis with variable treatment was a significant predictor of 5-year distant metastasis. Thus, pretreatment levels of apoptosis or mitosis might be useful for predicting treatment outcome of SQ and AC/LC subsets of NSCLC when analyzed separately and for predicting metastatic incidence of AC/LC.

Prognostic biomarker study in pathologically staged N1 non-small cell lung cancer.

PURPOSE: The prognostic influence of 6 biomarkers correlated to histologic subtypes of non-small cell lung cancer (NSCLC) on loco-regional control, overall survival, disease-free survival (DFS), and distant disease control (DDC) rates, all measured at 5 years, were examined. MATERIALS & METHODS: Cell blocks from the primary tumors of 137 patients with pathologically staged N1 NSCLC at MDACC were analyzed by 6-biomarker status correlated to histological subtypes and their outcomes. RESULTS: The ranges of biomarker values were as follows: apoptotic index, 0.2-2.8%; mitotic index, 0-1.8%; the proportion of cells in S+G2M, 3-36%; p53 status, 0-100%; Ki-67, 0-9.3%; DNA index, 1.0-2.74. Subtypes of 137 cases from the postoperative pathology specimen showed that 74 patients had squamous carcinoma and 63 patients had adenocarcinoma. Mean and median lengths of follow-up were 4.21 years and 2.43 years, respectively. Patients with squamous cell carcinoma (SCC) had a better 5-year survival (p = 0.006), DFS (p = 0.002), and distant metastasis control (p = 0.002) than patients with adenocarcinoma (AC). Among patients with AC, the DNA index was a significant predictor of 5-year DFS (p = 0.02), DDC rate (p = 0.04), and local-regional control (p < 0.05). Higher apoptosis (p = 0.03) and mitosis indices (p = 0.03) were also univariate predictors of increased distant disease among patients with AC. Multivariate analysis of patients with AC revealed that the DNA index and Ki-67 were the only significant independent predictors of distant metastasis (p < 0.04 and p < 0.02, respectively) and DFS (p < 0.04 for both). Among patients with SCC, univariate analysis showed that S+G2M proportion (p < 0.05) and Ki-67 levels (p < 0.02) were significant predictors for local-regional control; for SC, multivariate analysis showed that only mitosis was a significant predictor in this case for overall survival (p < 0.04). CONCLUSION: Spontaneous apoptotic index and Ki-67 were significantly higher in SC than in AC. Patients with SC had less distant metastasis better DFS and overall survival than those with AC. Multivariate analysis revealed that DNA index and Ki-67 status were significant predictors for DDC and DFS in patients with AC, but only mitotic index was a significant predictor of overall survival for patients with SCC.

Superior sulcus tumors: treatment selection and results for 85 patients without metastasis (Mo) at presentation.

Superior sulcus (Pancoast) tumors (SST) are uncommon carcinomas of the lung with distinctive failure patterns and a somewhat more favorable prognosis than other sites of lung cancer. The most effective use of surgery (S), radiation (R), and chemotherapy (C) is not resolved. Most reported series include patients treated before the era of computed tomography (CT). A retrospective study was undertaken of all previously untreated patients with SST who received definitive management at the University of Texas M.D. Anderson Cancer Center between January 1977 and December 1987. Eighty-five patients were treated: the male:female ratio was 2.7:1, and the ages ranged from 35 to 80 (median 59) years. Karnofsky performance status (KPS) was 80 or more in 70 patients (82%). Thirty patients (35%) had lost 5% or more body weight. All had histologic or cytologic confirmation of carcinoma: 25% were squamous cell, 2% small cell, 54% adenocarcinoma, and 6% were large cell carcinoma (12% were not classified). After complete evaluation, 43 were classified as clinical Stage IIIA and 42 were Stage IIIB. One Stage IIIA patient received surgery, 13 surgery + radiation therapy, 2 surgery + radiation therapy and chemotherapy, 19 radiation therapy and 8 radiation therapy + chemotherapy. Seven Stage IIIB patients received surgery + radiation therapy, 12 radiation therapy, 2 surgery + radiation therapy + chemotherapy, 17 radiation therapy + chemotherapy and 4 chemotherapy. Surgery was a component of therapy more frequently in Stage IIIA than IIIB (p less than .05) and systemic treatment chemotherapy was used significantly more often (p less than .01) in Stage IIIB. Twenty-six patients (31%) lived 2 years or more (25+ to 131+ months) after treatment. Stage IIIA patients had a 46.5% 2-year survival rate compared to 20.6% for Stage IIIB (p = .0042). The one patient treated with surgery alone lived 2 years; 23% (7/31) of patients who had radiation therapy alone and none of the 4 who had chemotherapy lived 2 years. When surgery was a component of treatment, 52% (13/25) lived 2+ years, compared with 22% (13/60) when surgery was not part of treatment. When radiation therapy was part of treatment 31% lived 2 years and when chemotherapy was used, 18% lived 2 years. Fifty-two patients (61%) had control of the local tumor: their survival was significantly greater (p less than .01) than those who had local failure.(ABSTRACT TRUNCATED AT 400 WORDS)

Modeling the anticarcinogenic action of retinoids by making use of the OASIS method. 3. Inhibition of the induction of ornithine decarboxylase by arotinoids.

A series of 15 congeneric aromatic retinoids (arotinoids) was subjected to a study of the conformational dependence of basic molecular descriptors, and the anticarcinogenic potency of the compounds was modeled by the sophisticated OASIS (optimized approach based on structural indices set) method. A high correlation was obtained for both two-variable models and three-variable models. The best models of these two kinds had correlation coefficients of 0.956 vs 0.988 and standard deviations s2 = 0.14 vs 0.04, respectively. The most significant variables were several interatomic and topological distances, which specify the optimum geometric drug-receptor fit. The group of significant electronic descriptors included characteristic pi-bond orders, the electronic charge at one atomic position in the tetrahydronaphthalene ring, the total electronic energy, and two electronic-topological indices. An electrostatic drug-receptor interaction was conjectured on this basis. A contribution of the through-cell membrane transport was inferred from the importance of molecular refraction in the best three-variable model. The models derived were validated by the leave-one-out procedure and by reproducing the activities of five arotinoids not included in the correlation sample.

Modeling the anticancer action of some retinoid compounds by making use of the OASIS method.

The powerful OASIS (optimized approach based on structural indices set) approach is applied to the anticancer activity of a series of vitamin A analogs. The best three- and four-variable models obtained via the OASIS technique have correlation coefficients of 0.973 vs. 0.990 and standard deviations s2 = 0.11 and 0.05, respectively. The models incorporate the hydrophobicity factor log P, two geometric parameters (topological indices and/or 3-D steric ones), and the molecular dipole moment. For a set of 15 compounds studied here, the activity measured by ED50 was well correlated by models with approximately equal contribution of the through cell membrane transport and the geometric drug-receptor correspondence while weak nonspecific electronic interaction was also found to play some role. Comparison to previous treatments of this data is given and extension to larger sets is discussed.

Revisions in the International System for Staging Lung Cancer.

Revisions in stage grouping of the TNM subsets (T=primary tumor, N=regional lymph nodes, M=distant metastasis) in the International System for Staging Lung Cancer have been adopted by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer. These revisions were made to provide greater specificity for identifying patient groups with similar prognoses and treatment options with the least disruption of the present classification: T1N0M0, stage IA; T2N0M0, stage IB; T1N1M0, stage IIA; T2N1M0 and T3N0M0, stage IIB; and T3N1M0, T1N2M0, T2N2M0, T3N2M0, stage IIIA. The TNM subsets in stage IIIB-T4 any N M0, any T N3M0, and in stage IV-any T any N M1, remain the same. Analysis of a collected database representing all clinical, surgical-pathologic, and follow-up information for 5,319 patients treated for primary lung cancer confirmed the validity of the TNM and stage grouping classification schema.

Expanded possibilities for surgical treatment of lung cancer. Survival in stage IIIa disease.

Two anatomic subsets of patients with stage IIIa non-small cell cancer of the lung are candidates for definitive surgical treatment. The first group includes patients with T1, T2, or T3 primary tumors and regional lymph node metastases confined to the ipsilateral mediastinal and subcarinal lymph nodes (N2 disease). There is controversy over the selection of this group of patients for surgery; some physicians do not believe that resection is an option if there is any evidence of mediastinal lymph node involvement. The second group is composed of patients with limited, circumscribed extrapulmonary extension of the primary tumor and lymph node metastasis, if present, limited to the hilar and peribronchial nodes (T3 N0-1 M0 disease). Peripheral tumors invading the chest wall, tumors originating in the superior sulcus of the lung, and those with limited involvement of the pericardium or the main bronchus are included. A five-year cumulative survival rate of 28 percent was documented for 198 consecutive patients undergoing complete resection for stage IIIa non-small cell lung cancer, 21 percent for the T1-3 N2 group, and 39 percent for the T3 N0-N1 patients. Cell type was not a statistically significant variable for survival; however, a superior outcome was observed for patients with squamous cell carcinoma in every TNM category. The results support surgical treatment as a valid option for selected patients with extrapulmonary extension of the disease.

Regional lymph node classification for lung cancer staging.

Recommendations for classifying regional lymph node stations for lung cancer staging have been adopted by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer. The objective was to unify the two systems that have been in common use for the past 10 years; that is, the schema advocated by the AJCC, adapted from the work of Tsuguo Naruke, and the schema advocated by the American Thoracic Society and the North American Lung Cancer Study Group. Anatomic landmarks for 14 hilar, intrapulmonary, and mediastinal lymph node stations are designated. This classification provides for consistent, reproducible, lymph node mapping that is compatible with the international staging system for lung cancer. It is applicable for clinical and surgical-pathologic staging.

Patterns of mediastinal metastases in bronchogenic carcinoma.

The location and frequency of metastases to the lymph nodes were documented in a review of 200 patients with bronchogenic carcinoma who underwent pulmonary resection and total lymph node resection. No nodal metastases were found in 120 patients (60 percent). Metastases were present in only lobar or hilar nodes (or both) in 32 patients (16 percent), and 34 (17 percent) had metastases in mediastinal nodes as well as in lobar or hilar nodes. Only mediastinal nodal metastases were found in 14 patients (7 percent). Previously described lymphatic pathways can explain the presence of metastases in mediastinal nodes alone. Unexplained findings were the higher prevalence of mediastinal nodal metastases in adenocarcinoma vs squamous cell carcinoma and a much higher frequency of mediastinal metastases without lobar or hilar involvement (or both) in patients with adenocarcinoma compared to those with squamous cell carcinoma.

The role of preoperative mesenteric arteriography in colon interposition.

In a series of mesenteric arteriograms, the marginal artery in the right colon was present in six of 20 studies (30 percent); in the left colon it was present in all of the 20 cases studied (100 percent). Such preoperative knowledge of the vascular pattern permits the surgeon to choose a suitable segment of bowel for successful colon interposition and assists him in shortening the operative time. When this information was applied in 19 consecutive left colon interpositions, only one major suture line dehiscence in the neck was encountered (5.3 percent).

Open lung biopsy in immunocompromised patients.

Increased use of open lung biopsy in the search for a treatable etiology of acute interstitial pneumonitis (AIP) in immunocompromised patients is based on the assumption that examination and cultures from biopsy specimens will yield significant information leading to beneficial treatment of the condition. To assess the true impact of the results of open lung biopsy on the subsequent treatment and outcome in such patients, a retrospective study was done of 64 consecutive patients undergoing the procedure in a recent five-year period. When open lung biopsy was performed for the diagnosis of AIP in immunocompromised patients after empiric broad spectrum treatment failed, it rarely missed a specific, treatable etiology, if present. However, the results from open lung biopsy infrequently lead to a change in the treatment that improves the patient's clinical course.

Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma.

Studies of regional pulmonary function using radioactive 133xenon gas and spirometric tests (forced vital capacity and forced expiratory volume in the first second) were performed before and after unilateral pulmonary resection for cancer of the lung. Ninety-one patients were evaluated; 47 underwent total pneumonectomy, and 44 underwent lobectomy. The postoperative serial evaluations were classified into short-term and long-term studies (less than or more than three months, respectively). The preoperative and postoperative data were utilized to derive formulas for predicting an estimate of the overall functional loss after pulmonary resection based on the number of segments removed. The correlation between the predicted and measured postoperative values was good for resections involving more than three segments (r = 0.83). Prediction for smaller resections was unreliable. While both regional and overall pulmonary functions were relatively stable after pneumonectomy, there was a disproportionate early loss, followed by significant functional improvement with time following lobectomy. The anticipation of and preparation for this early loss of function may be crucial in the treatment of these patients.

Critical evaluation of the gallium-67 scan for surgical patients with lung cancer.

Seventy-five patients with lung cancer underwent a gallium scan and thoracotomy with total mediastinal nodal dissection. Evaluation of mediastinal lymph nodes by means of the gallium scan showed a sensitivity of 23 percent (3/13), a specificity of 82 percent (31/38), an accuracy of 67 percent (34/51), a positive predictive valve of 30 percent (3/10), and a negative predictive value of 76 percent (31/41) in those patients whose primary tumors demonstrated uptake of radioactive gallium. The low sensitivity was due to an inability to detect microscopic disease in mediastinal lymph nodes. The specificity was decreased by gallium-67 uptake in enlarged inflamed nodes that contained no metastases. These results do not support the use of the gallium scan in the selection of patients with lung cancer for thoracotomy.

Regional and overall pulmonary function changes in lung cancer. Correlations with tumor stage, extent of pulmonary resection, and patient survival.

Spirometry and regional pulmonary function studies using xenon 133 gas were performed in 251 patients who had primary lung cancer. Surgical resection was undertaken in 150 while the remainder were treated with nonsurgical modalities. Pulmonary function studies were repeated postoperatively in 54 patients. Regional ventilation and perfusion of the tumor-bearing lung were decreased in patients with larger primary tumors and in those with involvement of ipsilateral hilar lymph nodes. Reduced regional function was also directly related to the proximity of the primary tumor to the hilum. Significant hypoperfusion did not contraindicate operation in 14 patients; however, 13 of them required pneumonectomy. Estimated postoperative forced expiratory volume in 1 second (FEV1.0), derived from preoperative spirometry and regional function of the tumor-bearing lung, correlated well with the measured postoperative values. These estimations were valuable in determining the extent of safe resection and correlated well with short-term survival. Long-term survival correlated better with the stage of disease.

Modern thirty-day operative mortality for surgical resections in lung cancer.

Modern postoperative mortality rates for resectional operations for lung cancer are not readily available. In recent publications estimating the risk factors for surgical resection, mortality rates of 10% to 15% for pneumonectomy and 5% to 7% for lobectomy are frequently quoted. In order to determine modern operative mortality rates (up to 30 days postoperatively), the Lung Cancer Study Group (LCSG) analyzed the surgical mortality rates of the various participating centers during the years 1979 to 1981. A total of 2,200 resections for lung cancer were available for analysis. Of the 2,220 resections performed, 1,058 were lobectomies, 569 were pneumonectomies, and 143 were lesser resections (segmental or wedge). Eighty-one postoperative deaths occurred from among the 2,220 resections (3.7%). The mortality rate for pneumonectomy was 6.2% and for lobectomy, 2.9%. Lesser resections carried a 1.4% mortality rate, not statistically different from lobectomy. In patients under the age of 60 years, the mortality rate was 1.3%, 60 to 69 years, 4.1%, and over 70 years, 7.1%, all significantly different (p less than 0.01). The postoperative mortality rate for patients 70 years or older was 7.1% (pneumonectomy 5.9% and lobectomy 7.3%). It is obvious that greater care was taken in selection among the older pneumonectomy patients. The striking similarity of postoperative mortality rates for resectional operations for lung cancer among the various centers of the LCSG and among the various institutions within these centers suggest that these data are a reasonably accurate analysis of modern surgical mortality rates in the treatment of lung cancer.

Assessment of the role of surgery for control of lung cancer.

When morphologically stratified, the classification of patients according to surgical stage provides an objective basis for evaluating the results of surgical treatment. In a review of 794 patients according to surgical staging criteria, the data supported concepts regarding differences in the behavior of each cell type as well as major differences in survival between each stage of disease. The overall cumulative five-year survival was 37% for squamous cell carcinoma, 27% for adenocarcinoma, and 27% for undifferentiated large cell carcinoma. Fewer than 1% of patients with undifferentiated small cell carcinoma survived. Survival for patients with surgical Stage I disease was 53%, for Stage II 29%, and for Stage III 16%. The results of surgical treatment for patients with limited disease extent are much better than is generally realized. Fifty to 60% of such patients in this series survived five years. Survival studies by surgical stage permit resonable estimates of the presence of occult metastatic disease and supply insights necessary to the design and appropriate selection of adjunctive therapeutic programs.

The biological operability of stage III non-small cell lung cancer.

Stage III non-small cell lung cancer represents a broad spectrum of anatomical and histological subsets of patients with differing biological characteristics and prognostic expectations. Our experience with 161 consecutive patients undergoing complete resection for Stage III non-small cell lung cancer at the M. D. Anderson Hospital and Tumor Institute from 1965 through 1980 includes 69 patients with T3 N0 or N1 disease and 92 patients with an N2 classification. The cumulative 5-year survival overall was 30%: 35.6% for the T3 N0 or N1 group and 26% for the N2 patients. Seventy-three patients had squamous cell carcinoma and 76, adenocarcinoma. Small numbers of patients had other miscellaneous classifications (N = 12). In the T3 N0 or N1 subset, 43% of the patients with squamous cell carcinoma (N = 37) and 23% of those with adenocarcinoma (N = 25) survived 5 years. In the N2 subset, 39% of the patients with squamous cell carcinoma (N = 36) and 14% of the group with adenocarcinoma (N = 52) achieved long-term survival. Failure of treatment was clinically documented in 61 patients. The first observed recurrence or metastasis was at a distant site in the majority of these patients. Operative intervention for patients with Stage III M0 non-small cell lung cancer is effective and reflects the impact and limitations of resection on disease progression. Adjuvant irradiation was not shown to improve the outcome over the results of operation alone. Effective systemic therapy will be required to produce substantial changes in end results.