Chest Tumor Response During Lung Cancer Chemotherapy

Chest Tumor Response During Lung Cancer Chemotherapy* Computed Tomography vs Fiberoptic Bronchoscopy Eric Parrat, M.D.; Jean-Louis Pujol, M.D., Ph.D.; Yeronique Gautier; M.D.; Francois-Bernard Michel, M.D., RC.C.E; and Philippe Godard, M.D., RC.C.E

Tumor response is one of the most important criteria in the analysis of chemotherapy. A chest computed tomographic (CT) scan and 6beroptic bronchoscopy (FOB) might give different results, as they analyze different aspects of the effects of chemotherapy on lung cancer. The response of the chest tumor in 103 patients with stage m or IV lung cancer (35 with small-cell lung cancer [SCLC] and 68 with non-small-cell lung cancer [NSCLC]) who prospectively entered chemotherapy trials was studied in order to determine the concordance between the chest CT scan and FOB. The chest cr scan allowed an assessment of tumor response in almost all patients, whereas FOB was not able to evaluate this response in 15 ofthe 103. The frequency of an evaluable endobronchial lesion did not depend on histology (SCLC, 97 percent; NSCLC, 93 percent; XJ=O.85; not significant [NS]) or tumor T classi6cation (TI-2, 83 percent; T3, 94 percent; T4, 97 percent; XI = I . 4 9 ; NS). Tumor location in the bronchial airway did not differ when SCLC and NSCLC

e mothe rapy for both small-cell lung cancer C h(SCLC) and non-small-cell lung cancer (NSCLC)

is still an experimental approach requiring careful methods of evaluation. 1 Tumor response is one of the most important criteria for analyzing chemotherapy for lung cancer. Thus, the methods used to define this response might be considered as a critical milestone in reporting results. This is especially true in phase 2 chemotherapy trials, inasmuch as the selection of single drugs or drug combinations for a wider application in phase 3 trials is determined by both antitumor activity (percentage of tumor responses) and toxic effects in a risk-benefit evaluation. 2 Fiberoptic bronchoscopy (FOB) is a part of the staging procedure of lung cancer and is a useful tool for obtaining valid biopsy specimens for histologic study," however, the use of endobronchial abnormalities as indicator lesions for determining tumor response is still inaccurate. The recommendations of the

*From the Service des Maladies Respiratoires, Universite de Montpellier, Hopital de I'Aiguelongue, Montpellier, France. Supported by grants from the French League against Cancer (Herault and Aude Committees) and the "Croupement des Entreprises Franeaises dans la Lutte contre Ie Cancer." Manuscript received July 20; revision accepted September 30. Reprint requests: Dr. Pujol, HOpital AmtiUd de Vdleneuver, CHU de MontpeUier, 34059 MontpeUier, France

were compared. Thus, it is not possible to predict a subgroup of patients in whom FOB may be optional. In the group of 88 patients who were evaluable for response using both FOB and CT scan, a statistical concordance of the response classification was observed. The response was overevaluated by CT scan in 22 patients for whom data obtained by FOB appeared to be critical in the evaluation of tumor response. The concordance of response data obtained when the 2 methods were used was lower in NSCLC in comparison with SCLC. Thus, the use of FOB in the analysis of tumor response might be important, especially for NSCLC, inasmuch as FOB modulates the CT-evaluated response. (ehe., 1993; 103:1495-1501)

= =

GM CSF granulocyte macrophage-colony stimulating factor; NSCLC non-smaIl-ceU lung cancer; SCLC smaIl-eeU lung cancer

=

World Health Organization (WHO) for reporting the results of cancer treatment clearly define response criteria for solid tumors such as lung cancer and propose the use of the computed tomographic (CT) scan and endoscopy as methods to classify tumor response." The results of the chest cr scan may be expressed as bidimensional tumor measurements, whereas abnormalities observed by means of FOB are essentially nonmeasurable. In contrast, the analysis of biopsies obtained by FOB gives the opportunity to control the response to chemotherapy histologicall~5.6 It can be hypothesized that both methods give different results, as they analyze different aspects of the effects of chemotherapy on lung cancer; however, authors of many well-conducted chemotherapy trials in lung cancer have not reported the use of FOB results as a criterion of response, even though others considered this method as obligatory to determine complete response.V Thus, the importance of FOB examination in the definition of the response to chemotherapy of both SCLC and NSCLC is still unclear. In a recent study, we analyzed whether standard chest roentgenography is as effective as cr in evaluating tumor response. We concluded that a careful assessment of tumor response requires the measureCHEST /103 / 5 / MA~

1993

1485

ment of indicator lesions using chest cr scanning during chemotherapy in almost all patients with lung cancer. 8 We report herein the findings from a prospective study of 103 patients with lung cancer entering chemotherapy trials where chest tumor response was assessed by both cr scan and FOB. This study has been conducted to determine the concordance between the cr scan and FOB and to determine whether this concordance differs between SCLC and NSCLC. MATERIALS AND METHODS

lbtients One hundred three consecutive patients with previously untreated and histologically proven primary lung cancer of any histologic type were entered into controlled chemotherapy trials and prospectively evaluated for tumor response. Patients' characteristics are shown in the following tabulation listing numbers of patients: No. of patients

MIF ratio Mean (± SD) age, yr (range)

Histology SCLC NSCLC Stage of disease NSCLC Ina

103

87/16 58± 10 (30-74)

T2N2MO T3N2MO

IIIb

T3N3MO T4N3MO T4N2MO T4NOMO IV TIN3MI T2N2MI T3N3MI T4N2-3MI

SCLC Limited disease TIN2MO T3N2-3MO T4N2-3MO

Extensive disease

35 68 22 2

20

19 1 6 10 2 27 1 2

10 14 16 1

7 8 19

T3N2-3MI 12 T4N2-3MI 7 Among the patients, 35 had SCLC and 68 had NSCLC according to the WHO classmcation. It Pretreatment staging was performed by

an exhaustive procedure according to the new international staging system lO and the map of regional pulmonary nodes of the American Thoracic Socie~ II For all patients, the staging procedure included a clinical examination; standard chest roentgenography; CT scans of the chest, upper abdomen, and brain; FOB; liver sonography; and bone scanning. In addition, II patients with stage IlIa NSCLC underwent a cervical mediastinosco~ This procedure was used to prove the existence of nodal metastases.

7mltments As a result of both histologic type and staging, patients were eligible to take part in one of the five chemotherapy trials conducted at our institution and summarized in the following tabulation listing numbers of patients:

SCLC Trial 1 Doxorubicin (adriamycin), 50 mg/m 2; day 1, cycles I, 3, 5 Cyclophosphamide, 1 g/m!; day 1, cycles 1,3,5 Vincristine, 2 mg; day 1, cycles 1, 3, 5

1488

29

Cisplatin, 25 mg/m l days 1-4, cycles 2,4,6 Etoposide, 100 mg/m l ; days 1-4, cycles 2, 4, 6 Trial 2 Doxorubicin, 50 mg/m 2 ; day 1 Cyclophosphamide, 1 '11m 2 ; day 1 Etoposide, 80 mg/m 2; (Jays 1-3 ±GM CSF, 10 ..,glkg; days 4-14 NSCLC Trial 3 Cisplatin, 120 mg/m 2 ; day 1, every 4 wk Vinorelbine, 30 mg/m 2 ; day 1, every week or vindesine, 3 mg/m 2 ; day 1, every week vs Vinorelbine, 30 mg/m 2; day 1, every week Trial 4 Cisplatin, 120 mg/m l ; day 1, every 4 wk Fotemustine, 100 mg/m 2 ; days 1, 8, and 40 Trial 5 Cisplatin, 25 mg/m 2 ; days 1-4, every 3 wk IfoSfamide, 1,500 mg/m 2 ; days 1-4, every 3 wk Etoposide, 100 mg/m 2 ; days 1-4, every 3 wk

6

26

18 6

18

Trial 1 is a monocentric phase 2 study of alternating chemotherapy in SCLC. 11 Trial 2 is an international randomized phase 2 trial of standard combination chemotherapy and granulocyte macrophagecolony stimulating factor (GM CSF) in extensive SCLC. Trials 3 and 4 are controlled multicentric studies in which our institution has been involved. Trial 5 is a neoadjuvant chemotherapy trial in locally advanced NSCLC.6 These trials have been approved by local, national, or international ethics committees. Before the chemotherapy protocol started, predefinition of indicator lesions was obtained by both CT scan and FOB. In all of these trials, assessment of response by means of the evaluation of indicator lesions defined at the time of staging was required 10 to 12 weeks after the beginning of the treatment. None of the patients had received prior chemotherapy, chest radiotherapy, or surgery. No radiation therapy was applied until the evaluation of response had been made. Computed 7bmography The CT scans were carried out using a fourth-generation scanner (CGR CE 12000 or Siemens), and contiguous l-cm scans were obtained during the injection of contrast agents (rate, 1 mVs) from the lung apices to the level of the adrenal glands. The CT scans were viewed using multiple window settings for viewing lung and mediastinum. The response of the chest tumor, analyzed by CT scan, was assessed using the WHO response criteria." Indicator lesions, as evaluated by the CT scan before treatment, were separated into two groups: (1) where two-dimensional measurements could be made, the indicator lesion was defined as a measurable tumor; and (2) in cases where no more than a one-dimensional measurement could be made, the indicator lesion was considered as nonmeasurable but evaluable only Indicator lesions were clearly predefined before the patient entered the trial. We have previously published that a correlation was observed between the response calculated with only one indicator lesion and the response obtained with two indicator lesions. 8 Thus, in this study the primary tumor was always used as the only indicator lesion. Calculation of the response rate (as a percentage) was done as follows: response

(initial D X initial D') - (final D X final D') (initial D X initial D')

where D and D' are the longest perpendicular diameters of the indicator lesion (which was the primary tumor in all cases). A complete response was defined as the complete disappearance of all lesions; a partial response was defined as equal to or greater than a 50 percent reduction in the product of the two longest perpendicular diameters of the indicator lesions for measurable tumors or an improvement equal to or greater than 50 percent for Chest TumorResponse DuringLung CancerChemotherapy (Parrat et aI)

evaluable-only tumors. Stable disease was defined as a less than 50 percent reduction and a less than 25 percent increase in this product. Finally, progressive disease was defined as equal to or greater than a 25 percent increase in this product or the appearance of new lesions.

Fiberoptic Bronchoscopy Bronchoscopy was performed with a 8exible fiberoptic instrument (Olympus BF type ITIO) 15 min after premedication consisting of 0.25 mg of atropine and local anesthesia with 15 ml of 1 percent lidocaine. The biopsies of bronchial tumors were done with forceps (FB-2OC), and a minimum of three biopsies were taken. The FOB was done at the time of diagnosis and was repeated at the time of response evaluation. A performance status equal to or greater than 3 according to the WHO scale was considered as a contraindication for the second FOB. Moreover, no biopsy was done if the platelet count was lower than 100,0001..,1. Three new biopsies of the initial site of the lesion were done even in the case of a complete response. For each FOB the information recorded included the site of the lesion (segmental, lobar, intermediate, main bronchus, or trachea), the degree of bronchial obstruction (incomplete obstruction versus stenosis), and involvement of the proximal bronchial division. No indirect sign of tumor was taken into account except vocal cord paralysis. Results of histologic analyses of bronchial biopsies were also recorded. Definition of response and progression was standardized as follows: a complete response was considered as a complete disappearance of all endobronchial lesion, or a nonspecific scar, such as a minimal obstruction of a segmental bronchus with a negative bronchial biopsy; a partial response referred to the change of a stenosis (complete obstruction) into a partial obstruction or the disappearance of the bronchial division involvement (or both); conversely, progression was considered as the change of a partial obstruction into complete stenosis or the appearance of a bronchial division involvement or the appearance of vocal cord paralysis (or both); other cases were considered as stable disease. We did not use photographic documents, as their interpretation depends on the magnification used.

Design of Study The following method was applied to analyze the cr scan films and FOB data: patients entered the study prospectively Two radiologists and two chest physicians from our chest deparbnent read the films, and the results of the measurements were taken into account only when all of the panel's participants were in agreement. Lesions difficult to measure bidimensionally which led to interobserver disagreement were considered as evaluable only. The cr scans were read independently of FOB results. The four chest physicians from our institution who performed the FOB had knowledge of chest roentgenography which was done at the same time, but they were not aware of the results of tumor response measurements. A maximum of 6 days separated the performance of the cr scan and FOB. As a control of tumor measurement and in addition to the internal panel described previously, an outside panel composed of oncologists and chest physicians involved in lung cancer chemotherapy trials reviewed 68 of the 103 films (66 percent) and found no discrepancies in assessment of tumor response.

Statistical Analyses The K coefficient of reliability" and the McNemar test of symmetry" were used to test the concordance of the tumor response calculated by means of cr scans and that defined by FOB data. These coefficients of reliability were calculated in the entire population, in SCLC and in NSCLC subgroups. The comparison between the coefficients of the two subgroups was obtained by the following formula:

Table 1- Site ofEndobronchitJl Tumor According to HiBtologic Type.

Site of Endobronchial Lesion Segmental Lobar Intermediate Main bronchus Not seen

No. With Histologic Type (%) SCLC* 4 16 4 10 1

NSCLC*

(11) (46) (11) (29) (3)

6 (9) 36 (53)

7 (10) 14 (21) 5 (7)

*Table data are numbers of patients; numbers within parentheses are percents. txl = 1.86; NS.

V[SI)I(K I)+SDI(K2)] -N (0.1) The Xl test was used to compare qualitative data, and Yates· correction was applied when appropriate; a p level of less than 0.05 was considered as significant. Survival was defined as the time from the first day of chemotherapy to the date of death. Probability of survival was estimated by the Kaplan-Meier method. Univariate analysis of survival was done by means of Wilcoxon and log-rank tests. The BMDP software package was used. RESULTS

Thmor Evaluation by Initial FOB

Using FOB, an endobronchial tumor was seen in 97 out of 103 patients. The sites of the endobronchial tumors were a segmental bronchus in 10 patients, a lobar one in 52, the intermediate bronchus in 11, and a main bronchus in 24. Among these 97 patients with a visible endobronchial tumor, histologic analysis of a bronchoscopically obtained bronchial biopsy was abnormal in 85 (88 percent). Other histologic diagnoses were obtained either by percutaneous fine-needle biopsy or mediastinoscopy Iuctors Affecting FOB Evaluability ofThmor

The location of the endobronchial lesion in the airway did not significantly differ when SCLCs were compared with NSCLCs (xi = 1.86; NS; Table 1).Sixtythree out of the 68 patients with NSCLC (93 percent) and 34 of the 35 patients with SCLC (97 percent) Table 2-Eooluation ojChat Tumor Using FOB and SUe ofTumor* FOB Tumor Classification

Endobronchial Tumort

Not Seen

TI-2

5 (83) 47 (94)

1 (17) 3 (6) 2 (4)

1'3

T4

45 (96)

*Table data are numbers of patients; numbers within parentheses are percents. tFor increase in frequency down Tclassification, Xl = 1.49; NS. CHEST /103 / 5 / MA'f, 1993

1417

shared endobronchial abnormalities (X2= 0.85; NS). The percentage of abnormal findings on histologic examination of bronchial biopsies did not differ when SCLCs were compared with NSCLCs (respectively, 82 percent and 82 percent; X2= 0.004; NS). According to the T classification, the frequency of an evaluable endobronchial tumor increased from TI to T4 (T1-2, 83 percent; T3, 94 percent; T4, 97 percent), but this difference did not reach statistical significance (x2= 1.49; NS; Table 2). The frequency of abnormal histologic findings on biopsy did not significantly differ according to the tumor T classification (x2= 1.27; NS) or according to the site of the endobronchial tumor (X2=2.69; NS). 7bmor Response by FOB and Chest CT Scan Among the 103 patients, 6 had no endobronchial lesion as observed by the first FOB. For these patients a second FOB performed at the time of response evaluation disclosed no tumor, and thus they were nonevaluable for response using this method. Nine of the 97 remaining patients did not undergo a second FOB (patient's refusal in 4 instances; performance status impairment in 5). Among the 88 patients evaluable for response using FOB, 27 had a complete response (disappearance ofall macroscopic lesions and normal biopsies), 27 had a partial one, and 14 had stable disease; progression, as observed by FOB in 20 instances, consisted of the change of a partial obstruction into complete stenosis in 12 cases, appearance of a bronchial division involvement in 4, appearance of vocal cord paralysis in 3, and a combination of the first 2 progression modalities plus appearance of a new lesion in the opposite main bronchus in 1. Histologic findings for the new tumor biopsies were similar to the one obtained during the first evaluation except in one patient for whom the histologic type switched from SCLC to a large cell carcinoma. All patients but one were evaluable for response by means of chest cr scan. This allowed a bidimensional tumor measurement of 94 patients, whereas the indicator lesion was considered as evaluable only in 8 cases and as nonevaluable in the remaining 1. Thus, assessment of tumor response was achieved in 88 of 103 patients (86 percent) using FOB and in 102 of 103 patients (99 percent) using the chest CT scan (xi = 13.2; p
Table 3-Evaluation afChest Tumor Using FOB and CT Scan·

cr Scan FOB

Measurable

Nonmeasurablet

Evaluable endobronchial tumor Not evaluable

83 (88);

5 (56);

11 (12)

4 (44)

*Table data are numbers of patients; numbers within parentheses are percents. tNine evaluable only; 1 nonevaluable chest indicator lesion. ;X2 = 4.62; p
qualify the type of response to chemotherapy as defined by the WHO recommendations is shown in Figure 1. A statistical concordance was observed between cr scan and FOB assessment of response (K coefficient of reliability = 0.335; p
••c !•

CR

•

0

Q,

'a

I

PR

:I

"i

• • > c u

NC

• I

o ~

PO

..00

• • • 00

00 ••••• 0

......

••

•• •••••• ••• 0

PO

NC

00 ••0000

••••••• •••• ••••• PR

000 000000 000000 •••••0 • • • • 00

CR

Flberoptlc bronchoscopy evaluated response

FIGURE 1. cr scan versus FOB classification of response in 88 patients evaluable by both techniques. Open circles, SCLC; closed circles, NSCLC; CR, complete response; PR, partial response; NC, no change; and PD, progressive disease (K coefficient of reliability = 0.335; p
5°1 J! e

I

r

40

.!

~

30

~

o

'E 20 Q) (J

... Q)

a.

10

o

PO

HC . . CT evaluation

PR

c::=J CT

CR

- FOB evaluation

FIGURE 2. Comparison of Cf and Cf- FOB classification of response.

PD, progressive disease; NC, no change; PR, partial response; and CR, complete response.

NSCLC groups, respectively Therefore, although a statistical concordance was observed in both groups, the reliability of FOB and chest CT scan classifications of response was higher for the SCLC group (comparison of the coefficients of the 2 subgroups = 2.25; p
Univariate analysis of survival showed that patients with a complete response proved to have a significantly longer overall survival than those for whom a partial response, no change in disease, or progressive disease has been demonstrated (log rank p = O.()()() 1; Wilcoxon p=O.OOOI; Table 4). DISCUSSION

Metastatic disease is the leading cause of localregional treatment failure in both SCLC15 and NSCLC .16 This observation is one part of the rationale of intensive lung cancer chemotherapy research. The SCLC is a chemosensitive tumor, and a high percentage of response has been reported with numerous combinations of chemotherapy; however, the occurTable 4-Univariate Analysis of Survival According to Results ofCT and FOB Evaluation

Response

n

Complete response Partial response No change Progression

21 26 19 22

Median Survival, wk

SE

57.8* 46.4 50.9 24.7

6.2 3.8 7.4 5.2

*Wilcoxon p = 0.0001; log-rank p = 0.0001.

Censored, %

19.0 7.6 33.3 0.0

renee of chemoresistant relapses leads to a secondary failure of the treatment.F Different modalities of intensive chemotherapy (alternating chemotherapy; high-dose chemotherapy with growth factors) are under evaluation in an attempt to circumvent chemoresistance. On the other hand, the efficacy of chemotherapy in NSCLC is still a subject of controversy." In patients with unresectable NSCLC, recent reports suggest a small, but statistically significant improvement of survival using combination chemotherapy when compared with best supportive care. 19 Other studies aimed at treating the microscopic metastatic disease used neoadjuvant chemotherapy 6,20 Therefore, chemotherapy for lung cancer is still under experimental evaluation and requires uniform criteria to determine both the activity and efficacy of new protocols. Response to chemotherapy is a major criterion to evaluate the activity of new drugs or new combinations. The WHO recommendations are widely used in order to standardize reports of chemotherapy trials;' however, little is known about the correct technique, or combination of techniques, able to accurately evaluate the response of lung cancer to chemotherapy. Fiberoptic bronchoscopy is widely used as a part of the initial staging and as a means of obtaining valid bronchial biopsies for htstologic'-" or immunohistochemical" studies. The relationship between roentgenographic and FOB data obtained at the time of initial cTNM evaluation has been studied. 23-28 Whereas some reports suggest a good CT-FOB correlation." others show possible discordances between the two methods. 23 ,27 Moreover, the study by Gelb et al29 has emphasized the complementary nature of both FOB and the chest CT scan. Thus, it is widely accepted that both techniques are part of the diagnostic and staging procedure of lung cancer. The concordance of response assessment using FOB and standard chest roentgenography has been studied in SCLC30 and NSCLC,31 cases of discordance were observed, but the coefficient of reliability was difficult to determine. In a previous study we demonstrated that measurement of tumor response to chemotherapy required a chest CT scan in almost all cases; however, in a subgroup of highly selected patients, .in whom twodimensional indicator lesions could be assessed by standard chest roentgenography, the analyzed response correlated well with the one assessed by CT scan." Thus, the chest cr scan might be considered as the standard of roentgenographic techniques to assess tumor response, and the analysis of concordance between CT scan and FOB response assessment may be of interest. In this study, the chest CT scan allowed an assessment of tumor response in almost all patients, whereas FOB was not able to evaluate this response in 15 CHEST I 103 151 MA'f, 1993

1499

percent. It is noteworthy that a higher percentage of abnormal bronchoscopic findings is observed in our study in comparison with previously published studies, such as the one by Naidich et al, ss who found 60 percent endoscopically abnormal pulmonary nodules or masses. A possible explanation is that in our stud}'; the common criterion for eligibility for all five trials of lung cancer chemotherapy was an advanced stage (III or IV). This stage is often associated with proximal and endobronchial lesions accessible to FOB. Therefore, the probability of an evaluable endobronchial lesion might be higher in a selected population of patients with locally advanced or metastatic lung cancer treated by chemotherapy On the opposite, our study demonstrated that restaging does not need a second FOB in patients for whom no endobronchial lesion has been seen during the first FOB. In our experience the evaluability of an endobronchiallesion did not depend on histologic type, tumor T classification, or tumor location in the bronchial airway Thus, it is not possible to predict a subgroup of patients in whom FOB may be optional. In the group of patients who were evaluable for response using the two methods, a statistical concordance of classification of response was observed; however, the response was overevaluated by cr scan in 22 patients and underevaluated in 11 others for whom data obtained by FOB appeared to be critical in response evaluation. The concordance ofresponse data obtained using both methods was higher in the SCLC group in comparison with the NSCLC one. The high rate of complete response observed in the former group might be responsible for a better reliability of the results of response analysis when the two methods are used. Thus, major discrepancies between FOB and cr are mainly seen in NSCLC. It appeared that endoscopic findings frequently tended to moderate results of tumor response measurement calculated by means of cr scan, particularly in NSCLC. In many instances, FOB disclosed a progression of the endobronchial lesion at the time when cr scan diagnosed stable disease; other cases classified as partial response using cr scan had a stable endobronchial lesion. In this stud}'; we defined the criteria ofendobronchial progression as accurately as possible to avoid misinterpretation of endoscopic data; it seemed to us that the appearance ofa complete stenosis, the involvement ofa previously normal bronchus division, or the appearance ofvocal cord paralysis (or both) may be considered by chest physicians as acceptable criteria of endobronchial progression. Thus, the FOB response was evaluated using clearly predefined criteria. We did not consider slight modifications as a partial response, and therefore these were considered as no change in the disease. This prevented misinterpretation ofslight modifications. In 1500

spite of these criteria, our classification did not lead to an abnormal number of patients in the "no change" category The frequent discrepancy between CT and FOB evaluation of response might be illustrated by the observation of a patient with NSCLC for whom the cr scan performed at the time of response evaluation was considered as normal. He had, in fact, an unchanged endobronchial lesion with abnormal histologic findings on bronchial biopsy The study by Shure'" might explain this discrepancy; this author found 36 radiographically occult endobronchial obstructions in a group of 81 completely obstructive endobronchial tumors. She concluded that bronchoscopy has to be considered as obligatory in the diagnostic and staging procedure of all lung cancers. We suggest from the data of our study that FOB may also be considered as a part of the assessment of tumor response for all patients who undergo chemotherapy It might be hypothesized that the relationship between survival and response depends on the accuracy of the response evaluation. The analysis of survival in our patients according to the response classification demonstrated a strong relationship between outcome and response when it is defined as the worst results of FOB or cr. These data are a clue in favor of the use of both cr and FOB in response evaluation. The use of histologic findings of bronchial biopsies taken at the time of response assessment is confirmed by two findings in our own study; some patients who had a complete disappearance of both roentgenographic and bronchoscopic indicator lesions had a persistent malignant disease at the microscopic stage and therefore must be considered as partial responses instead of complete ones. One patient in our study underwent alternating chemotherapy for a SCLC (classic one according to the WHO histologic classification); at the time of response assessment, both the cr scan and FOB concluded that it was a partial response, but the histologic findings of the new bronchial biopsies identified a large cell carcinoma. Metastatic progression occurred 5 weeks later. This finding might be explained by the frequent phenotypic heterogeneity of lung cancer.P with a possible emergence of a chemoresistant phenotype selected by the induction treatment. According to the WHO recommendations, "progression in any site indicates disease progression, despite objective responses in other sites,"! Thus, it may be suggested that the use of a single method to assess tumor response leads to an overevaluation of the results of antitumor activity of chemotherapy protocols. We conclude that the use of FOB in the analysis of tumor response is significant, inasmuch as it modulates the cr-evaluated response. This warrants further studies to determine the clinical importance of a combination of FOB and cr methods in evaluating ChestTumor Response During LungCancerChemotherapy (Parratet aJ)

tumor response. ACKNOWLEDGMENT: We thank Mrs. Jo Balssus for help in preparing the manuscript.

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