ABSTRACT: The introduction of newer therapies and approaches for management has led to a renewed excitement in the field of lung cancer. This trend has continued in 2010 with the adoption of the new staging system recommended by the International Association for the Study of Lung Cancer (IASLC). Novel targets, such as EML4-ALK, have been identified and agents targeting these abnormalities have shown promise in uncontrolled clinical trials, while other strategies, including combining targeted agents with cytotoxic chemotherapy in unselected patients, have not proven to be successful. This review summarizes important recent clinical advances that could have a significant impact on the future care of patients with lung cancer.
Exciting advances in understanding the biology of lung cancer have occurred over the last few years. These biological advances, coupled with the availability of newer agents and newer surgical techniques and radiation modalities, have led to the design of trials exploring the clinical value of newer treatment approaches. The rapidity of advances across several disciplines makes the task of keeping up with these advances formidable not only for the general oncologist, but also for specialists in lung cancer. This review aims to summarize the most important recent clinical advances that could impact the management of lung cancer.
Selenium has long been thought to protect against development of cancer. Secondary analysis of a double-blind placebo-controlled trial showed that selenium(Drug information on selenium) supplementation decreased the incidence of lung cancer. In an attempt to confirm these findings, a large double-blind placebo-controlled trial was conducted. Selenium supplementation did not decrease the risk of secondary primary tumors either in the lung or overall, when administered to patients with resected stage I non–small-cell lung cancer (NSCLC). The incidence of second primary tumors (lung/overall) was 1.366/3.66 per 100 person-years for placebo vs 1.91/4.11 per 100 person-years for selenium (P = .15).
Advances in imaging technology have renewed an interest in lung cancer screening. However, all published studies of low-dose helical computed tomography (CT) screening are nonrandomized observational cohorts of volunteers; these studies have not been able to determine whether lung cancer–specific mortality is decreased with CT screening. The National Lung Screening Trial (NLST) was a prospective randomized study of high-risk individuals (≥ 30 pack-years, ages 55 to 74 years) in which individuals were randomized to CT scans or chest x-rays annually for 3 years. The recently announced results of this study demonstrated that CT scan screening decreased lung cancer–specific mortality by approximately 20% and reduced all-cause mortality by about 7%, leading to early closure of the study. (For more information, please link to http://www.cancer.gov/newscenter/pressreleases/NLSTresultsRelease.)
|TABLE 1 |
The revised staging system (AJCC [American Joint Committee on Cancer] Cancer Staging Manual, 7th edition, 2010) for lung cancer has recently been implemented based on the recommendations of the International Association for the Study of Lung Cancer (Table 1). The revised staging system was externally validated using a large prospective clinical trial database. Using prospectively collected data from 1,037 patients enrolled in the American College of Surgeons Oncology Group (ACOSOG) Z0030 trial, the investigators showed that use of the 7th edition of the AJCC lung cancer staging system produced results demonstrating monotonic progression, distinction between groups, and homogeneity within groups.
Determining whether or not mediastinal lymph nodes are involved is critical in the management of patients with NSCLC, since that is the single most important determinant of the suitability of primary surgical resection. In the past few years newer nonsurgical approaches to sample mediastinal lymph nodes have been developed, including endobronchial ultrasound (EBUS)-guided transbronchial needle aspirate (TBNA) and transesophageal endoscopic ultrasound–guided fine needle aspiration (EUS-FNA), that appear to confer an advantage over conventional bronchoscopy with blind TBNA for sampling mediastinal lymph nodes.
Mediastinal staging with EUS-FNA and EBUS-TBNA in resectable NSCLC reduced futile thoracotomies. Among the patients randomized to endoscopic ultrasound followed by surgical staging (ES-SS), nodal metastases were found in 50% of patients, compared with 35% of patients randomized to surgical staging (SS) alone (P = .019). Thoracotomy was futile in 7% of ES-SS patients versus 18% of SS patients (P = .009). The rate of complications during staging was similar in both arms. In another single-institution study, Tupayachi et al showed that EBUS-TBNA had better accuracy for nodal staging versus CT (94% vs 77%, P = .004) and PET (96% vs 73%, P = .019) scans.
Local Therapies for Early-Stage NSCLC
Surgical resection is the gold-standard treatment for fit patients with early-stage NSCLC. Newer radiation techniques offer the promise of being equally effective but without the need for major surgery. These techniques are not considered standard of care, and surgery remains the treatment of choice.
Ramirez et al evaluated the quality of surgery in 746 operations performed by 21 community-based, board-certified cardiothoracic or general thoracic surgeons. They found that seven surgeons failed to meet NCCN (National Comprehensive Cancer Network) criteria and five failed to meet RADIANT trial criteria of good-quality surgery in 100% of cases, affecting 168 and 134 patients, respectively. In another study, the same group compared operating surgeons’ claims of mediastinal lymph node dissection to the pathology report and to comments from an independent surgery reviewer who assessed the operative report in a blinded fashion. They found a high proportion of suboptimal mediastinal lymph node excision (71% per independent surgical review; 92% based on pathology report).
|TABLE 2 |
Stereotactic radiosurgery (SRS) (60 Gy in 3 fractions) appeared to be equivalent to standard radiation therapy in patients with medically inoperable early-stage NSCLC in a prospective multicenter study. Among 70 patients evaluable for response, complete response was observed in 11 patients (16%), partial response in 37 (53%), stable disease in 20 (28%), and progression in 2 patients (3%). The probability of 2-year overall-survival for the entire group was 62% (95% CI = 42%–77%) and median recurrence-free survival (RFS) was 43 months. Volumetric image-guided (VIGRT) stereotactic lung radiotherapy (stereotactic body radiation therapy [SBRT]) produced excellent local control for stage I NSCLC. This analysis of 434 patients treated uniformly by this technique showed 2-year rates of local recurrence, regional recurrence, and distant metastasis of 8%, 13%, and 26%, respectively. Overall survival (OS) and cause-specific survival rates at 2 years were 58% and 84%, respectively.
Although the baseline physical functioning and global quality of life (QOL) of patients referred for SBRT for stage I NSCLC were far poorer than those reported in the surgical literature, health-related QOL (HRQOL) scores did not decline during the first year after SBRT in an analysis of 382 consecutive SBRT patients from 70 Dutch centers. This may be an advantage over surgery, since HRQOL is often compromised in the first 6 months after surgery, and generally fails to return to baseline values, particularly in elderly patients.
Neoadjuvant chemotherapy for early-stage disease carries the theoretical advantages of earlier treatment of micrometastases, a decrease in tumor volume resulting in better local control with definitive local therapy, and better tolerance compared with adjuvant chemotherapy.
In an updated analysis of a previously published study, IFCT (Intergroupe Francophone de Cancérologie Thoracique) demonstrated that preoperative chemotherapy with two cycles of mitomycin(Drug information on mitomycin), ifosfamide(Drug information on ifosfamide), and cisplatin(Drug information on cisplatin), and two additional postoperative cycles for responding patients, did not significantly increase long-term survival. There was a stable long-term 8% survival benefit in favor of neoadjuvant chemotherapy, however. The benefit for neoadjuvant chemotherapy seemed to be more pronounced in patients with stage I and II disease (23% vs 38% rates of 10-year survival), while the difference in stage IIIA patients was not significantly different. Patients who had a lobectomy but not a pneumonectomy seemed to benefit from chemotherapy.
In patients with pathologically proven N2 or N3 disease, concurrent chemoradiation with carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel), along with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to gross disease, achieved a mediastinal nodal sterilization rate of 63%. In this RTOG (Radiation Therapy Oncology Group) phase II study of 60 patients, median OS was 26.6 months and the 1-year OS rate was 77%. The survival rates exceed those of the SWOG (Southwest Oncology Group) phase II and III studies using neoadjuvant cisplatin-based chemotherapy combined with radiotherapy in patients with stage III disease.
Adjuvant chemotherapy for early-stage NSCLC
Adjuvant chemotherapy is now considered standard of care for patients with completely resected stage II and IIIA NSCLC. In an analysis from the Ontario Cancer registry, Booth et al found that the proportion of cases receiving adjuvant chemotherapy increased from 7% in 2001–2003 to 31% in 2004–2006 (P = .0001). During the study period there was a significant improvement in 4-year survival among all surgical cases, from 52.5% to 56.1% (P = .007). Younger age, less comorbidity, shorter length of surgical hospital stay, more extensive surgery, stage II/III disease, and region where surgery was performed were independently associated with administration of adjuvant chemotherapy.
Adjuvant gefitinib(Drug information on gefitinib) (Iressa) did not confer an advantage in disease-free survival (DFS) or OS when administered to an unselected group of patients with stages IB–IIIA NSCLC. The absence of a KRAS mutation or increased EGFR gene copy number did not predict for benefit from gefitinib; however the small numbers of patients in these subgroups prior to premature study closure should temper the interpretation of this subgroup analysis. In a randomized phase III study of 158 patients, those treated with a combination of docetaxel(Drug information on docetaxel) (Taxotere) and cisplatin had similar DFS (70.1% vs 71.4%; P = .88) and OS rates (87.7% vs 81.8%; P = .37) at 20 months compared with patients who received cisplatin and vinorelbine (Navelbine).