Stage IIIB Non-small Cell Lung Research Articles

Stage IIIA and IIIB Non-Small Cell Lung Cancer: Results of Chemotherapy Combined With Radiation Therapy and Analysis of Prognostic Factors

Most patients with stage III non-small cell lung cancer (NSCLC) are not candidates for surgery but can benefit from chemotherapy combined with radiation therapy. The objective of the present study was to analyze the results of sequential chemotherapy and radiation therapy and the prognostic value of initial clinical and laboratory variables. We carried out a retrospective study of 92 patients with stage III NSCLC treated with a sequential regimen of chemotherapy (carboplatin-etoposide, carboplatin-gemcitabine, and carboplatin-paclitaxel), and radiation therapy (6000 cGy in daily doses of 200 cGy, 5 d/wk). Response to therapy, overall survival, and the prognostic value of epidemiological, clinical, and laboratory variables were evaluated using univariate and multivariate analyses. Median survival time was 14 months, with a 3-year survival rate of 16.1%. Poor performance status (score of 2 on the Eastern Cooperative Oncologic Group [ECOG] scale), anemia, and elevated serum concentrations of carcinoembryonic antigen were predictive of poorer survival in the multivariate analysis. In the univariate analysis, weight loss and diagnosis before the year 2000 were also associated with poorer prognosis (P<.01). TNM stage was not significantly correlated (P=.08). Toxicity was low, with 1 death and few cases of grade 3 or 4 toxicity according to World Health Organization criteria. The use of chemotherapy combined with radiation therapy should be considered contraindicated in cases of poor performance status (ECOG scale score of 2). Weight loss, an elevated serum concentration of carcinoembryonic antigen, and a hemoglobin concentration of 12 g/dL or less carry a poor prognosis.

Lessons to learn from EORTC study 08981: A feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer

The present EORTC phase II feasibility study in stage IIIB (T4-N3) NSCLC was conducted to investigate whether an induction regimen with concurrent chemoradiotherapy followed by surgery after restaging by re-mediastinoscopy and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) was feasible in a multicenter setting. Unfortunately, the study closed prematurely because of poor accrual. The combination of more stringent selection criteria, the incorrect prevailing view of Ethical Boards that a tri-modality approach is too toxic, competing studies in the participating centers and the fact that patients with N3 disease could only be enrolled if a re-mediastinoscopy could be performed, underlie the low accrual. Although this study illustrates that the conduct of a tri-modality study across Europe appeared to be difficult at that time, the number of centers with highly qualified and experienced specialists involved in this kind of multi-modality approaches is rapidly increasing. Future initiatives should, therefore, certainly be encouraged. Minimally invasive procedures such as EUS and EBUS should preferably be used for up-front mediastinal staging, mediastinoscopy with or without EUS should preferably be reserved for restaging, and especially right-sided pneumonectomies should be avoided. Though evident, the feasibility to complete this kind of studies within a reasonable time period is still a condition sine qua non.

Rational drug sequencing of paclitaxel, gemcitabine and carboplatin in patients with untreated stage IV and select stage IIIB non-small cell lung cancer

To conduct a phase II study evaluating the efficacy of rationally sequenced paclitaxel, gemcitabine, and carboplatin in patients with stage IV or select stage IIIB non-small cell lung cancer (NSCLC). Patients with select stages IIIB (pleural effusion) and IV NSCLC with an ECOG performance status of 0-1 and no prior chemotherapy for their disease were eligible to participate. Treatment was delivered as follows: paclitaxel at 70 mg/m2 followed by gemcitabine at 300 mg/m2 on day 1, with carboplatin (AUC 5) on day 2 of a 28-day cycle. Response was assessed after every two cycles of therapy. The primary endpoint of this trial was response rate, with secondary endpoints of time to progression and 1 year overall survival. Twenty patients were enrolled on protocol, one of whom never received chemotherapy. The median number of cycles delivered was 3 (range 0-8). A partial response rate of 42% (8/19; 95% CI: 20-67%) and a stable disease rate of 11% (2/19; 95% CI: 1-33%) were observed. The median overall survival time was 9.6 months (95% CI: 4.6-16.6), with a 1 year overall survival rate of 42.1% (95% CI: 24.9-71.3%). Eight patients (42%) stopped treatment due to toxicity. Paclitaxel followed by gemcitabine and then carboplatin is an active, albeit complex, regimen in the treatment of patients with advanced NSCLC with insufficient advantage to justify continuation of this regimen.

Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation therapy for Stage IIIB non-small cell lung cancer

17090 Background: We conducted a phase II study of Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation in patients with stage IIIB non-small-cell lung cancer to evaluate the response and toxicity profiles. Methods: All enrolled patients were scheduled to receive 2 cycles of induction chemotherapy with paclitaxel (175 mg/m2) intravenous infusion on day 1 and cisplatin (75 mg/m2) intravenously on day 1 every 3 weeks. All non-progressing patients were subsequently treated with concurrent chemoradiation. Concurrent chemoradiation included paclitaxel (60 mg/m2) plus cisplatin (25 mg/m2) intravenously for 6 weeks on day 43, 50, 57, 71, 78, and 85 and once-daily thoracic irradiation. Results: Between July 2000 and October 2005, 39 patients diagnosed as stage IIIB non-small cell lung cancer were enrolled in this study. Four patients achieved a complete response (10.3%) and 21 patients achieved a partial response (53.8 %), for an overall response rate of 64.1% [95% C.I. (49.4%–79.2 %)]. The 1, 2, and 3 year overall survival rate of all 39 patients were 66.7%, 40.6%, and 27.4% respectively, with a median survival time of 20 months. The median progression free survival was 10.7 months [95% C.I. (4.5%–16.9%)]. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 18 patients (45%). Conclusions: Induction chemotherapy with paclitaxel and cisplatin followed by concurrent chemoradiation for stage IIIB non-small cell lung cancer seems to be effective treatment. However, Physicians should also be aware of severe esophagitis to require inpatient parenteral nutrition support and pain control. No significant financial relationships to disclose.

Effect of Concomitant Use of Pentoxifylline and Alpha-Tocopherol with Radiotherapy on the Clinical Outcome of Patients with Stage IIIB Non-Small Cell Lung Cancer: A Randomized Prospective Clinical Trial

We evaluated the effects of pentoxifylline (PTX) and alpha-tocopherol on the clinical outcome of 66 patients with stage IIIB non-small cell lung cancer in a randomized clinical trial. All patients received 46 Gy of external radiotherapy to the primary tumor and regional lymph nodes, with an additional 14-Gy dose to the primary tumor. Thirty-three of the 66 patients also received PTX (400 mg, three times daily) and alpha-tocopherol (300 mg, twice daily) during radiotherapy, followed by 400 mg of PTX and 300 mg of alpha-tocopherol daily for 3 mo after radiotherapy. The remaining 33 patients (control group) received radiotherapy only. After a mean follow-up time of 12 mo, 18 patients remained alive. During follow-up, there were local recurrences in 14 patients and distant metastases in 18 patients. In patients who received PXT and alpha-tocopherol, 1- and 2-yr overall survival rates were 55% and 30%, respectively, and median survival was 18 mo. In control patients, 1- and 2-yr overall survival rates were 40% and 14%, respectively, with a median survival of 10 mo. These differences were statistically significant (p = 0.0175). In patients who received PXT and alpha-tocopherol, progression-free survival rates for 1 and 2 yr were 48% and 23%, respectively; median survival was 12 mo. In the control group, the corresponding rates were 24% and 18%; median survival was 8 mo (p = 0.0223). We conclude that the use of PTX and alpha-tocopherol combined with radiotherapy offers a possible survival advantage in this patient population.

Neoadjuvant Chemotherapy and Pneumonectomy in a Lung Cancer Patient on Hemodialysis

Major pulmonary resections are rarely performed in non-small cell lung cancer patients on hemodialysis. To date only two cases of pneumonectomy performed in such patients are reported in the literature. Moreover, chemotherapy, as a treatment for advanced non-small cell lung cancer, is not routinely administered to patients with end-stage renal disease requiring hemodialysis. We present the case of a stage IIIB non-small cell lung cancer patient on hemodialysis who successfully underwent neoadjuvant chemotherapy followed by pneumonectomy. To our knowledge, this is the first case of non-small cell lung cancer patient on hemodialysis reported in the literature who successfully underwent this type of combined therapy.

Phase II Study of Neoadjuvant Chemotherapy With Gemcitabine and Vinorelbine in Resectable Non-small Cell Lung Cancer

We assessed the efficacy of a non-platinum-containing doublet chemotherapy of gemcitabine and vinorelbine as induction therapy prior to surgical resection in patients with stage IB-IIIA and selected stage IIIB non-small cell lung cancer (NSCLC). The primary clinical end point was radiographic disease response rate, and the secondary end points were pathologic response rate, treatment-related toxicity, surgical resectability and outcome, and overall and disease-free survival. Patients underwent staging with CT of the chest and upper-abdomen, whole-body F-18 fluorodeoxyglucose positron emission tomography, bronchoscopy, and mediastinoscopy. The patients had to have medically and surgically resectable disease. Chemotherapy consisted of gemcitabine, 1,000 mg/m(2), and vinorelbine, 25 mg/m(2), administered on days 1, 8, 22, and 29. Imaging studies were repeated between days 43 and 50. Disease response was assessed by response evaluation criteria in solid tumors, and patients with resectable disease were offered surgery between days 50 and 70. Patients were followed up every 3 months for 2 years with chest CT. Between January 2000 and March 2004, 27 patients with stage IB NSCLC, 15 patients with stage II NSCLC, and 20 patients with stage III NSCLC were entered. After induction chemotherapy 34% (95% confidence interval [CI], 23 to 48%) had an objective radiographic response, 2% had a complete pathologic response, 90% underwent thoracotomy, and 77% underwent a complete resection. There were four deaths in the 6-week period following surgery, and there were no deaths related to chemotherapy. There were no unexpected morbidities from surgery or chemotherapy. The 1-year and 2-year overall survival rates were 80% (95% CI, 68 to 88%) and 65% (95% CI, 50 to 76%), and the median overall survival was 38.2 months. Induction chemotherapy with gemcitabine and vinorelbine results in 1-year and 2-year survival rates and a median survival time comparable to those obtained with platinum-containing doublets. However, it appears to be less efficacious in terms of radiographic and pathologic response rates compared with platinum-containing chemotherapy doublets.

PD-075 Consolidation docetaxel (D) following concurrentchemoradiotherapy (chemoRT) in stage IIIB non-small cell lung cancer (NSCLC): Updated five-year survival results from Southwest Oncology Group trial S9504

PD-075 Consolidation docetaxel (D) following concurrentchemoradiotherapy (chemoRT) in stage IIIB non-small cell lung cancer (NSCLC): Updated five-year survival results from Southwest Oncology Group trial S9504

52 A pilot study of celecoxib with docetaxel/radiation and consolidation docetaxel/cisplatin in inoperable stage IIIa and IIIb non-small cell lung cancer (NSCLC)

52 A pilot study of celecoxib with docetaxel/radiation and consolidation docetaxel/cisplatin in inoperable stage IIIa and IIIb non-small cell lung cancer (NSCLC)

Long term survival in stage IIIb non-small cell lung cancer (NSCLC) treated with consolidation docetaxel following concurrent chemoradiotherapy (SWOG S9504)

7059 Background: The optimal approach to chemoradiotherapy for unresectable stage III NSCLC remains unclear. We have previously reported the efficacy of consolidation docetaxel (D) following concurrent cisplatin-etoposide (PE) and thoracic radiotherapy (RT) in stage IIIb NSCLC in which documentation of T4 (non-effusion) or N3 status was required (S9504). Methods: Here we update results in regard to survival at 5 years in 83 patients (pts) treated with P: 50 mg/m2 days 1, 8, 29 and 36, E: 50 mg/m2 days 1–5 and 29–33 and concurrent thoracic RT starting day 1: 61 Gy (1.8–2.0 Gy/day), followed by consolidation docetaxel 75–100 mg/m2 every 21 days for 3 cycles. Results: Median age 60 (34–80), male/female: 61/22, performance status: 0–1/2:78/5, TNM: T4N0–1: 31, T4N2: 22, N3: 30. Median follow-up: 71 months (mos). Median progression-free survival (PFS): 16 mos. Median survival (MST): 26 mos. 5 year survival: 29%. MST and 5 year survival for Stage IIIb subsets: T4N0–1: 32 mos and 29%: T4N2: 26 mos and 37%; N3: 16 mos and 20%. Survival data are compared below to SWOG 9019, which treated a similarly staged IIIb cohort of 50 pts with identical concurrent chemoradiotherapy, differing only in substitution of consolidation docetaxel for continued PE. Conclusions: 1) Long term survival endpoints achieved in S9504 in documented Stage IIIb NSCLC compare favorably with the SWOG historical control (S9019) and other published series in this pt population. 2) 5 year survival of stage IIIb subsets ranges from 20–37%. 3) Ongoing intergroup trial S0023 is further evaluating the S9504 regimen followed by maintenance therapy with the EGFR inhibitor gefitinib or placebo (Supported by CA 30102). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

Physician practice of statin usage and lipid monitoring among patients with advanced lung cancer

8009 Background: The benefit of statins (HMG-CoA reductase inhibitors) for prevention of cardiovascular disease is well established; however, its use among patients with advanced cancers with limited life expectancy is controversial. Besides, the risk of liver dysfunction may increase among patients with liver metastasis or receiving chemotherapy. We investigate physician practices of prescribing statin and monitoring lipids among advanced lung cancer patients. Methods: Cancer registry at a large, suburban VA hospital was searched for deceased patients who presented with metastatic or stage IIIB non-small cell lung cancer (NSCLC) or extensive stage small cell lung cancer during 1999 to 2003. Patients were included if they were on statins at or after the time of cancer diagnosis, survived for at least one month after diagnosis, and had at least one documented contact with their physicians within 6 months before death. Results: Fifty patients met the search criteria: 49 were on statins at the time of cancer diagnosis, and 1 was started on statin afterward. Median age was 71 years, 26% had extensive stage SCLC, 52% metastatic NSCLC, and 22% stage IIIB NSCLC. Most had history of cardiovascular disease or diabetes. The overall median survival was 360 days. There were 42 patients (84%) who had statin prescription filled at least once after cancer diagnosis. Of these, 16 (38%) continued to have adequate supply until death. Median duration from the last statin medication until death was 72 days. Lipid was monitored at least once after cancer diagnosis in 26 patients (52%). Of these, the median duration from the last test until death was 149 days. Meanwhile, hospice referral before death was initiated in 31 patients (62%). Of these, the median duration from the date of hospice referral until death was 30 days. Conclusions: The majority of patients with advanced lung cancer who received statins continued this medication until near the date of death; lipid monitoring was also prevalent. Effort should be made to re-direct patients and physicians to other realistically beneficial interventions. No significant financial relationships to disclose.

Induction and Concurrent Chemotherapy with Concomitant Boost Radiotherapy in Non-Small Cell Lung Cancer

This study was designed to evaluate the tolerability and therapeutic activity of paclitaxel and carboplatin combination therapy followed by radical thoracic radiotherapy with a concomitant boost technique with concurrent weekly paclitaxel in good performance status of patients with stage IIIA and IIIB non-small cell lung cancer. Patients with newly diagnosed inoperable non-small cell lung cancer received paclitaxel (100 mg/m(2)) as a 1-h infusion on d 1,8,15,28,35, and 42. Carboplatin (area under the curve of 6) was given as a 30-min infusion on d 1 and 28. Radiotherapy commenced on d 49 and was delivered with accelerated fractionation with concomitant boost at 1.8 Gy/fraction/d, 5 d/week and 1.5 Gy/fraction/d to a boost field as a second daily treatment for the last 10 treatment days to 60 Gy/35 fractions/5 wk. During radiation treatment, paclitaxel (60 mg/m(2)) was given as a 1-h infusion once weekly for 5 wk. Twenty-four patients were enrolled in the study. Hematologic toxicities and alopecia were the major acute toxicities during induction chemotherapy; 8.7% of the patients experienced grade 3-4 neutropenia and alopecia. The main acute toxicity of concurrent chemoradiotherapy was esophagitis; grade 3 esophagitis was documented in 23.5% of the patients. No major late toxicity was seen. Overall response rate to the treatment was 65.2%. The median and 1-yr overall-survival rates were 24.9 mo and 63.8%, respectively. The median and 1-yr progression-free survival rates were 9.0 mo and 27.8%, respectively. The main acute toxicities were hematologic toxicity, esophagitis, and alopecia. The response rate and the survival rates achieved with this treatment regimen are particularly noteworthy, especially considering the advanced stage of the patients treated.

High-Dose-Rate Brachytherapy in Combination with Stenting Offers a Rapid and Statistically Significant Improvement in Quality of Life for Patients with Endobronchial Recurrence

Symptomatic endobronchial recurrence after treatment failure is common in advanced non-small cell lung cancer. Optimal palliation has yet to be defined. We examined the combination of near-simultaneous, high-dose-rate (HDR) brachytherapy with stenting in this cohort of patients. Informed consent for intervention was obtained for 10 patients experiencing severely symptomatic (hemoptysis and oxygen-dependent shortness of breath), biopsy-proven endobronchial recurrence. All patients (eight men, two women, aged 52-77 years) had failed to respond to chemoradiotherapy for stage IIIB non-small cell lung cancer. Intervention consisted of placement of a self-expanding metallic stent (Nitinol/Ultraflex stent, Boston Scientific Co., Natick, MA) into the obstructing region. During that same bronchoscopy, HDR catheters were introduced. A dose of 6 Gy at 0.5 cm from the catheter was then delivered via an HDR unit. Two additional HDR sessions followed at weekly intervals for a total dose of 18 Gy. Patients under went follow-up bronchoscopes 1 month after the last HDR and when clinically indicated. All patients completed the prescribed therapy. No morbidity was noted from bronchoscopy, HDR, or stenting. All patients had rapid relief of signs and symptoms. At 1 week after stenting/first HDR, a statistically significant improvement in Karnofsky status was noted. Pulmonary palliation was maintained for the duration of their survival. The radio-opaque stent also offered significant advantages for catheter placement and verification during the HDR procedure. Although this series is small, the beneficial outcome obtained deserves further evaluation.

The ability of whole body FDG18 PET imaging to predict pathologic response to induction chemoradiotherapy in stage IIIA and IIIB non-small cell lung cancer. Results of a phase I/II subanalysis

Whole body FDG18 PET imaging has been shown to have 99% sensitivity in detecting primary tumor at initial workup for non-small cell lung cancer. Furthermore, it has been shown to have 91% sensitivity at detecting mediastinal lymph nodes pre-operatively. In this phase I/II study of neoadjuvant chemoradiotherapy followed by surgical resection for stage IIIA and IIIB non-small cell lung cancer patients, PET imaging was obtained before and after induction chemoradiotherapy in order to assess its ability to accurately assess pathologic response.

The ability of whole body FDG18 PET imaging to predict pathologic response to induction chemoradiotherapy in stage IIIA and IIIB non-small cell lung cancer. Results of a phase I/II subanalysis

The ability of whole body FDG18 PET imaging to predict pathologic response to induction chemoradiotherapy in stage IIIA and IIIB non-small cell lung cancer. Results of a phase I/II subanalysis

UFT after sequential chemo and radiotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC)

7294 Background:Chemotherapy added to radiotherapy decreases systemic progression in patients with locally advanced NSCLC. However,distant failure remains a significant cause of morbidity and mortality in these patients. Randomized studies from Japan showed that UFT improves survival in patients (pts) with early NSCLC. The reduction in systemic relapsed is due to its effect on the micrometastatic disease.We conducted a phase II study to evaluate the effect of UFT on the systemic progression of pts with stage IIIB NSCLC. Methods:Patients with stage IIIB NSCLC were included. Pts had ECOG performance status (PS) 0 or 1 and normal end organ function.Pts were treated with induction chemotherapy with two cycles of cisplatin (100mg/m2 days 1 and 29) and vinblastine (5mg/m2/week for 5 weeks) followed by 60Gy of thoracic radiotherapy. Two weeks after the completion of radiotherapy they were started on a fixed dose of 400mg/day of UFT, administered continuously for one year. Results:Between May 1999 and October 2003 twenty four pts were included. Patient's characteristics: 15 male (62%), 10 adenocarcinoma and 10 squamous cell, 4 pts had NSCLC not otherwise classified, median age was 55 years, all pts had PS of 1. Only one pt was not a former or current smoker. Toxicity of the chemo/radiotherapy phase of the study was compatible with published literature with no toxic deaths. Toxicity of UFT was minimal. The most common side effect was fatigue. Median time on UFT was 6 months.In 6 pts (50%) the first clinical sign of progression was local, and in the other 6 patients it was systemic (2 brain). Five pts (21%) completed 12 months on UFT and 5 are on treatment. With a median follow-up of 12 months the median survival was 14 months. The actuarial 1,2 and 3-year survivals were 52, 35 and 25%, respectively. Conclusions:UFT in this fixed dose schedule was very well tolerated. However our results are almost identical to the published literature with sequential chemo and radiotherapy in stage IIIB NSCLC. This finding suggests that UFT may have little effect on the control of micrometastatic disease in pts with locally advanced NSCLC. Local control remains a critical issue in stage IIIB patients. No significant financial relationships to disclose.

UFT after sequential chemo and radiotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC)

UFT after sequential chemo and radiotherapy in patients with stage IIIB non-small cell lung cancer (NSCLC)

Reply

As noted in the commentary by Cesario et al. (1), an evidence-based consensus on the role of surgery in multimodality treatment for stage IIIB non-small cell lung cancer (NSCLC) (excluding patients with pleural effusion) is indeed needed. These authors point out that several studies that have examined outcomes of patients with IIIB disease treated with neoadjuvant therapy followed by surgery, including our Phase I study, typically considered surgery only in patients with clinical downstaging from neoadjuvant therapy (2, 3). The best evidence for this approach is provided by the Phase II Southwest Oncology Group (SWOG) 8805 study, in which 126 patients with stage IIIA or B NSCLC received induction cisplatin and etoposide plus concurrent thoracic radiotherapy (2). Resection was attempted in patients without progressive disease. Fifty-one patients (40%) had stage IIIB (T4 primary or N3 nodes) disease. In this subset, resectability was 80%, and 3-year survival was 24%, similar to results for the stage IIIA group. The strongest predictor of survival after surgery was nodal status at the time of resection. In patients with pN0 disease at resection, 3-year survival was 44%, versus 18% in patients with involved nodes (P = 0.0005). The fact that this survival difference was seen in patients with both IIIA and IIIB disease suggests that treatment decisions should not only take anatomic staging into account but should also consider tumor biology and response to therapy. Thus, some patients with stage IIIB disease, for whom guidelines typically recommend combined chemoradiotherapy without surgical resection (4), may, by virtue of an excellent response to neoadjuvant treatment, be able to enjoy the benefits of resection, as would a patient with similarly responsive stage IIIA disease. The final report of the randomized intergroup trial 0139 (RTOG 93-09), investigating the outcomes of patients with stage IIIA NSCLC from combined chemoradiotherapy alone versus chemoradiotherapy followed by surgery, is pending (5). Preliminary data suggest similar overall survival in both groups of patients but improved progression-free survival in the surgical arm. Further analysis may shed light on who will benefit from the full trimodality approach to therapy for locally advanced NSCLC.Based on our results, in which 3 of 12 IIIB patients were deemed resectable, and the SWOG 8805 data, we agree with Cesario et al. (1) that surgical resection after neoadjuvant therapy can be considered in selected patients with stage IIIB (T4 primary or N3 nodes) after neoadjuvant therapy. The patient in question with T4 disease had radiographic evidence of invasion into the mediastinum on presentation, not a satellite nodule or carinal involvement that might meet the more typical guidelines for resectability. The question remains how to best identify patients who may benefit from surgery. In our Phase I study, all patients were restaged by computed tomography (CT) alone after both induction chemotherapy and chemoradiotherapy. Of the 14 patients eligible for surgery based on restaging CTs showing the equivalence of stage IIIA disease or better, 7 of the preoperative CT scans did not accurately predict the postoperative pathological stage. Of these, six patients were downstaged to N0 status or had a pathological complete response to neoadjuvant therapy, indicating that restaging by CT alone is not fully reliable.Alternative approaches to restaging include positron emission tomography (PET) and repeat mediastinoscopy. PET restaging is attractive because it offers the possibility of both characterizing locoregional response to neoadjuvant therapy and identifying clinically unrecognized distant metastatic disease, thereby sparing those patients unnecessary treatment (6). Unfortunately, the data available to date include unacceptable numbers of false positives and false negatives for PET restaging alone to be considered a standard approach to determining resectability of stage III NSCLC after neoadjuvant therapy (7, 8). Repeat mediastinoscopy, as Cesario et al. (1) have observed, can be technically challenging in the postchemoradiotherapy setting and is therefore not routinely performed. As a result, it is difficult to recommend a standardized approach to restaging after neoadjuvant therapy in patients with stage IIIB NSCLC to determine resectability. Nevertheless, the favorable outcomes that can be seen in selected stage IIIB NSCLC patients in response to trimodality therapy do indicate that further study in identifying appropriate surgical candidates is clearly needed.

Invited commentary

Doctor Ichinose and colleagues opportunely point out several current controversial topics: (1) benefit of surgery in stage IIIB disease; (2) feasibility of surgical resection after CRT; (3) rationale of using UFT (a combination of Tegafur and Uracile) concurrently with Cisplatin and radiation therapy; (4) relevance of the T4 descriptor in present staging system; (5) coherence of team skills for multicentric trials. Stage IIIB disease includes several situations in which surgical resection can be performed as an adjuvant local control after CRT. This is currently shown and particularly quoted in the paper by Ichinose and colleagues. For instance, our study found a 5-year survival rate of 28% following surgery in patients who were not controlled by CRT [1Grunenwald D.H. André F. Le Péchoux C. et al.Benefit of surgery after chemoradiotherapy in stage IIIB (T4 and/or N3) non-small cell lung cancer.J Thorac Cardiovasc Surg. 2001; 122: 796-802Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. Feasibility of surgical resection after CRT has been demonstrated in numerous phase II studies, and confirmed in a large multicenter randomized trial in North America [2Albain KS, Scott CB, Rusch VR, et al. Phase III comparison of concurrent chemotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIA (pN2) non-small cell lung cancer (NSCLC): initial results from intergroup trial 0139 (RTOG 93-09). Proceedings of the ASCO 2003;A2497Google Scholar]. Improvement of surgical outcome in attempting to avoid the 4%–5% postoperative mortality would involve a large number of specialists together because such a multidisciplinary approach is teamwork, including anaesthesiologists and ICU physicians. Doctor Ichinose and colleagues used an original combination of UFT and Cisplatine concurrently with radiotherapy as an induction strategy. UFT is an oral, well-tolerated antimetabolite, which was proven effective in previous trials. An impressive 5-year survival benefit (11%) was found for T2N0 adenocarcinomas in a large randomized trial of adjuvant UFT [3Kato H, Tsuboi M, Ohta M, et al. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage 1 (T1N0M0, T2N0M0) adenocarcinoma of the lung. Proceedings of the ASCO 2003;A2498Google Scholar]. Interestingly, a majority of patients in Dr Ichinose's study had adenocarcinomas. These findings could raise the question of biological similarities between colon cancer and lung adenocarcinoma. A major issue is relevance of T4 descriptor in the current staging system, according to recent surgical advances. Since 1974, the staging system for NSCLC has paradigmatically divided the patients into two groups according to the surgical resectability [4Mountain C.F. Carr D.T. Anderson W.A.D. A system for the clinical staging of lung cancer.Am J Roentgenol. 1974; 120: 130-138Crossref Scopus (229) Google Scholar]. Surgery must be the crucial component to sort out different clinical presentations since it remains the only curative method. Actually, patients must be subdivided into three categories: (1) early stage who could be surgically cured; (2) advanced stage who will never meet a surgeon; (3) marginally resectable tumors. This latter category where upfront surgery is either not possible or unable to achieve a long-term prognosis is the ground for combined treatment modalities. But the landmarks between these therapeutic groups given by the current TNM descriptors are too imprecise and would deserve to be clarified. The French proposition suggests subdivision of T4 descriptor into two subgroups: (1) definitively nonresectable tumors, as oesophageal involvement, malignant pleural or pericardial effusion, bulky invasion of the heart, called T4-2; (2) other T4 cases, including left atrial, vascular, carinal, carinal, and even vertebral invasion, called T4-1, fit for induction strategies followed by surgery [5Grunenwald D.H. Surgery for advanced stage lung cancer.Semin Surg Oncol. 2000; 18: 137-142Crossref PubMed Scopus (27) Google Scholar]. Evolving concept of resectability for T4 tumors addresses the issue of homogeneity in team skills for clinical trials of multimodality treatment. In fact, aggressivity and ability of thoracic surgeons to perform extended resections are limited to several centers throughout the world.

Phase II study of gemcitabine–cisplatin–paclitaxel triplet as induction chemotherapy in inoperable, locally-advanced non-small cell lung cancer

Purpose: Our objective was to determine the activity in terms of response rate, surgical resectability, and the tolerability of the new three-drug combination gemcitabine–cisplatin–paclitaxel (GCP) in unresectable stage IIIA(N2) and IIIB non-small cell lung cancer (NSCLC). Patient and methods: Forty-two chemo-naive patients with stage IIIA(N2)–IIIB NSCLC, median age of 59 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and the ability to tolerate pneumectomy, received gemcitabine (Gem) 1000 mg/m 2 IV days 1 and 8, cisplatin (CDDP) 50 mg/m 2 IV days 1 and 8, paclitaxel 125 mg/m 2 1 h infusion IV days 1 and 8, every 21 days for 3 cycles. After induction chemotherapy, patients were evaluated for surgery or definitive radiotherapy. Results: Grade 3–4 neutropenia was the main hematologic toxicity, occurring in 28% of patients. Grade 3–4 thrombocytopenia was observed in only 11% of cases. No neutropenic fever or bleeding episodes were recorded. Severe non-hematologic toxicity was uncommon. Thirty (71%, 95% CI: 57.2–84.7%) of the 42 eligible patients had objective responses (1 complete and 29 partial responses). After induction chemotherapy, 21 patients (50%) went to surgery. Complete resection was obtained in 16 patients (38%). Viable tumor was present in 18 of 21 resection specimens. In three cases only necrotic tumor cells were identified, for a pathological complete response of 7%. With a median follow-up of 13.9 months, median time to progression was 17.4 months, median survival 21.7 months and estimated 1-year survival 92%. Conclusions: GCP combination is active and well tolerated in locally-advanced, non-resectable NSCLC. The activity profile, in terms of response and surgical resection rate, is comparable to that obtained with standard doublets.