Arguably the clearest practice changing standard to emerge from the 2012 SABCS conference is the long-anticipated data supporting shortening the duration of radiation therapy after surgery. The results of the START trial were discussed by the British Dr. Yarnold during the General Session on Thursday and again at the morning Plenary Lecture on Friday. Already the UK has adjusted their standard of care based on this data.
This year important 10 year follow up data was presented from the UK START (or Standardization of Breast Radiotherapy) trial, which looks at varying schedules and doses of radiation. Five year results were presented in 2008 and showed that a shorter, more intense dose of radiation had similar outcomes to the current standard US dose. This follow up analysis looks at 10 year data, which is important given the fact that adverse effects of radiation generally arrive late (after 5 years) and the importance of ensuring that anti-cancer effects also last.
The fundamental issue with radiation dose is identifying ways to be gentle on normal tissue but not too gentle on breast cancer—which would have no advantage. Indeed, as Dr. Yarnold noted, because tumors are not somehow more sensitive to radiation than normal tissue, the concern is that a lower dose to protect healthy tissue may not have the desired effect on the tumor. The START trial evaluates this question.
The study treated women with early breast cancer (stage 1-3 operable disease). The relatively simple design randomized women into two groups:
• Arm A used the standard dose and duration in the US: 50 Gy [note: I cannot explain radiation doses which are “fractionations” and am simply reporting this aspect of the trial without further explanation] over 5 weeks (25 days)
• Arm B increased the dose to 40 Gy and shortened the duration to 3 weeks (15 days)
Median follow up of data presented was just under 10 years. Primary outcome to be evaluated was recurrence in the area of the original tumor and additional endpoints included local regional relapse and secondary endpoints included disease free survival, overall survival and effects on normal tissue (including patient self reported outcome, independent assessment of photographs, etc.)
Long term outcomes of both arms were equivalent, with suggestion of better cosmetics (less breast hardening and shrinkage) in the shorter “Arm B”. Furthermore, acute effects of radiation were more tolerable with shorter duration (despite higher dose) of radiation with regard to skin damage.
The findings of this trial support higher dose, shorter duration radiation therapy which has now become the new standard of treatment in the UK, treating for 3 weeks at 40Gy (as opposed to 5 weeks at 50 Gy as currently done in the US).
It is worth noting that this data is not entirely new—although the long term data presented is important. There has been a migration toward this trend in the US but it has been a slow migration. Several radiologists noted that the primary barrier to changing is the current method of reimbursement for radiation therapy, which is to bill by the week. Thus this move to shorten treatment would effectively remove 2/5 (or early half) of a radiation oncologist’s revenue from each individual breast cancer patient.
One argument frequently provided against higher dose, shorter duration is cardiac toxicity. There is no safe dose of radiation for the heart: the total dose is the issue and the heart needs to be protected during radiation. Dr. Yarnold gave a cost-free, drug-free, toxic-free solution: if a woman takes in a deep breath and holds it during the 40 seconds or so of radiation, the air in the lung creates a space which protects the heart (without additionally exposing the lung).
One commentator noted that once the door is open to start evaluating shorter courses of radiation, there may be uses for existing radiotherapy techniques that are not currently used in breast cancer such as intensity modulated radiotherapy or image guided radiotherapy. Currently targeted machines used in head and neck cancers are too expensive for use in 5 week series for breast cancer but may become options if the dose is increased and duration shortened. As always, the doctors will seek to push it to the limit – how large a dose for how short a time?
Indeed the results of the TARGIT trial looked at single dose in the operating room—or in radiation oncologist jargon to give a sense of the SABCS experience, “single fraction delivered to the resection cavity”.
The TARGIT trial stands for TARGeted Intraoperative radio Therapy and uses a device, which was developed for brain tumors. It provides a single large dose of radiation in the operating room delivered directly to the tumor cavity for 25 minutes after tumor removal. This was compared to the standard external beam radiation therapy.
Thirty-three centers in 10 countries participated in the trial, which started in Europe but included Australia and the US. Patients who entered had generally good prognosis but the study included younger women.
Scientific rationale for TARGIT is that despite the fact that breast cancer is frequently multicentric—meaning there are multiple lesions of different size in multiple locations of the breast(s)—most recurrences happen near the original tumor. So the researchers decided to target radiation to the tumor bed.
The majority of data was just under two and a half years (median follow up 2 years 5 months). While there was not a difference in local recurrence at follow up, the likely number of events in that short duration is low enough that it will take more time to fully evaluate.
There was a reduction in overall mortality for the TARGIT group and the researcher claimed that TARGIT’s benefit is in reduced cardiac mortality even though there is slightly higher recurrence.
However, Dr Crownover expressed surprise at reported significant improvement in mortality, suggesting it is a statistical fluke related to the short time of follow up. He noted that most secondary malignancies develop after 5 years and acute effects of radiation also typically have later onset. Furthermore, there was no observed connection between left and right sided events, which put into question the plausibility of a protective mechanism related to cardiac mortality.
The take away, based on START protocols in the US should be revised to the higher dose, shorter duration UK standard on which the trial was based. It is vital, as always, that patient interest and well-being is not compromised because the current reimbursement for radiation therapy means this new protocol will represent nearly a halving of revenue. There may be additional studies further shortening the duration and increasing the dose of radiation therapy but, for now, the data on TARGIT is too short to say much with any confidence.