Stéphane Renaud

Is radiofrequency ablation or stereotactic ablative radiotherapy the best treatment for radically treatable primary lung cancer unfit for surgery

A best evidence topic was constructed according to a structured protocol. The question addressed was whether radiofrequency (RF) offers better results than stereotactic ablative therapy in patients suffering from primary non-small-cell lung cancer (NSCLC) unfit for surgery. Of the 90 papers found using a report search for RF, 5 represented the best evidence to answer this clinical question. Concerning stereotactic ablative therapy, of the 112 papers found, 10 represented the best evidence to answer this clinical question. A manual search of the reference lists permitted us to include seven more articles. The authors, journal, date, country of publication, study type, group studied, relevant outcomes and results of these papers are given. We conclude that, on the whole, the 23 retrieved studies clearly support the use of stereotactic ablative therapy rather than RF in patients suffering from primary NSCLC unfit for surgery. Indeed, stereotactic ablative therapy offered a 5-year local control rate varying between 83 and 89.5%, whereas the local control rate after RF ranges from 58 to 68%, with a short follow-up of ∼18 months. Furthermore, both overall survival and cancer-specific survival were better with stereotactic ablative therapy, with a 3-year overall survival ranging from 38 to 84.7% and the 3-year cancer-specific survival from 64 to 88%, whereas the 3-year OS, only reported in two studies, ranged from 47 to 74% for RF. Moreover, the post-interventional morbidity was superior for RF ranging from 33 to 100% (mainly composed by pneumothorax), whereas radiation pneumonitis and rib fracture, ranging, respectively, from 3 to 38% and 1.6 to 4%, were the primary complications following stereotactic ablative therapy. Hence, the current evidence shows that stereotactic ablative therapy is a safe and effective procedure and should be proposed first to patients suffering from primary NSCLC unfit for surgery. However, the published evidence is quite limited, mainly based on small studies of <100 patients. Moreover, so far there is no blind, prospective control, randomized study comparing these two techniques. Consequently, despite the encouragement of these preliminary results, they must be interpreted with caution.

Does nodal status influence survival? Results of a 19-year systematic lymphadenectomy experience during lung metastasectomy of colorectal cancer

OBJECTIVES Resection of pulmonary metastases originating from colorectal cancer is increasingly considered. While several adverse risk factors for long-term outcome are known, the selection of patients who may benefit from surgery remains unclear. In particular, few studies have addressed the impact of lymph node involvement, and signification of the hilar or mediastinal level of extent. METHODS We retrospectively reviewed the data of 320 patients operated in two thoracic departments between 1992 and 2011. Appropriate statistical tests were used to compare groups at risk. RESULTS There were 105 women and 215 men with a mean age of 63.3 years (range: 27-86) at the time of metastasectomy. Lymph node involvement appeared as a significant prognostic factor in both the univariate and multivariate analyses [median survival: 94 months N0 vs 42 months N+, P < 0.0001; OR = 0.573 (0.329-1), P = 0.05]. Survival was similar for hilar and mediastinal locations (median survival: 47 months vs 37 months, respectively, P = 0.14). Associated hepatic metastases had a negative impact on survival in both univariate and multivariate analyses [median survival: 74 months vs 47 months, P < 0.01; OR = 0.387 (0.218-0.686), P = 0.001]. Multiple lung metastases significantly decreased survival in univariate analysis only (median survival: 81 months vs 55 months, P < 0.01). Disease-free survival and preoperative carcinoembryonic antigen had no impact on survival. CONCLUSIONS While lymph node involvement was associated with decreased survival, the impact of mediastinal location on survival did not differ from that of hilar location. Consequently, these patients should not be excluded from surgical treatment.

KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer

Background:We evaluated KRAS (mKRAS (mutant KRAS)) and BRAF (mBRAF (mutant BRAF)) mutations to determine their prognostic potential in assessing patients with colorectal cancer (CRC) for lung metastasectomy.Methods:Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011.Results:Molecular analysis revealed mKRAS in 93 patients (51.7%), mBRAF in 19 patients (10.6%). In univariate analyses, overall survival (OS) was influenced by thoracic nodal status (median OS: 98 months for pN−, 27 months for pN+, P<0.0001), multiple thoracic metastases (75 months vs 101 months, P=0.008) or a history of liver metastases (94 months vs 101 months, P=0.04). mBRAF had a significantly worse OS than mKRAS and wild type (WT) (P<0.0001). The 5-year OS was 0% for mBRAF, 44% for mKRAS and 100% for WT, with corresponding median OS of 15, 55 and 98 months, respectively (P<0.0001). In multivariate analysis, WT BRAF (HR: 0.005 (95% CI: 0.001–0.02), P<0.0001) and WT KRAS (HR: 0.04 (95% CI: 0.02–0.1), P<0.0001) had a significant impact on OS.Conclusions:mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy. Further studies are necessary.

Systematic lymph node dissection in lung metastasectomy of renal cell carcinoma: an 18 years of experience.

Pulmonary metastasectomy of renal cell carcinomas (RCC) remains controversial. Thoracic lymph node involvement (LNI) is a known prognostic factor. The aim of our analysis is to evaluate whether patients with LNI, and particularly N2 patients, should be excluded from surgical treatment.

Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases

Background:Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC).Methods:We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012.Results:mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs Cohort: 60 months; DFS: KRAS G12V: 15 months vs Cohort: 24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS; HR: 0.67 (0.48–0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001).Conclusions:mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.

Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery

Background:We aimed to evaluate whether EGFR mutations (mEGFR) and KRAS amino acid substitutions can predict first site of recurrence or metastasis after non-small-cell lung cancer (NSCLC) surgery.Methods:Data were reviewed from 481 patients who underwent thoracic surgery for NSCLC between 2007 and 2012.Results:Patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs 16%, P<0.0001). This was confirmed in multivariate analysis (MA) (odds ratio (OR): 0.113 (95% confidence interval (CI): 0.055–0.231), P<0.0001). Significantly, more patients with mEGFR developed liver and brain metastases compared with the remainder of the cohort (30% vs 10%, P=0.006; 59% vs 1%, P<0.0001, respectively). These were confirmed in MA (OR: 0.333 (95% CI: 0.095–0.998), P=0.05; OR: 0.032 (95% CI: 0.008–0.135), P<0.0001, respectively). Patients with KRAS G12V developed significantly more pleuro-pericardial metastases compared with the remainder of the cohort (94% vs 12%, P<0.0001). This was confirmed in MA (OR: 0.007 (95% CI: 0.001–0.031), P<0.0001). Wild-type patients developed significantly more lung metastases (35% vs 10%, P<0.0001). This was confirmed in MA (OR: 0.383 (95% CI: 0.193–0.762), P=0.006).Conclusion:Epidermal growth factor receptor mutation and KRAS amino acid substitutions seem to predict site-specific recurrence and metastasis after NSCLC surgery.

Should mediastinal lymphadenectomy be performed during lung metastasectomy of renal cell carcinoma

A best evidence topic was constructed according to a structured protocol. The question addressed was whether radical mediastinal lymphadenectomy should be performed during lung metastasectomy of renal cell carcinoma (RCC). Of the 13 papers found through a report search, seven represent the best evidence to answer this clinical question. The authors, journal, date, country of publication, study type, group studied, relevant outcomes and results of these papers are given. We conclude that on the whole, the seven-retrieved studies support the realization of systematic radical mediastinal lymphadenectomy. The published literature showed a prevalence of lymph node involvement (LNI) that approaches 30%. The majority of the studies conclude that LNI is a significant, independent prognostic of survival. Indeed, some authors did not report any 5-year survival in the case of LNI. On the contrary, however, a 5-year survival of ~50% was reported when no LNI was present. To date, the published data do not allow conclusions to be drawn regarding the prognosis of hilar vs mediastinal LNI: only one paper focused on the difference between hilar and mediastinal location and showed no difference. In addition, only one study has compared the survival of patients with or without lymphadenectomy, showing greater survival when mediastinal lymphadenectomy was performed. Despite the poor prognosis of patients with LNI, surgery seems to be the best treatment for potentially curative RCC with metastases. It is known that RCC metastases do not respond well to chemotherapy and radiotherapy. Indeed, reported 5-year survival rate ranged between 3 and 11% for non-operated patients. Consequently, resection must be as complete as possible and include a systematic total mediastinal lymphadenectomy, which will probably yield better loco-regional control and evaluation of prognostic factor. However, the published evidence remains quite limited and mainly based on retrospective studies on highly selected patients, with a low level of evidence. Indeed, most patients referred to surgery are younger, fitter, and have fewer metastases. Consequently, the survival gain could be biased, related more to the resectability and the good performance status rather to the resection itself. Consequently, although these preliminary results are interesting, they must be interpreted with caution.

Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer

BACKGROUND Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild-type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS.

Mediastinal downstaging after induction treatment is not a significant prognostic factor to select patients who would benefit from surgery: the clinical value of the lymph node ratio

OBJECTIVES Multimodal management of N2 non-small-cell lung cancer is still a matter of debate. In particular, the place of surgery for persistent N2 after induction treatment is controversial and surgery is usually reserved for patients experiencing a mediastinal downstaging (pN1 and pN0). We aimed to evaluate whether there might exist subgroups of pN2 according to the lymph node ratio (LNR). METHODS Between 1996 and 2012, we retrospectively reviewed the data from 152 potentially resectable cN2 patients who underwent an induction treatment before surgery. RESULTS The median follow-up time was 32 months (2-112). The average age at the time of diagnosis was 58.52 ± 10.47 years. In univariate analysis, overall survival (OS) was significantly influenced by extracapsular spread (32 ± 5.33 vs 24 ± 12.73 months, P = 0.01), pN after surgery (65 ± 2.45 months for pN0, 44 ± 2.14 months for pN1 and 19 ± 1.72 months for pN2, P <0.0001) and LNR ≥ 1/3 (30 ± 3.77 months vs 16 ± 1.39 months, P <0.0001). When pN0 and pN1 patients were staged according to the LNR, the OS was divided by two for pN1 patients with an LNR ≥ 1/3 (48 ± 2.64 months vs 26 ± 5.65 months, P <0.001), whereas it decreased from 26 ± 0.87 to 15 ± 1.85 months (P <0.0001) for pN2 patients. OS was significantly better with adjuvant radio-chemotherapy than with chemotherapy or radiation therapy alone (P <0.0001). In multivariate analysis, mediastinal downstaging {Hazard Ratio (HR): 0.184 (95% confidence interval (CI): 0.084-0.403), P <0.0001} and LNR [HR: 0.359 (95% CI: 0.194-0.665], P = 0.001) remained significantly independent prognostic factors. CONCLUSIONS The LNR may potentially identify subgroups of pN+ patients and allow enhancement of adjuvant treatments. Because pN2 with a low LNR had an equivalent survival to pN1 with a high LNR, mediastinal downstaging does not seem to be a sufficient prognostic factor to exclude patients after induction treatment from surgery.

The intrathoracic lymph node ratio seems to be a better prognostic factor than the level of lymph node involvement in lung metastasectomy of colorectal carcinoma

OBJECTIVES Data on thoracic lymph node involvement (LNI) in lung metastasis of colorectal cancer (CRC) are conflicting, with a 5-year overall survival (OS) ranging from 6 to 40%. We aimed to evaluate whether there are subgroups of patients according to the lymph node ratio (LNR). METHODS We retrospectively reviewed the data from 106 patients who underwent a thoracic procedure for CRC lung metastasis with pathologically proven thoracic LNI. RESULTS In the univariate analysis, the median OS was significantly poorer for a pN2 location of LNI (26 vs 16 months, P = 0.04), LNR ≥50% (30 vs 17 months, P = 0.005), high preoperative CEA (32 vs 16 months, P = 0.02), hepatic metastases (27 vs 11 months, P <0.0001) and disease-free survival < 24 months (32 vs 17 months, P = 0.05). When pN1 and pN2 patients were staged according to the LNR, the median OS was significantly better for an LNR <50% (27 vs 17 months for pN1, 32 vs 12 months for pN2, P = 0.01). In the multivariate analysis, a high preoperative CEA [hazard ratio (HR): 2.256 (1.051-4.841), P = 0.04], pN1 status [HR: 0.337 (0.162-0.7), P = 0.004] and the absence of hepatic metastases [HR: 0.395 (0.180-0.687), P = 0.02] remained significant prognostic factors. There was an upward trend for patients with LNR <50% [HR: 0.565 (0.296-1.082), P = 0.08]. Otherwise, low LNR was significantly associated with a decreased risk of loco-regional recurrence (HR: 0.36, 95% confidence intervals: 0.14-0.96, P = 0.04). CONCLUSIONS The LNR seems to be a more reliable prognostic factor than LNI for CRC lung metastasis. Prospective studies are necessary.