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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
Pain from Bone Metastases: Treatment Approaches, Focusing on Radiation
We’ve established that bone metastases are common, and now we’ll talk about approaches to manage pain that often accompanies them. As I mentioned previously, sometimes a metastases occurs in a weight-bearing bone, in which case we often recommend a prophylactic surgical procedure to stabilize the bone at risk for fracture. Radiation can also reduce the risk for fracture and improve pain.
Aside from the risk of fracture, reducing pain is an appropriate goal by itself. There are no randomized trials that compare medication to radiation therapy, and either or both can be used. Pain with bony metastases can be caused by many things, but most typically it’s inflammation and swelling of tissues on the outer surface of the bone, which can lead the nerves in the periosteum (the membrane on the outside of the bone) to transmit pain. External beam radiation (also known as radiation therapy, RT, or XRT) is often very effective in reducing inflammation and killing living tumor cells in that area. Up to 90% of patients have complete or partial improvement in their pain with XRT, and about half of the responding patients have complete relief of their pain (Hoegler summary abstract here). While radiation to a painful metastasis has often been given historically as daily fractions Monday-Friday for 2-3 weeks, recent studies have demonstrated that even a single-day radiation treatment can provide the same degree of pain relief 3 months later, although the single-day treatment had a higher likelihood of needing to re-treat the area, and no differences in survival or likeliood of a later pathologic fracture (Hartsell randomized comparison study, abstract here; summary “meta-analysis” abstract here). The more recent trial, with the abstract above, focused on patients with breast or prostate cancer but would presumably be equally applicable to metastases from other cancers. Overall, multiple trials have shown that a short course of 1-5 “fractions” of radiation can achieve comparable pain control and overall results as longer courses of radiaion. There can sometimes be more side effects to surrounding tissues if a single treatment or just a few are done, so this is a particularly appealing for metastases to extremities, where internal organs are not included in the radiation field.
Although it’s rarely done, there was actually a study that demonstrated that patients who received steroids in combination with XRT had more rapid and prolonged pain relief than the patients who received XRT alone (Teshima abstract here). Steroids do have acute and chronic side effects, including overall bone loss. Overall, this isn’t commonly practiced, but it’s a reasonable option.
There are several additional approaches for the common problem of bone metastases, so I’ll continue on this topic next time.
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
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
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.
Prophylactic Cranial Irradiation for SCLC
Prophylactic cranial irradiation, or PCI, for SCLC, usually limited disease (LD-SCLC), remains a controversial issue, although this is generally recommended for patients with LD-SCLC who have a complete response to treatment (no evidence of disease). However, the idea of radiating the brain of someone who has no evidence of cancer there and may never get it is something that many patients and also some oncologists (radiation oncologists and medical oncologists) may not embrace. So how did we get to a point where we standardly recommend radiation to prevent brain metastases from developing?
Well, as I mentioned in previous posts, the brain is remarkably fertile soil for brain metastases for SCLC, which has a consistent propensity to spread there. In some studies, up to two thirds of patients with SCLC who don’t receive PCI develop brain metastases within two years. Several small trials in the 1970s and 1980s consistently showed a reduced risk of developing brain metastases but no clear improvement in survival from PCI, although these trials were really too small to show any significant benefits. Continue reading
Current Standards of Care for Limited Disease SCLC
While SCLC accounts for only about 13% of lung cancer, and only approximately one third of patients with SCLC have limited disease SCLC (LD-SCLC), this remains a high stakes area with the potential for being cured, so it needs to be treated as optimally as possible. I’m going to give a brief history and highlight some of the current principles of what has developed as the current standard of care.
As mentioned in my prior posts that included general information about SCLC and extensive disease, limited disease is defined as SCLC in which full staging shows that all visible disease is confined to what can be reached in a single radiation port, so generally localized to one half of the chest. Whether patients who have SCLC cells in fluid outside of the lung (a malignant pleural effusion) or the neck/upper chest on the side opposite the main cancer mass is controversial. Only 5-10% of patients with SCLC have their cancer detected before it is at least involving the mediastinal (or middle of the chest) lymph nodes, so SCLC is usually either locally advanced or metastatic. It is quite uncommon to find a single lung nodule of SCLC without significant lymph node involvement, unlike NSCLC, where a larger minority of fortunate patients can have stage I or II disease detected. Continue reading
Small Cell Lung Cancer 101: An Introduction
After several weeks of posts on other aspects of lung cancer, I am long overdue to write on small cell lung cancer (SCLC). Although it is good to see the number of SCLC cases decreasing over time, and becoming a smaller and smaller percentage of lung cancer cases overall (only about 13% in the US and steadily falling), this has translated into fewer clinical trials and less of a focus on SCLC in the lung cancer community. However, there are some promising developments that may lead to some long overdue progress in the field.
First, this post will start with some general concepts and an introduction to SCLC, and this will be followed in the next few weeks by posts describing current and emerging ideas for the basic stages of small cell lung cancer, and also a discussion of prophylactic cranial irradiation for small cell, where it has been most extensively studied. Continue reading
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