Intensive follow up after primary. PRO: Pierfranco Conte

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1 Intensive follow up after primary curative therapy PRO: Pierfranco Conte

2 Follow up : Guidelines Mammography PE BSE Intensive Follow-up BMD (DEXA) Gynecologic examination AIOM 1 (2012) yearly Q 3/6 m for 5y then yearly not reported Not recommended If clinically indicated If clinically indicated ESMO 2 (2011) yearly Not specified not specified Not recommended Not specified Not specified NCCN 3 (2012) yearly Q 4/6 mesi for 5y then yearly not specified Not recommended After OFS and with AI Yearly while on tamoxifen ASCO 4 (2006) yearly Q 3/6 m y1-3 Q 6/12 m y 4-5 Q yearly >5 y monthly Not recommended not specified If clinically indicated Canadian No evidence No evidence not specified Not not specified Not specified Task Force 5 supporting supporting clinical recommended (1999) clinical practice practice 1. Linee guida neoplasie della mammella, AIOM Aebi et al. Ann Oncol 2011: vi12-v NCCN Breast Cancer Guidelines v ; nccn.org 4. Khatcheressian et al. J Clin Oncol 2006: Temple L.K.F. et al. CMAJ 1999:

3 Intensive follow up: Pro Mission impossible? RCTs and guidelines I can only raise my from major oncology societies i recommend AGAINST an intensive follow-up my opponent has been the PI of one pivotal trial on follow up... but. let have a closer look

4 Intensive follow up A closer look Do doctors follow these guidelines? Is available evidence good enough? Are breast cancers all the same? Are curative therapies available? Do we need more information on patient outcome and treatment related toxicities?

5 Surveillance of patients with Breast Cancer from ASCO members Modality Year 1 Year2 Year 3 Year 4 Year 5 Mean SD Mean SD Mean SD Mean SD Mean SD Office Visit CBC Liver function test Ca CEA Mammogram Ultrasonography Breast MRI CT chest CT abdomen Bone scan PET scan Margenthaler JA, et al. J Oncol Pract 2012;8:79 83

6 CIPOMO survey on follow up after curative treatment for breast cancer Tipo di follow-up Linee guida + personalizzato 4,8% Linee guida 33,9% Study coordinators: L Manzione, S Cinieri Di minima 3,2% Intensivo 22,6% Cadenza Annuale Personalizzato 35,5% 0,0% 10,0% 20,0% 30,0% Ecografia Pelvica 65,4% Fonte: Ns elaborazione % dei Casi Marker tumorali ed esami ematochimici i i 92,5% Visita ginecologica 81,1% Ecocardiogramma 47,2% Mammografia 100,0% Visita clinica 100,0% 0,0% 25,0% 50,0% 75,0% 100,0% Fonte: Ns elaborazione % Casi

7 Intensive follow up A closer look Many physicians advise a more intensive follow up Is available evidence good enough? Are breast cancers all the same? Are curative therapies available? Do we need more information on patient outcome and treatment related toxicities?

8 Clinical vs intensive follow up. Overall Mortality at 5 years

9 RCTs on follow up and expected benefit Primary End Point: Overall Survival Sample size in the 2 studies: 2563 # events observed at 5 yrs: patients with 500 events can detect a HR of 0.75 (α = 0.05, β 0.80) Taxanes, new antimetabolites, eribulin, AIs, BPS, Taxanes, new antimetabolites, eribulin, AIs, BPS, trastuzumab and bevacizumab were not available when the two studies were conducted

10 Intensive follow up A closer look Many physicians advise a more intensive follow up The evidence is suboptimal but this is the best we have Are breast cancers all the same? Are curative therapies available? Do we need more information on patient outcome and treatment related toxicities?

11 Annual hazard of recurrence and baseline prognostic factors All patients Node 0 Node (+4) Tumour size <1 cm Tumour size >3 cm 0.2 ER+ (n = 2257) ER- (n = 1305) ,5 1,5 2,5 3,5 4,5 5,5 6,5 7,5 8,5 9,5 10, Years HER2 + Saphner T. J Clin Oncol 1996; Romond EH, ASCO 2005

12 Many Breast Cancer Diseases HR % All Breast Cancers HER % TN 15%

13 METABRIC: Outcome of breast cancer clusters Curtis C et al, Nature 2012

14 Intensive follow up A closer look Many physicians advise a more intensive follow up The evidence is suboptimal but this is the best we have Breast cancers subtypes have different annual rates and different sites of relapse Are curative therapies available? Do we need more information on patient outcome and treatment relatedrelated toxicities?

15 Why should we spend time on follow up if..site and extent of metastatic spread are not relevant for prognosis...metastatic breast cancer is always an incurable disease...aims of treatment are the same irrespectively of patient conditions, tumor biology and site of metastases..no survival benefit can be obtained in metastatic disease, whatever the treatment..the only meaningful endpoint is quality of life..

16 Treatments that induce a survival prolongation in mbc Docetaxel 1,2 Vinorelbine 3 FAC 4 Doxorubicin + paclitaxel 5 Doxorubicin + docetaxel 6 Docetaxel + capecitabine 7 Paclitaxel + gemcitabine 8 Eribulin 9 Chemotherapy + trastuzumab 10,11 Docetaxel + trastuzumab + pertuzumab 12 TDM-1 13 Anastrozole + fulvestrant Jones et al. J Clin Oncol 2005;23: ; 2. Nabholtz et al. J Clin Oncol 1999; 17: ; 3. Jones et al. J Clin Oncol 1995; 13: ; 4. Stewart et al. J Clin Oncol 1997; 15: ; 5. Jassem et al. J Clin Oncol 2001; 19: ; 6. Bontenbal et al. J Clin Oncol 2005;23:7081-8; 7. O Shaughnessy et al. J Clin Oncol 2002; 20: ; 8. Albain et al. J Clin Oncol 2008; 26:3950-7; 9. Cortes J et al. Lancet 2011; 377:914-23; 10. Slamon et al. NEJM 2001; 344:783-92; 11. Marty et al. J Clin Oncol 2005;23: ; 12. Baselga J et al. NEJM 2012; 366: ; 13. Verma S et al. NEJM 2012 (ahead of print); 14. Mehta R et al. NEJM 2012; 367:

17 Metastatic Breast Cancer 5-10% with metastatic disease at diagnosis 15-30% will develop metastases despite adjuvant treatment 5-12% with oligometastatic disease Solitary or few metastatic lesions usually limited to a single organ Systemic therapies -Hormone Therapy -Chemotherapy -Targeted therapies Loco-regional treatments -Surgical resection -Radiofrequency -Chemo-embolization -Laser ablation -Stereotactic radiotherapy -IMRT POTENTIALLY CURATIVE INTENT

18 Early Detection of Isolated Breast Recurrences and Survival: A Meta analysis Log [Hazard Ratio] Hazard ratio (fixed) Hazard ratio (fixed) Sample Studies (SE) 95% CI 95% CI size Ciatto S (0.7301) 2.04 (0.49, 8.54) 339 Kaas R (0.4461) 3.03 (1.26, 7.27) 275 Te Boekhorst S (0.1354) 1.66 (1.27, 2.16) 270 Voogd AC (0.2741) 2.09 (1.22, 3.57) 266 Tomin R (0.1439) 1.60 (1.21, 2.12) 248 Perrone MA (0.1549) 1.67 (1.23, 2.26) 221 Kindler M (0.1696) 1.27 (0.91, 1.76) 175 Stierer M (0.3504) 1.77 (0.89, 3.52) 133 Doyle T (0.5172) 2.65 (0.96, 7.30) 112 Orel SG (0.7082) 2.15 (0.54, 8.62) 72 Imoto S (0.3556) 1.29 (0.64, 2.58) 65 Wagman LD (0.2879) 2.15 (1.22, 3.78) 64 Hussain ST (0.7454) 9.54 (2.21, 41.13) 33 Total (95% CI) 1.68 (1.48, 1.91) Test for heterogeneity: Chi square = 13.02, df = 12 (P = 0.37) Test for overall effect: Z = 7.93 (P < ) Late detected Early detected Lu et al. Breast Cancer Res Treat 2008

19 Intensive follow up A closer look Many physicians advise a more intensive follow up The evidence is suboptimal but this is the best we have Breast cancers subtypes have different annual rates and different sites of relapse Systemic therapies prolong survival and locoregional treatments can be curative for selected patients Do we need more information on patient outcome and treatment related toxicities?

20 Intensive follow up: still something to learn? HER2+ and TN breast cancers relapse frequently in CNS and early detection allows for more conservative and more efficacious therapies Tumor characteristics may change from primary tumor to metastatic sites and this can have prognostic implications ONJ was unknown before the use of BPS and probably would still be unknown if had to be recognized by dentists Cardiac effects of antiher2 therapies were unpredictable oncologists working with cardiologists have learned to recognize, prevent and manage this toxicity And you can go on fertility, cognitive functions, second primaries and all the issues related to cancer survivorship

21 Intensive follow up after curative treatment for EBC YES NO is intensive FUp evidence-based? are guidelines consistent? in the absence of evidence, are the biological and financial costs of intensive FUp justified? is breast cancer an heterogeneous group of diseases with different biological and clinical characteristics? can available therapies alter the course of mbc? can «unexpected» toxicities of new therapies be recognised because of oncology expertise?

22 Intensive follow up after curative treatment for EBC A perspective from a clinician: «followup of long term survivors is both heartening and educational and remains an essential aspect of being a medical oncologist» by Mayer EL, JCO 2012 A perspective p from a clinical investigator: Heterogeneity of breast cancers, sensitivity and accuracy of new diagnostic tools, availability of effective systemic and loco regional therapies.. a lot of good reasons to RE THINK FUp! (this is a conditional PRO for follow up)