Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Addressing the unmet need in lung cancer: The potential of immuno-oncology.

Chemotherapy is currently the standard of care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Furthermore, only a small percentage of patients derive benefit from later-line therapy, with most experiencing deteriorating quality of life and significant toxicities. More recently, molecular targeted therapies have provided improvements in outcomes. However, these treatments only offer a clear benefit in subsets of tumours harbouring the appropriate genomic alteration (mutation, amplification, translocation). Most of the genomic abnormalities susceptible to therapeutic intervention are detected in adenocarcinoma, mainly in never smokers, while alterations in the genome of other histological subtypes are known but specific agents targeting these alterations have yet to be developed. Thus, the therapeutic management of these subtypes represents an ongoing challenge. Recent advances in immunotherapy have highlighted the potential of immuno-oncology based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. This review discusses the current unmet medical needs in NSCLC, the limits of current first-line and later-line chemotherapy and targeted agents, and the emergence of new therapeutic strategies.

Vaccination therapy for non-small-cell lung cancer: review of agents in phase III development.

The historical results of cancer vaccination for non-small-cell lung cancer (NSCLC) were disappointing. In the current decade, however, new insights in the interaction between tumours and the immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Modern NSCLC vaccine strategies rely on better identification of antigenic targets, addition of strong immunoadjuvants, and use of more efficient delivery systems. These treatments have convincingly demonstrated to elicit potent immune responses and have shown promising efficacy signals and excellent tolerability in phase II randomised studies. This-together with recent positive phase III data in indications other than NSCLC-has helped to establish the proof of principle for cancer vaccination. In NSCLC, ongoing phase III trials are investigating this approach in different treatment settings: the Melanoma AntiGEn A3 vaccine in resected early-stage NSCLC, the L-BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy, and belagenpumatucel-L, the epidermal growth factor and the TG4010 vaccine in advanced stage, either as an adjunct to chemotherapy or as maintenance after completion of chemotherapy. Mode of action, development, available clinical data, and currently ongoing phase III studies are reviewed.

Cost-utility analysis of chemotherapy in symptomatic advanced nonsmall cell lung cancer.

When using chemotherapy in patients with a short life expectancy, outcomes such as symptom improvement or clinical benefit receive increasing attention. Outcomes of subjective benefit to the patient can be rated as a utility in order to perform health economic analyses and comparisons with other treatment conditions. A cost-utility analysis has been performed alongside a prospective randomised clinical trial comparing single agent gemcitabine to cisplatin-based chemotherapy in symptomatic advanced nonsmall cell lung cancer patients. Global quality of life as well as resource utilisation data were collected during first-line chemotherapy for both treatment arms. Incremental costs, utilities and cost-utility ratio were calculated. Per patient, an incremental cost of 1,522 was obtained for gemcitabine compared to cisplatin-vindesine, mainly as a consequence of the direct cost of the cytotoxic drugs. When combined with utilities, this resulted in an incremental cost-utility ratio for gemcitabine of 13,836 per quality-adjusted life year gained. In conclusion, although the least expensive strategy is cisplatin-vindesine, the greater clinical benefit of gemcitabine, resulting in an acceptable incremental cost-utility ratio as compared with other healthcare interventions, balances its higher cost. The gains in subjective outcome achieved with palliative chemotherapy are critical from both a clinical and a health economic point of view.

Early versus late chest radiotherapy for limited stage small cell lung cancer.

BACKGROUND: It is standard clinical practice to combine chemotherapy and chest radiotherapy in treating patients with limited-stage small cell lung cancer. However, the best way to integrate both modalities is unclear. OBJECTIVES: To establish the most effective way of combining chest radiotherapy with chemotherapy for patients with limited-stage small cell lung cancer in order to improve long-term survival. SEARCH STRATEGY: The electronic databases MEDLINE, EMBASE, Cancerlit and the Cochrane Central Register of Controlled Trials (CENTRAL), reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished. SELECTION CRITERIA: Randomised controlled clinical trials comparing different timing of chest radiotherapy in patients with limited-stage small cell lung cancer. DATA COLLECTION AND ANALYSIS: Seven randomised trials were reviewed. There were differences in the timing and the overall treatment time of chest radiotherapy, the overall treatment time of , and the type of chemotherapy used. MAIN RESULTS: No significant differences in the 2-year and the 5-year survival were found, whether chest radiotherapy was delivered within 30 days after the start of chemotherapy or later. When the only study that delivered chest radiotherapy during cycles of non-platinum chemotherapy was excluded, a trend for the 5-year survival was observed (RR:0.93, p=0.07) in favour of early radiation, but not for the 2-year survival. Survival at 5 years, but not at 2 years, was significantly better for those having early chest radiotherapy delivered in an overall treatment time of less than 30 days compared with a longer treatment time (RR: 0.90, p=0.006). These results, however, should be interpreted with caution because the largest trial has follow-up data at three years, but not later. It remains to be seen what the effect of longer follow up will be for 5-year survival rates. Local tumour control was not significantly different between early and late chest radiotherapy. The incidence of severe pneumonitis or severe oesophagitis was not significantly different for early versus late thoracic radiotherapy. However, a trend for a higher chance to develop pneumonitis when early chest radiotherapy was delivered during non-platinum based chemotherapy was observed. AUTHORS' CONCLUSIONS: At present, it is uncertain whether the timing of chest radiotherapy as such is important for survival. The optimal integration of chemotherapy and chest radiotherapy in patients with limited-stage small cell lung cancer is unknown. Therefore, further research is needed to establish the most effective combination of radiotherapy and chemotherapy in this disease.

Imaging in lung cancer: positron emission tomography scan.

In the past 5 yrs, positron emission tomography (PET), usually used with 18F-fluoro-2-deoxy-glucose (FDG), has become an important imaging modality in lung cancer patients. Currently, the use of FDG-PET in respiratory oncology is mainly for diagnosis and staging. Standard indications are the evaluation of an indeterminate solitary pulmonary nodule or mass, where FDG-PET has proven to be significantly more accurate than computed tomography (CT) in the distinction between benign and malignant lesions. Several studies have also convincingly demonstrated that locoregional lymph node staging by FDG-PET (in correlation with CT images) is significantly superior to CT, with a negative predictive value equal or even superior to mediastinoscopy. FDG-PET also improves extrathoracic staging, through the detection of lesions missed at conventional imaging or characterization of lesions that remain equivocal on conventional imaging. Many European countries now have or plan reimbursement in these indications. Large-scale randomized studies should now focus on the impact this accurate tumour imaging technique has on treatment outcome and cost-efficacy. Ongoing studies in specialized centres focus on the use of FDG-PET in more advanced clinical applications, such as planning radiotherapy, response evaluation after radiotherapy or (induction) chemotherapy, follow-up and early detection of recurrence, and prognostic information in this in vivo measurement of tumour glucose metabolism. After a short note on the technique used and a summary of the current common indications of diagnosis and staging, this paper will deal mainly with two of the more advanced clinical applications of FDG-PET in locally advanced nonsmall cell lung cancer: radiation treatment planning and assessment of induction chemotherapy. Finally, it should be mentioned that a whole new field of applications of positron emission tomography in molecular biology, using new radiopharmaceutical probes, is under extensive investigation. These techniques are promising for future use in very early response monitoring during chemo- or radiotherapy, in evaluation of novel molecular-targeted lung cancer therapies, or even gene therapy.

Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine.

BACKGROUND: The modest improvement in median survival of advanced non-small-cell lung cancer (NSCLC) by cisplatin-based chemotherapy has led to the current opinion that clinical benefit for the patient is at least as important an end-point as objective response rate (ORR) or survival. Clinical benefit response was the primary end-point of this prospective randomised trial in symptomatic, advanced stage IIIB/IV NSCLC, comparing single agent gemcitabine (GEM) to cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m2, days 1, 8 and 15) or cisplatin (100 mg/M2, day 1) plus Vindesine (3 mg/m2, days 1 and 15) (PV), both every four weeks. Clinical benefit was measured by a simple metric based on changes in a visual analogue symptom score list, the Karnofsky performance status and the weight. RESULTS: One hundred sixty-nine patients were randomised (84 GEM, 85 PV). Prognostic factors and baseline symptoms were well balanced between the two arms. Most of the the objective responders and about half of the patients with disease stabilisation experienced clinical benefit. Compared to PV, a significantly larger number of GEM-treated patients experienced a clinical benefit (48.1 vs. 28.9%, P = 0.03) that lasted significantly longer (median duration 16 vs. 10 weeks, P = 0.01). No important differences in ORR, time-to-progression or median survival were observed. Grade 3 + 4 toxicity was significantly higher in the PV-group for leukopenia (P = 0.0003), neutropenia (P < 0.0001), nausea/vomiting (P = 0.0006), alopecia (P < 0.0001), and neurotoxicity (P = 0.04). Some severe pulmonary toxicity to GEM was noted. CONCLUSION: Comparison of GEM with cisplatin-based therapy in symptomatic, advanced NSCLC demonstrates that GEM produces significantly a stronger and longer-lasting clinical benefit, probably due to its equal effectiveness in terms of ORR, time-to-progression or survival, combined with significantly less severe therapy-related toxicity.

Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up.

OBJECTIVES: To examine the survival after surgical treatment of patients presenting with two synchronous suspect lung lesions, and to reflect on the recent TNM classification, which has upgraded patients with two malignant lung lesions of the same histology into the T4 (both lesions in the same ipsilateral lobe) or M1 (different lobes or lungs) category. METHODS: Retrieval of all consecutive patients with a diagnosis of two synchronous suspect lung lesions in the prospective database of the Leuven Lung Cancer Group in the interval between 1990 and 1994. Analysis of characteristics and survival of all patients, who underwent surgical resection with intention to cure for both lesions. RESULTS: Forty-eight of 54 patients had surgical resection with curative intent. Thirty-five of these proved to have two malignant lesions, in 13 the second lesion was benign. The 5-year survival rate in the patients with two malignant lesions was 33% (95% CI: 17-49). The median survival time was 28 months. Although the number of patients in the subgroups was small, there were no obvious differences between patients with two lesions in the same or in different lobes, if a complete resection could be achieved. CONCLUSIONS: An aggressive surgical approach in carefully selected patients presenting with two suspect pulmonary lesions can be rewarding. Although some degree of upstaging is appropriate in patients with two malignant lung tumours of the same histology, their current stage IIIB or IV classification probably underestimates their prospects for long-term survival after radical resection.

The role of positron emission tomography with 18F-fluoro-2-deoxy-D-glucose in respiratory oncology.

In the past 5 yrs, positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG) has become an important imaging modality in lung cancer patients. At this time, the indication of FDG-PET as a complimentary tool to computed tomography in the diagnosis and staging of nonsmall cell lung cancer has gradually gained more widespread acceptance and also reimbursement in many European countries. This review focuses on the data of FDG-PET in the diagnosis of lung nodules and masses, and in locoregional and extrathoracic staging of nonsmall cell lung cancer. Emphasis is put on the potential clinical implementation of the currently available FDG-PET data. The use of FDG-PET in these indications now needs further validation in large-scale multicentre randomized studies, focusing mainly on treatment outcome parameters, survival and cost-efficacy. Interesting findings with 18F-fluoro-2-deoxy-D-glucose-positron emission tomography have also been reported for the evaluation of response to radio- or chemotherapy, in radiotherapy planning, recurrence detection and assessment of prognosis. Finally, a whole new field of application of positron emission tomography in molecular biology, using new radiopharmaceuticals, is under extensive investigation.

Syndrome of inappropriate antidiuretic hormone associated with chemotherapy-induced tumour lysis in small-cell lung cancer: case report and literature review.

A patient with a small-cell lung cancer (SCLC) developed an asymptomatic hyponatremia, with all features of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), two days after the start of his first cycle of chemotherapy with vindesine, ifosfamide and cisplatin. Progression of the tumour with an increase in paraneoplastic SIADH, or drug-induced causes of hyponatremia, could be ruled out by his further clinical course. The event was interpreted as a consequence of ADH release during the initial tumour cell lysis after effective chemotherapy. The occurrence of hyponatremia during the initial phase of chemotherapy for SCLC should be interpreted with caution. Although it is most commonly due to an increase in paraneoplastic ADH secretion reflecting ineffective therapy, it can also be due to release of ADH from malignant cells in the period of rapid tumour lysis, reflecting effective therapy. Based on this rare occurrence, a review of the aetiology, clinical findings, diagnosis, prognosis and treatment of SIADH in general is presented.

The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.

PURPOSE: (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with computer tomography (PET-CT) is superior to CT alone in mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). We studied the potential impact of this non-invasive LN staging procedure on the radiation treatment plan of patients with NSCLC. PATIENTS AND METHODS: The imaging and surgical pathology data from 105 patients included in two previously published prospective LN staging protocols form the basis for the present analysis. For 73 of these patients, with positive LN's on CT and/or on PET, a theoretical study was performed in which for each patient the gross tumour volume (GTV) was defined based on CT and on PET-CT data. For each GTV, the completeness of tumour coverage was assessed, using the available surgical pathology data as gold standard. A more detailed analysis was done for the first ten consecutive patients in whom the PET-CT-GTV was smaller than the CT-GTV. Theoretical radiation treatment plans were constructed based on both CT-GTV and PET-CT-GTV. Dose-volume histograms for the planning target volume (PTV), for the total lung volume and the lung volume receiving more than 20 Gy (V(lung(20))), were calculated. RESULTS: Data from 988 assessed LN stations were available. In the subgroup of 73 patients with CT or PET positive LN's, tumour coverage improved from 75% when the CT-GTV was used to 89% with the PET-CT-GTV (P=0.005). In 45 patients (62%) the information obtained from PET would have led to a change of the treatment volumes. For the ten patients in the dosimetry study, the use of PET-CT to define the GTV, resulted in an average reduction of the PTV by 29+/-18% (+/-1 SD) (P=0.002) and of the V(lung(20)) of 27+/-18% (+/-1 SD) (P=0.001). CONCLUSION: In patients with NSCLC considered for curative radiation treatment, assessment of locoregional LN tumour extension by PET will improve tumour coverage, and in selected patients, will reduce the volume of normal tissues irradiated, and thus toxicity. This subgroup of patients could then become candidates for treatment intensification.

Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group.

PURPOSE: The amount of radio-labeled (18)F-fluoro-2-deoxy-glucose (FDG) uptake, a measurement of the increased glucose metabolism of non-small-cell lung cancer (NSCLC) cells, has recently been correlated with proliferation capacity. The Standardized Uptake Value (SUV), a semi-quantitative measurement of FDG uptake on positron emission tomography (PET) scan, could thus be of prognostic significance. PATIENTS AND METHODS: We analyzed the follow-up of 125 potentially operable NSCLC patients, previously included in three of our prospective PET protocols. Performance status, maximal tumor diameter, tumor-cell type, SUV, and final staging were analyzed for their possible association with survival. RESULTS: Sixty-five patients had stage I or II NSCLC, 37 had stage IIIA, and 23 had stage IIIB. Treatment was complete resection in 91 cases. In a univariate analysis, performance status (P =.002), stage (P =.001), tumor diameter (P =.06), tumor-cell type (P =.03), and SUV greater than 7 (P =.001) were correlated with survival. For SUV, group dichotomy with a cut-off SUV of 7 had the best discriminative value for prognosis, both in the total and surgical cohort. A multivariate Cox analysis identified performance status (P =.02), stage (P =.01), and SUV (P =.007) as important for the prognosis. In the surgical group, patients with a resected tumor less than 3 cm had an expected 2-year survival of 86%, if the SUV was below 7, and 60%, if above 7. Nearly all resected tumors larger than 3 cm had SUV's greater than 7 and an expected 2-year survival of 43%. CONCLUSION: We conclude that the FDG uptake in primary NSCLC on PET has an important prognostic value and could be complementary to other well-known factors in the decision on adjuvant treatment protocols.

Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer.

Anaemia commonly occurs in cancer patients receiving chemotherapy, often necessitating blood transfusion. This multicentre study was designed to evaluate the efficacy and safety of epoetin alpha in preventing the decline in haemoglobin (Hb) level, and to determine whether the transfusion requirement could be reduced, in patients receiving 4-6 cycles of primarily platinum-based combination cyclic chemotherapy for small cell lung cancer (SCLC). A total of 130 non-anaemic SCLC patients were randomized to receive no additional treatment (n = 44), epoetin alpha 150 IU kg(-1) subcutaneously (s.c.) three times a week (n = 42) or 300 IU kg(-1) s.c. three times a week (n = 44). Reductions in epoetin alpha dosage were made during the study if Hb level increased to >15 g dl(-1). The mean weekly dosage was 335 and 612 IU kg(-1), respectively, in the two active treatment groups. Significantly fewer (P < 0.05) epoetin alpha-treated patients experienced anaemia (Hb < 10 g dl(-1)) during the course of chemotherapy (300 IU kg(-1), 39%; 150 IU kg(-1), 48%; untreated, 66%). This was reflected in the significantly lower number of treated patients transfused [300 IU kg(-1), 20% (P< 0.001); 150 IU kg(-1), 45% (P< 0.05); untreated, 59%]. Epoetin alpha was well-tolerated, and there was no evidence of sustained, clinically significant, hypertension. In summary, epoetin alpha is effective and well-tolerated in maintaining Hb level and reducing transfusion requirement in patients undergoing cyclic chemotherapy for SCLC.

Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group.

BACKGROUND: Clearance of viable tumour cells in mediastinal lymph nodes (MLN) by induction chemotherapy (IC)--so-called MLN downstaging--is an important aspect of combined-modality treatment of N2-NSCLC. Reassessment of MLN after IC by CT is far from accurate, while re-mediastinoscopy is often technically difficult. Based on our previous results with FDG-PET in the initial staging of N2 disease, we investigated whether PET after IC could be helpful in predicting MLN downstaging and therapeutic outcome. PATIENTS AND METHODS: Patients underwent a first PET before IC. After three cycles of platinum-based IC, a second PET was performed before locoregional therapy, either surgery or radiotherapy. PET results were correlated with pathology of the MLN when available, and with survival. RESULTS: Fifteen surgically staged N2-NSCLC patients were prospectively included. Locoregional therapy after IC consisted of surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting MLN downstaging was 100% (six true negatives; three true positives), whereas for CT it was only 67% (two false pos; one false neg). Reassessment with PET after IC was correlated with the outcome after the entire combined modality treatment. Survival was significantly better in patients with mediastinal clearance (P = 0.01) or with a greater than 50% decrease in the Standardised Uptake Value (SUV) of the primary tumour (P = 0.03) after IC. CONCLUSIONS: Mediastinal PET after IC accurately assesses pathologic MLN downstaging in N2-NSCLC. The data suggest a possible correlation of early survival with mediastinal clearance and an important decrease of SUV in the primary tumour. Confirmation of these preliminary findings would establish PET as a useful non-invasive tool to select patients for intensive locoregional treatment after IC.

FDG-PET scan in potentially operable non-small cell lung cancer: do anatometabolic PET-CT fusion images improve the localisation of regional lymph node metastases? The Leuven Lung Cancer Group.

Exact localisation of thoracic lymph nodes (LNs) on fluorine-18 fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) can be hampered by the paucity of anatomical landmarks. In non-small cell lung cancer (NSCLC) patients referred for locoregional LN staging, we prospectively examined to what extent localisation of LNs at PET reading could be improved by visual correlation with computed tomography (CT), or by anatometabolic PET+CT fusion images. Fifty-six patients with potentially operable NSCLC underwent CT, PET and surgical staging. Prospective reading was performed for CT, PET without CT, PET+CT visual correlation and PET+CT fusion. Reading was blinded to surgical pathology data and noted on a standard LN map. Surgical staging was available for 493 LN stations. In the evaluation per individual LN station, CT was accurate in 87%, PET in 91% and visual correlation and fusion in 93%. In the identification of the nodal stage, CT was correct in 28/56 patients (50%), PET in 37/56 (66%), visual correlation in 40/56 (71%), and fusion in 41/56 (73%). It is concluded that in the exact localisation of metastatic thoracic LNs, the accuracy of reading of PET is increased if the PET images can be visually correlated with CT images. PET+CT anatometabolic fusion images add only a marginal benefit compared with visual correlation.

Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients.

PURPOSE: To compare the accuracy of computed tomography-(CT) scan and the radiolabeled glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) visually correlated with CT (PET + CT) in the locoregional lymph node (LN) staging of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-eight patients with potentially operable NSCLC underwent thoracic CT, PET, and invasive surgical staging (ISS). Imaging studies were read prospectively and blinded to the surgical and pathologic data. A five-point visual scale was used for the interpretation of LNs on PET. Afterwards, with knowledge of the pathology, the relationship between standardized uptake values (SUVs) and the presence of metastasis in LNs was explored in a receiver operating characteristic (ROC) analysis, and the likelihood ratios (LRs) for SUVs of LNs were determined. RESULTS: ISS was available for 690 LN stations. CT correctly identified the nodal stage in 40 of 68 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET + CT was accurate in 59 patients (87%), with understaging in five patients and overstaging in four patients. In the detection of locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy of CT were 75%, 63%, and 68%, respectively. For PET + CT, this was 93%, 95%, and 94% (P = .0004). In the ROC curve, the best SUV threshold to distinguish benign from malignant LNs was 4.40. The analysis with this SUV threshold was not superior to the use of a five-point visual scale. The LR of a SUV less than 3.5 in an LN was 0.152; for a SUV between 3.5 and 4.5, it was 3.157; and for a SUV greater than 4.5, it was 253.096. CONCLUSION: PET + CT is significantly more accurate than CT alone in LN staging of NSCLC. A five-point visual scale is as accurate as the use of an SUV threshold for LNs in the distinction between benign and malignant nodes. The very high negative predictive value of mediastinal PET could reduce the need for mediastinal ISS in NSCLC substantially.

Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small-cell lung cancer: a prospective study. Leuven Lung Cancer Group.

PURPOSE: In the pioneer data from the Memorial-Sloan-Kettering group, preoperative mitomycin-C-vindesine-platinum (MVP) induction chemotherapy in N2-NSCLC was accompanied with substantial pulmonary toxicity. In this study, the efficacy and toxicity of three-drug VIP induction chemotherapy, the pathologic response in resection specimens, the early survival and relapse patterns are examined. PATIENTS AND METHODS: Between June 1995 and March 1997, 39 consecutive patients with pathology proven N2-NSCLC were treated with three cycles of VIP induction, followed by definitive locoregional treatment (resection and mediastinal dissection or radical radiotherapy). Several patients had unfavorable prognostic characteristics with respect to clinical and biological findings, tumor location and bulk of disease. RESULTS: The response rate to chemotherapy was 59% (95% Confidence Interval 34-75). Twenty-three responding patients had radical locoregional treatment: radical radiotherapy in four, resection in 19. Downstaging was present in nine of the 19 resection specimens, with two pathologic complete responses. The median survival time (MST) of all patients is 19 months, with a projected two-year survival of 49%. In patients responsive to chemotherapy who received definitive local treatment, the MST is not yet reached, and the projected two-year survival is 57%. Relapses were mainly distant, with isolated brain relapse as a disturbing finding. The main toxicity's were leukopenia and vomiting, but they were manageable. In contrast with MVP, no severe pulmonary toxicity occurred. CONCLUSIONS: VIP is a suitable induction regimen for N2-NSCLC, demonstrating a good activity and very acceptable toxicity.

Clinical prognostic factors in surgically treated stage IIIA-N2 non-small cell lung cancer: analysis of the literature.

There remains controversy on the prognostic value of several common clinical factors in NSCLC patients with resected N2-disease. The aim of this paper is to give a comprehensive overview of the available data on this issue. Literature data on surgically treated N2-NSCLC-patients from 1980-1995, peer reviewed and listed in Index Medicus, were analysed. Reported and calculated or estimated survival data were indexed. Eighteen series were selected: in 12 of them, direct comparisons between survival curves of subgroups are reported; six contained sufficient data to make comparisons of survivors at 5 years; three of them also made a multivariate Cox model. The analysis of prognostic factors in a single study was often hampered by the limited number of patients. Nonetheless, it could be concluded that patients with a clinical N0- or N1-status (so-called unforeseen N2) do better. There was no clear difference between patients undergoing lobectomy or pneumonectomy. There was strong evidence that N2-patients with a less advanced primary tumour (T-stage) have a better prognosis, and this is the case for all operable T-stages (T1 versus T2, T1 versus T3, T2 versus T3). Squamous cell type was a favourable prognostic factor, as was the presence of only one metastatic mediastinal lymph node station or absence of metastases to the subcarinal nodes. There was some evidence that the presence of extracapsular spread in metastatic MLN is an unfavourable finding. Stratification for these prognostic factors could help in the planning of future trials on combined modality treatment in N2-NSCLC.