Chemotherapy and Survival in Non-Small Cell Lung Cancer: The Old Vexata Questio

Abstract

The history of chemotherapy for unresectable non-small cell lung cancer (NSCLC) is a history of alternation of therapeutic enthusiasm and nihilism.Following the results of the VALCG pioneer study,1Green RA Humphrey E Close H Patno ME Alkylating agents in bronchogenic carcinoma.Am J Med. 1969; 46: 516-525Abstract Full Text PDF PubMed Scopus (285) Google Scholar cytotoxic chemotherapy became, progressively through the 1960s and 1970s, the mainstream of the treatment for both protocol and out-of-protocol patients. All potentially active drugs and any possible variation of dosages and drug combination were tested. Emphasis was given to objective response rates, toxicity, and survival of selected subgroups (responders to chemotherapy vs nonresponders). Analysis of what was happening in the same years for the treatment of the small cell variant of lung cancer shows an increased rate of tumor response was expected to result in improved overall survival. Phase II and III clinical trials increased in number year by year.In spite of efforts, however, the goal remained unreached, the rate of responders remained far behind that observed in really sensitive tumors, and, as so often happens in medicine, the pendulum swung too fast in the opposite direction. A wave of widespread pessimism came over lung cancer experts.2MacKillop WJ O'Sullivan B Ward GK Non-small cell lung cancer: how oncologists want to be treated.Int J Radiat Oncol Biol Phys. 1987; 13: 929-934Abstract Full Text PDF PubMed Scopus (51) Google Scholar The attention was switched from tumor response and related variables to overall survival. It was recognized that almost no placebo-controlled study was available after thousands of patients had received the disputed treatment. Aggressive chemotherapy ended in being acceptable only for rigorous trials with a control arm and informed consent of the patients.3AnonymousAggressive treatment of lung cancer—How much benefit for the patient? [editorial].Lancet. 1985; 1: 222Google Scholar It is quite paradoxic that the revision was stirred up by the publication in 19824Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar of a study demonstrating for the first time the superiority of modern polychemotherapy regimen vs placebo. That year might be considered the birth-year of a new era of skepticism, which lasted to the present.Must we think, indeed, that the efforts of almost half a century have produced nothing and that we are still at the starting point? Are there new data concerning the old vexata questio of chemotherapy and survival benefits for NSCLC?.Since 1982, seven additional studies with a nochemotherapy control arm either have been reported5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar, 6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar or presented at international meetings.9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar, 10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar, 11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar There is much inhomogeneity among them. Two studies were limited to patients with metastases,8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar,9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar whereas locally advanced disease was usually included and consisted of roughly 50 percent of the sample. Only two studies adopted nonplatinum-based chemotherapy.4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar,11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar Planned duration of chemotherapy varied from the minimum of two cycles plus four cycles for responders6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar to the maximum policy of giving chemotherapy until disease progression.7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Rates of objective responses to chemotherapy ranged widely from the minimum of 8 percent11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar to 39 percent.9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar Prognostic factors were generally well balanced within studies but less among studies. As a consequence, the same survival duration of the control patients was not uniform, ranging from 8.54Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar to 21.6 weeks.7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Four studies reached statistical significance;4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar,5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar,9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar,11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar four others did not,6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar,10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar though in two it was approached for some subgroups.6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar,7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Conclusions ranged from the statement that chemotherapy “does benefit patients with inoperable NSCLC and that no patient with this type of cancer should go untreated,”4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar though the more dubious but still positive suggestion of “offering cytotoxic chemotherapy to good prognosis patients and then reevaluating,”5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar to the entirely negative position of not using chemotherapy at all as routine treatment.6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar,8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google ScholarThere is, however, a constant element in this mixup of data and this element has to be considered carefully in order to reach a possible final judgment. As everyone can easily note by personally reviewing the published reports,4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar, 5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar, 6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar, 9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar, 10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar, 11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar the median survival was prolonged by chemotherapy in each of the studies, ranging from 1 to 22 weeks. This was true even when the differences were not statistically significant, unless very large, clinical trials are not always capable of detecting modest but real differences at the significance level.12Freedman LS The size of clinical trials in cancer research—what are the current needs.Br J Cancer. 1989; 59: 396-400Crossref PubMed Scopus (22) Google Scholar On the other hand, the cumulative evidence from many small, nonsignificant studies can be very compelling, if their results lead in one direction & and a unidirectional bias can be excluded. Actually, one could hypothesize that oncologists, investigating the value of chemotherapy for NSCLC, would have preferred a result legitimizing their time-consolidated therapeutic approach or to have had some other reason for partiality (read: publication bias). On the contrary, it happened that the authors of nonsignificant reports emphasized in all their articles—and often in the very title—the negativity of results, clearly showing an unconscious inclination against chemotherapy. In this regard, our case is exemplary. After accruing 86 patients, we performed a preliminary analysis of the results.13Buccheri GF Ferrigno D Curcio A Rosso A Vola F Mazza R MACC-chemotherapy does not improve survival of patients with advanced lung cancer [abstract].Eur Resp J. 1988; 1 (suppl. 2): 243sGoogle Scholar Obviously, the power of the test was not great, but, nonetheless, we entitled it: “MACC-chemotherapy does not prolong survival &” Later, we had to reverse this title—and opinion—when the continuation of the study unequivocally contradicted our position.11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle ScholarIn conclusion, the overall survival benefit of chemotherapy for unresectable NSCLC must be real, since eight concordant results from eight independent studies cannot be obtained solely by chance and the existence of a unidirectional bias is very unlikely. The real size of the survival improvement, however, must be small or quite modest; hence, the difficulty of detecting it at the statistical level of significance. In this setting, other end-points, such as quality of life and costs, become important and warrant new specifically addressed trials. By now, the equilibrated judgment of the available evidence should suggest that we offer chemotherapy to all suitable patients with unresectable NSCLC. This suggestion will continue to be valid in the future, unless negative reports from ongoing psychosocial studies should come to light in the literature of this intriguing argument. The history of chemotherapy for unresectable non-small cell lung cancer (NSCLC) is a history of alternation of therapeutic enthusiasm and nihilism. Following the results of the VALCG pioneer study,1Green RA Humphrey E Close H Patno ME Alkylating agents in bronchogenic carcinoma.Am J Med. 1969; 46: 516-525Abstract Full Text PDF PubMed Scopus (285) Google Scholar cytotoxic chemotherapy became, progressively through the 1960s and 1970s, the mainstream of the treatment for both protocol and out-of-protocol patients. All potentially active drugs and any possible variation of dosages and drug combination were tested. Emphasis was given to objective response rates, toxicity, and survival of selected subgroups (responders to chemotherapy vs nonresponders). Analysis of what was happening in the same years for the treatment of the small cell variant of lung cancer shows an increased rate of tumor response was expected to result in improved overall survival. Phase II and III clinical trials increased in number year by year. In spite of efforts, however, the goal remained unreached, the rate of responders remained far behind that observed in really sensitive tumors, and, as so often happens in medicine, the pendulum swung too fast in the opposite direction. A wave of widespread pessimism came over lung cancer experts.2MacKillop WJ O'Sullivan B Ward GK Non-small cell lung cancer: how oncologists want to be treated.Int J Radiat Oncol Biol Phys. 1987; 13: 929-934Abstract Full Text PDF PubMed Scopus (51) Google Scholar The attention was switched from tumor response and related variables to overall survival. It was recognized that almost no placebo-controlled study was available after thousands of patients had received the disputed treatment. Aggressive chemotherapy ended in being acceptable only for rigorous trials with a control arm and informed consent of the patients.3AnonymousAggressive treatment of lung cancer—How much benefit for the patient? [editorial].Lancet. 1985; 1: 222Google Scholar It is quite paradoxic that the revision was stirred up by the publication in 19824Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar of a study demonstrating for the first time the superiority of modern polychemotherapy regimen vs placebo. That year might be considered the birth-year of a new era of skepticism, which lasted to the present. Must we think, indeed, that the efforts of almost half a century have produced nothing and that we are still at the starting point? Are there new data concerning the old vexata questio of chemotherapy and survival benefits for NSCLC?. Since 1982, seven additional studies with a nochemotherapy control arm either have been reported5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar, 6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar or presented at international meetings.9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar, 10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar, 11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar There is much inhomogeneity among them. Two studies were limited to patients with metastases,8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar,9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar whereas locally advanced disease was usually included and consisted of roughly 50 percent of the sample. Only two studies adopted nonplatinum-based chemotherapy.4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar,11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar Planned duration of chemotherapy varied from the minimum of two cycles plus four cycles for responders6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar to the maximum policy of giving chemotherapy until disease progression.7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Rates of objective responses to chemotherapy ranged widely from the minimum of 8 percent11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar to 39 percent.9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar Prognostic factors were generally well balanced within studies but less among studies. As a consequence, the same survival duration of the control patients was not uniform, ranging from 8.54Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar to 21.6 weeks.7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Four studies reached statistical significance;4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar,5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar,9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar,11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar four others did not,6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar,10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar though in two it was approached for some subgroups.6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar,7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar Conclusions ranged from the statement that chemotherapy “does benefit patients with inoperable NSCLC and that no patient with this type of cancer should go untreated,”4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar though the more dubious but still positive suggestion of “offering cytotoxic chemotherapy to good prognosis patients and then reevaluating,”5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar to the entirely negative position of not using chemotherapy at all as routine treatment.6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar,8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar There is, however, a constant element in this mixup of data and this element has to be considered carefully in order to reach a possible final judgment. As everyone can easily note by personally reviewing the published reports,4Cormier Y Bergeron D La Forge J Lavandier M Fournier M Chenard J et al.Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma.Cancer. 1982; 50: 845-849Crossref PubMed Scopus (122) Google Scholar, 5Rapp E Pater JL Willan A Cormier Y Murray N Evans WK et al.Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer—Report of a Canadian multicenter randomized trial.J Clin Oncol. 1988; 6: 633-641Crossref PubMed Scopus (667) Google Scholar, 6Woods R Williams CJ Levi J Page J Bell D Byrne M et al.A randomised trial of cisplatin and vindesin versus supportive care only in advanced non-small cell lung cancer.Br J Cancer. 1990; 61: 608-611Crossref PubMed Scopus (159) Google Scholar, 7Cellerino R Tummarello D Porfiri E Guidi F Isidori P Raspugli M et al.Non small cell lung cancer (NSCLC). A prospective randomized trial with alternating chemotherapy CEP/MEC versus no treatment.Eur J Cancer Clin Oncol. 1988; 24: 1839-1843Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 8Ganz PA Figlin RA Haskell CM La Soto N Siau J Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.Does chemotherapy make a difference? Cancer. 1989; 63: 1271-1278Google Scholar, 9Quoix E Dietemann A Charbonneau J Boutin C Maurice JC Pauli G et al.Disseminated non small cell lung cancer (NSCLC): a randomized trial of chemotherapy (CT) versus palliative care (PC) [abstract].Lung Cancer. 1988; 4 (suppl. 1): 127aGoogle Scholar, 10Kaasa S Lund E Host H Hatlevoll R Combination chemotherapy versus symptomatic treatment in patients with non small cell lung cancer, extensive disease.5th European Conference on Clinical Oncology. 1989; (London, September 3–7, (0–0007))Google Scholar, 11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar the median survival was prolonged by chemotherapy in each of the studies, ranging from 1 to 22 weeks. This was true even when the differences were not statistically significant, unless very large, clinical trials are not always capable of detecting modest but real differences at the significance level.12Freedman LS The size of clinical trials in cancer research—what are the current needs.Br J Cancer. 1989; 59: 396-400Crossref PubMed Scopus (22) Google Scholar On the other hand, the cumulative evidence from many small, nonsignificant studies can be very compelling, if their results lead in one direction & and a unidirectional bias can be excluded. Actually, one could hypothesize that oncologists, investigating the value of chemotherapy for NSCLC, would have preferred a result legitimizing their time-consolidated therapeutic approach or to have had some other reason for partiality (read: publication bias). On the contrary, it happened that the authors of nonsignificant reports emphasized in all their articles—and often in the very title—the negativity of results, clearly showing an unconscious inclination against chemotherapy. In this regard, our case is exemplary. After accruing 86 patients, we performed a preliminary analysis of the results.13Buccheri GF Ferrigno D Curcio A Rosso A Vola F Mazza R MACC-chemotherapy does not improve survival of patients with advanced lung cancer [abstract].Eur Resp J. 1988; 1 (suppl. 2): 243sGoogle Scholar Obviously, the power of the test was not great, but, nonetheless, we entitled it: “MACC-chemotherapy does not prolong survival &” Later, we had to reverse this title—and opinion—when the continuation of the study unequivocally contradicted our position.11Buccheri GF Rosso A Ferrigno D Vola F Cecchini C Castellino R Polychemotherapy does prolong the survival of patients with advanced non-small cell lung cancer. A controlled study.XVI World Congress on Diseases of the Chest. 1989; (Boston, October 30-November 3): 118sGoogle Scholar In conclusion, the overall survival benefit of chemotherapy for unresectable NSCLC must be real, since eight concordant results from eight independent studies cannot be obtained solely by chance and the existence of a unidirectional bias is very unlikely. The real size of the survival improvement, however, must be small or quite modest; hence, the difficulty of detecting it at the statistical level of significance. In this setting, other end-points, such as quality of life and costs, become important and warrant new specifically addressed trials. By now, the equilibrated judgment of the available evidence should suggest that we offer chemotherapy to all suitable patients with unresectable NSCLC. This suggestion will continue to be valid in the future, unless negative reports from ongoing psychosocial studies should come to light in the literature of this intriguing argument.