Ansökningsformulär FoU-medel för år 2008

Transkript

1 FoU-centrum Namn: Sara Salminen / Louise Olsson Ansökningsformulär FoU-medel för år 2008 Projekttitel: Early detection of colorectal cancer recurrences and plasma APC mutations Sammanfattning av sökt forskningsprojekt: (max 1500 tecken) På bara några få år har synen på uppföljning efter radikaloperation av kolorektal cancer genomgått en stor förändring. Anledningen är en snabb utveckling inom leverkirurgin med nu goda möjligheter att framgångsrikt behandla levermetastaser. Det har inneburit att det idag råder konsensus om att det lönar sig att hitta fjärrmetastaser i ett så tidigt skede som möjligt. Stora internationella studier genomförs i syfte att hitta optimal uppföljningsregim med CT buk / thorax. Efterfrågan på radiologiska resurser för att screena för metastasering postoperativt kan därför förväntas öka i framtiden. Föreliggande pilotstudie syftar till att utvärdera muterat APC i plasma som en lovande markör både vad gäller sensitivitet och specificitet för generalisering av kolorektal cancer. Möjligheterna till selektion av patienter inför CT-undersökning under en postoperativ tvåårsperiod efter en frekvent sjukdom som kolorektal cancer torde innebära avsevärd klinisk nytta, vilket gör att studien är angelägen. Studien inkluderar patienter som genomgått radikaloperation av kolorektal cancer vid Mälarsjukhuset och som inte har tecken till spridning initialt. Plasmaprover för analys av APC var tredje månad kommer att jämföras med utfallet av CT buk thorax var sjätte månad (golden standard). Studien planeras fortgå till tio patienter utvecklat (CT-verifierade) metastaser under pågående studie. Materialinsamlingen beräknas vara klar under Bakgrund: Follow-up of patients after curative resection for colorectal cancer has long been a controversial issue. Clinical practice is known to vary widely (1). The benefit of systematic postoperative surveillance has been inconclusive in several randomised studies (2-6). However, recent meta-analyses of these studies have indicated that intensive postoperative follow-up is associated with a reduction in all cause mortality (7, 8). Absolute mortality reduction has been estimated to 9-13 %, which compares favourably with for instance clinically well established adjuvant chemotherapy among patients with cancer Dukes C. Up-dated guidelines now support intensive follow-up using CT and frequent measuring of CEA for the detection of extramural recurrences in order to enhance the chances of curative intent resections (9-11). Intramural recurrences seem to have little impact on mortality (8). At least two larger studies have been initiated with the purpose of identifying an optimal regime for postoperative follow-up (12, 13). Surgery for recurrence of colorectal cancer, mainly hepatic but also pulmonary, peritoneal and local recurrence operative technique has improved substantially lately. 5-year survival among patients operated upon Kungsgatan Eskilstuna Tfn: Fax: fou-centrum@dll.se ORG NR Y:\Ledningsstab\Enheter\\Enheten för FoU\Sektioner\Sektionen för opererande spec\fou-projekt\2008\salminen SID 1(1) Sara\Ansökningsformulär omgång I FoU okt 2007 (2).doc Utskriftsdatum: 14:01

2 with a curative intent due to these recurrences is now reported up to about 40 % (14-17). Available randomised studies evaluating follow-up of colorectal cancer (2-6) are predating this improvement. Likewise, the initiation of chemotherapy earlier in the metastatic stage, before the onset of symptoms has been shown to cause a survival benefit (18). Carcinoembryonic antigen (CEA), first decribed in 1965 (19), is the most widely used colorectal cancer marker. However, there are no conclusive data concerning the value of CEA surveillance and a definite survival advantage (20). Accuracy for detecting recurrences depends largely on the chosen cutoff level for CEA. Sensitivity is reported from 34 % (21) to 91 % (22), with the highest sensitivity for low abnormal cutoff and frequent monitoring. Sensitivity of CEA is found to depend on site of recurrence with the highest values for liver metastases reported to % and lower for local recurrence (21, 23). The preoperative level of CEA is recognised to be of definite prognostic importance (24), for primary cancers (25) and also for hepatic metastases (26). Failure to normalize a preoperatively elevated level of CEA within weeks from surgery is considered highly suspicious for a generalization of the disease (27). Just recently a new method for the determination of APC mutations in plasma of patients with colorectal tumours was elaborated (28). Interestingly, both the number of APC gene fragments per ml plasma and the percentage of mutant fragments were higher in patients with distant metastases compared to localised cancer. Possibly these mutant DNA fragments are derived from necrotic neoplastic cells, engulfed by macrophages and then released into the circulation. Possibly this mechanism and the recently developed technology could be used for detecting patients developing a generalised disease. Syfte och problemställningar: The principal aim of this study is investigating whether mutated APC in plasma could be used to indicate recurrences of colorectal cancer, compared with CT and plasma CEA. Hypotheses High levels of mutant papc indicate recurrence of colorectal cancer, possible to detect by CT. Low levels of mutant papc (below a certain cut-off level) indicate no recurrence of the disease compared to CT. Material och metod: Patients SID 2(2)

3 All patients admitted to the Colorectal unit at the Department of Surgery and Urology at Mälarsjukhuset, Eskilstuna for planned surgery of colorectal cancer from January 2007 will be asked to participate in the study. The inclusion of patients will continue until there are ten patients with a diagnosed recurrence and all scheduled plasma samples collected and all scheduled CT scans performed. Sample collection A preoperative plasma sample will be collected from all patients accepting the study on the evening before surgery. A postoperative sample will be collected at the regular out-patient consultation one month after the operation. Patients who by their principle surgeon have been considered eligible for surgery of distant metastases and with a pathology report confirming a microscopically radical operation for colorectal cancer Dukes B or C will be considered for further participation in the study. These patients, identified before the one-month visit, will be asked to have a plasma sample collected every third month during two years. These patients should also be willing to have a CT scan of their abdomen and thorax every six month. For every APC plasma sample, a CEA measurement will also be analyzed. Tidsplan: Materialinsamlingen beräknas vara klar till hösten Status studien Inklusionstakten har varit helt enligt den förväntade. F n återkommer 11 patienter regelbundet för plasmaprov och CT. Många patienter har visat sig ha fjärrmetastasering redan vid diagnos och några har också avlidit av andra orsaker under pågående studie. All logistik sköts oklanderligt av leg ssk Sara Salminen och studien rullar på helt enligt planerna. Kostnadskalkyl: CT och CEA prov ingår i sedvanlig uppföljning vid kliniken för kirurgi och urologi, MSE och bekostas därifrån. Analys av APC kommer att göras vid Kimmel Cancer Center, Baltimore och bekostas där. Logistiken för insamlandet av prover är tidskrävande varför medel ansökts för forskningssköterska 10 % Ansöker om kronor för transport av nedfrysta prover till laboratoriet i Baltimore. Etisk bedömning: Studien godkänd av etisk kommitté Stockholm 2006/ /2 Betydelse: Om ett plasmaprov visar sig kunna minska behovet av screening med CT direkt bland patienter primärt radikalopererade för kolorektal cancer i syfte att påvisa tidig fjärrmetastasering är den kliniska nyttan av studien avsevärd. Referenser: SID 3(3)

4 1. Mella J, Datta SN, Biffin A, Radcliffe AG, Steele RJ, Stamatakis JD. Surgeons' follow-up practice after resection of colorectal cancer. Ann R Coll Surg Engl 1997;79(3): Kjeldsen BJ, Kronborg O, Fenger C, Jorgensen OD. A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997;84(5): Makela JT, Laitinen SO, Kairaluoma MI. Five-year follow-up after radical surgery for colorectal cancer. Results of a prospective randomized trial. Arch Surg 1995;130(10): Ohlsson B, Breland U, Ekberg H, Graffner H, Tranberg KG. Follow-up after curative surgery for colorectal carcinoma. Randomized comparison with no follow-up. Dis Colon Rectum 1995;38(6): Pietra N, Sarli L, Costi R, Ouchemi C, Grattarola M, Peracchia A. Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 1998;41(9): Schoemaker D, Black R, Giles L, Toouli J. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998;114(1): Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2002(1):CD Renehan AG, Egger M, Saunders MP, O'Dwyer ST. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. Bmj 2002;324(7341): Anthony T, Simmang C, Hyman N, Buie D, Kim D, Cataldo P, et al. Practice parameters for the surveillance and follow-up of patients with colon and rectal cancer. Dis Colon Rectum 2004;47(6): Desch CE, Benson AB, 3rd, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005;23(33): Figueredo A, Rumble RB, Maroun J, Earle CC, Cummings B, McLeod R, et al. Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer 2003;3: Assessment of frequency of surveillance after curative resection in patients with stage II and III colorectal cancer; COLOFOL study. In; Grossmann EM, Johnson FE, Virgo KS, Longo WE, Fossati R. Follow-up of colorectal cancer patients after resection with curative intent-the GILDA trial. Surg Oncol 2004;13(2-3): Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, et al. Trends in long- SID 4(4)

5 term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235(6): Hahnloser D, Nelson H, Gunderson LL, Hassan I, Haddock MG, O'Connell MJ, et al. Curative potential of multimodality therapy for locally recurrent rectal cancer. Ann Surg 2003;237(4): Inoue M, Ohta M, Iuchi K, Matsumura A, Ideguchi K, Yasumitsu T, et al. Benefits of surgery for patients with pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 2004;78(1): Sugarbaker PH. A curative approach to peritoneal carcinomatosis from colorectal cancer. Semin Oncol 2005;32(6 Suppl 9):S Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and metaanalysis. Colorectal Cancer Collaborative Group. Bmj 2000;321(7260): Gold P, Freedman SO. Demonstration Of Tumor-Specific Antigens In Human Colonic Carcinomata By Immunological Tolerance And Absorption Techniques. J Exp Med 1965;121: Fakih MG, Padmanabhan A. CEA monitoring in colorectal cancer. What you should know. Oncology (Williston Park) 2006;20(6):579-87; discussion 588, 594, 596 passim. 21. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen C. An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. Jama 1993;270(8): Minton JP, Hoehn JL, Gerber DM, Horsley JS, Connolly DP, Salwan F, et al. Results of a 400-patient carcinoembryonic antigen second-look colorectal cancer study. Cancer 1985;55(6): McCall JL, Black RB, Rich CA, Harvey JR, Baker RA, Watts JM, et al. The value of serum carcinoembryonic antigen in predicting recurrent disease following curative resection of colorectal cancer. Dis Colon Rectum 1994;37(9): Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement Arch Pathol Lab Med 2000;124(7): Harrison LE, Guillem JG, Paty P, Cohen AM. Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg 1997;185(1): Adam R, Pascal G, Azoulay D, Tanaka K, Castaing D, Bismuth H. Liver resection for colorectal metastases: the third hepatectomy. Ann Surg 2003;238(6):871-83; discussion Arnaud JP, Koehl C, Adloff M. Carcinoembryonic antigen (CEA) in diagnosis and prognosis of colorectal carcinoma. Dis Colon Rectum 1980;23(3): SID 5(5)

6 28. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A 2005;102(45): Uppgifter om sökanden kortfattad meritförteckning: Bifogade bilagor: De ifyllda anmälnings- och ansökningsblanketterna, tillsammans med övriga handlingar skickade som bifogade bilagor, måste vara FoU-centrum tillhanda som senast den 19 oktober 2007, under adress: Fou-centrum@dll.se SID 6(6)