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Pushing the Envelope: Surgery after Full Dose Radiation with Chemo
As I described in a prior post, pre-operative chemo and radiation are one very reasonable, aggressive option for stage IIIA NSCLC, particularly if the mediastinal lymph nodes involved are not large and there is only a single lymph node area involved. However, the radiation that is generally used before surgery is about 45-50 Gray (Gy) over about 5 weeks, not the “definitive” radiation dose we use if we aren’t planning to pursue surgery, which is more like 61-66 Gy at most centers. We have not generally given full dose radation followed by surgery, out of concern for the difficulty of surgery in a heavily radiated, scarred field, and the risk of severe complications after that. However, in unusual cases we have pursued that option, sometimes with very good results, and the concept has also been the subject of published work. Continue reading
Lung Cancer Work-Up and Surgery: Worth Finding A Well-Trained Thoracic Surgeon
As a medical oncologist, my primary role is to direct general management plans for many cancer patients and to develop chemotherapy and targeted therapy regimens. These regimens are sometimes directly administered through my office, and sometimes are coordinated with oncologists closer to a patient’s home. The treatment is pretty much a cookbook approach, so it’s really the same no matter who administers it. On the other hand, for the approximately 1/3 of NSCLC patients who are candidates for surgery, there are major differences in clinical outcomes depending on the skill level of the surgeon. Here I’ll illustrate some of the key differences that make it compelling to work with the best surgeon you can find, ideally a trained thoracic surgeon, and not just the closest surgeon or the first who has an opening on their schedule. Continue reading
Maintenance Chemotherapy for Extensive-Disease Small Cell Lung Cancer (ED-SCLC)?
As I described in a post describing the general principles of SCLC, it is typically responsive to treatment initially, but upon recurrence it is much less likely to respond. Given that pattern, the value of maintenance therapy has been tested in ED-SCLC, where treatment with initial standard doublet chemo was followed immediately by single-agent “maintenance chemotherapy”, in hopes of delaying progression to a point where a resistant, progressive SCLC emerges. Continue reading
Aggressive Chemoradiation for Unresectable Stage III NSCLC: A Double-Edged Sword
As I noted in prior posts on the subject of unresectable stage III NSCLC, there is a general consensus that overlapping chemo and radiation is associated with better cure rates for this stage of locally advanced NSCLC than doing one followed by the other. At the same time, however, the overlapping, or concurrent chemo and radiation approach is associated with more challenges in terms of side effects, particularly esophagitis, as well as greater drops in blood counts, and potentially more inflammation in the lungs, or pneumonitis. The approach that I have generally advocated in the last few years, at least for patients fit enough to pursue it, is the concept of concurrent cisplatin-based chemo with concurrent chest radiation, followed by consolidation (“chaser”) chemo with a different agent than what the patient received with the radiation.
This approach is based on some really pretty much unprecedented results in the SWOG trial 9504 that I’ve already described. 83 eligible patients received cisplatin/etoposide with concurrent chest irradiation for about 6 weeks, and then after a three week break started taxotere every 3 weeks. To go on the trial, you needed to not only have stage IIIB NSCLC (without a malignant pleural effusion) and be reasonably fit, you needed to have quite favorable breathing tests (pulmonary function tests) showing a good lung reserve in case there was significant damage from treatment. Many patients in the general world don’t meet such stringent requirements. But the trial was hugely influential because nearly 1/3 of the patients on the trial remained without evidence of disease progression three years later (published abstract here), and even with longer follow-up appeared to do remarkably well (updated results here), with about twice as many patients as long-term survivors compared to what we’d expect historically.
(click to enlarge) Continue reading
Single-Agent Zactima/ZD6474 in Advanced NSCLC
As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I’ll focus on the research that gave it as a single agent and where it has led us in terms of current trials.
As I mentioned in my previous post, an early phase I trial just trying to establish an optimal dose showed some activity zactima as a single-agent, as 4 of 9 patients with NSCLC in a Japanese trial showed significant tumor shrinkage on zactima. From there, Dr. Ron Natale at Cedars-Sinai Medical Center in Los Angeles led a randomized phase II trial (abstract here) that compared zactima as a single agent at the higher dose of 300 mg by mouth per day, pretty close to the maximal feasible dose, to iressa at 250 mg by mouth daily. The trial was designed to allow cross-over to the other drug after patients experienced either progression or problematic side effects. So the design was as shown here:
(click to enlarge) Continue reading
Zactima (ZD6474) in NSCLC: Part I
In prior posts I’ve described the idea of combining targeted agents like Tarceva and Avastin, but there are also some single agents that inhibit multiple targets within cancer cells. I’ve described sorafenib/nexavar in a prior post. Today I’ll focus on another multi-targeted agent, known previously as ZD6474, and with a marketing name of Zactima. Similar to the combination of avastin and tarceva, this single oral drug is anti-angiogenic and also blocks EGFR. Although less well studied, it also blocks a protein called RET and can inhibit cell proliferation that way.
(click to enlarge)
To be more specific, whether Zactima has anti-EGFR activity depends on the dose: it is primarily an anti-angiogenic drug at lower doses, such as 100 mg per day. At higher doses starting around 300 mg, it inhibits EGFR as well. Continue reading
EGFR Inhibitor Therapy as Maintenance Therapy in Stage III NSCLC: A Cautionary Tale
The oral EGFR inhibitors Iressa and Tarceva both have activity in advanced NSCLC, with proven responses in a minority of patients and improvements in cancer-related symptoms as well. While Iressa ultimately did not prove to have a significant survival advantage over a placebo in previously treated advanced NSCLC patients (ISEL trial abstract here), and is therefore no longer used in the US outside of trials or in patients who have already shown a response, Tarceva did show a significant survival benefit compared to placebo (BR.21 trial abstract here) and is one of our more commonly used agents in previously treated advanced NSCLC.
Patients and physicians have noted that in the advanced/metastatic NSCLC setting, the potential improvements are limited. While some fortunate patients have a very prolonged response or non-progression, the average improvement in survival on the major tarceva trial was two months. If we turn to earlier stage, potentially curable NSCLC, can we add EGFR inhibitors to actually improve the cure rates? The studies thus far have been limited but have at this point mostly highlighted how much we still need to learn about these agents.
Single-Agent Erbitux Studies in NSCLC
Yesterday I reviewed a series of studies of the EGFR monoclonal antibody cetixumab, or Erbitux, combined with chemotherapy. Overall, these trials are modestly encouraging, without what I would consider to be a potential antagonistic effect when chemo and EGFR tyrosine kinase inhibitors (TKIs) like Iressa or Tarceva. However, we still don’t have studies big enough to establish any role for erbitux. Today, I’ll cover the very limited experience of single-agent Erbitux in advanced NSCLC. Continue reading
EGFR Monoclonal Antibody Therapy in NSCLC: A Focus on Erbitux
Most of the discussion with about inhibiting the EGFR axis in lung cancer has focused on the orally available tyrosine kinase inhibitors (TKIs) that work inside the cells. However, another way to inhibit the cells is by giving an IV “monoclonal antibody” which is a protein that attaches to the outside of the cell at the EGFR target and can block activity. A figure of the two approaches is shown here, with the antibody circled in red:
(Click to enlarge)
Cetuximab, or erbitux, is by far the most studied in cancer. This agent, you may recall, is the one that Martha Stewart was indicted over:
It’s now approved in colon cancer and also in head and neck cancer, but it’s been the subject of much less research in lung cancer than the EGFR TKIs like Iressa and Tarceva. Continue reading
Timing EGFR Inhibitors and Chemo: Why I Don’t Give Them Concurrently
Both standard chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) have been approved in NSCLC, and other anti-EGFR agents like erbitux/cetuximab and vectabix/panitumumab are also commercially available for treating other cancers and are being studied in lung cancer. Iressa was previously approved as a single agent in previously treated patients with advanced NSCLC, and Tarceva is now available but approved also as a single agent therapy. However, some oncologists give EGFR inhibitor therapies in combination with standard chemo. I don’t favor that approach, but I think it will be helpful to review the issue and my rationale for avoiding concurrent chemo and EGFR inhibitor therapy, at least until there is some evidence suggesting a benefit of combined therapy.
It’s fair to say that treatment combinations are a key cornerstone of medical oncology. The idea of combining anti-cancer drugs with different mechanisms of action and non-overlapping side effects has been central in our field for decades, and combinations are now standard therapy that often are far superior to single-agent approaches. Targeted therapies like EGFR inhibitors, specifically Iressa and Tarceva initially, generally have very different side effects than chemo and were shown to be active as single agents in the second and third line settings and beyond for chemo-pretretaed patients. So there was a great deal of hope that we could improve clinical outcomes for advanced NSCLC patients by adding Iressa and/or Tarceva to standard chemo doublets in previously untreated patients. There were several clinical trials done to test this idea, and the entire lung cancer community was disappointed to see no benefit for combined chemo and EGFR TKI therapy. Continue reading
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