Patient compliance with radiation schedules

A new study by Ohri et al. (with additional information in the ASCO Post) found that for certain cancers, there was a 22% non-compliance rate at the Montefiore/Albert Einstein Cancer Center in NY. Non-compliant patients extended their total treatment time by about a week. The recurrence rate was 7% among compliant patients, but was significantly higher, 16%, among non-compliant patients. Now, the authors only looked at compliance with radiation schedules for head and neck, breast, lung, cervix, uterus and rectal cancers. Should prostate cancer radiation oncologists and their patients be concerned?

All cancers are different. It is impossible to generalize from one cancer to another. This is as true for radiation treatments as it is for medical treatments. Prostate cancer has some very unique characteristics that affect radiation treatments:

(1) Prostate cancer is very slow growing. For certain cancers like some head and neck cancers, the tumor growth is so fast that multiple radiations sessions must be scheduled each day (called hyperfractionation) in order to keep ahead of the high cancer cell repopulation rate. In fact, the repopulation rate increases as radiation progresses for such cancers. In contrast, even high-risk prostate cancers repopulate so slowly that delays of a few days to a week are insignificant. In fact, some treatment schedules for SBRT and HDR brachytherapy are a week apart with no apparent loss of efficacy.

(2) Prostate cancer responds to fewer, higher doses of radiation – hypofractionation. Prostate cancer has a peculiarly low radiobiological characteristic, called an alpha/beta ratio, which means it is killed more effectively by hypofractionated radiation. Two major randomized clinical trials have proved that shortened radiation schedules (20 fractions or 28 fractions) have equivalent effectiveness and no worse toxicity than the traditional fractionation of 40-44 treatments. The most extreme kinds of hypofractionation, SBRT and HDR brachytherapy, typically only need 4 or 5 treatments. Recent HDR brachytherapy protocols are using as few as 2 treatments. Therefore, patient compliance isn’t much of an issue. For cancers with a high alpha/beta ratio, more fractions with lower dose per fraction are needed to kill the cancer. Showing up every day for many weeks can be burdensome to the patient.

(3) Fatigue increases with the number of fractions, so reducing the number of prostate cancer treatments helps maintain vigor. With normally fractionated prostate radiation, fatigue peaks at 4-6 weeks after the start of therapy (See this link.). While fatigue scores increased a month after SBRT, it was not a clinically meaningful change (See this link.). Fatigue reported from prostate cancer radiation is less than from radiation to head and neck, alimentary and lung cancers (See this link.); therefore, non-compliance due to fatigue from radiation is probably less important for prostate cancer, particularly with hypofractionation. Other issues sometimes associated with extended fractionation include anxiety, nausea, lost days of work and financial burden. Ohri et al. found that compliance was worse among those of lower socio-economic class.

(4)    Prostate cancer’s alpha/beta ratio is much lower than the ratio attributable to healthy surrounding tissues – a therapeutic advantage. This means that prostate cancer cells are more efficiently killed by the hypofractionated regimen, but the healthy tissues of the bladder and rectum that respond quickly to radiation are not killed at all efficiently. So a total SBRT dose of, say, 40 Gy in 5 fractions, has much more cancer killing power than an IMRT dose of, say 80 Gy in 40 fractions, but less acute toxicity to healthy tissues.   This contrasts with other cancers where the alpha/beta ratio of the cancer is similar to that of nearby healthy tissues. In that case, the only way to mitigate damage to healthy tissues is to deliver the radiation in much smaller fractions, and allow time in between for sub-lethally damaged healthy tissues to self-repair. It doesn’t take long, only a few hours, but for practical purposes, treatments are a day apart.

(5) Prostate cancer is multi-focal in at least 80% of men. Tumors are almost always distributed throughout the entire prostate, so the entire organ is irradiated. This contrasts with many other cancers where there is a single large tumor growing in the organ, at least for a long time. For non-prostate cancers, it is rare for the entire organ to be treated.

(6) There are many important organs (including the bladder, rectum, penile bulb and femur) that fall, at least in part, within the radiation field. Prostate radiation requires sophisticated image-guidance and intensity modulation to treat the prostate and nothing else. Unlike radiation for other cancers where there are toxic effects due to treating the organ itself, there is almost no toxicity due to irradiation of the prostate itself (other than loss of seminal fluid). Discomfort from bladder and rectal toxicity arrives only towards the end or after the end of treatments, so there is little reason to discontinue or miss treatments.

(7) Unlike the other organ cancers that were treated in the study, the prostate is deep within the body. Higher energy X-rays are needed for that depth, and that spares closer-to-surface organs. Consequently, radiation burns of the skin rarely occur, and there is no discomfort associated with each treatment. There are exceptions in men who are hypersensitive to radiation, but burns, necrosis, and fistulas have rarely been reported.

There are some radiobiological considerations that are similar to other cancers that respond to radiation (not all of them do). Some cancer cells may self-repair sub-lethal damage to the DNA, and poor tumor-tissue oxygenation (hypoxia) may protect the tumor from radiation damage. For these reasons, it is important to deliver enough radiation to overcome the hypoxia and kill all the cancer cells. Dose escalation has improved the curative potential of radiation for prostate cancer.

An argument in favor of longer treatment regimens is that cancer cells are more vulnerable during certain phases of their cell cycle; therefore, there will be more opportunities to kill them over a longer treatment schedule. Another argument for longer schedules is that hypoxic protection of the tumor is worn away by the treatments, and subsequent growth of blood vessels around the tumor will re-oxygenate it, thus radio-sensitizing it. The greater local control we’ve seen with extreme hypofractionation suggests that it may elicit unique radiobiological mechanisms that might overcome hypoxia and cell cycle phase issues.

Because of prostate cancer’s low repopulation rate, higher quality of life during treatment, and with increasing use of hypofractionation (both moderate and extreme) there is no reason why patient compliance with prostate cancer treatment schedules should be a problem as it is for other cancers.

(Update 12/6/20) In the National Cancer Database, patient non-completion of SBRT for prostate cancer was 1.9% vs 12.5% for conventionally fractionated treatment.