Click on the image to enlarge

Lung Cancer Update Issue 2, 2008

DR MARK G KRIS: Recently Cancer Care Ontario and the American Society of Clinical Oncology published practice guidelines on adjuvant therapy, and I would like to point out the unanimity of the group in agreeing that adjuvant therapy — particularly adjuvant cisplatin-based chemotherapy — improves survival. It is important to deliver that message.

The devil is in the details. Agreement was reached that the data are strong for Stage II and Stage IIIA disease, and the guidelines represent a standard. However, in some areas the recommendations are not as strong. One of these areas is Stage IB disease — only one clinical trial specifically addressed that group (CALGB-9633), and it did not show a survival benefit.

In other adjuvant trials that showed a benefit — IALT, CAN-NCIC-BR10 and the ANITA trial — the primary endpoint was improvement in five-year survival for the entire study population. All those trials included patients with Stage IB disease, and they were all convincingly positive.

Therefore, I believe patients with Stage IB disease should be offered adjuvant therapy, and I would probably offer it to patients with Stage IA disease also. Even with the new staging system, the five-year survival for these patients is such that we’d recommend adjuvant therapy if it were breast cancer.

Lung Cancer Update Issue 1, 2008

DR ANTOINETTE J WOZNIAK: The big question when selecting chemotherapy in the adjuvant setting is whether to use cisplatin or carboplatin. In practice, I believe most physicians prefer using carboplatin because it’s easier to administer and perceived as being less toxic. However, all the evidence, even in the advanced-disease setting, indicates that cisplatin is likely more effective. It may not make a difference for patients with metastatic disease, but it may make a difference in the adjuvant setting. Generally, I use cisplatin whenever possible, combined with either vinorelbine or docetaxel.

Most of the trials, including the Canadian trial and the ANITA trial, used vinorelbine. In IALT, approximately 25 percent of the patients received vinorelbine and approximately half of the patients received etoposide. In advanced disease, TAX-326 compared cisplatin/vinorelbine to cisplatin/docetaxel and carboplatin/docetaxel. The cisplatin/docetaxel arm was better in that trial, which is why many people use that combination as adjuvant treatment.

Lung Cancer Update Issue 4, 2007

DR MARTIN J EDELMAN: Generally, in the adjuvant setting I use cisplatin and docetaxel because I believe the weight of data supports a cisplatin-based regimen. If one wants to be completely data driven, cisplatin/vinorelbine is probably the most validated regimen out there, but it’s difficult to administer. In Stage IV disease, cisplatin/docetaxel is at least as good, possibly even superior, and probably better tolerated than cisplatin/vinorelbine, so I consider that a reasonable regimen.

Other possible regimens include cisplatin/vinorelbine, cisplatin/gemcitabine and, despite all the controversy, I believe carboplatin/paclitaxel is also reasonable. Another key issue is adjuvant therapy for Stage IB disease. It has been pointed out that to conduct an adequately powered study of patients with Stage IB disease, you’d have to enroll approximately 2,000 patients.

So the CALGB carboplatin/paclitaxel study that showed an improvement in progression-free survival in Stage IB disease was probably underpowered. If you consider the subgroup of patients with tumors of four centimeters or larger, those patients clearly fared better with the chemotherapy. I don’t believe carboplatin/paclitaxel is inactive in this setting — occasionally we use that. We use it because some patients cannot tolerate cisplatin-based therapy.

It is not unusual for us to start with a cisplatin-based therapy and switch the patient after one or two cycles because he or she cannot tolerate it. So for their final couple of cycles, these patients are switched to a carboplatin-based regimen.

Lung Cancer Update Issue 3, 2007

DR MARK A SOCINSKI: The question I hear most frequently is regarding the approach to node-negative disease. Controversy has existed since ASCO 2006 about the role of chemotherapy for patients with Stage IB disease. These patients were included in the positive adjuvant trials, although the subset analyses were negative.

I don’t put much weight on the subset analyses not powered to show a difference. So if the trial had the eligibility criteria of Stage IB to IIIA disease and it was positive, then to me the patients with Stage IB to IIIA disease are eligible for that treatment.

I believe we will ultimately prove that the potential benefit of adjuvant chemotherapy for patients with Stage IB disease is as good as it is for patients with Stage II or Stage III disease in terms of the relative risk reduction. I’m banking on the precedent in other solid tumors that we’ll see the same results.

So if you have a patient with a Stage IB tumor who is a good candidate for adjuvant therapy, it’s reasonable to offer treatment.

Meet The Professors Lung Cancer Issue 1, 2008

DR ROGERIO C LILENBAUM: The patient’s age and performance status are considerations when deciding whether to use adjuvant therapy for patients with Stage III disease. We have little data for octogenarians with Stage III disease. In fact, if you examine all the major combined-modality trials evaluating chemotherapy and radiation therapy in different sequences, there have been few patients older than 75, and it’s difficult to extrapolate from the data we typically use for the 65-year-old patients.

Based on a retrospective analysis of two of the RTOG studies published by Corey Langer, we do know that patients up to age 75 who maintain a good performance status and are felt to be eligible for aggressive chemotherapy and radiation therapy fare as well as younger patients with regard to efficacy. In his analysis, older patients did experience more side effects, particularly hematological toxicities, but not necessarily treatment-related deaths.

If I believe that they can handle a combination regimen, my approach for the elderly or a patient with a poor performance status with Stage III NSCLC is to use induction chemotherapy, specifically two cycles of an attenuated carboplatin/paclitaxel regimen, before radiation therapy. This gives me a sense of how responsive the disease is, because the truth is, if it is not responsive to chemotherapy, it is not the local modality that will lead to long-term benefit. It also gives me a sense of whether the patient will be able to tolerate combined-modality therapy.

Perhaps the most important reason for induction therapy is that we can often improve a patient’s performance and functional status simply by palliating their symptoms and improve quality of life with the initial chemotherapy. For a younger patient, say a 60-year-old, I would have difficulty justifying the induction component and would proceed with the chemoradiation therapy.

Click on the image to enlarge

Lung Cancer Update Issue 2, 2008

DR JULIE R BRAHMER: Some investigators believe that EGFR mutations are the major predictors of response, while others believe that EGFR gene expression, as measured by FISH, determines benefit from tyrosine kinase inhibitors. We know that patients treated with EGFR inhibitors will respond better if they have EGFR mutations, but will they live longer? The large Canadian trial CAN-NCIC-BR21, which evaluated erlotinib versus placebo, retrospectively addressed this issue, and patients with EGFR mutations did not live any longer than those without the mutations when treated with erlotinib.

However, patients treated with erlotinib who had increased EGFR gene expression as determined by FISH did live longer. Data from the INTEREST study, evaluating gefitinib versus docetaxel, may reverse those findings.

The first-line trials evaluating erlotinib in patients with EGFR mutations will answer whether we should move erlotinib to the first-line setting for those patients. I don’t believe the mutations will indicate whether a patient will live longer with erlotinib versus another treatment, but those patients with EGFR mutations probably need erlotinib up front rather than chemotherapy.

Lung Cancer Update Issue 4, 2007

DR EDELMAN: Erlotinib is a fascinating agent because it has shown efficacy in nonsmokers, never smokers and women with adenocarcinomas and bronchoalveolar carcinoma features. Patients with these characteristics are coming into my office with increasing frequency. I am seeing two to three never smokers per month in my clinic and an increasing number of patients who smoked for only one year or so. For an enriched population in which you believe that the EGFR marker is present — either because of positive prognostic factors or because you have actually tested for it — adjuvant study of erlotinib is reasonable.

Click on the image to enlarge

Lung Cancer Update Issue 2, 2008

DR ROMAN PEREZ-SOLER: The RADIANT study is evaluating adjuvant chemotherapy followed by erlotinib administered for two years. It selects patients with EGFR-positive disease as determined by IHC or FISH.

The RADIANT trial is a good study for any patient who clearly has EGFR-positive disease. The issue will be whether a patient can receive erlotinib for two years — if that would be tolerable.

I believe that it will be tolerable for most patients. The first two months may be difficult, but after two months of erlotinib, the majority will find that the toxicity subsides and the skin rash improves. A minority will require a dose reduction or will not be able to tolerate the drug.

Lung Cancer Update Issue 4, 2008

DR DAVID JABLONS: For an adenocarcinoma, I use either pemetrexed/carboplatin or pemetrexed/cisplatin, if the performance status is good. I believe that in the future patients with Stage IIIA disease will receive a pemetrexed-based platinum regimen with full-dose radiation therapy.

They are well tolerated, or better tolerated than etoposide/cisplatin, and you can use full-dose radiation therapy with these combinations, unlike paclitaxel/carboplatin.

Lung Cancer Update Issue 1, 2008

DR WOZNIAK: Few Phase III data sets exist for patients with unresectable Stage III disease, so my treatment decision depends on the patient’s performance status and tumor volume. But my preference is to recommend concurrent chemotherapy and radiation therapy because it has been reported to offer a modest survival benefit. Unfortunately, concurrent treatment has inherently more toxicity and it is important to determine whether the patient can tolerate the two modalities together. I use the SWOG approach, cisplatin/etoposide and radiation therapy with the cisplatin split on day one, day eight and then repeated four weeks later.

Selecting therapy to administer after radiation therapy is controversial. Many used consolidation treatment, particularly docetaxel, based on the Phase II SWOG-S9504 trial. The median survival was 26 months, which is a superb median survival for patients with unresectable Stage III/IIIB disease, but we cannot base our practices on promising Phase II trials. At last year’s ASCO meeting, the HOG trial reported no benefit with docetaxel consolidation, even though the survival was good on both arms.

I still believe additional treatment after chemoradiation therapy is important, and since the HOG study many of my colleagues have simply administered additional etoposide and a platinum agent after radiation therapy. It is important to understand that the HOG study does not dismiss consolidation as an option. It suggests that docetaxel doesn’t work for everyone in terms of controlling the systemic disease.

The patients on the HOG study were in poorer physical condition than those enrolled on the SWOG study. Many had poor pulmonary function, which could have influenced the outcome. In the subset analysis, the patients with poor pulmonary function did not fare as well. I believe we have a lot of work to do in this arena. It seems the idea of administering additional treatment with a slightly different mechanism of action after surgery is good, but we need to determine which drugs to use.

Lung Cancer Update Issue 1, 2008

DR NASSER H HANNA: In 2003, SWOG published results from their Phase II trial, S9504, which included 83 patients with Stage IIIB disease who were treated with two cycles of cisplatin/etoposide concurrent with 61 Gray of radiation followed by three cycles of docetaxel. The median survival was 26 months. This population should have had a median survival of about 13 months. They had a five-year survival of 29 percent. Historically, that group should have had a five-year survival of five, seven or eight percent.

This regimen engendered a lot of enthusiasm and became a de facto standard for many physicians based on a single, small Phase II trial. We sought to confirm that the strategy was effective and conducted a randomized Phase III study for patients with Stage IIIA and Stage IIIB disease.

A total of 243 patients entered our trial. All patients received cisplatin/etoposide and concurrent radiation at 59.4 Gray. Then, after a rest period of four to eight weeks — and as long as they had not experienced disease progression and remained eligible — patients were randomly assigned to either three cycles of docetaxel or observation.

We reported several provocative findings. No difference was observed in progression-free survival between the two randomization arms, and no difference was observed in overall survival.

The p-value was 0.9, and the curves were completely superimposable. We determined that no evidence existed that consolidation docetaxel after chemoradiation therapy improves outcomes, but it does significantly increase risks for patients, including treatment-related death and serious toxicities such as febrile neutropenia, infections and Grade III/IV pneumonitis.

Select Publications