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.

Unlike locally advanced NSCLC, where the old standard was radiation before chemo was found to be helpful to add, up into the early 1990s LD-SCLC was treated primarily by chemotherapy before the value of radiation therapy was found to be beneficial enough to include along with chemotherapy. For those of you who have read my other posts on SCLC (or other sources of information), you know that SCLC is often very responsive to initial chemotherapy. The problem is that when it comes back, it is not curable, and it is also often much less responsive to chemo than it was initially.

While the initial trials that added radiation were generally too small to demonstrate a significant survival benefit for chemo and radiation compared to chemo alone, there was a meta-analysis that pooled results from 13 different trials of radiation added to chemotherapy in LD-SCLC, over 2100 patients, and found that there was a survival benefit of approximately 14% overall, leading to an absolute 5% improvement in three-yearsurvival (cure rate) compared to chemotherapy alone. Interestingly, the greatest benefit was seen in patients under 55, and there was actually no clear benefit from radiation in patients over 70. Over the past 15 years or so, integrated chemo and radiation have been the general approach used, and current guidelines do not specifically recommend RT only for younger patients.

One question that has emerged as important has been the timing of the radiation, whether it should be done with the first or second cycle of chemo or follow most or all of the chemo that is being given. The trials have supported earlier administration. First, a trial led by Dr. Nevin Murray in Vancouver included just over 300 patients with LD-SCLC who received 6 cycles of chemo that alternated between an old standard of CAV (cyclophosphamide, adriamycin, and vincristine), and the "newer" (now old school) cisplatin/etoposide. Both arms of the trial received six cycles of this alternating chemo, followed by prophylactic cranial irradiation (to be discussed in a subsequent post), and also chest (also known as thoracic) radiation therapy. One group received the radiation starting with the second cycle, and the other group received it with the last cycle, as per the schema shown here:

(Click to enlarge image)

The results are shown in the table on the right. There was a higher complete response rate (no visible disease), approaching two thirds of the patients, with earlier chest radiation, which was also associated with a better survival, nearly doubling the proportion of patients alive 5 years after treatment (20%). Interestingly, earlier radiation also markedly decreased the risk for developing brain radiation, suggesting that controlling disease in the chest earlier reduced the risk of seeding metastatic disease in the brain. Since then, other trials have corroborated that early radiation is better than late, such as a Japanese trial by Takeda and colleagues that compared radiation at the start of chemo (with cisplatin/etoposide) and the same radiation after completion of the same chemo:

Results shown below:

So again the response rate and survival are better with early (here, concurrent vs. sequential) radiation with chemo.

At this point, radiation with either the first or second cycle of chemo has become the standard approach. Some give it with the first cycle, as early as possible, and others wait until after one cycle, so the cancer begins to shrink down and may lead to a less extensive area that needs to be radiated. There's no clear best answer about whether to start with the first or second cycle.

One of the current issues is about whether radiation should be given once daily or twice daily, with chemo at the same time. An important trial by Turrisi and colleagues, published in the New England Journal of Medicine, tested this and found that patients had a better survival, although more severe esophagitis (burning of the esophagus with treatment) if they received radiation twice daily instead of once daily. The schema for the trial and results are shown below:

Result shown below:

Well, even though that trial was published in the prestigious New England Journal of Medicine, this approach hasn't been widely adopted. Why? The argument is that the same dose of radiation was used in both arms (45 Gray (abbreviated Gy), a unit of radiation dose), but it is a stronger amount of radiation effect and not biologically equivalent if given twice daily vs. once daily. And it is also inconvenient for patients and docs to have patients come in twice per day, 6 hours apart, to get their radiation. It is more common to have radiation doctors recommend that patients come in once per day but receive a higher dose than 45 Gray, more like 60-70 Gray in total, which would be a biologically similar radiaiton effect. And while there have been discussions about running a trial to directly compare radiation given twice daily to a total dose of 45 Gy against once daily radiation to something in the range of 64-67 Gy, that hasn't quite happened yet.

Beyond that, in LD-SCLC the oncology community has done studies of bone marrow transplants and other aggressive approaches, such as adding another chemo to cisplatin and etoposide, but there have been no clear improvements in the cure rates from these, and often higher risk of side effects and even dying from treatment. Prophylactic cranial radiation (PCI), or radiating the brain to minimize the chance of cancer popping up there, has also been studied and is a recommended approach to reduce that risk and improve overall survival. More on that in another post.