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.
In early 2003, Janet S was a 53 year-old woman who quit smoking several years before developing a cough and left chest pain that was evaluated by her primary physician, who found on a chest x-ray and then CT that she had a 10 cm left upper lobe mass, confirmed on biopsy to be an adenocarcinoma subtype of NSCLC. Her CT also showed bulky left-sided mediastinal (mid-chest) lymphadenopathy. She was referred to me, and further staging showed no evidence of brain metastases, and a PET confirmed that her primary tumor lit up brightly, as did her left mediastinum. My plan was to follow the approach of aggressive chemo and concurrent radiation, followed by more chemo, with curative intent, although Janet's primary care physician initially thought I was misleadingly to delusionally optimistic in offering that hope. I treated Janet along the lines of the SWOG approach (described in a post here), with cisplatin-based chemo and concurrent radiation to 63 Gy (administered by a radiation oncologist closer to her home about 45 minutes away from my office). She was very fit and tolerated this aggressive therapy well, but when I gave her consolidation taxotere, she developed worsening shortness of breath and infiltrates on her chest x-ray consistent with radiation pneumonitis. After two of three planned cycles, I felt that the risk of another cycle exceeded any further benefit, and we decided to stop treatment and follow her. Her CT scans demonstrated a very good partial response, at least, with a very significant decrease in the tumor, but there were residual abnormalities in the left upper lobe. However, as is typical after chemo and radiation, it was really impossible to determine whether the residual abnormalities on CT represented post-treatment scarring (and no living cancer) or remaining viable cancer. Because PET scans detect inflammation as well as cancer, for the first few weeks to months after radiation PET, when inflammation in the radiation field is likely to be present, PET scans really cannot discriminate residual cancer from post-radiation inflammation. However, they are useful for evaluating changes over time, since post-treatment effects diminish with time, but cancer becomes increasingly prominent on PET scans over time.
Unfortunately, the ambiguous findings on her scans became increasingly clear over the next few months, when first her CT scan showed some subtle but increased prominence around the remaining soft tissue at the center of the treated area/residual scarring vs. mass. Her PET scan then showed a clear increase in the SUV in that same area, but no uptake anywhere else. Now more than a year out from starting treatment, the overall picture was highly consistent with a localized recurrence/residual viable disease, with no evidence of distant disease, after aggressive, full-dose chemo and radiation.
We reviewed her case and all of the films at our multidisciplinary thoracic tumor board, and we discussed the possibility of having her go to surgery to remove her left upper lobe and what was almost certainly viable cancer. She proceeded to a lobectomy, which was technically challenging, but she fortunately had a very skilled and well-trained thoracic surgeon available to navigate through the procedure. The pathology demonstrated an approximately 3 cm area of viable NSCLC with a very large area of necrotic tissue (dead, from effects of chemo and radiation) around it).
Since then, she has had a pleural effusion on the left side that I feared might represent recurrent cancer, but multiple thoracenteses (removal of fluid) confirmed as inflammatory, with no evidence of cancer cells. Since that surgery, she has been living her life, traveling extensively, and has had no evidence of progression of her cancer over more than two years. She is approaching four years out from her diagnosis, and I am very hopeful that she is truly cured.
This is definitely NOT a standard approach, but this case shows that an approach of full-dose radiation and chemo can be followed by surgery, with good results both in terms of the safety of the operation and the long-term outcome of the cancer. There have been limited published experiences of promising results from such a strategy. Dr. Sonnett, a thoracic surgeon at Columbia University in NYC, reported their results on a diverse group of patients who underwent radiation to 60 Gy or more, along with concurrent platinum-based chemo, followed by surgery (abstract here). They noted no post-operative deaths and an encouraging overal survival, but the group is so diverse it is hard to say more than the fact that this approach is reliably safe if the treatment team and particularly the surgical team are especially well-trained and inclined to push beyond the current standards.
Another excellent thoracic surgeon asking whether we can do better by doing more is Dr. Robert Cerfolio at the University of Alabama at Birmingham. He has published his experience (abstract here) on a series of 104 patients there who received either full dose (60 Gy or higher) radiation with chemo before surgery (54 patients) or a lower dose of radiation with chemo before surgery (50 patients). The two groups were pretty comparable in terms of age, stage, gender, and NSCLC subtype. Not surprisingly, patients who received higher dose radiation were significantly more likely to have a complete response (26% vs. 10%). Complete response rates by stage are shown here:
More impressively, the disease-free survival rate was significantly superior in the patients who received higher dose radiation, and there was also a strong trend toward better overall survival in the high-dose group:
In Dr. Cerfolio's hands, there was no real difference in major complication rates, which were 8% in the low-dose RT group and 9% in the high-dose RT group. These complications were usually pneumonia or aspiration pneumonia. However, Dr. Cerfolio cautions that this was not a randomized trial but rather one where some patients were selected or had self-selected for more conventional RT while others were directed toward higher-dose radiation, and the tendency was for more higher dose radiation more recently -- there could be a beneficial effect of increasing experience seen more in the high dose RT group.
However, my case and Dr. Cerfolio's report illustrate that it is certainly feasible in very well-trained hands to have patients safely undergo high-dose, definitive radiation followed by surgery. At my center, we don't plan up front to have patients undergo definitive radiation with concurrent chemo followed by surgery, as Dr. Cerfolio and his colleagues sometimes do, but for cases like Janet's, where there is evidence of a single focus of viable cancer after aggressive treatment, it's a reasonable option. However, whether this is a better option than cyberknife or other emerging radiation techniques that could allow for re-irradiation of a previously radiated area, it is impossible to say. We didn't have cyberknife technology at our center when Janet had her surgery, but we would discuss the pros and cons of surgery vs. cyber-knife or other radiation techniques today.
Overall, it's great to see that there are options for pushing the envelope like this, but I would say that this is really most appropriate at centers that have a particular interest and specialization in this type of work. As much as surgical skill matters for routine lung surgery (see post here), it is particularly important when we are moving beyond the usual treatment approaches.