Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†.

BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients.

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.

Quality of life and comorbidity score as prognostic determinants in non-small-cell lung cancer patients.

BACKGROUND: Both quality of life (QoL) and comorbidity influence therapy and prognosis of non-small-cell lung cancer (NSCLC). We previously developed a lung cancer disease-specific simplified comorbidity score (SCS) and demonstrated the prognostic impact of this disease-specific instrument. This study aimed at validating the SCS in a prospective bicentric NSCLC population by measuring its relative prognostic determinant impact taking into account well-established variables such as QoL, performance status (PS), Charlson comorbidity index (CCI) and disease stage. PATIENTS AND METHODS: Prognostic values of different pretherapeutic features were tested in univariate and multivariate analyses in a population of 301 NSCLC. RESULTS: Median survival was 17 months. One-third of patients reporting difficulties in their normal daily activities and an overall poor QoL. The following pretreament variables were independent determinants of a shorter overall survival: advanced disease, SCS, Lung Cancer Symptoms Scale global symptoms score, anaemia, hyponatremia, serum alkaline phosphatases level, serum CYFRA 21-1 and serum neuron-specific enolase. CONCLUSION: In this extended validation population, the SCS is more informative than the CCI in predicting NSCLC patient outcome as the former is also more disease specific. Combination of both SCS comorbidity score and LSCC QoL yields a more accurate information that conventional analysis of PS.

[The Delivery of the message, from concept to practice]. / Le dispositif d'annonce, du concept à la pratique.

Communication in oncology often means communicating in difficult circumstances. Moreover, "to tell" is an essential requirement in medicine. We need to make this communication a series of realistic proposals and proceed step by step. This is probably one of the greatest challenges that we have to face in oncology. The Delivery of the message consists of using the first consultation as an opportunity to speak of what is possible. In so doing we present the patient with the means to fight the disease and also give him support. Support is not palliative, not a "lack of...", but a vital part of our work that can not be reduced to a technique.

[Diagnostic. Announcing cancer. From concept to practice]. / Le dispositif d'annonce. Du concept à la pratique.

Communicating in oncology belongs to communicate in difficult circumstances. Moreover, "to say" is a medical requirement. We need to make this communication a field of realistic proposals and proceed step by step. This is probably one of the greatest challenges that we have to face in oncology. Organizing first medical consultation in oncology might offer an opportunity to speak with patient of any possible issues. In doing so, give it the means to fight and it is also accompany him. Accompanying this is not a palliative, not a "lack of...". This is the noble part of our work that can not be reduced to the technique.

[Small cell lung cancer and immuno-oncologic agents: End of the cisplatin - etoposide era?] / Cancer bronchique à petites cellules et agent onco-immunologique : peut-on sortir de l'ère du tout cisplatine étoposide ?

In the setting of small cell lung cancer (SCLC), the development of immuno-oncological agents, particularly those targeting Programmed cell Death protein 1 (PD-1) and Programmed cell Death protein Ligand 1 (PD-L1), is still at an early stage. Two critical elements need to be considered : the current data are extracted from Phase I and Phase II trials and the level of evidence from phase III trials has not been reached as it has been for non-small cell lung cancer (NSCLC) or for malignant melanoma ; The second aspect is the slow development of predictive factors for response to the immuno-oncological agents targeting the PD-1 receptor and its ligand. The clinical data are still too fragmentary to produce recommendations, although the improvement in progression-free survival seen in different phase II studies is promising. The expectation of clinicians dealing withSCLC is an indication of the challenge that this disease currently poses to oncology and justifies a focused clinical research effort.

[What do chemotherapy specialists expect of lung cancer?] / Qu'attendent les médecins spécialistes de la chimiothérapie des cancers du poumon ?

OBJECTIVE: In an attempt to understand physicians' expectations of chemotherapy, a group of lung cancer specialists was involved in an online survey investigating their opinions by a self-questionnaire. The questionnaire described five different chemotherapy prescription situations for lung cancer patients (stages IIIB or IV). METHOD: A total of 30 expert specialists were invited; 22 responded (73%). For each of the clinical situations, the expert was asked for his opinion on 3 items: cure, prolongation of survival and alleviation of symptoms. Each item was judged on a Likert scale with categories between -2 "not at all probable" and +2 "quite likely". RESULTS: For "cure", the percentage of -2 responses differed significantly according to the clinical situation (Fisher test: P<0.00001). The trend test showed a relationship between the percentage of -2 responses and the suspected order of the clinical situations (Cochran-Armitage trend test: P<0.0001). For symptom alleviation, the percentage of responses +2 and +1 differed significantly according to the clinical situation (Fisher test: P=0.00013, trend test: P<0.0001). CONCLUSION: What specialist physicians expect of chemotherapy in terms of curability and symptom relief differs according to the actual statistical prognosis of each situation as presented in the literature. The worst prognostic situation leads to the strongest expectation in terms of symptom relief and, conversely, the lowest for curability.

[Smoking cessation in patients with lung cancer]. / Indications et méthodes d'aide au sevrage tabagique chez un patient fumeur atteint de cancer bronchique.

Smoking cessation is an important part of the management of patients with lung cancer. Continued smoking has been found to diminish treatment efficacy, to exacerbate side effects and to have a detrimental effect on survival. Smoking increases postoperative pulmonary complications and tolerance and efficacy of medical treatment (chemotherapy, targeted therapy, radiotherapy) are diminished. Moreover, the quality of life of current smokers is lower and the risk of a second primary malignancy is increased. Hospitalization is a good opportunity to propose smoking cessation. Clinical practice guidelines recommend the use of combined behavioral and pharmacological therapies. The efficacy of smoking cessation programs for cancer patients has been demonstrated. There is a clear dose-response relationship between number of contacts, intensity level of person-to-person contact and total amount of contact time. Multidisciplinary approaches increase abstinence rates. First line phamacotherapies (nicotine replacement therapy and sustained-release antidepressant bupropion) have been found to be safe and effective. Varenicline is a new drug for smoking cessation but it remains to be evaluated in oncology patients.

Imaging of postoperative complications following surgery for lung cancer.

The complications following surgery for lung cancer vary depending upon the comorbidities and the type of surgery. Hemorrhage, infections and pulmonary edemas are not specific to the type of resection but frequently occur following pneumonectomies. Morbidity following pneumonectomies is related to the significant changes in the contents of the intrathoracic space. Pulmonary infarction and torsion are emergency situations that develop following lobectomy. CT shows features of localized congestion and stenosis or occlusion of a vein or bronchus. Rapid identification of severe events, in particular by systematic CT is essential for appropriate management of a postoperative or delayed complication of lung cancer surgery.

Immune response induced in small-cell lung cancer by maintenance therapy with interferon gamma.

BACKGROUND: Chemotherapy, with or without radiotherapy, results in a 30%-40% complete response rate in small-cell lung cancer (SCLC), but approximately 90% of patients who have complete remission die within 2 years after relapse with chemoresistant disease. Randomized clinical studies of maintenance chemotherapy after complete response have failed to demonstrate survival advantage. However, studies have shown that the human cytokine interferon gamma (IFN-gamma) induces immune response in humans, including T-cell activation and expression of class II major histocompatibility complex (HLA-DR) and receptor for the Fc portion of immunoglobulin on monocytes. It has also been demonstrated that recombinant IFN-gamma (rIFN-gamma) induces immunomodulation and has antiproliferative activity. PURPOSE: In vivo effects of rIFN-gamma treatment were characterized by flow cytometric analysis of peripheral blood mononuclear cells in patients with SCLC who received rIFN-gamma as maintenance treatment. METHODS: After induction chemotherapy and radiotherapy, 100 patients who achieved a complete remission were randomly assigned to receive rIFN-gamma at a dose of 0.2 mg (4 x 10(6) units) once a day, subcutaneously, for 6 months, or observation only. In 31 patients, peripheral mononuclear cells were obtained prior to the study and at weeks 4, 8, and 12 for serial monitoring of immune response. By flow cytometric analysis, we identified the lymphocyte and monocyte populations using characteristic differences in electronic volume and right-angle scatter. In these populations, we determined the mean fluorescence channel after staining for CD14 (antigen expressed on monocytes), CD3 (antigen expressed on T lymphocytes), and HLA-DR (HLA class II expressed by monocytes and activated lymphocytes). To determine the number of Fc receptors per cell, an Fc receptor assay was performed using the monocyte cell line U937 as a standard. RESULTS: At weeks 4, 8, and 12, expression of HLA-DR and Fc receptors on monocytes in patients who received rIFN-gamma was significantly higher than that in untreated patients, and the difference was statistically significant. The number of Fc receptors per monocyte consistently increased during the rIFN-gamma treatment and reached a fivefold elevation at week 12. There was no statistically significant difference in lymphocyte surface antigen expression between the treated and untreated groups. CONCLUSION: The dose of rIFN-gamma used in this study resulted in immune stimulation in patients with SCLC who had complete remission after induction therapy. The in vivo immunomodulatory activity of rIFN-gamma in such patients is characterized by a strong monocyte activation but no significant alteration in T-cell activation.

Etoposide plus cisplatin with or without the combination of 4'-epidoxorubicin plus cyclophosphamide in treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study.

BACKGROUND: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). METHODS: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m(2) on days 1-3 plus cisplatin at 100 mg/m(2) on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m(2) on days 1-3 and 4'-epidoxorubicin at 40 mg/m(2) on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. RESULTS: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P =.02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P =.0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P =.0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P =.22). The global health status showed similar improvement in both arms during treatment. CONCLUSION: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.

[Chemotherapy treatment for anti-Hu paraneoplastic syndrome without active malignancy]. / Traitement par chimiothérapie d'un syndrome neurologique paranéoplasique anti-Hu sans cancer actif associé

INTRODUCTION: Anti-Hu associated paraneoplastic neurological syndromes are rare and characterized by poor prognosis. The research and treatment of a related cancer, a small-cell lung cancer most of the time, remains the best therapeutic strategy. CASE REPORT: We describe the clinical course of a paraneoplastic subacute sensory neuronopathy associated with anti-Hu antibodies in a male smoker treated by an early chemotherapy active against a small-cell lung cancer although no tumor could be found at repeated evaluations. In spite of this treatment, the neurological state deteriorated with the appearance of a cerebellar degeneration, and limbic encephalitis which resulted in a loss of autonomy. A small-cell lung cancer was found and treated 65 months after the onset of the neurological symptoms. The treatment of the underlying malignancy, when it can be found, is still considered as the optimal treatment for paraneoplastic neurological syndromes. Although no tumor could be found, we treated our patient with an empirical chemotherapy active against the most frequent malignancy associated to anti-Hu syndrome in a smoker man, without any improvement. CONCLUSION: Active and repeated research for a cancer related to an anti-Hu neurological syndrome and its treatment are undispensable. For our patient without any identified cancer empirical chemotherapy treatment was unable to stop neurological worsening. When no tumor can be identified by conventional imaging techniques, an early FDG-PET scan should be considered and then repeated if normal.

[Treatment of epithelial thymic tumours: towards a multidisciplinary management]. / Traitement des tumeurs épithéliales thymiques.

INTRODUCTION: Thymic epithelial tumours (TET) are rare. Their optimal management is still not well defined on account of their rarity and the consequent difficulty of clinical research into the subject. This review presents the current clinical and therapeutic data, emphasising the need for a multidisciplinary management of advanced stage TET. CURRENT SITUATION: Three situations may be defined: localised tumours requiring radical surgery following a careful search for associated paraneoplastic syndromes; tumours with capsular invasion requiring surgery and adjuvent radiotherapy; advanced stage TET where only multimodal treatment is capable of improving the prognosis by increasing the percentage of complete resections while optimising local control with adjuvent radiotherapy. VIEWPOINT: An evaluation of the multimodal strategies for the treatment of advanced stage TET requires the establishment of multidisciplinary collaborative trials. The contribution of new therapies, somatostatin analogues and targeted therapies needs to be defined. CONCLUSIONS: The management of advanced stage TET should rest upon a multidisciplinary dialogue between a team of specialists, ideally in the framework of collaborative trials.

[Small cell lung cancer (CPC). Small cell bronchial carcinoma: therapeutic management]. / Les cancers à petites cellules (CPC). Prise en charge thérapeutique.

Small cell bronchial carcinoma holds a prominent position among malignant tumours on account of its high incidence and the problems of its treatment. The diagnostic approach is dictated by the concern not to overlook any metastatic sites. Small cell bronchial carcinoma is often metastatic at the time of diagnosis and should be considered an actual or potential systemic disease. Chemotherapy is therefore the basis of treatment. It should consist of at least a two drug regime combining cisplatin and etoposide. In extensive disease, that is when all the disease cannot be contained within one irradiation field, chemotherapy alone is recommended. In limited disease combined simultaneous radiotherapy and chemotherapy is recommended. Prophylactic cranial irradiation is indicated in patients in complete remission after chemotherapy. The therapeutic armamentarium has recently been enlarged by the development of new antineoplastic drugs and the development of non-toxic targeted agents including those influencing angiogenesis. The understanding of the specific mechanisms of drug resistance and the study of the tumour phenotypes and genotypes will allow, in the future, the development of treatments adapted for each patient.

Serum fragment of cytokeratin subunit 19 measured by CYFRA 21-1 immunoradiometric assay as a marker of lung cancer.

Cytokeratin 19 is a subunit of cytokeratin intermediate filament expressed in simple epithelia and their malignant counterparts. Therefore, it is expressed by respiratory epithelium cells and has been detected in lung cancer specimens. An immunoradiometric assay was used to detect a fragment of the cytokeratin 19, referred to as CYFRA 21-1, in the serum of 165 patients with histologically proved lung cancer (128 non-small cell and 37 small cell lung cancers). This prospective study was conducted to evaluate the reliability of this immunoradiometric assay and to identify the relationship between serum CYFRA 21-1 and different features of lung cancer including prognosis. The minimal detectable concentration detected by this assay was 0.06 ng/ml. The reliability of the immunoradiometric assay was demonstrated by the linear relationship between CYFRA 21-1 measurement and dilution of the serum, the reproducibility of the dosage in intraassay and interassay, and the high sensitivity of the method in discriminating low CYFRA 21-1 concentrations. Using a threshold of 3.6 ng/ml, sensitivity and specificity were 0.52 and 0.87, respectively. The sensitivity of the marker was highest in squamous cell carcinoma and lowest in small cell carcinoma. In non-small cell lung cancer patients, the marker varied significantly according to both stage of the disease (Kruskal-Wallis, 13.7; P < 0.005) and performance status (Kruskal-Wallis, 9.16; P < 0.05) inasmuch as a high serum CYFRA 21-1 level was associated with advanced stages, mediastinal lymph nodes, and poor performance status. Consequently, the marker was significantly lower in patients who were operated upon when compared with unresectable ones. Lung cancer patients with serum CYFRA 21-1 over 3.6 ng/ml proved to have a significantly shorter overall survival than those with a normal serum level (log rank, P = 0.007; Wilcoxon, P = 0.001). The negative prognostic effect of CYFRA 21-1 was highly significant in squamous cell carcinomas whereas it was nonsignificant for the other histologies. In Cox's model analysis, performance status, stage grouping, and CYFRA 21-1 were the only significant determinants of survival. This study supports the use of the serum fragment of cytokeratin subunit 19 CYFRA 21-1 as an independent prognostic marker of squamous cell carcinoma of the lung.

In situ evaluation of growth fraction determined by monoclonal antibody Ki-67 and ploidy in surgically resected non-small cell lung cancers.

Ploidy and growth fraction were analyzed by means of a computer-assisted image processor in surgically resected non-small cell lung cancer (NSCLC). This study was done in order (a) to evaluate the distribution of anti-Ki-67 immunostaining and (b) to correlate this distribution to ploidy status and pTNM stage of NSCLC. Thirty-two patients underwent a surgical resection for primary NSCLC following complete staging. Indirect immunoperoxidase reactions of monoclonal antibody Ki-67 were done on frozen tissue sections. Integrated optical density and index of stained nuclear surface were calculated by means of a computer-assisted image processor in 120 fields of each preparation in order to quantify the Ki-67 immunostaining. DNA content was determined by means of cytometry of Feulgen-stained cytological prints. The ploidy status was defined for each tumor by DNA index, percentage of hypodiploid cells, and type of DNA content histogram (near diploid, hyperdiploid, hypodiploid, and multiploid). Reproducibility of immunostaining quantitative analysis was demonstrated by iterative measurements of the same slide. Intratumoral heterogeneity of Ki-67 immunostaining induced integrated optical density variation assessed on six nonconsecutive tissue sections from at least two regions of the same tumor. This intratumoral variability was 15 times lower than integrated optical density variability between tumors. The Ki-67 immunostaining varied significantly according to the DNA content histogram type (P less than 0.05, Kruskal-Wallis test); most of the specimens with high Ki-67 immunostaining were multiploid or hypodiploid. Moreover, Ki-67 immunostaining correlated to the percentage of hypodiploid cells. Ki-67 immunostaining and ploidy status did not vary significantly according to the tumor-nodes-metastasis stage. We conclude that (a) quantitative analysis of Ki-67 immunostaining is a reliable evaluation of growth fraction in NSCLC if a large number of fields are analyzed to take into account intratumoral variability, (b) hypodiploidy and multiploidy are frequent abnormalities of DNA content, (c) Ki-67 immunostaining is significantly higher in hypodiploid and multiploid tumors. Thus, determination of growth fraction and ploidy in surgically resected NSCLC specimens may be considered as complementary prognostic parameters independent of the stage of the disease.

Phenotypic heterogeneity studied by immunohistochemistry and aneuploidy in non-small cell lung cancers.

Non-small cell lung cancers (non-SCLC) differ from small cell lung cancers (SCLC) by many clinical features and prognosis. However, recent studies suggest that lung cancer heterogeneity frequently leads to the association of SCLC and non-SCLC in the same tumor. This phenotypic heterogeneity can be analyzed by immunohistochemistry using monoclonal antibodies (Mab) raised against differentiation related antigens. It may have clinical relevance inasmuch as the diversification of malignant cells is a well-known factor of tumor progression and may be due to chromosomal instability because inappropriate gene expression leads to the formation of antigens unrelated to cell lineage. Chromosomal instability in cancer leads to aneuploidy detectable by cell DNA content analysis. In a prospective study, we analyzed, in parallel, the expression of neuroendocrine related antigens by immunohistochemistry and the cell DNA content in frozen specimens from 40 patients who underwent complete surgical resection of primary non-SCLC in an attempt (a) to characterize the phenotypic heterogeneity and (b) to determine whether this heterogeneity is correlated with aneuploidy and clinical staging. Three Mabs were used in association as a marker of neuroendocrine antigen expression (S-L 11.14, MOC-1, and NE-25); reactivity of these Mabs in 9 SCLC and 3 lung carcinoid tissue sections was used as positive control. All SCLC and 2 of 3 lung carcinoids tested were homogeneously positive with Mabs S-L 11.14, MOC-1, and NE-25; 13 of 40 non-SCLC were homogeneously positive and 11 additional specimens focally positive with Mabs S-L 11.14, MOC-1, and NE-25. The frequency of this abnormal phenotype was significantly higher in poorly differentiated squamous cell carcinomas (chi 2 10.08; P less than 0.005), in clinical stage III non-SCLC (chi 2 5.93; P less than 0.02), and in tumors involving mediastinal lymph nodes (chi 2 5; P less than 0.03). The percentage of cells in the modal DNA of G0-G1 phase was significantly lower in non-SCLC homogeneously positive with Mabs S-L 11.14, MOC-1, and NE-25 [27.4 +/- 10.3% (SD)] in comparison with non-SCLC negative with these same Mabs [56.8 +/- 21.3%; P less than 0.01, Mann-Whitney U test]. We conclude that (a) mixed SCLC-non-SCLC differentiation is frequent and can be assessed by immunohistochemistry, (b) neuroendocrine differentiation in non-SCLC is mainly observed in poorly differentiated tumors and in advanced clinical stages, and that (c) this heterotopic phenotype is correlated with aneuploidy and has clinical implications.