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Stage 3 Lung Cancer

Introduction: Since 1974, a tumor size of 3 cm in diameter has been regarded as the prognostic threshold in the staging of bronchogenic carcinoma.

Objective: To study the prognostic behavior of surgical-pathologic tumor size in non-small cell lung cancer (NSCLC) with complete resection.

Design: Four-year multi-institutional prospective study from 1993 to 1997.

Patients: Consecutive cases of NSCLC in pathologic stages IA-IB (pIA-pIB) treated surgically with complete resection in hospitals belonging to the Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S).

Methods: The Schoenfeld procedure was used to identify different prognostic groups, considering 1 cm as the measurement unit.

Results: Based on the 1,020 cases evaluated, four prognostic groups were identified: 0 to 2 cm (group A; n = 147), 2.1 to 4 cm (group B; n = 448), 4.1 to 7 cm (group C; n = 336), and > 7 cm (group D; n = 89). At 5 years, survival was 0.63 (95% confidence interval [CI], 0.58 to 0.68), 0.56 (95% CI, 0.53 to 0.59), 0.49 (95% CI, 0.46 to 0.52), and 0.38 (95% CI, 0.32 to 0.44) for groups A, B, C, and D, respectively. Differences between paired groups (log-rank) were significant: 0.0074 between groups A and B, 0.0048 between groups B and C, and 0.0034 between groups C and D.

Conclusions: In initial stages (pIA-pIB) of NSCLC, the 3-cm value was not found to behave as a prognostic threshold; in this study, four surgical-pathologic tumor size groups were identified with strong prognostic differences: from 0 to 2 cm, from 2.1 to 4 cm, from 4.1 to 7 cm, and > 7 cm.

Key words: lung cancer; lung neoplasms; size; surgery

Abbreviations: CI = confidence interval; GCCB-S = Bronchogenic Carcinoma Co-operative Group of Spanish Society of Pneumology and Thoracic Surgery; NSCLC = non-small cell lung cancer

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Since 1974, (1) 3 cm has been regarded as the only tumor size to establish a prognostic threshold in the staging of bronchogenic carcinoma. Even though the staging classification has been updated repeatedly (the last update being in 1997), (2) criteria for tumor size has remained unchanged for the last 25 years.

There is a need to conduct further research on other clinical or molecular biological prognostic factors in patients with lung cancer; therefore, it becomes essential for the basic anatomic classification of tumors to be founded on solid grounds. A new prognostic factor could only be considered useful, and included as part of the tumor classification, if it has the ability to modify the prediction and accuracy of the TNM anatomic classification. (3)

The TNM classification is simplified to make its use easier; however, that simplicity may lead to decreased prognostic certainty or, in other words, a loss of prognostic discrimination. Repeatability or validation of the prognostic values for the main pathologic stages in a surgical population with non-small cell lung cancer (NSCLC) has been demonstrated in the United States, Japan, Germany, and Spain. (4) Nonetheless, and as it was to be expected, it has now been acknowledged that the consideration of TNM descriptors was more predictive of prognosis than the assessment of tumor stages. (5)

The Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S) has recently evaluated its experience in the prognostic analysis of prethoracotomy clinical tumor size in lung cancer. (6) This study was able to identify four different prognostic groups of tumor size based on radiography. However, since this clinical staging was based on a population that in the end required surgery, it involved some problems: the greater the tumor size, the greater the probability to have invaded mediastinal lymph nodes at thoracotomy, even in cases of small NSCLC; or the higher frequency of exploratory thoracotomies or incomplete resections in larger tumors, among other limitations. (7-10) The goal of this study is to evaluate tumor size as a prognostic factor in patients with pT1-T2N0M0 NSCLC undergoing complete resection in a nonselected surgical population.

MATERIALS AND METHODS

Study Subjects

All the patients included prospectively in this study had NSCLC in initial stages (pIA-pIB) and underwent thoracotomy with complete resection in hospitals pertaining to the GCCB-S (11) between October 1993 and September 1997, both inclusive. Similar criteria for the functional operability of patients and oncologic operability of the tumor were used in all the GCCB-S hospitals. (12) The participating GCCB-S centers had a wide variety of activities, including a representative range of number of beds, type of activity (university and nonuniversity, community, public, and private ownership), and number of interventions per year (range, 8 to 100 interventions). The sample was complete, as verified by the inclusion in the registry of all patients undergoing complete surgical resection. Patients with death due to operative mortality or patients receiving neoadjuvant therapy were excluded from the analysis. The total number of NSCLC patients operated on with any pathologic stage and any type of surgery was 2,300. The final number of cases included in this study was 1,020. Data were collected prospectively, in real-time, over the 4-year study period, using a unified single self-copying form that included the original and a copy (the original form was filed at the hospital and a copy omitting affiliation data was sent to the GCCB-S headquarters). At the GCCB-S Registry, each classificatory component for the different T categories (tumor size, pleural tumor involvement, or tumor involvement of other endothoracic structures) was considered differently and on an individual basis for each patient. The diagnostic procedure employed was marked using a previously agreed-on code and the procedure showing the best resolution recorded in the registry. The surgical-pathologic size was obtained by measuring the greatest diameter of the fresh surgical specimen.

Surgical-pathologic stage N0 was assigned when there was no lymph node involvement after systematic nodal dissection or when sampling of at least four lymph node stations was performed (stations 2, only on the right side, 4, 7, and 10 ipsilateral to the tumor). (13) These criteria were similar to those proposed in recent recommendations, (14) such as the need to obtain six hilar-mediastinal lymph nodes, in order to define pN0. For the purpose of classifying the presence or absence of mediastinal lymph node involvement, a randomized study (15) demonstrated that sampling had a value similar to that of mediastinal lymph node dissection. The GCCB-S operational definition for standard complete resection requires the absence of tumor involvement of resection margins, extracapsular involvement of resected mediastinal lymph nodes, positive biopsy finding in unresected mediastinal lymph nodes, and the absence of tumor pleural effusion.

Internal and external audits were performed to review the ratio between the number of patients undergoing surgery and the number of cases included in the GCCB-S Registry (standard > 95%), and to review the presence and validity of the data collected and recorded for each case (standard > 75%), including the consistency of tumor staging. The criterion for the validity of survival data was established on the existence of a known follow-up of, at least, 85% of the case-patients registered in each hospital. In the hospitals that did not meet all these conditions, the cases corresponding to the anomalous period were excluded. Finally, correct data transmission from the paper record to the computer database was verified on two separate occasions.

These procedures were designed to control the following aspects: selection bias of surgical cases, registered cases over the total number of surgical cases, sample size, type of hospital, prognostic migration due to the prolonged period of case recruitment, classification with low or deficient degrees of certainty, contamination by data from incomplete series or erroneous data, and loss of adequate long-term follow-up.

Analysis

Tumor size has been analyzed in different studies (16,17) using different methods and perspectives. Notwithstanding, it is a known fact that compilation of observations of supposedly continuous variables is bound to include errors that affect both the accuracy and validity of such estimations. The terminal digit preference phenomenon and rounding up have been cited as typical examples. (18,19) The statistical reliability, the way the variable is distributed, and the accurate classification of the study subjects can be seriously affected as a result of this phenomenon. This study verified the distribution of the tumor size variable in order to choose the best method of analysis by observing the mentioned digit preference.

A distribution of absolute and relative frequencies of pathologic tumor size was performed, and the normality of such distribution of data subsequently analyzed using the Shapiro-Wilks method. The Schoenfeld procedure (20) was used to identify prognostic tumor size intervals. In this procedure, the continuous variable of tumor size was reclassified arbitrarily into intervals (centimeters in this case). A series of consecutive intervals was generated and its correlation with survival confirmed statistically using the Cox proportional risk procedure, (21) which revealed the magnitude of the relative risk of each stratum.

Different survival outcomes at various periods of time were analyzed and 95% confidence intervals (CIs) calculated using life tables (actuarial survival); survival curves were compared using the log-rank method. Statistical significance was adjusted using the Bonferroni correction for paired comparisons between strata. (22)

RESULTS

Distribution of Tumor Size Data

Figure 1 shows the histogram of pathologic tumor size, where those population subjects with a tumor size of [less than or equal to] 7 cm were selected, clearly showing the discontinuity and nonnormality behavior displayed by this variable. This is why the Schoenfeld procedure was used for analysis.

[FIGURE 1 OMITTED]

Population Characteristics

Of the 1,020 patients that comprised this series, 945 patients (93%) were men. Mean (SD) age was 64.1 (8.85) years (range, 36 to 87 years). By histologic typing of the surgical specimen, 607 tumors (60%) were epidermoid, 180 tumors (18%) were large cell, 136 tumors (13%) were adenocarcinomas, and the remaining 97 tumors (9%) were of an undefined type or a mixture of the previously mentioned types.

Prognosis According to Pathologic Tumor Size

Mean pathologic tumor size was 4.27 cm (SD, 2.2 cm; median, 4 cm; range, 0.4 to 15 cm). Table 1 shows the four prognostic intervals yielded by the Schoenfeld procedure (20) and the Cox procedure. (21) Figure 2 shows a graphic representation of the four survival curves for each prognostic stratum according to the pathologic tumor size.

[FIGURE 2 OMITTED]

DISCUSSION

This study comprised a large series collected in a short and recent time period. The study was multi-institutional and representative of cases of NSCLC treated surgically in Spain, with an initial design conceived to control the usual bias in prognostic and/or therapeutic studies. Even though, based on the pathologic stage, similar survival rates are seemingly reported in different experiences, (4) those aspects of the methodology are particularly important in view of the variations in survival reported by different series for the same prognostic TNM categories in NSCLC. (23)

This prospective multi-institutional analysis conducted by the GCCB-S between 1993 and 1997 included a prognosis-specific analysis of pathologic tumor size in 1,020 pIA-pIB NSCLC patients who underwent a complete resection. The analyses conducted point to the existence, in this population of subjects whose initial NSCLC was treated, of four different prognostic groups distributed according to tumor size; the 3-cm value is not a threshold of prognostic significance. The pathologic tumor size intervals yielded by this study (0 to 2 cm, 2.1 to 4 cm, 4.1 to 7 cm, and > 7 cm) are identical to those observed by our group (6) for the analysis of clinical tumor size although, evidently, with different survival values.

In resected pathologic stage I NSCLC, with a surgical specimen of 4.1 to 7 cm, survival at 4 and 5 years of 0.53 and 0.49, respectively (our study), is worse than the survival specified for pathologic stage IIA (0.61 and 0.55, respectively). (16) For tumors > 7 cm, the prognosis at 2, 3, 4, and 5 years (0.51. 0.45, 0.41, and 0.38, respectively) is identical to that reported for descriptors pT2N1M0-pT3N0M0 (stage IIB) [0.56, 0.46, 0.42, and 0.39, respectively]. (16)

Comparison between this GCCB-S series and that published by Mountain (16) in 1997 seems adequate, as both these series refer, in terms of pathologic staging, to NSCLC cases with complete resection, and both exclude operative mortality. In these last few years, there has been regained interest for the early screening and detection of lung cancer, due in part to the availability of procedures such as low-radiation CT for detection of small nodules. (24) Besides the controversy raised by the design of population screening research studies, contradictory data have been identified regarding prognosis within the different magnitudes in T1N0M0 lung cancer ([less than or equal to] 3 cm). One report (17) describes experiences that do not indicate prognostic differences among tumors of < 3 cm; however, another study (25) found such differences. Editorials (26) and letters (27) continue to fuel this current controversial issue.

Ten years ago, Watanabe et al (28) considered a 5-cm diameter to be a prognostic threshold for tumor size. He then proposed that category T2 be divided into two groups (a and b), depending on whether the tumor was above or below that diameter. (28) One study (29) evaluated the risk ratio for recurrence, taking into account the centimeters of the tumor. That risk ratio was 1.2 per centimeter (95% CI, 1.1 to 1.4).

Some European series (30) on surgical lung cancer of a predominantly squamous type (57%), and with the majority of patients being male (63%), have conducted a prognostic analysis on various strata of tumor size. When a size of [less than or equal to] 2 cm was taken as reference, strata of [less than or equal to] 4 and > 4 cm were shown to have a direct correlation with survival. Finally, other analyses have considered the magnitude of estimated tumor volume in NSCLC stages I and II. (31) The death risk increases in line with tumor volume for each of the stages, in a significant and independent fashion. The Schoenfeld procedure used in our study affords the advantages, in this type of tumor size analysis, of examining progressive changes in the dependent variable (survival), depending on the levels of the independent variable (tumor size), enabling delimitation of critical borderlines in which substantial changes in such dependent variable may occur.

Our study may have certain limitations and a specific reproducibility problem attached to it. The pathologic tumor size was obtained by measuring the actual surgical specimen. A possible problem with a double implication could be the presence of accompanying atelectasis or pneumonitis. Since atelectasis or pneumonitis is more likely to appear in large tumors, and such clinical picture is another criterion for T2, (16) the combination of these two factors could worsen the prognosis. In addition, such association could wrongly overestimate the presumed size of the tumor. In the present study, the frequency of surgical-pathologic atelectasis or pneumonitis, as measured in the four mentioned tumor strata, was 22%, 23%, 29%, and 21% for groups A, B, C, and D (Table 1), respectively.

In a previous GCCB-S study (6) on prognostic analysis of clinical tumor size, cases with visceral pleural involvement were excluded. In this study (1,020 patients with pIA-pIB), the presence or absence of visceral pleural involvement does not modify prognosis in the different pathologic tumor size strata. For instance, survival at 3 years for tumor groups A, B, C, and D (Table 1) was 0.83, 0.72, 0.61, and 0.42, respectively, if there was no visceral pleural involvement. If, however, there was visceral pleural involvement, survival at 3 years for the same groups was 0.93, 0.68, 0.60, and 0.51, respectively. Other groups (5,32) report similar experiences. Other classificatory or definer components for T2, such as proximal bronchial involvement, do not appear to add any prognostic value to tumor size. (25)

Our population may be regarded as representative of NSCLC in stage pIA-pIB with complete resection in Spain in view of the multi-institutional nature of the GCCB-S, the magnitude of our sample, and quality controls undertaken. Nonetheless, given that the majority of our patients in our study were male with an epidermoid type of tumor, with scarce presentation of adenocarcinoma, and infrequent bronchioalveolar carcinomas, extrapolating our experience to other communities (the United States or Japan) might be somewhat problematic.

Based on our criteria, and on the data shown in the evaluation of clinical tumor size for a surgical population and for pathologic tumor size, the prognostic groups observed must be taken into account when evaluating any new potential prognostic factor (biological, clinical, molecular, etc.) or when designing stratification criteria in clinical trials in which patients with initial tumor stages take part. In some studies on new prognostic factors, multivariate analysis only looks at tumor size as either > 3 cm or < 3 cm, (33) or as T1-T2. (34) New assessments that take the new prognostic spectrum of tumor size into account may or may not confirm the independent value of these new factors.

As previously discussed, prognostic accuracy improves when a more discriminative staging is performed using TNM descriptors instead of stages. (5) This improvement in prognostic discrimination also occurs, as shown in our study, when a classificatory component (such as tumor size) is examined in greater detail.

In conclusion, this multi-institutional study, conducted by the GCCB-S on NSCLC cases with complete resection, did not find the 3-cm value to be a prognostic threshold. The study did, however, identify four prognostic groups with different tumor sizes within initial pIA-IB stages.

APPENDIX: THE GCCB-S

Coordinators: Jose Luis Duque, MD (Hospital Universitario, Valladolid); Angel Lopez-Encuentra, MD (Hospital Universitario 12 de Octubre, Madrid); Ramon Rami-Porta, MD (Hospital Mutua de Terrassa, Barcelona).

Local representatives: Julio Astudillo, MD (Hospital Germans Trias i Pujol, Barcelona); Emilio Canalis, MD; Jose Belda, MD (Hospital Clinic, Barcelona); Antonio Canto, MD; Antonio Arnau, MD (Hospital Clinico, Valencia); Juan Casanova, MD; Manuel Marinan, MD (Hospital de Cruces, Bilbao); Jorge Cerezal, MD; Jose Maria Matilla, MD (Hospital Universitario, Valladolid); Antonio Fernandez de Rota, MD; Ricardo Arrabal, MD (Hospital Carlos Haya, Malaga); Federico Gonzalez Aragoneses, MD; Nicolas Moreno, MD (Hospital Gregorio Maranon, Madrid); Jorge Freixinet, MD; Pedro Rodriguez, MD (Hospital Nuestra Senora del Pino, Las Palmas); Nicolas Llobregat, MD, (Hospital Universitario del Aire, Madrid); Nuria Manes, MD (Fundacion Jiminez Diaz, Madrid); Miguel Mateu, MD; Guadalupe Gonzalez Pont, MD (Hospital Mutua de Terrassa, Barcelona); Jose Luis Martin de Nicolas, MD (Hospital Universitario 12 de Octubre, Madrid); Nuria Novoa, MD (Complejo Hospitalario, Salamanca); Jesus Rodriguez, MD (Complejo Hospitalario, Oviedo); Antonio Jose Torres Garcia, MD (Hospital Universitario San Carlos, Madrid); Mercedes de la Torre, MD (Hospital Juan Canalejo, La Coruna); Abel Sanchez-Palencia, MD; Ruiz Zafra, MD (Hospital Virgen de las Nieves, Granada); Andres Varela de Ugarte, MD; Pablo Gamez, MD (Clinica Puerta de Hierro, Madrid); Yat Wah Pun, MD (Hospital de la Princesa, Madrid).

Data analysis: Agustin Gomez de la Camara, MD; Francisco Pozo Rodriguez, MD; Paloma Ferrando, MSc (Hospital Universitario 12 de Octubre, Madrid).

Table 1--Risk Ratio (Death) and Survival According to
Different Strata of Pathologic Tumor Size

         Tumor Size
         Diameter,           Risk Ratio
Groups       cm       No.     (95% CI)

A            0-2      147   1
B          2.1-4      448   1.5 (1.1-2.2)
C          4.1-7      336   2.1 (1.5-3.1)
D           > 7        89   3.5 (2.3-5.4)

                Survival, yr

Groups    2      3      4      5     Log Rank

A        0.90   0.83   0.76   0.63    0.0074
B        0.81   0.71   0.65   0.56    0.0048
C        0.71   0.61   0.53   0.49    0.0034
D        0.51   0.45   0.41   0.38

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Angel Lopez-Encuentra, MD, PhD; Jose Luis Duque-Medina, MD, PhD; Ramon Rami-Porta, MD, PhD; Agustin Gomez de la Camara, MD, PhD; Paloma Ferrando, MSc; for the Bronchogenic Carcinoma Co-operative Group of the Spanish Society of Pneumology and Thoracic Surgery ([dagger])

* From Hospital Universitario (Dr. Duque-Medina), Valladolid; Hospital Universitario 12 de Octubre (Drs. Lopez-Encuentra and de la Camara, and Ms. Ferrando), Madrid; and Hospital Mutua de Terrassa (Dr. Rami-Porta), Barcelona, Spain.

([dagger]) A complete list of GCCB-S members is given in the Appendix. Partly financed by FIS grant 97/0011, FEPAR-1995 grant, Fundacion RESPIRA-2000 grant, and financial aid from Castilla-Leon regional government and Menarini Foundation.

Manuscript received July 2, 2001; revision accepted November 14, 2001.

Correspondence to: Angel Lopez-Encuentra, MD, FCCP, Pneumology Service, Hospital Universitario 12 de Octubre, Ctta. Andalucia 5.4, 28041 Madrid, Spain; e-mail: lencuent@h12o.es

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