8 gray single fraction radiotherapy for metastatic bone pain
Journal Club06.06.2013Abish Adhikari
Introduction• To determine the optimal dose of singlefraction conventional palliative radiationtherapy for the relief of pain caused bybone metastases.• 24 trials that cumulatively randomised3233 patients to 28 single fraction arms:two arms received 4 Gy, one 5 Gy, one 6Gy, twenty-two 8 Gy, one 10 Gy and one8–15 Gy.
Material & Methods• EMBASE, Medline, Cochrane weresearched for the keywords.• Papers reporting phase III trials thatrandomised patients to at least one arm ofSingle Fraction(SF) conventional externalbeam radiation therapy for the palliation ofbone metastasis were include.
Results• The initial database search produced 2696results. After screening, 40 satisfiedselection criteria and their full-text articleswere obtained.• Ultimately 26 articles reporting on 24clinical trials formed the final article set foranalysis.
Results• Two of the 24 trials were first published between1986 and 1989, nine between 1990 and 1999and 13 after 2000 AD.• Two trials compared SF arms only and theremaining 22 trials compared SF and MF arms.• The breakdown of patients according to dosewas: 4 Gy (n = 246), 5 Gy (n = 14), 6 Gy (n =108), 8 Gy (n = 2717), and 10 Gy (n = 134).
Results• Pain response rates that could be analysed werereported by all but two of the 24 trials.• Intention-to-treat rates were available for 20 trials.• Primary pain response criteria varied and werebased on qualitative categorical assessments (e.g.no pain, mild pain) in 16 trials, on quantitativeassessments (e.g. ordinal rating scales) in sixtrials and it was not clear in two trials.• Pain assessment ranged from 3–12 weeksfollowing radiation therapy for 18 trials, and timeswere either beyond 12 weeks or were unclear sixtrials.
Results• In general, higher doses produced higherresponse rates.– For the two 4 Gy arms, the intention-to-treatoverall pain response rates were 32% and 47%.– For the only 5 Gy arm assessable patient overallpain response rate was 72% and the assessablepatient complete pain response rate was 55%– For the only 6 Gy arm the overall pain responserate was 65% and the complete pain responserate was 21%.
Results• For the twenty-two 8 Gy arms, the overall painresponse rates ranged from 21% to 81% (ITT)• The complete pain response rates ranged from9% to 52% (ITT)• For the only 10 Gy arm the assessable patientoverall pain response rate was 84% and theassessable patient complete pain response ratewas 39%.
Results• Three trials directly compared different SF arms.– The first trial1, in 1992 (n = 270) reported superior painresponse rate at 4 wks for 8 Gy (76%) compared to 4Gy (53%), p < 0.01.– The second trial2, in 1998 (n = 327) reported superioroverall pain response rates at 4 weeks for 8 Gy (74%)compared to 4 Gy (47%) p = 0.000049.and for 6 Gy (65%) compared to 4 Gy (p = 0.0075), butnot for 8 Gy compared to 6 Gy (p = 0.16)– The third trial3, in 2002 (n = 42) reported a non-superiorassessable patient pain response rate within 60 daysfor 8 Gy (76%) compared to 5 Gy (72%) p > 0.051. Hoskin PJ et.al. 2. Jeremic B et.al. 3. Altundag MB et.al. 5Gy vs 8 Gy vs 30Gy/10#
Results• Toxicities inconsistently reported asintention-to-treat and assessable patient figures.• For two 4 Gy arms the intention-to-treat rateswere 20% and 42% up to 8 weeks post-treatment.• For the only 5 Gy arm, the assessable patientrate was 14%• For the only 6 Gy arm the intention-to-treat ratewas 44% up to 8 weeks post-treatment.
Results• For the 8 Gy arms intention-to-treat ratesranged from 9% to 38%.• For the only 4 Gy arm the intention-to-treatrate was 0% up to 8 weeks and 4%beyond 8 weeks.• The most commonly reported of theseother toxicities were nausea, vomiting, anddiarrhoea. The grading systems wereheterogeneous.
Discussion• This is the first systematic review to focus on therelative efficacy of different doses of SFconventional external beam radiation therapy forthe relief of pain due to bone metastasis.• 84% of all patients analysed had received thesame 8 Gy dose.• One could hypothesise that 8 Gy is required toachieve a certain threshold of tumour cell kill thatultimately translates into an ‘optimal’ painresponse as measured in these trials.
Discussion• Lower than 8 Gy doses may not achieve thisthreshold and higher cumulative doses may notprovide additional benefit.• This seems plausible, however the relationshipbetween tumour cell kill and pain response is notclear, nor are the exact mechanisms throughwhich bone metastases produce pain^.• The cumulative toxicity data show it to be a safedose to administer, and a retreatment rate ofapproximately 20% seems stable.Zaikova O, Fossa SD, Kongsgaard U, Kvaloy S, Giercksky KE, Skjeldal S. Painafter palliative radiotherapy for spine metastases. Clin Oncol (R Coll Radiol)2010;22:828–36.
Conclusion• 8 Gy was by far the most commonlyadministered SF dose within 24 randomisedtrials.• This dose should be the standard against whichfuture treatments are compared due to itsreproducible pain response and retreatmentrates, and its safe profile.• Whether 8 Gy is the optimal SF dose for therelief of pain is an open question, but data fromthe trials that directly compared different SFdoses show that it is superior to 4 Gy.