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Timing Post-Operative Chemo and Radiation
Adjuvant chemo has become increasingly established as having a survival advantage, at least for the general population of stage II and IIIA patients, and potentially for some with earlier stage disease (see adjuvant chemo post). However, post-operative radiation therapy, or PORT, does not have an established role. While historically there has not a clear advantage from PORT for patients with N1 nodal disease, for those with N2 nodes there has been a consistent improvement at least in local control and now emerging evidence of an survival benefit from PORT (see PORT post).
So for patients who undergo resection and had N2 nodes, there may be a benefit from both chemotherapy and radiation. One way to treat patients with N2 disease, if we know from a mediastinoscopy or another method that someone has N2 nodes involved prior to surgery, induction chemotherapy, or chemotherapy and radiation, are commonly used. In those cases, sometimes additional chemo is recommended after surgery, but not typically more radiation if it was given before surgery.
But there are also plenty of patients who either had unsuspected N2 disease until after surgery, or who undergo upfront surgery despite pre-operative staging showing N2 disease. Such patients were included on many of the trials testing the value of adjuvant chemo.
The problem of administering chemo and radiation after surgery is that it’s hard enough to take chemo after surgery, and adding another modality can escalate the challenge significantly. In the many clinical trials with cisplatin-based chemo after surgery, only approximately 70% of patients are able to get though the majority of planned chemo (carboplatin-based chemo is more feasible, with 85% of patients on the CALGB 9633 trial (initial positive 2004 abstract here, updated and now negative 2006 abstract here).
So when adding radiation to chemo, we need to balance the effectiveness with the safety and feasibility of what is now a tri-modality approach (surgery + chemo + radiation). In the ANITA trial that allowed radiation while testing the value of adjuvant chemo (abstract here), the patients who received both chemo and radiation did not receive them concurrently, but rather received chemo followed by radiation. Our experience with patients receiving chemo and radiation together for unresectable NSCLC has consistently demonstrated that concurrent chemoradiation is associated with a much higher likelihood of serious esophagitis, inflammation of the esophagus, that can limit the ability to eat and drink and make it very hard to continue treatment to completion. Continue reading
Post-Operative Radiation Therapy: Helpful or Harmful?
I’ve discussed the trials that have led to a general recommendation in favor of chemotherapy after surgery for patients who have stage II and IIIA NSCLC, with some ongoing questions about the value in stage IB NSCLC. I haven’t touched the issue of post-operative radiation therapy, but the question comes up from members who ask about the evidence for or against radiation, and how it might be given.
Adjuvant, or post-operative radiation therapy (PORT), has been a reasonable option for lung cancer patients for decades, but the concept took a big hit from the “PORT meta-analysis” published in the British Medical Journal in 1998 (abstract here). This meta-analysis aggregated the results from 9 different studies of surgery alone or surgery followed by radiation, for a total of over 2100 patients. Overall, the results demonstrated a significant detriment in survival from PORT, primarily from more cardiac and lung problems (2-year survival 55% vs. 48%) — the curve on the bottom is radiation, with a worse survival:
(click to enlarge) Continue reading
Mediastinal N2 Lymph Nodes after Induction Therapy as a Key Predictor of Outcome
For patients with locally advanced NSCLC, the question of whether to pursue a surgical or a non-surgical approach has a great deal to do with the extent of mediastinal (middle of the chest) lymph node involvement. The mediastinal nodes are shown here:
(click to enlarge)
First, at the time of initial staging, patients with bulky (>3 cm) disease in the mediastinum, or those with disease involvement more than one nodal station, are less appropriate candidates for surgery than those with non-bulky and single-station disease. In fact, a French retrospective review of over 700 patients with N2 disease who underwent surgery at any of six centers (Andre abstract here) demonstrated that there are quite varied long-term outcomes for different patients that all fall under the same stage of IIIA with N2 disease, and that the patients with a single-station and microscopic involvement (as opposed to clinical enlargement that is visible as abnormal on CT (greater than 1 cm in diameter):
That was in a group of patients who underwent surgery, and just a view of how patients did after the fact. Continue reading
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
Clinical Trial Focus: RADIANT Trial in Adjuvant NSCLC
As described in a prior post, chemotherapy after surgery is often recommended after surgery, at least for a subset of patients with stage IB to IIIA (without mediastinal lymph node involvement) NSCLC, based on a potential to increase cure long-term survival compared to surgery alone. At this point, two forms of targeted therapy (erlotinib, or Tarceva, as a single agent in second- and third-line advanced NSCLC, and bevacizumab, or Avastin, combined with carboplatin and paclitaxel for first-line treatment of advanced NSCLC) have been approved by the FDA for advanced NSCLC because they have demonstrated an improvement in survival. At this point, however, we don’t know whether adding targeted therapies as a strategy in earlier stage NSCLC can increase cure rates. But one key trial that is evaluating this possibility is the RADIANT trial.
RADIANT Trial; click to enlarge.
RADIANT is an acronym for Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva. This will be an international trial designed to enroll 945 patients who have undergone surgery, with no residual cancer left behind, for stage IB, II, or stage IIIA NSCLC. Patients may have received up to four cycles of chemotherapy after surgery, but patients who received no chemo are still eligible. Patients are then randomized to receive either tarceva or a placebo, with two-thirds of patients receiving the active drug and one-third receiving placebo. Because it is a double-blinded study, neither patients nor their treating doctor know who is getting tarceva or a placebo. This is appropriate because we don’t know whether Tarceva is going to be better, the same, or actually worse, with side effects of treatment but no added benefit.
Importantly, although Tarceva is approved by the FDA for all patients with previously treated advanced NSCLC, regardless of whether their tumor has high levels of EGFR, the target of Tarceva, or amplification of the EGFR gene in tumor cells. We still debate whether Tarceva works best, or perhaps only works at all, in patients with EGFR protein expression as detected by a test called immunohistochemistry (or IHC) or amplification (excess copies) of the EGFR gene by a test called fluorescence in situ hybridization (or FISH). Many trials that are investigating the future role for Tarceva are using more selected populations based on clinical characteristics such as never-smoking or BAC, or molecular characteristics such as EGFR overexpression by IHC, gene amplification by FISH, or presence of an EGFR mutation detected by gene sequencing. Perhaps the benefits of Tarceva can be found to be more pronounced and more consistent if we can identify and treat those patients most likely to do well with it, rather than use a “targeted therapy” unselectively.
Further information about eligibility details and participating centers can be found here.
Can We Define “Best Treatment” for Stage IIIA NSCLC?
Stage IIIA NSCLC, particularly with N2 lymph node involvement, is probably the NSCLC treatment setting that is most controversial. While it is the latest stage that we routinely consider surgery for, it is actively debated whether patients with stage IIIA NSCLC should have surgery or be treated with a combination of chemo and radiation without surgery.
For the patients who undergo surgery, most patients receive preoperative therapy before resection. This standard was established from a series of small randomized trials published more than a decade ago that demonstrated striking improvements in survival in the group of patients that received chemotherapy prior to surgery. Despite the clear conclusion that pre-op chemo improves survival, these trials were all very small (primarily because they were stopped early when the huge benefit of pre-operative treatment became apparent), the patients one the surgery arm of one key trial did much worse than expected, and there were problems with some prognostic factors not being well balanced between the two groups in one trial. Regardless, the benefits in the patients who received chemo before surgery were so great that this became a preferred approach, but there is no standard approach that has emerged as a best choice. Continue reading
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