非小细胞肺癌（NSCLC）的化疗宝典

Clin Lung Cancer. 2012 Jan;13(1):24-30. doi: 10.1016/j.cllc.2011.05.007. Epub 2011 Aug 10.
Brain metastases as the primary site of relapse in two randomized phase III pemetrexed trials in advanced non-small-cell lung cancer.
Ortuzar W, Hanna N, Pennella E, Peng G, Langer C, Monberg M, Scagliotti G.
SourceEli Lilly and Company or one of its subsidiaries, Indianapolis, IN 46285, USA. ortuzarwa@lilly.com

Abstract
BACKGROUND: Symptomatic brain metastases (BM) frequently occurs after initial treatment of non-small-cell lung cancer (NSCLC). Therefore, 2 large randomized trials that involved pemetrexed were retrospectively analyzed to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence.

METHODS: Two large phase III studies of pemetrexed in advanced NSCLC were included. One study compared pemetrexed with docetaxel in previously treated patients (n = 571); the other study tested cisplatin plus pemetrexed vs. cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (n = 1725). Patients with known BM at study entry were excluded from this analysis. Each study was analyzed separately, then jointly to determine the rate of BM reported as the only site of progressive disease by treatment group and histology. Logistic regression was used to obtain an odds ratio for the treatment effect on the overall occurrence of BM while controlling for potential confounding factors.

RESULTS: Overall, 71.5% of patients in pemetrexed-containing arms (819 of 1145), and 68.2% of patients in non-pemetrexed-containing arms (785 of 1151) experienced progressive disease. BM recurrence rates were 3.2% (95% confidence interval [CI], 2.1%-4.6%) in the pemetrexed-containing arms vs. 6.6% (95% CI, 5.0%-8.6%) in the non-pemetrexed-containing arms (P = .002). The odds ratio for BM recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32-0.76; P = .001). The beneficial effect of pemetrexed on BM was confined to patients with nonsquamous NSCLC.

CONCLUSIONS: Patients with advanced nonsquamous NSCLC treated with pemetrexed either in first-line or second-line therapy may reduce the risk of developing BM as the first site of progressive disease. This retrospective analysis is limited due to the lack of baseline and periodic brain scans, and it reflects symptomatic BM only. Regardless, these findings suggest a potential beneficial effect of pemetrexed-based treatments on the control of BM.

http://www.ncbi.nlm.nih.gov/pubmed/21831719

Outcomes associated with brain metastases in a three-arm phase III trial of gemcitabine-containing regimens versus paclitaxel plus carboplatin for advanced non-small cell lung cancer.
Edelman MJ, Belani CP, Socinski MA, Ansari RH, Obasaju CK, Chen R, Monberg MJ, Treat J; Alpha Oncology Research Network.
SourceUniversity of Maryland Greenebaum Cancer Center, Baltimore, Maryland 21201-1595, USA, medelman@umm.edu

Abstract
BACKGROUND: Brain metastases (BMs) are a common complication of non-small cell lung cancer (NSCLC). Because of historical data indicating a poor prognosis for patients with BM, few randomized phase III studies of advanced NSCLC have included patients with BM at presentation. Because the potential benefits of systemic therapy in patients with BM are uncertain, we analyzed data from a recent phase III study.

METHODS: One thousand one hundred thirty-five chemonaïve patients with stage IIIB/IV NSCLC were randomized to receive gemcitabine/carboplatin, gemcitabine/paclitaxel, or paclitaxel/carboplatin. Stratification was based on presence or absence of BM, stage, and baseline weight loss. Patients with BM were required to be clinically stable after treatment with radiotherapy or surgery before entry. Results were retrospectively analyzed by presence or absence of BM at study entry.

RESULTS: Rate of BM was 17.1% overall. The response rate was 28.9% for patients with BM (n = 194) versus 29.1% without BM (n = 941). Time to progression was 4.3 months with BM and 4.6 months without BM (p = 0.03). Median survival was 7.7 months (95% confidence interval: 6.7-9.3) among patients with BM (n = 194) and 8.6 months (95% confidence interval: 7.9-9.5) for patients without BM (n = 941), p = 0.09. Rates of hematologic adverse events were not different among patients with and without BM.

CONCLUSIONS: There were no significant differences in response, survival, or hematologic toxicity for patients with or without BM; however, patients with BM had a small but significantly shorter time to progression. Nonprogressing patients with treated BM are appropriate candidates for systemic therapy and entry into clinical trials.

http://www.ncbi.nlm.nih.gov/pubmed/20035187

Continuous pemetrexed treatment for brain metastasis in non-small cell lung cancer-A report of two cases.
Nobuaki Ochi, Hiromichi Yamane, Tomoko Yamagishi, Nagio Takigawa
Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.
Lung cancer (Amsterdam, Netherlands) (Impact Factor: 3.14). 12/2012; DOI:10.1016/j.lungcan.2012.12.010
Source: PubMed
ABSTRACT Brain metastasis is a major complication in patients with advanced non-small cell lung cancer (NSCLC), which is the malignancy that metastasizes most frequently to the central nervous system (CNS). Although the CNS is protected from cytotoxic agents by the blood-brain barrier under normal conditions, the blood-brain barrier is thought to become less functional in the presence of brain metastasis. Here, we describe two NSCLC patients who relapsed with brain metastases. Following brain stereotactic irradiation, salvage chemotherapy using pemetrexed was given. Continuous pemetrexed treatment resulted in no recurrence, including brain metastasis, over 2 years without whole-brain irradiation. Our experience suggests that pemetrexed suppresses brain metastasis after stereotactic irradiation.

http://www.researchgate.net/publ ... report_of_two_cases

Maintenance Therapy for Advanced Lung Cancer: Who, What, and When?
http://jco.ascopubs.org/content/31/24/2983

Efficacy assessment of pemetrexed treatment of an NSCLC case with brain metastasis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499519/
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Case Study: Maintenance Therapy in Squamous NSCLC
http://www.onclive.com/peer-exch ... y-in-Squamous-NSCLC
In the continuation of a case-based discussion, panelists describe the appropriateness of maintenance therapy for a functional 77 year-old man with squamous non-small cell lung cancer (NSCLC). The patient should receive an initial doublet therapy, administered on a weekly schedule, suggests Everett E. Vokes, MD. Following 4 to 6 weeks of treatment, maintenance therapy should be discussed as an option but should not automatically be administered, Vokes believes.

Erlotinib was suggested as a potential maintenance therapy; however, Karen L. Reckamp, MD, MS, notes that she does not utilize it in this setting. If a patient responds well to the initial regimen, such as gemcitabine, without significant toxicity, Reckamp suggests continuing this treatment. However, if the initial regimen includes a taxane, a break from treatment may be required.

While he would not automatically recommend maintenance therapy, Roy S. Herbst, MD, PhD, does discuss it as an option with his patients. If maintenance is required, Herbst recommends erlotinib or gemcitabine. Following the initial treatment, the patient should be observed for signs of continued tumor growth by imaging every 8 weeks to 3 months.

At this point, moderator Corey J. Langer, MD, changes the scenario by noting that the patient has adenocarcinoma rather than squamous cell NSCLC. Outside of this, the clinical presentation is the same. In this situation, Langer wonders if treatment with bevacizumab is appropriate. This patient should still be treated with an initial doublet regimen and not a single agent, Vokes emphasizes. Additionally, he adds, given the patient's age, there is not an advantage for adding bevacizumab to the doublet.

Case Study: Treating an Elderly Patient With Squamous NSCLC
http://www.onclive.com/peer-exch ... With-Squamous-NSCLC
In the first installment of the series, moderator Corey J. Langer, MD, introduces the panelists for an in-depth discussion on current and emerging treatments for patients with non-small cell lung cancer (NSCLC). The panelists include: Roy S. Herbst, MD, PhD, Karen L. Reckamp, MD, MS, Anne S. Tsao, MD, and Everett E. Vokes, MD.

To begin the discussion, Langer describes a scenario detailing the diagnosis of a functional 77 year-old man with squamous cell NSCLC. The patient presented with right upper quadrant pain and a cough. The initial chest x-ray showed a right upper lobe mass. As a result, a CT scan was administered and found a 4 cm spiculated lesion and hepatic metastases. Additionally, a physical examination by the patient's primary care physician found an enlarged right supraclavicular node and rhonchi at the right base. As a result, the patient underwent a core biopsy that revealed purely squamous cell carcinoma. However, Langer notes, the patient's performance status is intact and he wishes to continue with his daily activities, which include golf.

For elderly patients it is important to look at the performance status (PS), explains Tsao. In this case, the PS is low enough that a platinum-based doublet can be administered safely. In most cases, Tsao utilizes carboplatin with paclitaxel or docetaxel; however, she notes, other regimens have showed efficacy, including platinum-based therapy with gemcitabine or nab-paclitaxel (Abraxane). These alternate regimens offer unique attributes; for instance, Tsao notes, nab-paclitaxel allows for a higher taxane dose with less neuropathy, which is ideal in an elderly population.

There is a clear benefit for treating patients in this setting with a chemotherapy doublet, explains Reckamp. In a phase III trial comparing carboplatin plus paclitaxel to single-agent vinorelbine or gemcitabine the doublet was associated with a significant survival advantage. This trial included patients with PS 0-2, notes Reckamp. While the doublet did result in higher toxicities, the overall outcome was superior. As such, it is important to discuss these factors with the patient before proceeding with a treatment.

Herbst supports a platinum-based doublet; however, focusing on quality of life, the toxicity profile of nab-paclitaxel is promising, specifically since the patient mentioned a desire to continue playing golf.

Case Study: Mutation-Negative Patient With Adenocarcinoma
http://www.onclive.com/peer-exch ... With-Adenocarcinoma
Moderator, Corey J. Langer, MD, begins a case-based discussion on the treatment of a 46 year-old woman with a history of heavy smoking and a diagnosis of non-squamous, non-small cell lung cancer that is negative for mutations in EGFR, ALK, ROS1, and KRAS.

The patient presented after experiencing dyspnea on exertion and right-sided rib pain, explains Langer. A chest x-ray showed a 3 cm left upper lobe mass, suggesting hilar mediastinal adenopathy. Also, Langer notes, there is a clear lytic lesion in the rib. A CT and PET scan confirms these initial findings and shows areas of osseous metastases. However, an MRI of the brain returned negative.

Unfortunately, Roy S. Herbst, MD, PhD, notes, this patient tested negative for all 4 of the major driver mutations. Given the patient's performance status and age, Herbst feels she is a good candidate for a platinum-based therapy with carboplatin plus pemetrexed. Moreover, with the performance status intact, Herbst may add bevacizumab to the combination, per findings from the PointBreak trial.

When considering a combination it is important to consider toxicity, efficacy, and costs, believes Karen L. Reckamp, MD, MS. In the PointBreak trial, the regimen of carboplatin, paclitaxel, and bevacizumab followed by maintenance bevacizumab had similar outcomes to carboplatin, pemetrexed, plus bevacizumab with maintenance pemetrexed and bevacizumab. However, when considering costs, the addition of both pemetrexed and bevacizumab adds an additional $7,000 per cycle and up to $300,000 depending on the length of maintenance therapy.

As a result of the costs and similar efficacy, if utilizing bevacizumab in this space, Reckamp would opt for the carboplatin, paclitaxel, and bevacizumab regimen followed by maintenance bevacizumab. However, if omitting bevacizumab, Reckamp would administer pemetrexed plus carboplatin with single-agent pemetrexed as maintenance.

In the AVAPERL trial, maintenance therapy with bevacizumab plus pemetrexed demonstrated longer progression-free survival when compared to bevacizumab alone, points out Anne S. Tsao, MD. As a result, it remains unclear whether a combination or a single agent for maintenance therapy is superior. To address this concern, the phase III ECOG 5508 trial is comparing maintenance therapy with pemetrexed alone, bevacizumab alone, or pemetrexed plus bevacizumab following 4 cycles of carboplatin, paclitaxel, plus bevacizumab.   

The AVAPERL trial demonstrated similar findings to other maintenance therapy trials, such as JMEN that showed a survival advantage for single agent pemetrexed, suggests Everett E. Vokes, MD. When considering costs, and the similar efficacy of the combinations, Vokes recommends utilizing carboplatin, paclitaxel, and bevacizumab as an initial treatment followed by single-agent pemetrexed as maintenance.

The JMEN trial had limitations, points out Reckamp. However, when also considering the PARAMOUNT trial it remains clear that pemetrexed is an important maintenance drug. In this trial, single agent pemetrexed maintenance prolonged overall survival. At this point, equivalent data is lacking for maintenance bevacizumab, Reckamp notes.

PRONOUNCE Trial: Two Drug Versus Three Drug Regimens
http://www.onclive.com/peer-exch ... Three-Drug-Regimens
The phase III PRONOUNCE study compared a doublet of pemetrexed plus carboplatin followed by maintenance pemetrexed to a triplet of paclitaxel, carboplatin, and bevacizumab with maintenance bevacizumab as a treatment for patients with advanced nonsquamous non-small cell lung cancer (NSCLC). The trial had an unusual primary endpoint that assessed progression-free survival without grade 4 toxicity (G4PFS), explains Corey J. Langer, MD.

The question that the PRONOUNCE trial sought to answer is important, since these regimens are commonly used and demonstrated similar efficacy in separate trials, says Everett E. Vokes, MD. However, the PRONOUNCE trial fell short of answering this question, since a statistically significant difference in survival was not observed. Additionally, Vokes notes, the primary endpoint of G4PFS seemed engineered to favor pemetrexed. Despite the pemetrexed-containing doublet having a numerical advantage for G4PFS, this benefit was not statistically significant.

The primary endpoint of G4PFS has not been validated, notes Anne S. Tsao, MD. As such, it is not typically seen in clinical trials and may have limited utility. Adding to this criticism, Langer remarks that the G4PFS endpoint failed to include neuropathy, taxane-based toxicity, or lower grade events, which are more common. Had this endpoint included these factors, the trial may have been positive, Langer speculates.

Case Study: Second-Line Treatment of Adenocarcinoma
http://www.onclive.com/peer-exch ... t-of-Adenocarcinoma
In a case-based discussion, moderator Corey J. Langer, MD, describes a 46 year-old patient with a diagnosis of non-squamous, non-small cell lung cancer that is negative for mutations in EGFR, ALK, ROS1, and KRAS. The patient received an initial pemetrexed-containing regimen followed by maintenance bevacizumab along with zoledronic acid for 6 months. At this point, the patient progressed with bone metastases.

Docetaxel or erlotinib are potential treatment options in the second-line setting, suggests Roy S. Herbst, MD, PhD. However, utilizing erlotinib in the absence of an EGFR mutation doesn't demonstrate additional benefit, adds Herbst. However, for patients without an EGFR mutation, the VeriStrat test can be used to help predict response based on blood-based proteins.

In the phase III PROSE trial that examined the test, patients categorizes as good had similar survival outcomes when treated with erlotinib and chemotherapy. However, those with a poor status, benefit more from chemotherapy than erlotinib. Proteomic-based classifiers could help determine appropriate treatments; however, the VeriStrat test may still require further validation, Herbst believes. As a result, Herbst suggests utilizing docetaxel as a second-line treatment.

The PROSE trial did not indicate that VeriStrat was a positive predictor for benefit from erlotinib but it did suggests patients who would not benefit, Anne S. Tsao, MD adds. Moreover, many of the prognostic groups identified by the test coincided with other identifiable clinical factors. However, looking at the full picture, Herbst believes the limited benefit demonstrated by both docetaxel and erlotinib stresses the importance of new drug development in this setting.

Another options, Langer suggests, would be to readminister the initial carboplatin and pemetrexed regimen. This could represent an effective option, particularly if the initial response was high and the treatment was well tolerated, believes Everett E. Vokes, MD. Outside of this, docetaxel would make an excellent choice.

The continuation of bevacizumab after first-line treatment is an established paradigm for patients with colorectal cancer, notes Langer. However, many approaches that work in other disease types have not successfully translated to the management of NSCLC, adds Karen L. Reckamp, MD, MS. As a result of this, to investigate the efficacy of continued bevacizumab specifically in nonsquamous NSCLC, the phase IIIb AvaALL trial was formed and is currently in progress, notes Langer.