1. CATTEDRA DI RADIOTERAPIA Università Sapienza di Roma
VINCENZO TOMBOLINI
CATTEDRA DI RADIOTERAPIA
Università Sapienza di Roma

2. Rectum Carcinoma
CANCER WITH EXTENDING FROM THE ANAL MARGIN UP TO A MAXIMUM OF 15 cm (measured with a rigid sigmoidoscope)
LOWER RECTUM
UP TO 4 – 5 cm FROM ANAL MARGIN (rare 6-7%)

4. SELECTION OF PATIENTS FOR TREATMENT

5. MCR (Munich Cancer Register):
Prognostic Factors
MCR (Munich Cancer Register):
STAGE UICC: REMAINS THE MOST IMPORTANT PROGNOSTIC FACTOR EVEN WHEN CHECKED BY AGE, TYPE OF SURGERY AND ADJUVANT THERAPIES
IMPORTANCE OF CLINICAL STAGING
INFLUENCES THERAPEUTIC DECISIONS
Kerr J et al, Ann Oncol, 16, 664, 2005.

7. SELECTION OF PATIENTS FOR TREATMENT
T3 tumors form a heterogeneous group
tumors that barely extend beyond the lamina muscularis propria
extend to or invade the mesorectal fascia
5-year OS
Extramural 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.

8. SELECTION OF PATIENTS FOR TREATMENT
Itermediate risk group
Neoplasm extending beyond the rectal wall = cT3-T4a or N1-2 M0
WITHOUT urresctable infiltration to surroding organs (cT4b)
CONCLUSIONI
Valentini 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.

9. SELECTION OF PATIENTS FOR TREATMENT
N + poor prognosis?
as the nodal burden increases, the prognosis also became poorer correspondingly
3,791 patients PORT
5-year OS
T3 N %
T3 N %
T3 N %
T3 N %
T3 N ,4 %
T3 N ,5 %
CONCLUSIONI
Gunderson 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 Clin
Oncol 2010;28:256 –263.

10. SELECTION OF PATIENTS FOR TREATMENT
Extramural venous invasion (EMVI) associated with:
Local recurrence
Liver metatases
Relapse Free Survival
Low-lying tumors requiring abd- perineal
resection (APR) worse survival rates
than patients with low anterior resection.
local recurrence,
cancer-specific survival OS
CONCLUSIONI
Dresen 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 –236
den 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.

11. SELECTION OF PATIENTS FOR TREATMENT
Histological evidence of tumor within 1 mm of the potential circumferential resection margin (CRM) strongly predicts
local recurrence
poor survival
Total mesorectal excision (TME) is a standard surgical tecnique
The plane of dissection is formed by the mesorectal fascia (encloses the fatty mesorectum)
This fascia forms CRM
Nagtegaal 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.

12. Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging
CONCLUSIONI
The ability to accurately predict these risk factors preoperatively would allow stratification of patients to receive neoadjuvant therapy.

13. MRI Can highlight the invasion of the MRF
Can predict the potential CRM
Can highlight the TRG (Tumor Regression Grade)
Can distinguish between good and poor prognosis after neoadjuvant therapy and
Can be related to the long-term results

14. Stadio II-III
Mesorectal fascia involvement/potential circumferential resection margins
Treatment 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 MRFs
MDCT seems to be equivalent to MRI only in tumours in the mid/high rectum.

15. Mercury Study 2 important markers analyzed with preoperative MRI
mrTRG (tumor regression grade with RMI)
CRM (circumferential resection margin )
predict survival
opportunity 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

16. Tumor regression grade (TRG)

17. The impact of CR after Neo-Adjuvant Therapy
Local relapse

18. The impact of CR after Neo-Adjuvant Therapy
DISTANT METASTASES

19. The impact of CR after Neo-Adjuvant Therapy
OVERALL SURVIVAL

20. The impact of CR after Neo-Adjuvant Therapy
Disease Free Survival

21. MODERATE-RISK DISEASE
Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging

22. MODERATE-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)

23. Surgery alone versus preoperative Radiotherapy + Chemotherapy
MODERATE-RISK DISEASE
Surgery alone versus preoperative Radiotherapy + Chemotherapy

24. MODERATE-RISK DISEASE
Phase III trials of short-course radiotherapy =

25. MODERATE-RISK DISEASE
Phase III trials of long-course radiotherapy with or without CT chemotherapy

26. MODERATE-RISK DISEASE
Short-course RT and Long-course chemoradiotherapy CRT
Benefits in local control,
but NOT IN OS
(apart from the Swedish Cancer trial)
Lack of impact on reducing distant recurrences?

27. Local recurrence rates reduced in the CRT Arm
Preoperative SCRT versus preoperative CRT
Polish trial  Local failure, DFS, or OS = NS
Australasian trial Local failure, DFS, or OS = NS (trend > LC in CRT)
No difference in OS,DFS, LF
Preoperative 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 the
pre- and postoperative arms, respectively; p .048)
Local recurrence rates reduced in the preoperative Arm
No difference in DFS or OS rates
Preoperative CRT versus preoperative RT
EORTC 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% for
preoperative 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

28. MODERATE-RISK DISEASE
Complications of RT e CRT
Acute side effects and surgical complications only slightly increased
Long-term toxicity more problematic.
fecal incontinence,
bowel obstruction,
sexual dysfunction
second cancer (compromise long-term survival) Dutch TME study: follow-up 12 years
2° cancer
RT+ TME = %
TME = %

29. Can we have confidence in the clinical staging?
Stadio II
It has been suggested that some patients with
disease 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?

30. Stadio II
Conclusion
The 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+

31. Weakness of nodal staging by imaging? Is better a short course RT?
Stadio II
Weakness of nodal staging by imaging?
Is better a short course RT?

32. MODERATE-RISK DISEASE
What can we change?
Capecitabine incorporated in CRT in
clinical practice
comparing capecitabine with 5-FU-based CRT
Lancet Oncol 2012;13:579 –588. Trend toward improved survival in the
capecitabine arm, perhaps because of fewer distant metastases. > DFS in favor of capecitabine
J Clin Oncol 2011;29:3503. No significant difference in (pCR) rate between capecitabine and 5-FU with or without oxaliplatin.
Increase Tumor downstaging with SCRT
SCRT followed by a delay of 6–8 weeks may allow tumor downstaging and be a useful alternative to CRT
Polish 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 survival
The ongoing Stockholm III trial  SCRT with immediate (1–10 days) or delayed (4 –7
weeks) surgery

33. MODERATE-RISK DISEASE
What can we change?
Neoadjuvant chemotherapy
Schrag et al, 2010
exclude those with T4 or bulky disease (Schrag et al)
avoid radiotherapy-associated toxicity
6 cycles of neoadjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX) + bevacziumab
stable or progressive disease after chemotherapy  CRT
Selective postoperative CRT in a positive CRM
pCR rate of 27% (31 pt)
GEMCAD 0801, 2012
88% radiological response,
100% R0 resection
15% pCR
Schrag 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.

34. MODERATE-RISK DISEASE
What can we change?
Neoadjuvant chemotherapy: ongoing trials
North Central Cancer Treatment Group (NCCTG-N1048)
1060 pt cT2N1, T3N0, T3N1. Not below 5 cm
neoadjuvant FOLFOX followed by TME if > 20% tumor regression versus CRT
Phase 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 TME
Phase II trial, COPERNICUS (NCT )
neoadjuvant chemotherapy followed by SCRT for those with moderate-risk disease.

35. HIGH-RISK DISEASE
Prognostic classification of rectal cancer based on pretreatment staging magnetic resonance imaging

36. Intensification of CRT Radiation dose escalation
HIGH-RISK DISEASE
Potentially involved or threatened CRM
Increased risk of both local and distant recurrence
Poorer 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 practice
Intensification of CRT
Radiation dose escalation
More effective radiation sensitizers

37. The introduction of IMRT
HIGH-RISK DISEASE
What can we change?
Radiation dose escalation
Radiation doses to the pelvis restricted by:
potential small bowel toxicity,
sphincter preservation,
risks of surgical morbidity, including anastomotic dehiscence
French ACCORD12/0405 PRODIGE 2 J Clin Oncol 2012;30:4558–4565.
45 Gy vs 50 Gy (CAPOX)  No Difference
The introduction of IMRT
Highly conformal dose distributions
Minimize the doses to adjacent critical pelvic structures.

38. IMRT

39. HIGH-RISK DISEASE
What can we change?
Radiation dose escalation Kaplan-Meier curves stratified for the treatment factors: radiotherapy dose

40. Radiation dose escalation with IMRT
HIGH-RISK DISEASE
What can we change?
Radiation dose escalation with IMRT
Phase II Radiation Therapy Oncology Group (RTOG) 0822 study
Alternative methods of radiotherapy: contact radiotherapy and endorectal brachytherapy
Lyon R 96–02 randomized trial  RCT, 88 pt EBRT, 39
Gyin 13 fractions or the same EBRT plus endocavitary contact
radiotherapy boost (85 Gy in 3 fractions). The 10-year rate of
permanent colostomy halved in the contact RT group compared with EBRT alone.

41. Adding oxaliplatin to fluoropyrmidine-based CRT
HIGH-RISK DISEASE
What can we change?
Adding oxaliplatin to fluoropyrmidine-based CRT
Phase III trials of neoadjuvant chemoradiation with oxaliplatin and 5-FU/capecitabine

42. A pathological complete response was achieved in 23.75% of 80 patients
HIGH-RISK DISEASE
A pathological complete response was achieved in 23.75% of 80 patients
Local 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,

43. antiangiogenic antibody bevacizumab
HIGH-RISK DISEASE
Intensification of Chemotherapy or More effective radiation sensitizers
Irinotecan-based CRT
Targeted agents:
antiangiogenic antibody bevacizumab
antiepidermal growth factor receptor inhibitors cetuximab and panitumumab,

44. Alternative strategies to reduce distant metastases
HIGH-RISK DISEASE
What can we change?
Currently little room for further improvement with additional radiosensitizing agents
Systemic relapse is responsible for the majority of deaths in patients with rectal cancer
Alternative strategies to reduce distant metastases

45. NEW PERSPECTIVES
During and after CRT identify those with a cCR and a ‘true pCR’ who may be spared radical surgery
Indentify a subgroup in moderate risk that should not do therapy
Indentify a subgroup in high risk that should
have upfront chemotherapy, (particularly
patients who are likely to require chemotherapy as part
of their treatment strategy): neoadjuvant
chemotherapy CRT TME adjuvant
chemotherapy.

46. The 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.

47. Disegno 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?

48. mrTRG-1 (Assenza di ogni segnale tumorale)
mrTRG-2 (tumore residuo minimo, cicatrice predominante)
mrTRG-3 (aree miste di fibrosi a basso segnale e intensità di
segnale intermedio > 50% ma senza predominanza di
segnale tumorale)
mrTRG-4 (Intensità di segnale predominante a carattere
tumorale minima intensità di segnale basso di tipo
tumorale)
mrTRG-5 (assenza di fibrosi; visibilità solo di segnale tumorale)

49. Disegno e valutazione sperimentale
Stadio RM = cT3cN2a (> 3<6 N+)
RM con diffusione
Day -1
CRM < 1 mm

50. Disegno e valutazione sperimentale
RM con diffusione
Day 15
mrTRG 2/3

51. Disegno e valutazione sperimentale
RM con diffusione
Day 80
mrTRG 2/3

52. Disegno e valutazione sperimentale
Intervento chirurgico
Resezione anteriore del retto
E.I. Risposta patologica completa= ypT0, ypN0

53. Disegno e valutazione sperimentale
Stadio RM = cT2-N1b (>1<3N+)
RM con diffusione
Day -1

54. Disegno e valutazione sperimentale
RM con diffusione
Day 15
mrTRG 2

55. Disegno e valutazione sperimentale
RM con diffusione
Day 80
mrTRG 1 o 2?

56. Disegno e valutazione sperimentale
Intervento chirurgico
Resezione anteriore del retto
E.I. Risposta patologica completa
RM di controllo
Negativa per recidiva/residuo di malattia

57. Refertazione attuale Rm cT cN
Descrizione morfologica
Localizzazione
Dimensione
Lesione anulare
Ulcerazione
Perforazione
Mucinoso
Posizione dominante sul bordo di invasione tumorale
Distanza del bordo inferiore dal margine anale
Distanza dal bordo inferiore del tumore al m.pubo-rettale
Estensione trasversale del tumore
Estensione longitudinale del tumore
Rapporto tumore-riflessione peritoneale
Caratteristiche RM
Segnale T1
Segnale T2
Diffusione
Perfusione
Stadiazione T
Rm T
Si estende oltre la muscolare propria
Infiltrazione del peritoneo
Infiltrazione organi extraperitoneali
Se retto basso o ultrabasso ( a livello o sotto dell’anello pubo-rettale)
Piano intersfinterico-mesorettale
Sfintere esterno
m.. Pubo-rettale
Stadiazione N (numero e sede)
Stato dei margini di resezione circonferenziale (MRC)
Distanza minima del T dalla fascia Mesorettale (FMR): mm
Posizione in base ai quadranti dell’orologio
Distanza minima di una linfoadenopatia secondaria dalla FMR: mm
MRC invaso
Infiltrazione venosa Extramurali
Rm cT cN

58. CONCLUSIONI
Un approccio ottimale nella diagnosi e nella terapia Ca del retto prevede un approccio multidisciplinare ed integrato
Negli ultimi 30 anni si sono avuti notevoli progressi nella OS e DFS
Ancora esistono dubbi sull’approccio «ideale» o «standard»
Diagnosi precoce e stadiazione corretta sono indispensabili per una terapia ottimale

59. A Watch-and-Wait Approach to the Management of Rectal CancerPrajnan Das, Bruce D. Minsky and Prajnan Das, October 15, 2013
Instead of routine surgery in selected rectal cancer patients who have a clinical complete response (cCR) after chemoradiation.