A Randomized Trial Comparing Preoperative Chemotherapy Plus Surgery with Surgery Alone in Patients with Non-Small-Cell Lung Cancer
Rafael Rosell, Jose Gomez-Codina, Carlos Camps, Jose Maestre, Jose Padille, Antonio Canto, Jose Luis Mate, Shanrong Li, Jorge Roig, Angel Olazabal, Mercedes Canela, Aurelio Ariza, Zdenek Skacel, Jose Morera-Prat, and Albert Abad
Background The efficacy of surgery for patients with non-small-celllung cancer is limited, although recent studies suggest thatpreoperative chemotherapy may improve survival. We conducteda randomized trial to examine the possible benefit of preoperativechemotherapy and surgery for the treatment of patients withnon-small-cell lung cancer.
Methods We studied 60 patients (59 men and 1 woman) with stageIIIA non-small-cell lung cancer. The patients were randomlyassigned to receive either surgery alone or three courses ofchemotherapy (6 mg of mitomycin per square meter of body-surfacearea, 3 g of ifosfamide per square meter, and 50 mg of cisplatinper square meter) given intravenously at three-week intervalsand followed by surgery. All patients received mediastinal radiationafter surgery. The resected tumors were evaluated by means ofK-ras oncogene analysis and flow cytometry.
Results The median period of survival was 26 months in the patientstreated with chemotherapy plus surgery, as compared with 8 monthsin the patients treated with surgery alone (P<0.001); themedian period of disease-free survival was 20 months in theformer group, as compared with 5 months in the latter (P<0.001).The rate of recurrence was 56 percent in the group treated withchemotherapy plus surgery and 74 percent in the group treatedwith surgery alone. The prevalence of mutated K-ras oncogeneswas 15 percent among the patients receiving preoperative chemotherapyand 42 percent among those treated with surgery alone (P = 0.05).Most of the patients treated with chemotherapy plus surgeryhad tumors that consisted of diploid cells, whereas the patientstreated with surgery alone had tumors with aneuploid cells.
Conclusions Preoperative chemotherapy increases the median survivalin patients with non-small-cell lung cancer.
At present, the role of surgery in the treatment of patientswith non-small-cell lung cancer, stage IIIA (locally invasiveprimary tumors or tumors associated with involvement of theipsilateral mediastinal lymph nodes [N2]), is controversial1,2.An evaluation of the results of surgery is limited by variationsin the proportion of patients with stage IIIA disease detectableby computed tomography (CT) and the definition of complete resection3.In four separate studies of a total of 1180 patients who underwenttumor resection, the five-year survival rates ranged from 14to 30 percent1,3,4,5.
Preoperative chemotherapy may improve the prognosis for patientswith stage IIIA non-small-cell lung cancer. In one study theresponse rate was 60 percent, half the patients were able toundergo resection, and the median survival was increased byeight months6. In several phase 2 trials of preoperative chemotherapyin a total of 463 patients, the response rates ranged from 51to 77 percent, 63 to 90 percent of the patients had resectabletumors after chemotherapy, the median period of survival rangedfrom 13 to 32 months, and the 3- to 5-year survival rates rangedfrom 17 to 40 percent7,8,9,10,11,12,13. Factors such as theheterogeneity of the patients studied, variations in the extentof resection, and lack of a consensus about inclusion criterialimit the conclusions that can be drawn from these studies.A few randomized studies have addressed the benefit of preoperativechemotherapy14,15,16. Among the patients in these trials, thethree-year survival rate ranged from 25 to 40 percent for thosetreated with chemotherapy plus surgery and from 15 to 40 percentfor those treated with surgery alone. Our trial was designedto assess the effect of preoperative chemotherapy on the survivalof patients with stage IIIA non-small-cell lung cancer. Thechemotherapy regimen was designed to result in a 60 percentresponse rate, a rate of disease progression during chemotherapyof less than 10 percent, and only mild toxicity. We also testedthe effect of chemotherapy on tumor-cell DNA and examined themutational state of the K-ras oncogene. A combination of mitomycin,ifosfamide, and cisplatin, as described by Cullen et al.,17was chosen as the preoperative chemotherapeutic regimen.
Methods
Patients
We studied 60 patients with histologically confirmed non-small-celllung cancer in stage IIIA according to the tumor-node-metastasis(TNM) classification18. A bronchoscopy was performed, and biopsyspecimens and washings were obtained to determine the extentof involvement of the tracheobronchial tree. Eligibility criteriaincluded the presence of measurable lesions that could be evaluated,a Karnofsky performance score of 70 or higher, a leukocyte countabove 4000 per cubic millimeter, a platelet count above 100,000per cubic millimeter, normal renal and hepatic function, andadequate pulmonary function. Pulmonary function was assessedby calculating the ratio of the forced expiratory volume inone second (FEV) to the forced vital capacity (FVC). A predictedpostoperative FEV equal to at least 1 liter and more than 34percent of the normal value was required for enrollment in thestudy. In borderline cases, ventilation-perfusion scanning wasalso performed to predict postoperative pulmonary function19,20.
A medical panel composed of a thoracic surgeon, a radiologist,a chest physician, and a medical oncologist confirmed the stageof disease in each patient. Mediastinoscopy or mediastinotomywith a biopsy was carried out in all patients with N2 diseasedetected by CT (83 percent of the patients treated with chemotherapyplus surgery and 63 percent of those treated with surgery alone).CT of the brain was performed if the histologic studies showedthat the primary tumor was an adenocarcinoma or if neurologicsigns suggested that the disease involved the central nervoussystem. Radionuclide bone scanning was carried out if eitherthe clinical symptoms suggested bone infiltration or the serumalkaline phosphatase concentration was elevated. Lymphadenopathywas evaluated by CT; metastatic lymph nodes were defined asmediastinal nodes larger than 10 mm along their short axis orsubcarinal nodes larger than 15 mm21. If the radiologist onthe medical panel saw no adenopathy on the CT scan, the patientwas considered to have no mediastinal involvement. In all patientswith N2 disease that was confirmed histologically, the diseasewas apparent on the CT scan but not on the plain chest film.The presence of satellite nodules, defined as well-circumscribedaccessory foci of carcinoma adjacent to the primary tumor butclearly separated from it by normal parenchyma, was consideredto signify a subcategory of stage IIIA disease classified asT3 disease22.
The study protocol was approved by the research review committeefor the protection of human subjects at each institution participatingin the study. All patients gave informed consent.
Treatment
Patients were randomly assigned to undergo either immediatesurgery or surgery preceded by three courses of chemotherapygiven at three-week intervals. The chemotherapeutic regimenconsisted of mitomycin (6 mg per square meter of body-surfacearea given in an intravenous bolus dose), ifosfamide (3 g persquare meter mixed with mesna [1 g per square meter] and givenintravenously over the course of three hours), and cisplatin(50 mg per square meter given intravenously over the courseof one hour). Additional mesna and hydration were given as describedby Cullen et al.17. As antiemetic therapy, metoclopramide (3mg per kilogram of body weight) was given intravenously 30 minutesbefore and 90 minutes after the chemotherapy. Dexamethasone(20 mg) was given intravenously with the first dose of metoclopramide;lorazepam (1.5 mg per square meter) was given orally at thesame time. The chemotherapy was administered on an outpatientbasis. After the third course of chemotherapy, just before surgery,chest CT was repeated to assess the response to chemotherapy.The patients judged to have resectable tumors then underwentsurgery.
A thoracotomy was performed within four to five weeks afterthe third course of chemotherapy in the patients thought tohave resectable tumors. During the operation, the ipsilateralmediastinal and subcarinal lymph nodes were resected, as werethe subaortic, para-aortic, and paraesophageal nodes. However,mobilization of the aortic arch and the descending aorta toallow more extensive removal of the superior mediastinal nodeswas not performed23.
Patients randomly assigned to undergo surgery without chemotherapywere operated on within two weeks after enrollment. Both patientgroups received mediastinal radiation, begun approximately fourweeks after surgery and given in a combination of parallel opposed,anterior, and posterior oblique fields. A daily dose of 1.8to 2.0 Gy delivered in the central axis at the midplane wasgiven five days per week until the patient had received a cumulativedose of 50 Gy. Field outlines extended from the thoracic inletto 5 cm below the carina. The field included the bronchial stump,ipsilateral hilum, and vascular shadows of the mediastinum bilaterally.The total dose to the spinal cord was 40 Gy.
All patients were reevaluated every three months with a physicalexamination, laboratory tests, chest films, and chest and abdominalCT scans. A complete response to preoperative chemotherapy wasdefined as the absence of all radiographic abnormalities afterchemotherapy, and a partial response was defined as a reductionof 50 percent or more in the product of two perpendicular diametersof the tumor. Stable disease was defined as less than a 50 percentreduction in the tumor, less than a 25 percent increase in thesum of the products of two perpendicular diameters of all measuredlesions, and no new lesions. Progressive disease was definedas an increase of more than 25 percent in the product of twoperpendicular diameters of any measured lesion.
K-ras Oncogene Point Mutations
Tumor specimens obtained at the time of surgery were fixed withformaldehyde, embedded in paraffin, and evaluated for pointmutations at codons 12, 13, and 61 of the K-ras oncogene. DNAwas isolated from 15-microm sections of tissue blocks with arapid-lysis procedure. Conditions for the polymerase chain reactionand the detection of point mutations with mutation-specificoligonucleotides have been described by Slebos et al.24. Briefly,ras-specific sequences were amplified by the polymerase chainreaction for 35 cycles. DNA was subjected to electrophoresison 4 percent agarose gel and then stained with homidium bromide.The amplified products of the polymerase chain reaction weredenatured and dotted onto hybridization membranes. Each membranewas then hybridized separately for one hour with radiolabeled,mutation-specific oligonucleotide probes. Specific hybridizationwas detected by autoradiography at -70 °C for 18 to 24 hours.
Flow Cytometric Analysis
The tumors were analyzed by flow cytometry. Sections that were50 microm thick were cut from each paraffin block that containedat least 25 percent neoplastic tissue and had no secondary degenerativechanges (necrosis or hemorrhage). The tissue was deparaffinized,rehydrated, and incubated at 37 °C for one hour in a 0.5percent pepsin solution (pH 1.5). Disaggregated tissue was filteredthrough a 35-microm nylon mesh, incubated with ribonucleaseI (100 µg per milliliter), and then stained with propidiumiodide (50 µg per milliliter) at 4 °C for a minimumof 12 hours and a maximum of 16 hours. Nuclear-cell suspensionswere analyzed with a flow cytometer (FACScan, Becton Dickinson,San Jose, Calif.) and a CellFit program. An average of 10,000cells from each sample were evaluated. Non-neoplastic lung parenchymaincluded in the same paraffin block or in another block fromthe same patient was used as a diploid standard. Diploid tumorcells were defined as cells having only one G0/G1 peak witha coefficient of variation of less than 8.0. Aneuploid cellswere defined as cells with any distinct peak other than theG0/G1 peak, depending on the position of the aneuploid cellsafter the test sample had been mixed with the biologic standard(diploid control)25.
Study Design, Statistical Analysis, and Quality Control
The trial was designed as a prospective, randomized, nonblindstudy. Randomization of patients at participating centers wasaccomplished by telephone calls to the study office. The patientswere stratified according to the size and location of the primarytumor, its histologic characteristics, and the number of N2lymph-node groups that were positive for tumor cells. The primaryobjective was to determine whether preoperative chemotherapywould improve the anticipated five-year survival rate of 9 percentfor patients with resectable stage IIIA disease confirmed bymediastinoscopy. The secondary objectives were to determinethe rate of response to preoperative chemotherapy and relatedtoxicity and to analyze the DNA content and K-ras oncogene activationin tumor samples obtained during surgery. The start of the studywas considered to be the time of the first course of chemotherapyin the patients treated with chemotherapy plus surgery and thetime of surgery in those treated with surgery alone. Follow-upanalyses were carried out 12, 18, and 24 months after the startof the study by members of the Spanish Lung Cancer Group auditcommittee.
Parametric and nonparametric tests were used to compare theresults in the two treatment groups. Survival curves, constructedwith the date of randomization as the starting point, were computedaccording to the Kaplan-Meier method, and differences in survivalwere compared with the log-rank test for censored data. TheBrookmeyer-Crowley method was used to calculate the confidenceinterval for the median period of survival26. A proportional-hazardsregression analysis was used to determine the effects of differentvariables on survival. Six variables were analyzed: the sizeand location of the tumor, histologic characteristics, nodestage, number of lymph-node levels affected, and treatment group.A score was assigned to each variable for the regression analysis.Qualitative data (the location of the tumor, histologic characteristics,and treatment group) were analyzed with chi-square tests. Allreported P values are two-tailed; all analyses were performedwith BMDP software27.
Results
Between December 1989 and May 1991, we enrolled 63 patientsat the three hospitals participating in the study. An analysis28,29after 24 months showed a significant difference in survival,and enrollment was therefore stopped. Three patients who werelater found to be ineligible because of poor pulmonary functionat the time of randomization were excluded from the analysis.Among the remaining 60 patients, 30 were assigned to preoperativechemotherapy, and 30 to immediate surgery. The oldest patientwas 78 years old. All patients had a high Karnofsky score, andthe majority had squamous-cell carcinoma. The median durationof follow-up among the surviving patients was 24 months in thechemotherapy-plus-surgery group and 19 months in the surgerygroup.
There were no significant differences between the two groupsin any of the characteristics listed in Table 1. Twenty-fiveof the 30 patients in the chemotherapy-plus-surgery group hadN2 disease, as compared with 19 of the 30 in the surgery group.The remainder had T3N0 or T3N1 disease but with unfavorableprognostic factors, such as soft-tissue infiltration, rib involvement,or pericardial invasion. The median tumor size was larger than5 cm in both groups (Table 2); four patients in the chemotherapy-plus-surgerygroup had satellite nodules. A large proportion of patientshad lymph-node metastases at two N2 levels. All 30 patientsin the chemotherapy-plus-surgery group received the three coursesof chemotherapy as scheduled, with minimal or no toxic effects.The lowest leukocyte count was 2000 per cubic millimeter, andthe lowest platelet count was 100,000 per cubic millimeter.There were no life-threatening episodes of neutropenia, andno patients had nephrotoxicity. Nausea and vomiting, when theyoccurred, were mild. Most patients had grade 1 or 2 alopecia.
Table 2. Characteristics of the Tumors, According to Treatment Group.
In the chemotherapy-plus-surgery group, 16 patients (53 percent)had a partial radiographic response, and 2 patients (7 percent)had a complete response. At the end of the study, 11 patientswere deemed to have stable disease, and only 1 patient (3 percent)had progressive disease, as evidenced by liver metastases detectedafter chemotherapy; this patient did not undergo surgery. Onepatient who had a complete response and one who had a partialresponse refused the surgery. Twenty-three of the 27 patientswho underwent surgery had a complete resection. The tumors inthe other four patients were not resectable because of encasementof the great vessels. Only one patient, who had an adenocarcinomaand a complete response to chemotherapy, had no residual tumorin lung tissue or nodes removed during surgery. Four patientshad no detectable primary tumor, but microscopical foci werefound in the lymph nodes. In the surgery group, 27 of 30 patientshad complete resections. There were no significant differencesbetween the two treatment groups with respect to the surgicalprocedures that were used (Table 3). Four patients died within30 days after surgery, two in each treatment group (overallmortality rate, 7 percent): two patients died of pneumonia,one of an acute pulmonary embolism, and one of a bronchopleuralfistula and respiratory arrest.
Table 3. Response to Chemotherapy and Results of Surgery, According to Treatment Group.
There were significant differences in disease-free and overallsurvival between the two groups. The median period of disease-freesurvival in the surgery group was 5 months (95 percent confidenceinterval, 4 to 7), as compared with 20 months (95 percent confidenceinterval, 12 to 30) in the chemotherapy-plus-surgery group (P<0.001)(Figure 1). Similarly, the median overall survival in the surgerygroup was 8 months (95 percent confidence interval, 7 to 10),as compared with 26 months (95 percent confidence interval,16 to 34) in the chemotherapy-plus-surgery group (P<0.001)(Figure 2). The differences in survival between the two groupswere significant irrespective of the patient's age, the histologicsubtype of the tumor, its location and size, and the numberof N2 levels involved. The risk of death in the surgery groupwas five times that in the chemotherapy-plus-surgery group (hazardratio, 5; 95 percent confidence interval, 2 to 17). During follow-up,56 percent of the patients in the chemotherapy-plus-surgerygroup had a relapse, as compared with 74 percent of those inthe surgery group (P = 0.65). The tumor recurred at a localor regional site in 54 percent of the chemotherapy-plus-surgerygroup, whereas the tumor recurred as a metastasis in 55 percentof the surgery group.
Figure 1. Kaplan-Meier Plot of Disease-free Survival in Patients with Stage IIIA Lung Cancer Treated with Surgery Alone (Dashed Line) or Chemotherapy plus Surgery (Solid Line).
Bars indicate 95 percent confidence intervals at 12 months. The number of patients at risk is shown below the graph.
Figure 2. Kaplan-Meier Plot of Overall Survival in Patients with Stage IIIA Lung Cancer Treated with Surgery Alone (Dashed Line) or Chemotherapy plus Surgery (Solid Line).
Bars indicate 95 percent confidence intervals at 12 months. The number of patients at risk is shown below the graph.
Tumor Evaluation
Among the 50 patients who had complete resections, biopsy specimensfrom all but 4 yielded adequate tissue for isolation of DNAand amplification by polymerase chain reaction. Amplificationof DNA revealed K-ras oncogene point mutations in 3 of 20 patients(15 percent) in the chemotherapy-plus-surgery group and in 10of 24 (42 percent) in the surgery group (P = 0.05). In threeof the tumors from the surgery group, the normal DNA sequenceat codon 12, GGT (guanine, guanine, and thymine), encoding glycine,was replaced by GAT (guanine, adenine, and thymine), encodingaspartic acid instead of glycine; three tumors contained GTT(guanine, thymine, and thymine), encoding valine; and two containedTGT (thymine, guanine, and thymine), encoding cysteine. Theremaining two tumors contained mutations at codon 61, as didthe three tumors from the patients in the chemotherapy-plus-surgerygroup. Of the three patients in the chemotherapy-plus-surgerygroup whose tumors had mutated K-ras oncogenes, two had no objectiveresponse to treatment: one died of local and regional disease,and the other had brain metastases after 21 months of follow-upand died 5 months later. The third patient, who had a partialresponse, had brain metastases and died after 14 months of follow-up.Of the 10 patients in the surgery group whose tumors containedmutated K-ras oncogenes, 9 died: 5 had bone metastases, 2 hadliver metastases, 1 had distant lymph-node metastases, and 1had a recurrence of the tumor at local and regional sites.
Of the 46 specimens that contained enough tumor tissue for flowcytometry, 9 could not be analyzed (5 specimens from the surgerygroup and 4 from the chemotherapy-plus-surgery group) becauseof low-quality histograms. Only 5 of the 17 tumor specimensfrom the chemotherapy-plus-surgery group (29 percent) were aneuploid,whereas 14 of the 20 tumor specimens from the surgery group(70 percent) were aneuploid (P = 0.02). For three of the patientsin the chemotherapy-plus-surgery group, biopsy tissue obtainedbefore chemotherapy was analyzed, in addition to the tissueremoved during the surgery that followed chemotherapy. In allthree cases, the DNA content of the tumor was aneuploid in thespecimen obtained before chemotherapy but diploid in the specimenobtained afterward.
Discussion
This phase 3 trial addressed the effect of preoperative chemotherapyon the survival of patients with clearly defined, stage IIIAnon-small-cell lung cancer. The patients were stratified accordingto the location and size of the tumor and according to lymph-nodestatus, because in other series30,31 survival varied accordingto the location and size of the primary tumor and the numberof lymph-node levels involved. In our analysis, however, thelocation of the tumor, its size, and the number of N2 levelsinvolved were not significant predictors of survival. The resultsof this trial demonstrate that preoperative chemotherapy improvessurvival.
Patients who have tumors with K-ras oncogene point mutationsconstitute a subgroup with a low rate of response to treatment,regardless of the stage of the disease32,33. In our previousstudy we found ras gene mutations in 20 percent of the patientswith non-small-cell lung cancer whose tumors were resected,and this subgroup had the poorest survival34. The differencewas also confirmed in the 12 patients with microscopical N2disease: the median survival time was 15 months for the 9 patientswho had tumors without K-ras oncogene mutations, as comparedwith 5 months for the 3 patients who had tumors with K-ras mutations34.Paradoxically, in the present study, the survival of the 24patients in the surgery group who had complete resections wasnot related to the presence or absence of mutated K-ras oncogenes.This discrepancy may be explained by the fact that bulky disease(a large tumor and clinically detectable N2 disease) itselfsignifies an unfavorable prognosis, in comparison with microscopicalmetastases discovered in mediastinal lymph nodes after surgery.
The difference between the ploidy patterns in the two treatmentgroups can be attributed to the effect of chemotherapy or possiblyto a secondary effect of the relative decrease in the numberof tumor cells due to an increase in the number of inflammatoryand stromal cells. The differences in ploidy between the groupswere significant, indicating an effect of chemotherapy and confirmingits effect on different tumors35. Chemotherapy may reverse thepattern of ploidy by selecting tumor subclones in which theDNA content is close to the diploid value and destroying thosewith a larger number of alterations in the DNA content.
Although the rules for stopping the trial were strictly followed,the early interruption in the enrollment of patients may raisequestions about the validity of our results. However, the largeand significant difference in survival between the two groups(P<0.001) leads us to conclude that the sample size and earlytermination of the trial do not affect the clinical importanceof our results.
Supported in part by a grant from Bristol-Myers Squibb Company,Madrid, Spain.
We are indebted to the chest physicians, thoracic surgeons,medical oncologists, and radiotherapists at the participatinghospitals; to Drs. M.H. Cullen and M.R. Green for their criticalreview of the manuscript; to Drs. J.J. Sanchez and I. Morenofor their assistance in the statistical analysis; and to Ms.M. O'Sullivan for her editing of the manuscript.
Source Information
From the Departments of Medical Oncology (R.R., S.L., Z.S., A.A.), Thoracic Surgery (J.M., M.C.), Pneumology (J.R., J.M.-P.), Radiology (A.O.), and Pathology (J.L.M., A.A.), University of Barcelona, Hospital de Badalona Germans Trias i Pujol, Barcelona; the Departments of Medical Oncology (J.G.-C.) and Thoracic Surgery (J.P.), Hospital La Fe, Valencia; and the Departments of Medical Oncology (C.C.) and Thoracic Surgery (A.C.), Hospital General, Valencia -- all in Spain. Presented in part at the 28th annual meeting of the American Society of Clinical Oncology, San Diego, Calif., May 17-19, 1992.
Address reprint requests to Dr. Rosell at the Medical Oncology Department, University Hospital Germans Trias i Pujol, Box 72, 08916 Badalona (Barcelona), Spain.
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