RIX sham and cultural differences

Stimulated by Garcia et al 2019.[1]

This is rather a unique and striking study, published this week in an open access JAMA journal. It is the first large (n=399) three arm clinical trial in RIX (Radiotherapy-Induced Xerostomia), the first trial that performed the acupuncture from the start of radiotherapy, and the first acupuncture trial to include a centre in both China (Fudan University Cancer Centre, Shanghai) and the US (MD Anderson Cancer Centre, Texas).

Patients with oropharyngeal or nasopharyngeal squamous cell carcinoma who were to receive a minimum dose of 24Gy to at least one parotid gland were randomised to either true acupuncture (TA), sham acupuncture (SA) or standard care control (SCC). Randomisation was stratified based on a number of factors, but most importantly on the planned radiation dose to the parotid.

The primary outcome was the XQ score.[2] XQ stands for Xerostomia Questionnaire, and it is a PROM (a Patient Reported Outcome Measure). It is an 8 item questionnaire that is scored on a 0-10 ordinal Likert scale,[3] and then the score linearly transformed to a 0-100 score.

Xerostomia Questionnaire (XQ)

  1. Rate your difficulty in talking due to dryness
  2. Rate your difficulty in chewing due to dryness
  3. Rate your difficulty in swallowing solid food due to dryness
  4. Rate the frequency of your sleeping problems due to dryness
  5. Rate your mouth or throat dryness when eating food
  6. Rate your mouth or throat dryness while not eating
  7. Rate the frequency of sipping liquids to aid swallowing food
  8. Rate the frequency of sipping liquids for oral comfort when not eating

Each item is rated on a scale from 0 to 10. The higher the score, the worse the xerostomia.

The combined results from both centres demonstrated a significant benefit of TA over SCC (p=0.001), but not quite for TA over SA (p=0.06). The strange thing is that in Texas SA was significantly better than SCC, but TA was not, and in Shanghai SA had no apparent effect at all compared with SCC.

There was a small baseline difference between centres in XQ, and this could have been due to subtle differences in the Chinese version, or even systematic differences in typical food intake. More moist food in China corresponding to lower baseline scores on XQ perhaps.

Anyway, at the one year follow up, there was a 10-point difference between acupuncture and standard care in both centres, but whereas there was also a 10-point difference between true and sham in Shanghai, there was no difference at all between true and sham in Texas. So there was a 10-point difference between sham and standard care in Texas and no effect of sham at all in Shanghai.

An editorial in the same issue by researchers from Hannover discuss the cultural differences between the two sites and suggest that the credibility of sham may be different,[4] although there was no meaningful change in credibility scores.

Garcia et al mention systematic differences in the environment between the centres. Quiet individual rooms at MD Anderson compared with a busy loud semiprivate clinical space in Fudan.

So far I haven’t actually mentioned the acupuncture.

From a physiological perspective it was a mess!

Both penetrating needles with deqi elicited and non-penetrating sham needles were used in both acupuncture groups, and there were no needles placed near salivary glands because of concerns about the tissues in the radiation field. Obviously in the design stage must have been difficult with lots of factors to consider, but it is a real shame that potential mechanisms were not addressed in either the protocol or the final paper.

The true acupuncture group had 4 ear points in each ear (Shenmen, Point Zero, Salivary Gland 2 and Larynx), CV24 (midpoint of mental groove on the chin), LU7, KI6, and a sham needle at GB32 (right side).

The sham acupuncture group had 4 ear points on the helix, GB32 (right side) with deqi, and sham needles at so-called sham points in all 4 limbs and near CV24.

Sessions were performed 3 times a week for 6-7 weeks immediately before or after radiotherapy.

Both local and general mechanisms may be engaged to hypothesise protective effects, but local mechanisms are always likely to be more powerful where there is a somatic region of interest.

To quote from a previous blog on the same topic:

Early treatment directed close to salivary gland tissue seems the most logical.

References

1         Garcia MK, Meng Z, Rosenthal DI, et al. Effect of True and Sham Acupuncture on Radiation-Induced Xerostomia Among Patients With Head and Neck Cancer: A Randomized Clinical Trial. JAMA Netw open 2019;2:e1916910. doi:10.1001/jamanetworkopen.2019.16910

2         Eisbruch A, Kim HM, Terrell JE, et al. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:695–704. doi:10.1016/s0360-3016(01)01512-7

3         Likert R. A technique for the measurement of attitudes. Arch Psychol 1932;22:55.

4         Karst M, Li C. Acupuncture – A Question of Culture. JAMA Netw open 2019;2:e1916929. doi:10.1001/jamanetworkopen.2019.16929


Declaration of interests MC