ΟΣΤΙΚΕΣ ΜΕΤΑΣΤΑΣΕΙΣ ΚΑΙ ΑΚΘ

Transcription

1 ΟΣΤΙΚΕΣ ΜΕΤΑΣΤΑΣΕΙΣ ΚΑΙ ΑΚΘ Dr. V. Kouloulias MSc, MD, PhD, PhD Αναπληρωτής Καθηγητής Ακτινοθεραπευτικής Ογκολογίας Εθνικό Καποδιστριακό Πανεπιστήµιο Αθηνών Β Εργαστήριο Ακτινολογίας Μονάδα ΑΚΘ

2 ΟΣΤΙΚΕΣ ΜΕΤΑΣΤΑΣΕΙΣ Advanced stage breast cancer (70-80%). Prostate cancer (70-80%). Lung Cancer (10-50%). Berman et al., Clin Breast Cancer 2013 Coleman et al., Cancer Treat Rev 2001 Kuchuk et al., J Bone Oncol 2013 Ø Negative impact on survival Coleman et al., Oncology 2016, LeVasseur et al., Cancer Treat Rev 2016 Ø Multidisciplinary approach for palliation, QoL and survival Temel et al., N Engl J Med 2010, Ferrell et al., J Clin Oncol 2017

3 ΑΚΘ και ΟΣΤΙΚΕΣ ΜΕΤΑΣΤΑΣΕΙΣ External beam of RT (EBRT) is effective and safe producing significant palliation and pain relief. Chow et al., J Clin Oncol 2007 Pain relief after EBRT ranges 50-80% while 1/3 of the patients have complete response in terms of pain.. Lutz et al., Int J Radiat Oncol Biol Phys 2011 A huge number of prospective and retrospective studies reports on the optimum schedule for EBRT. Fairchild et al., Int J Radiat Oncol Biol Phys 2009

4 ΔΙΑΦΟΡΕΤΙΚΑ ΣΧΗΜΑΤΑ ΑΚΘ Study (year) Price et al. [17] (1986) Country/ institute UK Study Protocol Arm A: 8 Gy Arm B: 30 Gy Total No of patients No of patients in each arm (arm A vs arm B) vs 144 Schedule of follow up Patient records pain in diary at same time daily for 4 weeks then once weekly Partial pain response (arm A vs arm B) Complete pain response (arm A vs arm B) Overall pain response (arm A vs arm B) NR NR NR Gaze et al [29] (1997) Nielsen et al.[23] (1998) Edinburgh /UK UK and Denmark Arm A: 22.5 Gy/5 Arm B: 10 Gy/1fr 245 Arm A: 8 Gy /1fr Arm B: 20 Gy/ 5fr 131 vs vs week, 3-4 weeks after completion of treatment and 2-monthly thereafter. 56,6% vs 57.7% 38.8% vs 42.3% 83,7% vs 89.2% 4, 8, 12 and 20 weeks after the beginning of treatment NR NR 4 weeks: 49% vs 55% 8 weeks: 53% vs 65% 12 weeks: 60% vs 60% 20 weeks: 62% vs 71% Koswig et al.[18] (1999) Germany Arm A: 8 Gy /1fr Arm B: 30 Gy /10 fr 107 NR Day after EBRT, 6 weeks, 3 and 6 months after radiotherapy. NR 33% vs 31% 81% vs 78% Bone Pain Trial Working Party [24] (1999) UK and New Zealand Arm A: 8 Gy /1fr Arm B: 20 Gy /5 fr vs weeks and at 1,2,3,4,5,6,8,10 and 12 months after the start of treatment NR 57% vs 58% 78% vs 78% Steenland at al.[26] (1999) Steenland -Dutch Bone Metastasis Study (1999) Arm A: 8 Gy /1fr Arm B: 24 Gy /6 fr vs 578 Every week up to 3 months and every 4 weeks up to 2 years NR 37% vs 33% 72% vs 69% Roos et al.[25] (2005) Hartsell et al.[19] (2005) Australia, New Zealand and UK USA Arm A: 8 Gy /1fr Arm B: 20 Gy /5 fr Arm A: 8 Gy /1fr Arm B: 30 Gy /10 fr vs vs 443 At 2 and 4 weeks after commencement of treatment, then at 2 months, 3 months, and 3 monthly thereafter until treatment failure or death, At 2 and 4 weeks and at 2, 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months NR 26% vs 27% 53% vs 61% 50% vs 48% 15% vs 18% 66% Kaasa et al. [20] (2006) Norway and Sweden Arm A: 8 Gy /1fr Arm B: 30 Gy /10 fr vs 190 At 4, 8, 12, 20 and 28 weeks NR NR NR (8 Gy compared to multiple-fraction radiotherapy provides the same degree of pain relief) Arnalot Foro et al.[21] (2008) Spain Arm A: 8 Gy /1fr Arm B: 30 Gy /10 fr vs 82 At 3,12,24 and 48 weeks 3 weeks: 60% vs73% 3months: 52% vs 51% 3 weeks 15% vs13% 3 months 13% vs11% 3 weeks 75% vs 86% 3 months 65% vs 62% Gutiérrez Bayard L et al.[22] (2014) Spain Arm A: 8 Gy /1fr Arm B: 30 Gy /10 fr vs 45 At 15, 30, 60, 90 days of treatment completion, 6 months to a year 4 weeks:62% vs 70% 3 months: 53% vs 59% 4 weeks: 17% vs 18% 3 months: 13% vs 15% 4 weeks: 79% vs 88% 3 months: 66% vs 74%

5 Meta-analysis in 25 randomized trials Non significant difference between single or multi fractionated EBRT 60-61% of complete pain relief

6 ΕΦΑΠΑΞ ΑΚΘ 26 trials, 4 Gy, 5 Gy, 6 Gy, 8 Gy, 10 Gy and 8-15 Gy. Ø Ø 8 Gy is safe (gold standard at present time) Best dose not yet confirmed. Dennis et al., Radiotherapy and Oncology 2013 Randomized trial Phase III (IAEA) 4 Gy versus 8 Gy : Ø Significant improvement in the group with 8 Gy Hoskin et al., Radiother Oncol 2015

7 17 clinical trials 7 different schedules: 20 Gy/2 fr, 20 Gy/5 fr, 20 Gy/10 fr, 22.5 Gy/5 fr, 24 Gy/6 fr, 30 Gy/10 fr, 30 Gy/15 fr. Response: no difference Toxicity: no difference

8 Stereotactic Body Radiotherapy, SBRT Oligometastatic disease Two systems for categorization: v A recursive partitioning analysis (RPA) Chao et al., Int J Radiat Oncol Biol Phys 2012 v PRISM prognostic scoring system Tang et al., Int J Radiat Oncol Biol Phys 2015 NOMS: instrument for optimum therapeutic approach of bone metastases in the spinal cord. Laufer et al., Oncologist 2013

9 ΜΕΛΕΤΕΣ SBRT Study Primary cancer site SBRT Schedule No of patients/ No of lesions treated Median follow-up time (months) Tumour control Pain relief Toxicity Ryu et al. [52] (2014) RTOG 0631 phase III component Various primary malignancies 16 Gy/1fr 44/44 NR NR NR There were no grade 4 toxicity Deodato et al.[50] (2014) Various solid tumours Dose range Gy, median dose 18 Gy 65/ % at 12 months and 71.9% at 24 months NR Acute toxicity 32.3%, no grade 3-4 toxicities Owen et al.[53] (2014) Various solid tumours Dose range: 15 Gy/1 fr to 50 Gy/5 fr Most common schedules: 18 Gy/1 fr, 24 Gy/1 fr, and 30 Gy/3 fr 74/ st year: 91.8% 88% overall pain relief ( referred to symptomatic patients) There were no grade 3 or 4 acute toxicities. There were no grade 3 or 4 late toxicities. Wang et al.[49] (2012) Garg et al.[51] (2012) Various solid tumours Various solid tumours Gy/ 3fr 149/ st year: 80.5% 2nd year:72.4%, complete pain relief 6th month 53.9% No grade 4 toxicities, no radiation-related spinal cord myelopathy during the study Gy/ 1fr 61/ months: 88% NR 2 patients experience grade >3 neurologic toxicities Kamran et al. [48] (2011) Various solid tumours median dose of 24 Gy (range, Gy) in a median of three fractions (range, 1-5) 66/85 NR 1 year was 83.3% and 91.2% in patients with and without prior RT NR No grage 4 toxicities. Nguyen et al.[47] (2009) Renal cancer 30 Gy/5fr or 27 Gy/3fr or 24 Gy/1fr 48/ st year:82.1% complete pain relief 1st month 44% 12th month 52% No grade 4 toxicities, no myelopathy Chang et al. [46](2007) Various solid tumours 30 Gy/5fr or 27 Gy/3fr or 27 Gy/3fr 63/ year :84% No grade 4 acute toxicity, no grade 3-4 late toxicity

10 ΕΠΑΝΑΚΤΙΝΟΒΟΛΗΣΗ 30-40% of the patients will not be improved. Chow et al., Clin Oncol (R CollRadiol) categories of patients: 1. No benefit at first. 2. Partial response. 3. Pain recurrence after partial or complete response. Chow et al., Radiother Oncol 2002

11 58% of the patients will have an improvement from re-iradiation Time of responce: 3-5 weeks Duration of Response: weeks Recent systematic analysis in 25 trials: CR 20%, PR 50% In non-responding patients ABLATION might be the choice Wong et al., Radiotherapy and Oncology 2014

12 Biphosphonates and RT Study (year) Primary tumour Bisphosphonate regimen and protocol of administration Radiotherapy schedule No of patients Pain response rates Toxicity rates Kouloulias et al.[54] (2002) Breast 180 mg of pamidronate, every 4 weeks, for a period of 6months 30 Gy / 10 fr 18 OR: 100% CR: 77% PR: 23% 39% reported grade 1-2. There were no grade 3 or 4 Kouloulias et al. [55] (2003) Kouloulias et al.[56] (2003) Various tumours Arm A: mg pamidronate in a stepwise increase. Arm B: 180 mg of pamidronate Arm C: did not receive Breast 180 mg pamidronate every 4 weeks All arms received: 30 Gy / 10 fr 42 OR: 100% Arm A: 23% Arm B: 75% Arm C: NR 30 Gy / 10 fr 33 OR: 100% CR: 88% PR: 12% 39% mild toxicity Vassiliou et al. [57] (2007) Various tumours 6 mg ibandronate every 4 weeks, for a period of 10 months Range : Gy over weeks. 45 OR: 100% at 3 months OR: 85% at 6 months 13% Manas et al.[58] (2008) Various tumours 4 mg of zoledronic acid, every 4-5 weeks Arm A: 8 Gy / 1 fr Arm B: 6 Gy/ 1 fr 139 OR : 100% Not significant difference between arms Arm A: 22% Arm B: 14% Atahan et al.[59] (2009) Zaghoul et al.[60] (2010) Choudhury et al.[62] (2011) Gierloff et al.[61] (2015) Breast 4mg zoledronic acid, every 4 weeks Urinary bladder Various tumours Various tumours One week after the EBRT randomised between 4 mg zoledronic acid and placebo Randomised Arm A: 4 mg zoledronic acid Arm B: 6 mg ibandronate Arm C: 90 mg pamidronate All regimen every 3-4 weeks Randomised Arm A: 4 mg zoledronic acid after the first cycle of EBRT Arm B: 4 mg zoledronic acid in the morning before the start of the radiotherapy Arm A: 30 Gy/ 10fr Arm B: 15 Gy/ 5fr Arm A: 13 Gy/ 2 fr Arm B: 20 Gy/ 5 fr 8 Gy/ 1 fr or 20 Gy/ 5 fr Total dose range Gy in 2-3 Gy daily dose 100 Arm A vs B at 1 month: OR: 83.9% vs 80.4% CR: 30.7%vs 26.8% Arm A vs B at 3 months: OR: 94.5% vs 92.2% CR: 69.9%vs 46.7% 19/ 100 had mild toxicity 40 NR Similar toxicity rates between zoledronic acid and placebo acute and late 256/187 for final analysis Arm A vs B vs C at 3 months CR: 46.6% vs 42.2% vs 40% PR: 37.9% vs 31.3% vs 26.7% Arm A vs B vs C at 6 months CR: 17.6% vs 7.4% vs 18% PR: 9.8% vs 7.4% vs 10% No difference between the randomised arms. Only mild toxicity. 40 NR NR

13 Kouloulias et al. Acta Radiol. 2004;45: If n(i) is the number of pixels whose intensity is I and N is the total number of pixels in the region of interest, then the occurrence probability of intensity I is: P(I) = n(i) / N At eight-bit gray-level quantization, the resulting distribution takes the form of a first-order histogram with 256 bins, where each bin is one of the integer sample values I = 0,..., 255. Then the mean value of the gray-level histogram (MVGLH) is assessed as: 255! = I(PI) I=0 estimating the value around which central clustering occurs. Next, the energy of the gray-level histogram (EGLH) is assessed by: 255 energy = P(I) I=0

14 Kouloulias et al. Radiotherapy in conjunction with intravenous infusion of 180 mg of disodium pamidronate in management of osteolytic metastases from breast cancer: Clinical evaluation, biochemical markers, quality of life, and monitoring of recalcification using assessments of gray-level histogram in plain radiographs. Int. J. Radiat. Oncol. Biol. Phys. 2003;57: First-order statistics as an image processing technique for the evaluation of recalcification of bone lytic metastasis at the femur after radiotherapy. Mean value and energy (MVGLH, EGLH) at baseline (EGLH = 0.19, MVGLH = 155.1) and six months after initiation of multimodality treatment (EGLH = 0.17, MVGLH = 173.3). P(I) refers to the probability of intensity (I).

15 Increase of bone density after biphosphonates and RT More than 80% but not 100% of complete response and pain relief.

16 What else?

17 Analgesic effect of cementoplasty The analgesic benefit of cementoplasty in bone metastases is welldocumented in the medical literature as producing a reduction in pain in 80 to 97% of cases. This benefit is obtained irrespective of the bone site treated, whether vertebrae, long bones or flat bones Cementoplasty is also very effective for metastatic pain of the long and flat bones, producing a significant improvement in the pain in 91% of patients (the mean VAS/10 progressing from 8.7 to 1.9). This analgesic effect is obtained rapidly, generally between the first and third day following the procedure, permitting early postoperative mobilisation of patients and a short hospital stay (24 48 hours) Anselmetti. Semin Intervent Radiol, 27 (2) (2010) Alvarez et al. have shown that cementoplasty of a painful metastatic vertebra produced a significant reduction in pain in 81% of the patients treated (the mean of the VAS/10 progressing from 9.1 to 3.2) and the possibility of walking again in 77% of patients initially bedridden because of it. Eur Spine J, 12 (2003)

18 Cementoplasty of bone metastases Deschamps et al. Diagn Interv Imaging The role of cementoplasty compared with analgesic radiotherapy is still to be defined. It does indeed have a number of advantages its efficacy, the rapidity of its action, its action of consolidation, the possibility of treating areas already irradiated, and more and more oncologists are employing percutaneous techniques, and cementoplasty in particular, as a first course of action for managing bone metastases. This enables them firstly to keep radiotherapy in reserve for contraindications to local treatment

19 Interventional radiology and bone metastases Iannessi et al. Bull Cancer 2013 If the goal is pain relief, cementoplasty provides a very effective bone consolidation and pain control. Simple and low-risk, vertebroplasty is the technique of choice in case of lytic bone metastases with spinal fracture risk or after failure of analgesic radiotherapy. If the medical project is curative, the tumor ablation procedures are realised through thermic or embolic techniques. After 60 C, the heat induces a coagulative necrose. Under -20 C, the cold leads to destroy the tissues. The major advantage of the cryotherapy is the predictibility of the ablation zone due to the well-visualized ice ball on perprocedural images. This technique is much more adapted to spare the nervous structures closed to the metastasis.

20 Pelvic osteoplasty in osteolytic metastases: technical approach under fluoroscopic guidance and early clinical results. Kelekis A, et al. J Vasc Interv Radiol Methods: Twenty-three lytic metastases of the superior and inferior pubic rami and ischial tuberosities were treated in 14 consecutive patients. Percutaneous access of the bones was performed under fluoroscopy. All patients had pain refractory to radiation and narcotic therapy and were unsuitable candidates for surgery according to multidisciplinary consensus. RESULTS: Technical success was achieved in all cases. Clinically, effective pain relief was obtained in 92% of patients. One intraarticular asymptomatic minor complication and one major complication resulting from leakage near the pudendal nerve were observed. The latter was subsequently treated by radiofrequency ablation. CONCLUSION: Pelvic osteoplasty appears to be a safe and highly effective palliative therapy for painful osteolytic malignant bone metastases.

21 Something is missing!!!! RT produces 61% complete response in palliation. RT plus biphosphonates produces 70-80% complete response in palliation IR produces more than 80% of palliation Cementoplasty produces hyperthermia which has also a synergistic effect with radiotherapy!

22 ΤΟ ΜΕΛΛΟΝ: Συνδυασµός ΑΚΘ ογκολογίας και επεµβατικής ακτινολογίας

23 A new prospective trial is coming Finding the optimum sequence of irradiation and cementoplasty for painful bone metastases in an oligometastatic disease Primary endpoint: pain relief, QOL, bone reconstruction Secondary endpoint: survival Principal investigators: Kelekis A, Kouloulias V.

24 GUIDELINES???

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26 ΣΥΜΠΕΡΑΣΜΑΤΑ Η ΑΚΘ 'αρα!ένει η θερα'εία εκλογής στις οστικές!εταστάσεις. 4287!ελέτες το ε'ιβεβαιώνουν! 30 Gy σε 10 συνεδρίες, 24 Gy σε 6 συνεδρίες, 20 Gy σε 5 συνεδρίες, και 8 Gy εφά'αξ είναι ισοδύνα!α σχή!ατα ως 'ρος την ανακούφιση του άλγους α'ό τις οστικές!εταστάσεις. SBRT στο 'λαίσιο της ολιγο!εταστατικής νόσου και σε ασθενείς 'ου ανα!ένεται να έχουν 'ροσδόκι!ο ε'ιβίωσης. Ε'ανακτινοβόληση των οστικών!εταστάσεων είναι εφικτή!ε υψηλές τεχνικές και ασφαλής!ε SBRT αλλά 'ερί'ου το 40% των ασθενών!'ορεί να!ην ωφεληθούν. Η δράση των διφωσφονικων στην ακτινοθερα'εία των οστικών!εταστάσεων είναι 'ιστο'οιη!ένη Ακτινοθερα'εία!ετά α'ό χειρουργείο κατάγ!ατος ή σταθερο'οίησης της σ'ονδυλικής στήλης συνηθέστερο σχή!α 30 Gy σε 10 συνεδρίες. Ο συνδυασ!ός IR και AKΘ θα 'αίξει ση!αντικό ρόλο στο!έλλον. Χρειάζονται ό!ως 'ολλές ακό!α τυχιαιο'οιη!ένες!ελέτες!

27 IKARIA The Greek island with the best survival in Europe 100 years old 109 years old!