The role of surgery in the treatment of oligoprogression after systemic treatment for advanced non-small cell lung cancer.

OBJECTIVES: Patients with advanced stage non-small cell lung cancer (NSCLC) are generally considered incurable. The mainstay of treatment for these patients is systemic therapy. The addition of local treatment, including surgery, remains controversial. Oligoprogression is defined as advanced stage NSCLC with limited progression of disease after a period of prolonged disease stabilisation or after a partial or complete response on systemic therapy. In this retrospective study we evaluated outcome and survival of patients who underwent a resection for oligoprogression after systemic therapy for advanced stage NSCLC. MATERIALS AND METHODS: Patients with oligoprogression after systemic treatment for advanced NSCLC who were operated in the Antoni van Leeuwenhoek Hospital were included. Patient and treatment characteristics were collected in relation to progression free survival (PFS) and overall survival (OS). RESULTS: Between January 2015 and December 2019, 28 patients underwent surgery for an oligoprogressive lesion (primary tumor lung (n = 12), other metastatic site (n = 16)). Median age at time of resection was 60 years (39-86) and 57% were female. Postoperative complications were observed in 2 patients (7%). Progression of disease after resection of the oligoprogressive site was observed in 17 patients (61%). Median PFS was 7 months since date of resection (95% CI 6.0-25.0) and median OS was not reached. Seven patients (25%) died during follow-up. Age was predictive for OS and clinical T4 stage was predictive for PFS. M1 disease at initial presentation was predictive for better PFS compared to patients who were diagnosed with M0 disease initially. Patients who underwent resection because of oligoprogression of the primary lung tumour had a better PFS, when compared to oligoprogression of another metastastic site. CONCLUSION: Surgical resection of an oligoprogressive lesion in patients with advanced NSCLC treated with systemic treatment is feasible and might be considered in order to achieve long term survival.

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial.

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m⁻² and pemetrexed 500 mg·m⁻². Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

Resection of secondary pulmonary malignancies in head and neck cancer patients.

BACKGROUND: This study aimed to evaluate a single institute's experience with resection of metachronous pulmonary malignancy in patients treated for squamous cell carcinoma of the head and neck. METHODS: Sixty-three consecutive patients treated curatively for head and neck squamous cell carcinoma underwent surgical resection of malignant lung lesions. Survival was estimated and potential prognostic factors investigated. RESULTS: The median overall survival for the total group was 22.2 months. Fifty-one patients (81 per cent) had one lung lesion, while the remainder had multiple lesions (range, two to seven). In the 63 patients, 35 lobectomies, 4 pneumonectomies and 24 wedge resections were performed. For patients with pulmonary squamous cell carcinoma (n = 52), the three-year survival rate was 35 per cent (95 per cent confidence interval, 22-48); for patients with resected adenocarcinoma (n = 10), it was 50 per cent (95 per cent confidence interval, 18-75). The overall five-year survival rate was 30 per cent (95 per cent confidence interval, 19-42). CONCLUSION: In patients treated curatively for head and neck squamous cell carcinoma, resection of secondary pulmonary cancer is associated with favourable long term overall survival, especially for patients with adenocarcinoma lesions.

Soluble epidermal growth factor receptor (sEGFR) and carcinoembryonic antigen (CEA) concentration in patients with non-small cell lung cancer: correlation with survival after erlotinib and gefitinib treatment.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), a higher response rate can be achieved with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) when selection for therapy is guided by mutation analysis or gene amplification. However, both tests are complex and require tumour tissue. Simple methods to identify responders prior to EGFR-TKI treatment are urgently needed. This study aimed to define the relation between serum sEGFR levels, carcinoembryonic antigen (CEA) and survival in NSCLC patients treated with EGFR-TKIs. METHODS: Patients with stage III/IV NSCLC treated with gefitinib or erlotinib between July 2002 and December 2005 were reviewed. Levels of serum soluble EGFR (sEGFR) were determined by a sandwich quantitative enzyme-linked immunosorbent assay. A chemiluminescence immunoassay was used for CEA. The relation between sEGFR and survival was investigated. RESULTS: One hundred and two NSCLC patients, mainly stage IV (80%), were identified. Mean sEGFR at baseline was 55.9 µg/l (range 35.3-74.5 µg/l). The median CEA level was 11.1 µg/l (range <1.0-2938.0 µg/l). Median overall survival was 5.2 months (range 1-52 months). Decreasing log CEA values (HR 1.51, 95% CI 1.11-2.04, multivariate analysis) and increasing sEGFR values (HR 0.96, 95% CI 0.93-0.99, multivariate analysis) were both independently associated with prolonged survival. Higher levels of pre-treatment sEGFR were associated with lower risk of progressive disease within three months (p=0.04). CONCLUSIONS: Both baseline sEGFR and CEA levels in NSCLC patients receiving EGFR-TKIs showed a significant correlation with survival. To distinguish whether these factors have a predictive or a prognostic value, validation is warranted in an independent patient series containing a control arm without EGFR-TKI treatment.

A prognostic model for amputation in critical lower limb ischemia.

In a (negative) multicenter randomized trial on management for inoperable critical lower limb ischemia, comparing spinal cord stimulation and best medical treatment, a number of pre-defined factors were analyzed for prognostic value. We included a radiological arterial disease score, modified from the SVS/ISCVS runoff score. The purpose of this analysis was to evaluate clinical factors and commonly used circulatory measurements for prognostic modeling in patients with critical lower limb ischemia. We determined the incidence of amputation and its relation to various pre-defined risk factors. A total of 120 patients with critical limb ischemia were included in the study. The integrity of circulation in the affected limb was evaluated on five levels: suprainguinal, infrainguinal, popliteal, infrapopliteal and pedal. A total radiological arterial disease score was calculated from 1 (full integrity of circulation) to 20 (maximally compromised state). We used Cox regression analysis to quantify prognostic effects and differential treatment (predictive) effects. Major amputation occurred in 33% of the patients at 6 months and in 51% at 2 years. The presence of ischemic skin lesions and the radiological arterial disease score were independent prognostic factors for amputation. Patients with ulcerations or gangrene had a higher amputation risk (hazard ratio 2.38, p = 0.018 and 2.30, p = 0.036 respectively) as well as patients with a higher radiological arterial disease score (hazard ratio 1.17 per increment, p = 0.003). We did not observe significant interactions between prognostic factors and the effect of spinal cord stimulation. In conclusion, in patients with critical lower limb ischemia, the presence of ischemic skin lesions and the described radiological arterial disease score can be used to estimate amputation risk.

What is the evidence on efficacy of spinal cord stimulation in (subgroups of) patients with critical limb ischemia?

The use of spinal cord stimulation (SCS) has been advocated for the management of ischemic pain and the prevention of amputations in patients with inoperable critical limb ischemia (CLI), although data on benefit are conflicting. Several reports described apparently differential treatment effects in subgroups. The purpose of this study was to analyze the data on the efficacy of SCS and to clarify preselection issues. Five randomized trials have been performed with a total number of 332 patients. Primary outcome measures were mortality and limb survival. In the largest multicenter randomized trial (n = 120), which compared SCS treatment and best medical treatment alone in patients with inoperable CLI, we determined the incidence of amputation and its relation to various predefined risk factors. We used Kaplan-Meier and Cox regression analyses to quantify prognostic effects and differential treatment effects. Meta-analysis yielded a relative risk for amputation of 0.79 and a risk difference of -0.07 (p = 0.15). The risk factor analysis clearly showed that patients with ischemic skin lesions (ulcerations or gangrene) had a worse prognosis (i.e., higher risk of amputation) (relative risk 2.30, p = 0.01). We did not observe significant interactions between this prognostic factor (or any other) and the effect of SCS. The analysis did not indicate a subgroup of patients who might specifically be helped by SCS. Meta-analysis including all randomized data shows insufficient evidence for higher efficacy of SCS treatment compared with best medical treatment alone. Although some factors provide prognostic information as to the risk of amputation in patients with CLI, there are no data supporting a more favorable treatment effect in any group.

Surgical treatment in the management of malignant pleural mesothelioma: a single institution's experience.

BACKGROUND: A minority of patients with malignant pleural mesothelioma (MPM) are considered for surgery. To achieve a microscopically radical resection, combination with other treatment modalities is mandatory. The most effective combination is unknown. In our institute we have retrospectively analyzed the results of two combined modality regimens containing surgery. PATIENTS: Between January 2002 and September 2005, 15 MPM patients were treated with extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (RT; 54 Gy). Previously, between January 1999 and December 2001, 20 patients underwent a combination of cytoreductive surgery - pleurectomy or EPP - and intraoperative hyperthermic intrathoracic chemotherapy (HITHOC), followed by radiotherapy to the thoracotomy scar and drainage tracts (24 Gy). RESULTS: The median operating time for EPP/RT was shorter (5.3 versus 6.9 h; P < 0.0001). Postoperative complications occurred in 8 EPP/RT patients (53%) and in 14 HITHOC patients (70%). Two HITHOC patients died postoperatively. Median overall survival was 29 months for EPP/RT patients and 11 months for HITHOC patients (P = ns). The median time to local recurrence was not reached for EPP/RT patients, and was 9 months for HITHOC patients (P = 0.003). Local control was achieved in ten EPP/RT patients (67%) with a follow-up of 5-59 months compared to four HITHOC patients (20%) with a follow-up of 4-27 months. CONCLUSIONS: In highly selected patients local control can be achieved with combination therapy but is accompanied by a high rate of (surgical) complications. Distant failure rates warrant further studies exploring the role of systemic chemotherapy while the use of cytoreductive surgery with intraoperative chemoperfusion for MPM is not supported.

Non-small cell lung carcinoma of the superior sulcus: favourable outcomes of combined modality treatment in carefully selected patients.

The combination of radiotherapy and concurrent chemotherapy followed by surgery (trimodality treatment) is currently regarded as optimal treatment for non-small cell lung cancer of the superior sulcus (SST) or Pancoast tumour. The possibility to administer intensive combined modality treatment is influenced by tumour stage, comorbidity and performance status of these patients, and therefore a strict patient selection is necessary. This study focuses on patient selection and its results. We retrospectively evaluated choices of treatment and outcome of all patients with SST treated in the Netherlands Cancer Institute from 1994 to 2004. After identification of patients with SST in registration databases, the following characteristics were analyzed: symptoms, comorbidity, tumour stage, treatment characteristics, toxicity, local control, disease-free and overall survival. Fifty-two patients, 37 men and 15 women, were identified. They were diagnosed with stage IIB (27%), stage IIIA (8%), stage IIIB (42%) and stage IV (23%). Twelve patients after induction (chemo)radiotherapy underwent surgical resection. In eight patients a pathologic complete response was found. The 2- and 5-year survival after induction treatment and surgery was 75 and 39%, respectively. Other patients did not receive surgical treatment because of stage IV disease (n=12), comorbidity (n=8), irresectability (extensive tumour growth and/or persisting N2-3 status; n=14) or insufficient response to induction treatment (n=6). Eleven patients were treated with concurrent chemoradiotherapy (5-year survival 20%) and 17 patients with (sequential) radiotherapy and/or chemotherapy (5-year survival 6%). Local recurrence rates were 0% after induction treatment and surgical resection, 32% after concurrent chemoradiotherapy and 72% after (sequential) radiotherapy and/or chemotherapy. In conclusion, only 30% of M0 patients with SST were eligible for combined modality treatment followed by surgery. In this subgroup, concurrent chemoradiotherapy followed by surgery was associated with excellent local control and acceptable survival.

Spinal cord stimulation is not cost-effective for non-surgical management of critical limb ischaemia.

OBJECTIVE: To quantify the costs of treatment in critical limb ischaemia (CLI) and to compare costs and effectiveness of two treatment strategies: spinal cord stimulation (SCS) and best medical treatment. METHODS: One hundred and twenty patients with CLI not suitable for vascular reconstruction were randomised to either SCS in addition to best medical treatment or best medical treatment alone. Primary outcomes were mortality, amputation and cost. Cost analysis was based on resources used by patients for 2 years after randomisation. Both medical and non-medical costs were included. RESULTS: Patient and limb survival were similar in the two treatment groups. Costs of in-hospital-stay and institutional rehabilitation constituted the predominant part (+/-70%) of the total costs of medical care in CLI. Cost of SCS-implantation and complications (7950 euro per patient) exceeded by far cost due to amputation procedures (410 euro per patient). The total costs of treatment were 36,600 euro per patient over 2 years for the SCS-group vs. 28,700 euro for best medical treatment alone (28% higher for SCS-group, p=0.009). CONCLUSIONS: Total costs of treatment in CLI are high. Major components are hospital and rehabilitation costs. In contrast to recent reviews, there were no long-term benefits of SCS-treatment. Therefore, cost-effectiveness is reduced to cost-minimisation and SCS-treatment is considerably more expensive than best medical treatment.

Pain and quality of life in patients with critical limb ischaemia: results of a randomized controlled multicentre study on the effect of spinal cord stimulation. ESES study group.

We carried out an assessment of pain and quality of life of patients with critical limb ischaemia during the follow-up of a multicentre randomized trial in more detail than previously reported. In a multicentre clinical trial 120 patients were randomized between medical treatment and medical treatment plus spinal cord stimulation. Patients were selected on the basis of clinical symptoms and macrocirculatory data as described in the European consensus document on critical limb ischaemia. Data were collected at intake and then 1, 3, 6, 12 and 18 months later. Primary outcome measures were limb salvage, pain relief and quality of life. Patient and limb survival was estimated with the Kaplan-Meier method. Pain was evaluated using the visual analogue scale (VAS), the McGill pain questionnaire, the pain score of the Nottingham Health Profile (NHP) and the use of analgesics. Quality of life was evaluated using the NHP, the EuroQol and mobility subscore of the Sickness Impact Profile. The 2-year limb survival was 52% for SCS treatment and 46% for standard treatment (p =0.47). Pain relief was considerable in both treatment strategies (p<0.005) with no significant differences between the strategies. The improvement occurred within the first few months and remained stable during further follow-up. Patients with SCS used fewer non-narcotic and narcotic drugs (p<0.001 at t=1 and t=3, p<0.002 at t=6). The overall scores of quality of life improved significantly (p<0.05), with no difference in score between treatments. The subscores of mobility and energy of the NHP in non-amputated patients was significantly better in the SCS group (p<0.005). Amputation had a negative effect on mobility, resulting in a difficult rehabilitation but relieved pain substantially (p<0. 05). In contrast to the existing literature, the randomized trial revealed no major difference in overall pain and quality of life assessment between treatment groups. The effect on energy and mobility was significantly better in patients treated with SCS, who also used substantially fewer analgesics.

Technical data and complications of spinal cord stimulation: data from a randomized trial on critical limb ischemia.

This study was done to evaluate the effect of spinal cord stimulation (SCS) on critical limb ischemia and to report technical problems and complications. One hundred and twenty patients with critical limb ischemia were eligible for randomization between medical treatment and medical treatment plus SCS. Sixty received a spinal cord stimulator (Itrel II; Medtronic, Minneapolis, Minn., USA). Primary outcome measures were limb salvage and pain relief. The mean pain reduction in both treatment groups was 50% (from 5 to 2.5 on the visual analog scale). The 2-year limb survival was 52% (SCS) versus 46% (standard treatment; p = 0.47). The number of patients undergoing major amputations in the SCS group with intermediate TcpO2 values was half of that in the standard group (14 vs. 28; 24 vs. 48%; p = 0.17). Implantation was successful in 51 patients. Technical problems such as loss of stimulation due to lead displacement occurred in 13 patients (22%), local infection at the site of implantation occurred in 3 patients (5%), resulting in a total complication rate of 27%. Premature depletion of the battery occurred within 2 years in 3 patients (5%). There were no lead fractures, epidural infections, hematoma or cerebrospinal fluid leakage. Training of physicians and better reliability of the hardware should reduce the frequency of technical problems. Lead displacement remains the major technical problem. The search for prognostic factors of limb salvage is important. One microcirculatory measurement (TcpO2) seems to have a prognostic value, which remains to be described more precisely.

Spinal-cord stimulation in critical limb ischaemia: a randomised trial. ESES Study Group.

BACKGROUND: For patients with critical limb ischaemia, spinal-cord stimulation has been advocated for the treatment of ischaemic pain and the prevention of amputation. We compared the efficacy of the addition of spinal-cord stimulation to best medical treatment in a randomised controlled trial. METHODS: 120 patients with critical limb ischaemia not suitable for vascular reconstruction were randomly assigned either spinal-cord stimulation in addition to best medical treatment or best medical treatment alone. Primary outcomes were mortality and amputation. The primary endpoint was limb survival at 2 years. FINDINGS: The mean (SD) age of the patients was 72.6 years (10.3). Median (IQR) follow-up was 605 days (244-1171). 40 (67%) of 60 patients in the spinal-cord-stimulator group and 41 (68%) of 60 patients in the standard group were alive at the end of the study, (p=0.96). There were 25 major amputations in the spinal-cord-stimulator group and 29 in the standard group, (p=0.47). The hazard ratio for survival at 2 years without major amputation in the spinal-cord stimulation group compared with the standard group was 0.96 (95% CI 0.61-1.51). INTERPRETATION: Spinal-cord-stimulation in addition to best medical care does not prevent amputation in patients with critical limb ischaemia.

Design issues of a randomised controlled clinical trial on spinal cord stimulation in critical limb ischaemia. ESES Study Group.

OBJECTIVES: Review of the design of a clinical study to evaluate of the efficacy of epidural spinal cord electrical stimulation (ESES) as compared to best medical treatment in patients with nonreconstructible critical limb ischaemia. DESIGN: Randomised controlled clinical trial of pragmatic type, which will be analysed according to the intention-to-treat principle. The treatment strategies are ESES, in addition to best medical treatment, and best medical treatment alone. Patients are followed-up for at least 18 months. SETTING: The ESES-trial is an ongoing multicentre trial in 17 hospitals in The Netherlands. PATIENTS: Patients with critical limb ischaemia, nonsuitable for either primary intervention or reintervention after failing reconstructions. CHIEF OUTCOME MEASURES: Limb survival, patient survival, quality of life and cost-effectiveness. MAIN RESULTS: From November 1991 until May 1994 120 patients had been enrolled. Using life-table analysis, at one year 76% of these randomised patients were alive: 41% without amputation and 35% with amputation. Quality of life of the trial patients was low, even compared to other severely ill patient groups, such as liver and heart transplant candidates. CONCLUSIONS: Considering the high incidence of death and amputation, 18 months of follow-up seems adequate to detect a clinically relevant outcome improvement from ESES-treatment, if present. We hope to present the results of this study at the end of 1995.