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.
posted by Dr. West @ 4:32 pm link to this post
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March 12th, 2007 at 8:47 pm
Dear Dr. West,
I wanted to ask you a few questions I am concerned with.
After my mom completing chemorad since dx in September (LD-SCLC),
I had written to you re: findings on CT and PET (new nodule and areas of opacity RUL), which you told me you see these frequently - ambigious findings on scans upon completion of tx, not uncommon, radiation pneumonitis, etc.
Ok, my mom after completing a round of Augmentin, had a bronchoscopy done about mid Feb. showing a nodule (as seen on PET) they were unable to get to for bx, took biopsies around it and did bronchial washings, negative for malignant cells and biopsies show rad. pneumonitis.
Ok, now she has 6 more PCI treatments to go, and she was told by her oncologist on March 7 that she was in “clinical remission”.
My mother just tonight faxed me her follow up PET done on 3/2 which is the report the oncologist based his dx of remission on. I am reading just the opposite.
The report says there is a linear area of reactive fibrosis in the right upper lobe which has increased in size since previous study, appearance most consistent with radiation fibrosis/pneumonitis. An adjacent pulmonary nodule is present (1-1.2cm). The nodule and adjacent fibrotic lung demonstrate moderate FDG uptake, consistent with some residual active malignancy. Size of the nodule has not significantly changed since the previous study. The fibrotic lung and nodule are confluent with the right hilum. No definite active nodes are noted within the hilum or central mediastinum.
The conclusion says: Suspected radiation fibrosis/pneumonitis, RUL, with increase in fibrotic reaction, in comparison with previous study. Some residual increased FDG activity associated with the adjacent pulmonary nodule and fibrotic lung suggests persistent active malignancy. A portion of the increased activity is likely due to an inflammatory component as well.
NOW, doesn’t persistent active malignancy mean just that? What am I (the daughter who with the rest of my family are celebrating my mother’s remission) really to think? What do you think of these findings?
Is “moderate FDG uptake” a normal finding on patients who are in remission? I’m thinking it surely isn’t.
I am so disappointed and shocked after reading this. I absolutely am in such disbelief and I don’t understand. I haven’t told my mother or father of my fears but tomorrow I will be calling the oncologist and my sister is going to take the report and go see him in an effort to get some sort of explanation for this contradiction we have been hit with. I am completely sick at my stomach and do not know what to think.
I want to believe I (we) can trust this oncologist and have before now not had any reason not to. He has been so wonderful.
Just would like your opinion please.
Thanks, Bonnie
March 13th, 2007 at 7:33 pm
Bonnie,
I’m afraid I didn’t get to this until likely after you’ve discussed things with the oncologist. You’ve probably had that conversation, and I’d be interested to learn how that went. What I’d say is that the radiologists often have just the smallest bit of context, so their interpretations are often not exactly appropriate. If the metabolic uptake is going up after radiation has been completed, I’d say it’s worrisome for cancer, but residual uptake can still be inflammation, and I would favor that interpretation if the SUV was declining, even slightly. Either way, I think PET scans after chemo and radiation are still remarkably hard to interpret. There’s a reason they’re not part of routine management, even though many people do them. We don’t yet know what to do with the information we’re getting. I would certainly be concerned, but I’d be concerned about the potential for recurrence even if there was nothing to see, just knowing how often patients can have recurrences even after being treated completely by the book. Very often there just isn’t information to give a definite answer, but people want them. I wouldn’t presume that the oncologist is being deceitful, but rather that he’s trying to glean an answer from an ambiguous situation. I’d certainly be inclined to give him the benefit of the doubt, at least.
-Dr. West
March 16th, 2007 at 11:38 am
Hi Dr. West,
Thanks again for your response. Sorry for not getting back sooner but I am just getting back home where I have access to my computer.
We went to the oncologist yesterday and he logically, gently and convincingly explained his conclusion of “clinical remission”. We are all comfortable with what he said and have all slept well last night.
He told us that yes, the radiologist may see the area on the PET as a malignancy, but he is not the clinician who follows this patient. There is a different radiologist reading every one of these reports and documenting their opinion and they do have to cover themselves. Anyway, given my mother’s clinical picture, the great response to chemoradiation, the fact that the tumor was resolved prior to the 4th chemo, the negative biopsies in February is how he comes to the conclusion of clinical remission. He said if this nodule was malignant, that would mean it survived all that chemorad, how could it? Then the entire tumor would have been resistant all along and it wouldn’t have had the response it did. He also said that between himself, the rad. onc. and the pulmonologist who have been following her in clinic all agree she is in clinical remission.
I admit, I did feel my mother had been betrayed but I don’t believe it now. I completely trust the oncologist and the team of great physicians who take such good care of my mother.
I am glad we went in and got the explanation though.
I am still slightly bothered by the fact that the most recent PET report did not include SUV measurements at all, so we don’t know if it declined or increased. The oncologist said he doesn’t go by those numbers and he personally went and viewed the films.
But I am not going to dwell on it, I am relying on my gut feeling and the information I got yesterday which made so much sense.
Thanks for your input.
You are always right on the money. I greatly value your opinion.
Bonnie
November 20th, 2007 at 8:39 pm
I have a quick question after reading the original post. It appears that the findings show concurrent rad starting at round 1 or 2 is the most effective method, which to me seems logical.
My question is my Mom has an 8 cm tumor in her upper right lung (mixed histology of SCLC & NSCLC adenocarcinoma - stage III). The onc explained her tumor is too large to start radiation right now. She will go for a CT scan after round 2 to determine the responsiveness to the chemo (cisplatin & etoposide) and if it has shrunk enough to start the concurrent radiation. The above studies do not mention tumor size (that I saw). Is this a common issue? Also, the tumor is wrapped around the main passage into the lung (can’t remember what that’s called - too many terms to try and keep straight!!), so maybe that’s part of the reason why they’re waiting?
Thanks for your help!