Current treatment landscape for oligometastatic non-small cell lung cancer

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.     

Local treatment of oligometastatic recurrence in patients with resected non-small cell lung cancer

Objectives

We previously reported a retrospective study indicating the prognostic impact of the local treatment of oligometastatic recurrence after a complete resection for non-small cell lung cancer (NSCLC). In the present study, we prospectively observed postoperative oligometastatic patients and investigated the effects of local treatment on progression-free survival (PFS).

Methods

Using a prospectively maintained database of patients with completely resected NSCLC treated between October 2007 and December 2011, we identified 52 consecutive patients with postoperative recurrence, excluding second primary lung cancer. Of these patients, 31 suffering from distant metastases alone without primary site recurrence were included in this study. According to the definition of ‘oligometastases’ as a limited number of distant metastases ranging from one to three, 17 patients had oligometastatic disease. Of those 17 patients, four patients with only brain metastasis were excluded from the analysis.

Results

The oligometastatic sites included the lungs in five patients, bone in four patients, the lungs and brain in two patients, the adrenal glands in one patient and soft tissue in one patient. Eleven of the 13 patients first received local treatment. Three patients (lung, adrenal gland, soft tissue) underwent surgical resection, and the remaining eight patients received radiotherapy. The median PFS was 20 months in the oligometastatic patients who received local treatment. There were five patients with a PFS of longer than two years. The metastatic sites in these patients varied, and one patient had three lesions. On the other hand, the two remaining patients first received a systemic chemotherapy of their own selection. The PFS of these two patients was five and 15 months, respectively.

Conclusion

Local therapy is a choice for first-line treatment in patients with postoperative oligometastatic recurrence.     

Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions

Oligometastatic non-small cell lung cancer (NSCLC) describes an intermediate stage of NSCLC between localized and widely-disseminated disease. This stage of NSCLC is characterized by a limited number of metastases and a more indolent tumor biology. Currently, the management of oligometastatic NSCLC involves radical treatment (radiotherapy or surgery) that targets the metastatic lesions and the primary tumor to achieve disease control. This approach offers the potential to achieve prolonged survival in patients who, in the past, would have only received palliative measures. The optimal therapeutic strategies for the different scenarios of oligometastatic disease (intracranial vs extracranial disease, synchronous vs metachronous) remain undefined. Given the lack of head-to-head studies comparing radiotherapy to surgery in these patients, the decision to apply surgery or radiotherapy (with or without systemic treatment) must be based on prognostic factors that allow us to classify patients. This classification will allow us to select the most appropriate therapeutic strategy on an individualized basis. In the future, the molecular or microRNA profiles will likely improve the treatment selection process. The objective of the present article is to review the most relevant scientific evidence on the management of patients with oligometastatic NSCLC, focusing on the role of radiotherapy and surgery. We also discuss areas of controversy and future directions.     

初治晚期无症状脑转移非小细胞肺癌患者全脑放疗的时序探讨

目的:探讨无症状脑转移非小细胞肺癌(non-small cell lung cancer,NSCLC)患者进行全脑放疗(whole brain radiation therapy,WBRT)的时序.方法:对102例经CT或MRI确诊的无症状脑转移NSCLC患者进行回顾性分析,根据WBRT的时序进行分组:化疗后行WBRT(A组)、先WBRT后化疗(B组)和同步WBRT和化疗(C组).结果:A、B和C组的无进展生存(progression-free survival,PFS)时间分别为4.5、6.1和5.6个月(P=0.50),总生存(overall survival, OS)时间分别为11.1、13.0和11.7个月(P=0.18).3组患者治疗后的3～4级不良反应发生率经比较差异无统计学意义. 结论:先WBRT后行化疗可能有延长无症状脑转移NSCLC患者PFS和OS的趋势,但各组之间的生存时间和不良反应差异无统计学意义.     

A 42-year-old woman with breast cancer

This premenopausal women has a T1c, N1 (two nodes positive) ER-positive, PR weakly positive, HER2 FISH-positive, grade 3 invasive ductal carcinoma. She has been treated with lumpectomy and axillary node dissection. The recommendation of the panel is for her to join one of the randomized trials studying the role of trastuzumab in node-positive breast cancers. Off protocol, we would recommend adjuvant chemotherapy with doxorubicin/cyclophosphamide followed by docetaxel, although numerous options are available. Chemotherapy would be followed by radiation therapy and hormonal treatment. At this point, we recommend tamoxifen, with consideration to adding goserelin (Zoladex) if the patient does not remain amenorrheic. The patient chose to enter the Intergroup trastuzumab trial.     

Survival outcome according to KRAS mutation status in newly diagnosed patients with stage IV non-small cell lung cancer treated with platinum doublet chemotherapy

Introduction

Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear.

Methods

We undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods.

Results

All patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01).

Conclusions

KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy.     

Ⅳ期寡转移NSCLC同期放化疗后巩固化疗前瞻性Ⅱ期临床研究

目的 研究寡转移NSCLC行胸内病灶根治性同期放化疗后巩固化疗的疗效和不良反应。方法 2008—2013年间转移灶≤5个的NSCLC患者66例入组。放疗采用IGRT, 常规分割或大分割。同期及巩固化疗均以铂类为基础两药联合方案。治疗结束后评价患者近期疗效、不良反应和生存率。结果 64例完成治疗。胸内病灶PTV中位BED为72 Gy, 中位化疗周期数4个。胸内病灶客观缓解率为70%。随访率为97%。1、2、3年OS分别为72%、53%、31%, 中位OS时间25个月;1、2、3年PFS分别为56%、26%、7%, 中位PFS时间14个月。2+3级急性放射性肺炎、放射性食管炎发生率分别为11%和17%, 3+4级白细胞、血红蛋白、血小板计数减少率分别为39%、11%、16%。结论 寡转移NSCLC胸内病灶根治性放疗联合同期化疗及巩固化疗, 可获得较好近期疗效和长期生存, 不良反应可耐受。     

Advanced non-small cell lung cancer

Opinion statement The treatment of advanced non-small cell lung cancer requires histologic proof of diagnosis, careful staging, and assessment of each patient’s performance status and comorbidities. For patients with stage IIIB (pleural effusion) and stage IV disease who have a Cancer and Leukemia Group B performance status (PS) of 0 to 1, appropriate management consists of combination chemotherapy with a platinum (either cisplatin or carboplatin) combined with paclitaxel, gemcitabine, vinorelbine, docetaxel, or CPT-11. Dosages and schedules previously established by large phase II or phase III studies should be followed. Variations in the toxicity patterns, schedules of administra-tion, and economic considerations should guide the selection of the specific regimen. For patients who maintain a good performance status after first-line chemotherapy, second-line treatment may be considered. Current evidence supports the use of docetaxel as second-line treatment if the patient has not previously received this drug. Gemcitabine and paclitaxel may also have activity in this setting. Vinorelbine, ifosfamide, and CPT-11 appear to be inactive as second-line therapy for patients who have previously received platinum-based chemotherapy. For patients with a PS of 2, single-agent chemotherapy with vinorelbine, gemcitabine, or a combination of the two should be considered. Patients with poor performance status should be treated with supportive measures designed to relieve pain and acute complications because any tumor-directed therapy has limited benefit. Special situations exist in which curative therapy for metastatic disease is a possibility. Patients who present with solitary sites of metastatic disease, particularly after a long disease-free interval and in the CNS may undergo definitive surgery or radiotherapy with curative intent. Some have also reported favorable outcomes for patients with solitary adrenal or bone metastases as well. Surgical treatment or definitive radiotherapy should not be employed unless a thorough restaging evaluation is performed that includes computed tomography scan of the chest and abdomen through adrenals, brain magnetic resonance imaging, and positron emission tomography scan. A plethora of new agents targeting angiogenesis, tumor invasiveness, the hypoxic environment of tumors, and the cell cycle are currently in development.     

Stereotactic body radiation therapy: A good dance partner of oligometastatic non-small cell lung cancer to the sound of SINDAS study

The European Organization for Research on Treatment of Cancer Research published a consensus statement to establish the key criteria to define oligometastatic disease (OMD). According to those criteria, all lesions (both primary and metastatic) should be amenable to radical intent treatment with acceptable toxicity. Several retrospective studies have shown that adding local ablative therapy to the treatment of OMD improves outcomes; however, due to the diverse selection criteria and treatment strategies used in those studies, it is difficult to compare directly results to draw definitive conclusions. In recent years, prospective phase II trials, such as the SABR-COMET and "Oligomez" trials, have shown that stereotactic body radiation therapy (SBRT) improves outcomes in patients with OMD. More recently, interim results of the randomised phase 3 SINDAS trial were reported at the annual meeting of the American Society of Clinical Oncology 2020 demonstrating that upfront SBRT added to systemic treatment with tyrosine kinase inhibitors yielded a significant benefit in both progression-free survival and overall survival in patients with epidermal growth factor receptor-mutant oligometastatic non-small cell lung cancer. In the present editorial, we review the definition and historical context of advanced non-small cell lung cancer with OMD. In addition, we review the scientific evidence for local ablative therapy and SBRT and discuss the results of recently published prospective studies. We also discuss in depth the results of the SINDAS study, including the strengths and weaknesses of the study and the barriers to extrapolating these results to routine clinical practice.     

Outcome of patients admitted to the intensive care unit with newly diagnosed small cell lung cancer

Patients with newly diagnosed small cell lung cancer (SCLC) may be considered for admission to an intensive care unit (ICU). Even though SCLC is highly responsive to chemotherapy, it is not clear whether patient outcomes justify the resource use of an ICU. This paper reports the results of a retrospective review of 20 newly diagnosed cases of SCLC who were admitted to one of three ICUs in Melbourne, Australia. Patients who had more than one negative prognostic factor did uniformly poorly, with no survivors beyond 4 months. Five patients were treated with chemotherapy whilst intubated and receiving mechanical ventilatory support. Two of these patients responded to chemotherapy and were extubated 4 days later. Both of these patients were alive and free of tumour recurrence 7 months later. In contrast, patients not treated with chemotherapy died early (within 40 days). We conclude that some patients with SCLC achieve a medium to long-term survival following treatment with chemotherapy instituted during or around the time of their admission to an ICU. The admission to an ICU of selected patients with SCLC may be justified, and prognostic indicators may be of benefit in making these difficult treatment decisions.     

Prognostic value of combining a quantitative image feature from positron emission tomography with clinical factors in oligometastatic non-small cell lung cancer

Background and purpose

Oligometastatic non-small cell lung cancer (NSCLC) is a heterogeneous condition with few known risk stratification factors. A quantitative imaging feature (QIF) on positron emission tomography (PET), gray-level co-occurrence matrix energy, has been linked with outcome of nonmetastatic NSCLC. We hypothesized that GLCM energy would enhance the ability of models comprising standard clinical prognostic factors (CPFs) to stratify oligometastatic patients based on overall survival (OS).

Iressa治疗非小细胞肺癌的进展

分子靶向药物,如表皮生长因子受体酪氨酸激酶抑制剂,是近年来在血液和实体肿瘤治疗中涌现出的新治疗手段。现就表皮生长因子受体酪氨酸激酶抑制剂Iressa在非小细胞肺癌治疗中的进展作一综述。     

Iressa治疗非小细胞肺癌的进展

分子靶向药物，如表皮生长因子受体酪氨酸激酶抑制剂，是近年来在血液和实体肿瘤治疗中涌现出的新治疗手段。现就表皮生长因子受体酪氨酸激酶抑制剂Iressa在非小细胞肺癌治疗中的进展作一综述。     

A trial with single-agent vinorelbine in taxane-resistant non-small cell lung cancer

It is reported that the single-agent administration of vinorelbine (VNR) is improper in salvage therapy for non-small cell lung cancer. However, there are few reports on its use as second line in taxane-containing chemotherapy. We used single-agent VNR administration for nine cases of taxane-resistant non-small cell lung cancer, and an antitumor effect was seen in four cases. We present three of these cases. A factor for the high response rate is considered to be that vinca alkaloid is not used as a pre-treatment. Moreover, VNR may be effective even if there is a gene mutation for beta tubulin, which causes taxane resistance.     

初治寡转移鼻咽癌患者原发灶根治性放疗疗效分析

目的 初诊寡转移鼻咽癌患者原发灶根治性放疗预后因素分析。方法 2008—2011年39例初诊寡转移鼻咽癌患者接受1~6周期化疗及原发灶根治性放疗,其中10例常规放疗,26例IMRT。Kaplan-Meier法计算生存率,Logrank单因素预后分析,Cox模型多因素预后分析。结果 中位随访时间38个月,1、2、3年OS和PFS分别为97%及87%、87%及65%、70%及59%。年龄、转移灶数目、诱导化疗方案、是否同步化疗均是影响生存的因素,其中≤3个转移灶患者生存率更高(P=0.023),诱导化疗包含比不含多西他赛方案生存率明显提高(P=0.041)。结论 初治寡转移鼻咽癌患者接受诱导化疗及原发灶根治性放疗后仍可获得长期生存,尤其是年龄小及转移灶数目≤3个患者。含多西紫杉醇的方案或能使患者得到更大生存获益。