By Jack Gleason, M.D, radiation oncologist at Alliance Cancer Care
As radiation oncologists, a common clinical situation we encounter are patients with non-small cell lung cancer that has spread to their regional lymph nodes in the chest (hilum or mediastinum) but do not have any distant metastases (spread of cancer to areas outside the chest such as bone, brain, liver, etc). Patients in this situation are stage II or III. Stage III patients are rarely treated with surgery or stereotactic radiation (SBRT, SABR) as part of treatment given the extent of the disease. Instead, we use concurrent chemoradiation (i.e. chemotherapy and radiation together, also called chemo-RT). Many stage II patients who are not candidates for surgery are also treated with this same approach. The PACIFIC trial has revolutionized the treatment of these locally advanced lung cancer patients with lymph node spread and/or larger tumors. Following the results of the PACIFIC trial, discussed further below, all Stage III patients now receive consolidative immunotherapy after completing their 6-7 week course of concurrent chemoRT. Let us talk a little more about how far we have come over the last 30 years with better treatment and survival for these patients.
Prior to PACIFIC, the standard of care for non-operative management of stage II and stage III non-small cell lung cancer patients (NSCLC) had not changed in many years. Trials conducted in the 1990s and early 2000s showed ChemoRT, giving chemotherapy at the same time with 6-7 weeks (60-66 Gy) of chest radiation, was better than radiation alone or chemotherapy followed by radiation. That became the standard of care. After that, groups did numerous trials looking at whether additional chemotherapy/targeted therapies given before (neoadjuvant) or after (adjuvant) the chemoradiation for these stage III patients would improve cure rates. None of those trials showed any benefit beyond just concurrent chemoRT.
Investigators also did trials trying to see if any specific chemotherapy combination was best. Most regimens essentially have similar outcomes in this situation. Our colleagues in medical oncology, who prescribe and oversee chemotherapy treatments, choose from among those multiple acceptable standards for chemotherapy drugs based on individual patient factors. A more recent trial by the RTOG (Radiation Therapy Oncology Group, now part of the NRG) looked at whether escalating the radiation dose would improve outcomes. That randomized trial showed the higher dose of radiation did not improve the patient’s outcome.
As an aside, I should point out that even though the standard of care wasn’t changing over all these years, the average survival rates were improving over time even when patients were treated with this same 6-7 week course of concurrent chemoRT established 20 years ago. For example, the concurrent chemoradiation patients on RTOG 9410 had a median survival of 17 months and a 5-year survival of 16%; whereas, the nearly identical 6-week course of concurrent chemoRT on the standard arm of RTOG 0617 conducted 10-15 years later had a median survival of 28.7 months and 5-year survival of 32%. A quick refresher on statistics, median means half of the patients lived longer than the value.
Why were people doing better even with the same approach? Several factors likely played a part. One aspect is almost certainly the emergence of widespread PET utilization. PET allows us to see the metabolic activity (think growth rate) of areas we see on standard CT scans. This helps us both establish an accurate stage at diagnosis and know the areas that should be targeted with radiation. Radiation for lung cancer has also improved over time, allowing less toxicity and more accurate treatment delivery. Radiation target volumes are smaller as we only treat the known areas of disease on PET and CT; whereas prior generations of patients had their entire mediastinum treated electively with more side effects. Patients treated today have their targets defined based on 4D CT. We also saw in the RTOG 0617 trial mentioned above that a technique we use called IMRT (intensity-modulated radiation therapy) seemed to improve survival. The same dose is given to the tumor either way so the improved outcome with IMRT is likely related to lower radiation doses to healthy normal tissues in the chest (i.e. heart, lungs). The supportive care of patients undergoing chemotherapy has also advanced. As you can see, it wasn’t all bad news over the last couple of decades. Patients were living longer and having a better chance of cure even though the standard approach regarding treatment wasn’t necessarily changing. We were just refining the components of it.
Now to the part that is so promising today. Of all the studies published during my 14 years since completing medical school, the PACIFIC Trial is up there as one of the more exciting I have ever encountered! Why? Again, I see MANY lung cancer patients; it is a very common cancer diagnosis. The American Cancer Society estimates that 236,740 people will be diagnosed with lung cancer in the United States this year. Lung cancer is also the leading cause of cancer deaths in the US. More people die from lung cancer than breast, prostate, and colon cancers combined. Non-small cell lung cancer is the most common type of lung cancer and many patients have stage II or stage III disease that is treated with chemoRT (and now immunotherapy). The PACIFIC trial was the first study to show benefit with additional treatment beyond this standard chemoRT backbone. The patients in the experimental arm were treated with one year of immunotherapy (durvalumab, trade name Imfinzi) after they had completed standard chemoRT. The median survival increased to 47.5 months (meaning over half of the patients were living more than 4 years). 5-year overall survival among patients receiving chemoRT alone was 33.4% (similar to RTOG 0617); 5-year survival of those getting chemoRT followed by consolidative immunotherapy was 42.9%.
To summarize the sequential improvements over the last 30 years, median survival rates with induction chemo followed by radiation were 14.6 mo (RTOG 9410), concurrent chemoRT 17 months (RTOG 9410), improved modernized concurrent chemoRT 28.7 months (RTOG 0617), a now improved modernized concurrent chemoRT followed by immunotherapy 47.5 months (PACIFIC). We have gone from half of the patients living longer than a little 1 year to half of the patients living nearly 4 years. 33.1% of the PACIFIC trial patients who underwent chemoRT followed by Imfinzi were alive and with no evidence of cancer at 5 years meaning they are likely cured.
We have come a long way, but clinicians worldwide are committed to continuing to improve these outcomes. This is better but certainly not good enough. We want to get to a point where we can cure every patient’s cancer. The parts that you can control as a patient are two-fold. First, if you are a smoker, stop smoking. It is the largest risk factor for lung cancer, among other diseases. Second, if do have a history of smoking, get a low-dose lung cancer screening CT scan every year (hyperlink to Dr. McCarty’s screening blog). These scans allow us to catch your cancer earlier (just like a mammogram or colonoscopy for breast or colon cancer, respectively). Stage I lung cancers have a higher cure rate and we can treat them with surgical resection or a short 4-5 treatment course of pinpoint radiation (stereotactic radiation, SBRT, SABR). The American Cancer Society estimates that 12,000 lung cancer deaths each year could be avoided if we screened appropriate patients.
If you or a loved one were recently diagnosed with lung cancer, our team of experts is ready to help. Please call our office or reach out to us via our contact form.