Adjuvant Chemotherapy for NSCLC, updates on two influential trials

JCO this week: Two of the more influencial trials on adjuvant chemotherapy for resected NSCLC are updated, the JBR-10 and the IALT studies. The JBR-10 study continues to show a survival benefit out to almost 10 years, though the stage IBs seemed not to benefit. The IALT study continued to demonstrate a DFS benefit, but the OS figures had slipped to non-significance.

Links and abstracts:

Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non-Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10 [Thoracic Oncology]: "Purpose

Adjuvant cisplatin-based chemotherapy (ACT) is now an accepted standard for completely resected stage II and III A non–small-cell lung cancer (NSCLC). Long-term follow-up is important to document persistent benefit and late toxicity. We report here updated overall survival (OS) and disease-specific survival (DSS) data.

Patients and Methods

Patients with completely resected stage IB (T2N0, n = 219) or II (T1-2N1, n = 263) NSCLC were randomly assigned to receive 4 cycles of vinorelbine/cisplatin or observation. All efficacy analyses were performed on an intention-to-treat basis.

Results

Median follow-up was 9.3 years (range, 5.8 to 13.8; 33 lost to follow-up); there were 271 deaths in 482 randomly assigned patients. ACT continues to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). ACT resulted in significantly prolonged DSS (HR, 0.73; 95% CI, 0.55 to 0.97; P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms.

Conclusion

Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm."

Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer [Thoracic Oncology]

Purpose

Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non–small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up.

Patients and Methods

Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration.

Results

The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06).

Conclusion

These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

SBRT for NSCLC

In this weeks JCO there is an interesting article from investigators in Sweden and Norway reporting a phase II trial of 15Gy x 3 for T1 and T2, medically inoperable NSCLC. Of import, the dose was prescribed to the 67% IDL, meaning that the dose to the center of many of these tumors was much higher.

57 patients were enrolled, the majority were T1 (70%). 3 year OS was 60%, but perhaps more importantly, given their comorbidities, the CSS was 88%. 3 year LC was 92%. 16 patients experienced grade 3 toxicity (28%), and there was one patient with grade 4 dyspnea. No grade 5 toxicities were seen.



This lends even greater support to the practice, and is a great improvement over the prior standard of 70Gy to a postage stamp field to those that are not healthy enough for lobectomy. The next step of course is to look at this in the medically operable patient... stay tuned to ongoing clinical trials on this subject.

PET-CT for NSCLC

The NEJM this week has in interesting randomized trial on the utility of PET-CT in the preoperative workup of NSCLC.

Investigators from Denmark randomized 189 patients to receive either PET-CT or conventional CT as preoperative staging for NSCLC. Mediastinoscopy was performed in most patients in both arms(94%). After PET–CT, 38/98 patients were classified as having inoperable NSCLC compared to 18/91 patients in the CT arm. 60/98 in the PET–CT arm and 73/91 in the CT arm underwent thoracotomy (p=0.004). 21/60 surgeries in the PET–CT arm and 38/73 in the CT arm were futile (i.e. posiitive mediastinum, distant disease,p=0.05). Survival and number of curative surgeries were no different between the arms.

While it has been long known that PET added significantly to the sensitivity and specificity of lung cancer staging, this is the first study to demonstrate that it results in clinically meaningful results. A reduction in the number of unnecessary thoracotomies would represent a reduction in the cost of treating NSCLC, both financially and in terms of the morbidity and mortality of the procedure itself.

Developing a Genomic Signature for Epirthelial Mesenchymal Tranrsition

KH presents on Developing a Genomic Signature for Epithelial Mesenchymal Transition (EMT)

Background in the Potti lab. NEJM 2006; 355:570.
Gene expression patterns were examined in a Cohort of Duke patients with early stage NSCLC, then validated in two independent cohorts (CALGB, ACOSOG). 133 genes in the developed signature (k-ras, MDR upregulation, and down regulation of tumor suppression). Strong predictions of recurrence and survival.

Currently the lab is working wuth a 52 gene signature for radiation sensitivity which was developed initially at the University of Chicago. Resistant clones were selected from a cell line that was serially irradiated and the gene signature differentiates between the resistant selected clones and the initial sensitive cell line. The Potti lab has confirmed this in previously unirradiated cell lines, and has predictive value in predicting radiation response in vitro.

This signature is then clinically tested in samples from patients with head and neck cancer and in group with rectal cancer. Accuracy for response to RT was on the order of 75% for association with pCR in the rectal cancer patients, and (?radiographic) response in the Head and Neck patients.

A current direction is integrating mircoRNAs into the gene chips, which requires no additional technology, just different probes.

Switching gears to EMT.

Epithelial Mesenchymal Transition (EMT) occurs in normal embyogenesis. It is also implicated in Lung and Kidney fibrosis, and possibly radiation resistance. Perhaps most intriguingly, EMT is also implicated in the invasion and metastasis process of carcinomas (and an MET [mesenchymal to epithelial tranisition] process then occurs after establishement of a distant colony).

E Cadherin and multiple other pathways (including the Hedgehog pathway) regulate this process. Coculturing with myofibroblasts release Hh(hedgehog) into the microenvironment, and this has been shown to produce EMT in cholangiocytes.

Plan will be two develop an EMT model in NSCLC lines via either coculturing with myofibroblasts or transfection with adenovirus vectors carrying Hh DNA, then developing a gene signature for this process.

8.5Gy X 2 for Palliation of NSCLC

In chart rounds today, a question was brought up in re to palliation for lung disease.  A hypofractionated course of 8.5Gy x 2, separated by one week was prescribed and there were some questions about why this regimen was used.  

The best data supporting this is from a Randomized trial from France, published in the JCO by Sundstom in 2004.

421 patients with locally advanced stage III or stage IV NSCLC, with no curative options, with chest symptoms or centraltumor threatening the airways. 

Three arms: 

17 Gy / 2 fx 

42 Gy /15 fx 

50 Gy / 25 fx

There were no differences in survival or QOL measures.  

The caveats - in the 2 fraction arm, treatments were separated by 7 days.  They were also treated with steroids the day before, the day of, and the day after each fraction.  The length of spinal cord was limited to 12cm.  Also at three years there was a trend towards worse survival in the hypofractionated arm (3 yr OS 1% 2 fx, 9% 15 fx, 6% 25fx, p=0.06).

We have reserved this option for patients who's estimated survival is on the order of 3 months, and for whom transport for multiple fractions would be great hardship to them.

CALGB 9633

Journal Club – CALGB 9633

A chemotherapy question today: what is the role of adjuvant chemotherapy in stage IB NSCLC?

Started with a case of NSCLC: 7x6cm mass in the LLL. On resection, negative margins, histopathology revealed a large cell carcinoma of neuroendocrine differentiation. All nodes were negative (hilar and mediastinum sampled).

Comment at this time about the neuroendocrine differentiation: CK states that this would be approached according to the NSCLC algorithm rather than as SCLC due to the large cell morphology.

IB survival rates on the order of 50-55%, with 30-40% long term relapse rates.

Review of prior modern adjuvant CT trials:

1. ALPI – scagliotti JNCI 2003.

n=1209 I-IIIA NSCLC randomized to MVP x 3 vs observation (majority received PORT).

OS – no difference

2. Big Lung Trial

n= 381 I-III NSCLC randomized to Cis/Vind, Mito/ifos/cis, Mito/vinb/cis, vinor/cis or observation, 14% received PORT.

OS – no difference

3. IALT

n=1867 I-III NSCLC randomized to cisplatin based chemotherapy vs observation, fair amount of PORT in this trial

OS 44% vs 40% at 5 years – statistically significant

update at ASCO: now negative as of ASCO 2008

4. JBR 10 (Winton NEJM 2005)

n=482 IB-II NSCLC Randomized to cis/vinor

OS HR 0.69 (0.52-0.91) SS (NS in IB subgroup analysis)

5. ANITA (Douillard, lancet oncol, 2006)

n=840 randomized to cisplatin based chemotherapy vs observations

5y OS 51% vs 43% (SS). Posthoc IB subgroup – no benefit.

6. JLCRG (Kato, NEJM, 2004)

n=999 stage I adenocarcinoma randomized to UFT vs observation.

5y OS 88% vs 85% (SS)

LACE meta-analysis (Pignon, JCO 2008)

pooled #1-5 above (~4500 pts). 5yr os benefit 5.4%

CALGB 9633

T2N0 lobe or pneumonectomy randomized to paclitaxel/carboplatin vs observation

powered for 13% OS benefit at 5 years. Accrual goal: 500pts.

80% power using a two tailed log rank (p=0.05)

well balanced amoung the arms

at the planned interim analysis(Strauss JCO 2004): 4 year OS showed a HR 0.62. stastical tests changed to a one-tailed test, and the accrual was stopped early.

At 5 yr however, the OS HR had become 0.82 and was no longer statistically significant.

In subgroup analysis tumors of >= 4cm, an OS benefit was seen.

Commentary - This is an overall negative trial with a hypothesis generating signal for a benefit in tumors >=4 cm in size. At the CALGB, statistical analysis would suggest that even if the accural went all the way to 500, the trial would still be underpowered for the observed HR. Another critique has been that carboplatin was used, which is likely slightly worse than CDDP in efficacy. Many have interpreted this data to mean that cisplatin should be used in the adjuvant setting, and that with a tumor >= 4cm, chemotherapy may be more strongly considered. This is the current practice at Duke.

Ongoing investigations

Intergroup trial: Investigating Chemo +/- Bev, including IB >=4cm though IIIA

The Muligene Model from Duke (Potti, NEJM) associated a gene expression signature with a high risk of recurrence in stage I NSCLC. A CALGB Study was to go forward with randomizing IB (2-4cm) in the high risk cohort to chemotherapy or not, though now revised so that everyone is getting randomized (low or high risk).

Case Resolution: Patient recived 4 cycles of cisplatin/navelbine, however has since recurred in the pleural space.