The evolution of the surgical treatment of lung cancer.

The evolution of surgery for lung cancer is a story of discovery and innovation. From the fortuitous lung resections of the fifteenth century to the sophisticated operations of the twentieth century, surgeons have pursued the goal of bringing technology and science to bear on the effort to cure lung malignancy. Intrathoracic operations could not have developed without the advent of modern anesthesia, described in detail in another section of this issue. Great courage and insight were the hallmarks of those who first realized that surgical removal of primary lung cancer could become a reality and who pursued this goal in the face of discouraging results. The surgeons involved have worn many hats as experimentalists, physiologists, anesthetists, and biologists to bring all their knowledge and experience to bear on the surgical treatment of this disease. It is not possible in a brief review to identify the many physicians and scientists who contributed to the evolution of this treatment, but some of their stories have been included to illustrate the ideas involving major events over the past seven decades.

The international system for staging lung cancer.

The International System for Staging Lung Cancer is a consistent, reproducible classification for the anatomic extent of disease in patients with lung cancer. A revision of the system in use since 1986 included modifications of the rules for stage grouping the TNM (T-primary tumor, N-regional lymph nodes, and M-distant metastasis) anatomic subsets. More specific stage categories and consistency for reporting the end results for Stage I, Stage II, and Stage IIIA disease are provided. Survival data support the revised categories and confirm the significant relationship between the extent of the disease and prognosis for patients with this disease.

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.

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.

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.

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.

Prolonged stabilization of progressive squamous cell cancer of the cervix with interferon-alpha and 13-cis-retinoic acid: report of two cases and review of the literature.

Recurrent and metastatic cervical carcinoma has very poor prognosis, mainly because there is no effective systemic therapy which would increase the duration of survival. Biologic agents have recently been found to have activity in cervical carcinoma. The combination of interferon (IFN)-alpha and 13-cis-retinoic acid had additive and synergistic antitumor activity. Both have antiviral, immunoregulatory and antiangiogenic properties, and are known to modulate malignant cell differentiation and proliferation. We report two patients with recurrent squamous cell carcinoma (SCC) of the cervix who had small-volume progressive metastatic disease, and were treated with a combination of IFN-alpha and 13-cis-retinoic acid. The first patient had pelvic lymph node metastases and the other had lung metastases. The previously progressive diseases remained stable for a prolonged period of time, 3 and 4 years, with a good quality of life. These cases suggest the possibility of using IFN-alpha and 13-cis-retinoic acid as a treatment for small-volume residual disease or as postinduction therapy in patients at high risk for disease recurrence.

Survival in early-stage non-small cell lung cancer.

The duration of survival in early-stage lung cancer (stages I and II) varies between reports in the literature. Several reasons account for this: patient population heterogeneity, inconsistent staging, anatomic variability, dissimilar tumor morphology, and unpredictable tumor biology. This report addresses some of the issues in early-stage non-small cell lung cancer that relate to variability between estimates of survival in end stage reporting. We review several large series since the introduction of the International Staging System in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Overall survival for patients with pathologic stage I disease is 64.6% (range, 55% to 72%) and 41.2% for patients with stage II disease (range, 29% to 51%). Reducing morphologic differences by placing patients in groups based on the TNM subset and refinement in categorization by matching TNM subsets based on histology and other factors can improve considerably homogeneity and enhance prognostic predictability. The development of more accurate measures for predicting prognosis may serve to clarify the roles of primary and adjuvant treatment, particularly in those patients with early-stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

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.

The conformational flexibility of aromatic retinoids.

AM1 and PM3 complete geometry optimizations were performed on 19 arotinoids congeneric with (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1-propenyl] benzoic acid (TTNPB), a very potent agent in carcinoprevention and carcinotherapy. Sixteen TTNPB conformations with close energy were obtained and characterized; four representative conformations were then studied for 14 derivative compounds, for which we found a substantial non-planarity of the two aromatic moieties. Large rotational flexibility of the arotinoid ring fragments was predicted by both methods. Very low barriers (0.4-3.9 kcal/mol) were found for the tetralenyl ring rotation. The two methods also agreed in predicting benzoic acid moiety rotation in a wide range of torsion angle values except those close to 0 or 180 degrees for which the PM3 rotational barriers were found to be considerably lower than the AM1 ones. This high conformational flexibility of arotinoid molecules may facilitate their favorable orientation in the process of fitting to the receptor sites.

Surgery for stage IIIa-N2 non-small cell lung cancer.

BACKGROUND: The presence of ipsilateral mediastinal lymph node metastasis (N2 disease) in patients with non-small cell lung cancer presents a formidable challenge to the physician responsible for selecting therapy. The benefit of a surgical approach is controversial; however, it generally is agreed that only complete resection of all known tumor can provide a favorable outcome. This requires selecting patients for whom complete resection is a reasonable surgical objective. METHODS: Retrospective review of a collected data base comprising records for 2883 patients who underwent definitive surgical treatment was accomplished to emphasize the prognostic implications of regional lymph node metastasis. Patients making up the N2 subset (n = 307) were the focus of the investigation, and providing insight to the puzzle of appropriate patient selection was a major goal. RESULTS: Five-year cumulative survival rates for patients with N0, N1, and N2 disease were, respectively, 62%, 43% and 31%. Three factors significantly influenced the outcome: a complete lymph node dissection, the extent of mediastinal lymph node involvement, and apparent complete resection of all tumor. Important survival determinants were the number of nodes involved, the level of involvement (single or multiple levels), and a T1 primary tumor status. Criteria for unresectability and recommendations for patient selection were developed from (1) the end results of the study and (2) the contributions of imaging and invasive techniques to clinical staging and to the histologic verification of nodal disease.

Treatment of primary neoplasms of the trachea. The role of radiation therapy.

BACKGROUND: Primary tracheal tumors are a rare malignancy. Before 1960, most patients had a biopsy, followed by external orthovoltage irradiation or radon seed implantation. Advances in surgery and in radiation therapy during the past three decades have allowed more patients to undergo definitive treatment. METHODS: Between 1957 and 1988, 22 patients with primary tracheal malignancy were treated with curative intent at The University of Texas M.D. Anderson Cancer Center. Five patients underwent primary surgical resection (Group 1), 5 patients had surgical resection and adjuvant irradiation (Group 2), and 12 patients had primary irradiation (Group 3). RESULTS: Median survival times were 26 months for all patients; 16 months for Group 1; 61 months for Group 2; and 26 months for Group 3. Local control was attained in 1 of 5 patients in Group 1, 4 of 5 patients in Group 2, and 4 of 12 patients in Group 3. Among those treated with primary radiation therapy, local control was attained by three of four patients who received 60 Gy or higher and one of eight patients who received less than 60 Gy. Results of chi-square test (P = 0.03) were statistically significant. Severe complications, including treatment-related deaths, occurred in 2 of 5 patients in Group 1, 2 of 5 patients in Group 2, and 3 of 12 patients in Group 3. CONCLUSION: Radiation therapy has a role in the treatment of patients with tracheal malignancy, either as postoperative adjuvant therapy or as sole therapy for those who refuse surgery or have medically inoperable disease. Alternative methods for increasing the local administration of radiation therapy, such as endotracheal brachytherapy, should be investigated for improvement in local control.

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.

Lung cancer staging classification.

In presenting the staging system, I recognize that in a given patient the total tumor burden cannot be precisely quantitated, and the balance between host defenses and the heterogeneity of the malignancy is not measurable. These and other complex interacting biological variables will influence the subsequent course of the disease. However, our data support the premise that the straightforward indices of disease extent in the TNM system permit a simple yet valid classification that best reflects prognosis. Patients can be grouped together according to certain measurable common features of their disease so that within each stage group treatment options and survival expectations will be generally similar. In this manner reliable and valid comparisons of the results of different modalities of therapy can be made. Survival data according to staging criteria are a measure of the efficacy of available therapy for lung cancer; thus, the staging information serves as a valuable guide for treatment planning.

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)