5MCR (Munich Cancer Register): Prognostic FactorsMCR (Munich Cancer Register):STAGE UICC: REMAINS THE MOST IMPORTANT PROGNOSTIC FACTOR EVEN WHEN CHECKED BY AGE, TYPE OF SURGERY AND ADJUVANT THERAPIESIMPORTANCE OF CLINICAL STAGINGINFLUENCES THERAPEUTIC DECISIONSKerr J et al, Ann Oncol, 16, 664, 2005.
7SELECTION OF PATIENTS FOR TREATMENT T3 tumors form a heterogeneous grouptumors that barely extend beyond the lamina muscularis propriaextend to or invade the mesorectal fascia5-year OSExtramural spread < 5mm %Extramural spread > 5 mm ,1%CONCLUSIONI(p = .0001)Merkel S, Mansmann U, Siassi M. et al. The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 2001;16:298 –304.
8SELECTION OF PATIENTS FOR TREATMENT Itermediate risk groupNeoplasm extending beyond the rectal wall = cT3-T4a or N1-2 M0WITHOUT urresctable infiltration to surroding organs (cT4b)CONCLUSIONIValentini V. The right study design is needed to find out wich patients benefit from preoparitive chemioradiotherapy for intermediate staged rectal cancer. Onkologie 2011; 34, 6-8.
9SELECTION OF PATIENTS FOR TREATMENT N + poor prognosis?as the nodal burden increases, the prognosis also became poorer correspondingly3,791 patients PORT5-year OST3 N %T3 N %T3 N %T3 N %T3 N ,4 %T3 N ,5 %CONCLUSIONIGunderson LL, Sargent DJ, Tepper JE et al. Impact of T and Nstage and treatment on survival and relapse in adjuvant rectal cancer:Apooled analysis.J Clin Oncol 2004;22:1785–1796.Gunderson LL, Jessup JM, Sargent DJ et al. Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J ClinOncol 2010;28:256 –263.
10SELECTION OF PATIENTS FOR TREATMENT Extramural venous invasion (EMVI) associated with:Local recurrenceLiver metatasesRelapse Free SurvivalLow-lying tumors requiring abd- perinealresection (APR) worse survival ratesthan patients with low anterior resection.local recurrence,cancer-specific survivalOSCONCLUSIONIDresen RC, Peters EE, Rutten HJ et al..Eur J Surg Oncol 2009;35: 1071–1077.Ouchi K, Sugawara T, Ono H et al.Cancer 1996;78:2313–2317.Smith NJ, Barbachano Y, Norman AR et al.Br J Surg 2008;95:229 –236den DM, Putter H, Collette L et al. The abdominoperineal resection itself is associated with an adverse outcome: The European experience based on a pooled analysis of five European randomised clinicaltrials on rectal cancer.Eur J Cancer 2009;45: 1175–1183.
11SELECTION OF PATIENTS FOR TREATMENT Histological evidence of tumor within 1 mm of the potential circumferential resection margin (CRM) strongly predictslocal recurrencepoor survivalTotal mesorectal excision (TME) is a standard surgical tecniqueThe plane of dissection is formed by the mesorectal fascia (encloses the fatty mesorectum)This fascia forms CRMNagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008;26:303–312.
12Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging CONCLUSIONIThe ability to accurately predict these risk factors preoperatively would allow stratification of patients to receive neoadjuvant therapy.
13MRI Can highlight the invasion of the MRF Can predict the potential CRMCan highlight the TRG (Tumor Regression Grade)Can distinguish between good and poor prognosis after neoadjuvant therapy andCan be related to the long-term results
14Stadio II-IIIMesorectal fascia involvement/potential circumferential resection marginsTreatment strategy is dependent on MRF involvement.CRM can be defined only postoperatively by the surgical plane.MRI is the method of choice for the prediction of positivity of MRFsMDCT seems to be equivalent to MRI only in tumours in the mid/high rectum.
15Mercury Study 2 important markers analyzed with preoperative MRI mrTRG (tumor regression grade with RMI)CRM (circumferential resection margin )predict survivalopportunity to a multidisciplinary team to provide a therapeutic option before surgery.ypT e CRM postoperatori e (non lo status di N) sono importanti per predire l’andamento dei pazienti
17The impact of CR after Neo-Adjuvant Therapy Local relapse
18The impact of CR after Neo-Adjuvant Therapy DISTANT METASTASES
19The impact of CR after Neo-Adjuvant Therapy OVERALL SURVIVAL
20The impact of CR after Neo-Adjuvant Therapy Disease Free Survival
21MODERATE-RISK DISEASE Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging
22MODERATE-RISK DISEASE Short-course RT (25 Gy/ 5 fractions 5-7 days Surgery)Long-course chemoradiotherapy CRT (45–54 Gy in 25–30 fractions with concomitant fluropyrimidine-based chemotherapy 5-6 week Surgery)
23Surgery alone versus preoperative Radiotherapy + Chemotherapy MODERATE-RISK DISEASESurgery alone versus preoperative Radiotherapy + Chemotherapy
24MODERATE-RISK DISEASE Phase III trials of short-course radiotherapy=
25MODERATE-RISK DISEASE Phase III trials of long-course radiotherapy with or without CT chemotherapy
26MODERATE-RISK DISEASE Short-course RT and Long-course chemoradiotherapy CRTBenefits in local control,but NOT IN OS(apart from the Swedish Cancer trial)Lack of impact on reducing distant recurrences?
27Local recurrence rates reduced in the CRT Arm Preoperative SCRT versus preoperative CRTPolish trial Local failure, DFS, or OS = NSAustralasian trial Local failure, DFS, or OS = NS (trend > LC in CRT)No difference in OS,DFS, LFPreoperative CRT versus postoperative CRT(CAO/ARO/AIO-94) German Rectal Study Group after 11 years of follow-up (T3 LR = 7.1% vs. 10.1% in thepre- and postoperative arms, respectively; p .048)Local recurrence rates reduced in the preoperative ArmNo difference in DFS or OS ratesPreoperative CRT versus preoperative RTEORTC 22921 5 ys LR 8.7% for preoperative CRT vs 17.1% for preoperative RT (p.002); OS = NS; Acute G 3-4 toxicity 13,9% preoperative CRT; 7.4% for preoperative RT (p.001)FFCD LR 8.1% for preoperative CRT; 16.5% forpreoperative RT (p .004); OS = NS; Acute G 3-4 toxicity:14,6 % preoperative CRT; 2.7% for preoperative RT (p.05)Local recurrence rates reduced in the CRT Arm
28MODERATE-RISK DISEASE Complications of RT e CRTAcute side effects and surgical complications only slightly increasedLong-term toxicity more problematic.fecal incontinence,bowel obstruction,sexual dysfunctionsecond cancer (compromise long-term survival) Dutch TME study: follow-up 12 years2° cancerRT+ TME = %TME = %
29Can we have confidence in the clinical staging? Stadio IIIt has been suggested that some patients withdisease at lower risk of local recurrence (eg, proximal rectal cancer staged as cT3, cN0, M0, characterized by clear margins and favorable prognostic features) may be adequately treated with surgery + adjuvant chemotherapy.Can we have confidence in the clinical staging?
30Stadio IIConclusionThe accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CH-RT and perhaps as many as 30% to 40%, when one accounts for the downstaging encountered with preoperative CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CH-RT.Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CH-RT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.188 pt RT-CT preop. 22% pN+
31Weakness of nodal staging by imaging? Is better a short course RT? Stadio IIWeakness of nodal staging by imaging?Is better a short course RT?
32MODERATE-RISK DISEASE What can we change?Capecitabine incorporated in CRT inclinical practicecomparing capecitabine with 5-FU-based CRTLancet Oncol 2012;13:579 –588. Trend toward improved survival in thecapecitabine arm, perhaps because of fewer distant metastases. > DFS in favor of capecitabineJ Clin Oncol 2011;29:3503. No significant difference in (pCR) rate between capecitabine and 5-FU with or without oxaliplatin.Increase Tumor downstaging with SCRTSCRT followed by a delay of 6–8 weeks may allow tumor downstaging and be a useful alternative to CRTPolish study randomized: 154patients 55 Gy preoperative SCRT followed by surgery either 7–10 days or 4–5 weeks after RT 5-year survival rates 63% and 73% for the immediate and delayed surgery groups, respectively (p .24). The longer time interval resulted in greater downstaging rate (44.2% vs. 13%) better survivalThe ongoing Stockholm III trial SCRT with immediate (1–10 days) or delayed (4 –7weeks) surgery
33MODERATE-RISK DISEASE What can we change?Neoadjuvant chemotherapySchrag et al, 2010exclude those with T4 or bulky disease (Schrag et al)avoid radiotherapy-associated toxicity6 cycles of neoadjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX) + bevacziumabstable or progressive disease after chemotherapy CRTSelective postoperative CRT in a positive CRMpCR rate of 27% (31 pt)GEMCAD 0801, 201288% radiological response,100% R0 resection15% pCRSchrag D, Weiser MR, Goodman KA et al. Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer. J Clin 2010;28:3511.Fernandez-Martos C, Estevan R, Salud A et al.Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial. J Clin Oncol 2012;30:3586.
34MODERATE-RISK DISEASE What can we change?Neoadjuvant chemotherapy: ongoing trialsNorth Central Cancer Treatment Group (NCCTG-N1048)1060 pt cT2N1, T3N0, T3N1. Not below 5 cmneoadjuvant FOLFOX followed by TME if > 20% tumor regression versus CRTPhase II BACCHUS (NCT )moderate-risk rectal cancers (cT3-T4, N0-N2 tumors 4 cm from anal verge with a non threatened CRM or V2)6 cycles of bevacizumab + FOLFOX versus folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) followed by TMEPhase II trial, COPERNICUS (NCT )neoadjuvant chemotherapy followed by SCRT for those with moderate-risk disease.
35HIGH-RISK DISEASEPrognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging
36Intensification of CRT Radiation dose escalation HIGH-RISK DISEASEPotentially involved or threatened CRMIncreased risk of both local and distant recurrencePoorer prognosis.Local Recurrence rates from 40% to10% but…5-year distant metastasis rates of about 30%Long-course CRT with a radiation dose of 45–54 Gy and concomitant fluoropyrimidine chemotherapy is now widely accepted as standard practiceIntensification of CRTRadiation dose escalationMore effective radiation sensitizers
37The introduction of IMRT HIGH-RISK DISEASEWhat can we change?Radiation dose escalationRadiation doses to the pelvis restricted by:potential small bowel toxicity,sphincter preservation,risks of surgical morbidity, including anastomotic dehiscenceFrench ACCORD12/0405 PRODIGE 2 J Clin Oncol 2012;30:4558–4565.45 Gy vs 50 Gy (CAPOX) No DifferenceThe introduction of IMRTHighly conformal dose distributionsMinimize the doses to adjacent critical pelvic structures.
39HIGH-RISK DISEASEWhat can we change?Radiation dose escalation Kaplan-Meier curves stratified for the treatment factors: radiotherapy dose
40Radiation dose escalation with IMRT HIGH-RISK DISEASEWhat can we change?Radiation dose escalation with IMRTPhase II Radiation Therapy Oncology Group (RTOG) 0822 studyAlternative methods of radiotherapy: contact radiotherapy and endorectal brachytherapyLyon R 96–02 randomized trial RCT, 88 pt EBRT, 39Gyin 13 fractions or the same EBRT plus endocavitary contactradiotherapy boost (85 Gy in 3 fractions). The 10-year rate ofpermanent colostomy halved in the contact RT group compared with EBRT alone.
41Adding oxaliplatin to fluoropyrmidine-based CRT HIGH-RISK DISEASEWhat can we change?Adding oxaliplatin to fluoropyrmidine-based CRTPhase III trials of neoadjuvant chemoradiation with oxaliplatin and 5-FU/capecitabine
42A pathological complete response was achieved in 23.75% of 80 patients HIGH-RISK DISEASEA pathological complete response was achieved in 23.75% of 80 patientsLocal recurrences were observed in 8.75%Distant metastases in 21.25%Chemotherapy consisted of a 2-h oxaliplatin infusion (50 mg/m2) on the first day of each week of radiotherapy, and five daily continuous infusions of 5-FU (200 mg/m2per die). Patients received five or six cycles of oxaliplatin,
43antiangiogenic antibody bevacizumab HIGH-RISK DISEASEIntensification of Chemotherapy or More effective radiation sensitizersIrinotecan-based CRTTargeted agents:antiangiogenic antibody bevacizumabantiepidermal growth factor receptor inhibitors cetuximab and panitumumab,
44Alternative strategies to reduce distant metastases HIGH-RISK DISEASEWhat can we change?Currently little room for further improvement with additional radiosensitizing agentsSystemic relapse is responsible for the majority of deaths in patients with rectal cancerAlternative strategies to reduce distant metastases
45NEW PERSPECTIVESDuring and after CRT identify those with a cCR and a ‘true pCR’ who may be spared radical surgeryIndentify a subgroup in moderate risk that should not do therapyIndentify a subgroup in high risk that shouldhave upfront chemotherapy, (particularlypatients who are likely to require chemotherapy as partof their treatment strategy): neoadjuvantchemotherapy CRT TME adjuvantchemotherapy.
46The impact of pCR after neoadjuvant therapies The challenge remains to identify those with a cCR and a ‘true pCR’ who may be spared radical surgery and, similarly, patients with a pCR who may benefit from adjuvant chemotherapy to minimize the risk of subsequent local or distant failure.
47Disegno e valutazione sperimentale studio Sapienza (A. Laghi-V Disegno e valutazione sperimentale studio Sapienza (A.Laghi-V.Tombolini)RM con diffusione Mezzo previsionale di risposta al trattamento neo-adj?
48mrTRG-1 (Assenza di ogni segnale tumorale) mrTRG-2 (tumore residuo minimo, cicatrice predominante)mrTRG-3 (aree miste di fibrosi a basso segnale e intensità disegnale intermedio > 50% ma senza predominanza disegnale tumorale)mrTRG-4 (Intensità di segnale predominante a caratteretumorale minima intensità di segnale basso di tipotumorale)mrTRG-5 (assenza di fibrosi; visibilità solo di segnale tumorale)
49Disegno e valutazione sperimentale Stadio RM = cT3cN2a (> 3<6 N+)RM con diffusioneDay -1CRM < 1 mm
50Disegno e valutazione sperimentale RM con diffusioneDay 15mrTRG 2/3
51Disegno e valutazione sperimentale RM con diffusioneDay 80mrTRG 2/3
52Disegno e valutazione sperimentale Intervento chirurgicoResezione anteriore del rettoE.I. Risposta patologica completa= ypT0, ypN0
53Disegno e valutazione sperimentale Stadio RM = cT2-N1b (>1<3N+)RM con diffusioneDay -1
54Disegno e valutazione sperimentale RM con diffusioneDay 15mrTRG 2
55Disegno e valutazione sperimentale RM con diffusioneDay 80mrTRG 1 o 2?
56Disegno e valutazione sperimentale Intervento chirurgicoResezione anteriore del rettoE.I. Risposta patologica completaRM di controlloNegativa per recidiva/residuo di malattia
57Refertazione attuale Rm cT cN Descrizione morfologicaLocalizzazioneDimensioneLesione anulareUlcerazionePerforazioneMucinosoPosizione dominante sul bordo di invasione tumoraleDistanza del bordo inferiore dal margine analeDistanza dal bordo inferiore del tumore al m.pubo-rettaleEstensione trasversale del tumoreEstensione longitudinale del tumoreRapporto tumore-riflessione peritonealeCaratteristiche RMSegnale T1Segnale T2DiffusionePerfusioneStadiazione TRm TSi estende oltre la muscolare propriaInfiltrazione del peritoneoInfiltrazione organi extraperitonealiSe retto basso o ultrabasso ( a livello o sotto dell’anello pubo-rettale)Piano intersfinterico-mesorettaleSfintere esternom.. Pubo-rettaleStadiazione N (numero e sede)Stato dei margini di resezione circonferenziale (MRC)Distanza minima del T dalla fascia Mesorettale (FMR): mmPosizione in base ai quadranti dell’orologioDistanza minima di una linfoadenopatia secondaria dalla FMR: mmMRC invasoInfiltrazione venosa ExtramuraliRm cT cN
58CONCLUSIONIUn approccio ottimale nella diagnosi e nella terapia Ca del retto prevede un approccio multidisciplinare ed integratoNegli ultimi 30 anni si sono avuti notevoli progressi nella OS e DFSAncora esistono dubbi sull’approccio «ideale» o «standard»Diagnosi precoce e stadiazione corretta sono indispensabili per una terapia ottimale
59A Watch-and-Wait Approach to the Management of Rectal CancerPrajnan Das, Bruce D. Minsky and Prajnan Das, October 15, 2013Instead of routine surgery in selected rectal cancer patients who have a clinical complete response (cCR) after chemoradiation.