Feza H. Remzi MD, FACS, FASCRS Laparoscopy in Colorectal cancer: Where are we now? Feza H. Remzi MD, FACS, FASCRS Digestive Disease Center Department of Colorectal Surgery Cleveland Clinic

Conclusions Safe for colon cancer Return of earlier bowel function Less postoperative pain Better pulmonary postoperative function Shorter hospital stay Smaller incision Its application in rectal cancer needs to be determined

Conclusions Selection Early conversion Do not compromise for the sake smaller incision No short cuts and do not change your routine Patients come first

Issues and Questions Does the method of access (LAP vs. Open) in the resection of colon CA affect outcome? Short term recovery Long term oncologic outcome Is there enough data say LAP is safe? What will be the role of laparoscopy in the treatment of colorectal CA in 2007?

Colon

History First reports of LAP for colon CA in 1990 Technically difficult and challenging Time consuming Short-term benefits (pain, ileus, hospitalization) have not been pronounced compared to open surgery Has led to resistance among surgeons to learn the technique

Port Site Recurrence Recurrence of tumor in a trocar wound without advanced abdominal disease First report in 1993 Initially reported rates: 0 - 21%* NOT necessarily with advanced cancer Cast a dark shadow over laparoscopic surgery for malignancy *Berends, Lancet 1994

Port Site Recurrence Proposed Mechanisms Direct seeding of exfoliated cells at port sites Aerosolized cancer cells with pneumoperitoneum CO2 enhances tumor growth* Local conditions at port sites favor implantation Poor surgical technique (spillage of tumor cells at operation) Jones et al. Dis Colon Rectum 1995;38:1182-8. Wu JS. Surgery 1997;122:1-7. Jacobi et al. Surgery 1997;121:72-78. Bouvy et al. Annal Surg 1996;224:694-701. Nduka et al. Surg Endosc 1998;12:515. Mathew et al. Br J Surg. 1996;83:1087-1090. Watson et al. Arch Surg. 1997;132:166-168. Neuhaus et al. Surg Endosc 1998;12(5):516. Nduka et al. Surg Endosc 1998;12(5):515. Jacobi et al. Surg Endosc 1998;12(5):513. *

Port Site Recurrence Rates Mid 1990’s Study Year Recurrences Operations Percent Ramos 1994 3 208 1.4 Jacquet 1995 7 445 1.6 Lumley 1996 1 103 1.0 Kwok 1996 1 100 1.0 Fleshman 1996 4 372 1.1 Franklin 1996 0 191 0 Vukasin 1996 5 480 1.1 Huscher 1996 0 146 0 Total 21 2045 1.0 % *Series greater than 100 patients Hughes ’83, Reilley ’96 : Incisional recurrence 0.6 – 0.8 % in open surgery

Port Site Recurrence Rates Recent Series Study Year Operations Recurrences Percent Milsom 1998 55 Schiedec 1999 399 1 0.25 Regadas 470 2 0.4 Lechaux 2002 206 0.5 Lumley 181 0.6 Lacy 106 0.1 COST 2004 435 Total 1852 8 0.4%

Port Site Recurrence In experienced hands, the rates of PSR are acceptable High rates of PSR in earlier reports must have been due to poor surgical technique Animal models suggesting increased tumor growth with CO2 pneumo did not replicate “real-life” conditions

Background: LAP for Colon CA Our team started in 1991: Animals Cadavers Limited benign diseases Indications expanded in 1993: Malignancies

Background: Feasibility Studies Phase I Studies – Cadavers 1993 - Rt. Hemicolectomy (Bohm et. al) 1993 - Proctosigmoidectomy (Milsom et. al) 1993 - Abdominoperineal Resection (Decanini et. al)

LAP Surgery for Colorectal CA Early Large Prospective Series Franklin et al (‘96): 191 LAP / 224 OPEN At 3 yrs: No disadvantages, no port site mets, faster recovery COST Group (‘96): 372 pts LAP No early mets, no port site mets Poulin et al (‘99): 117 pts LAP 54% survival in stage III at 48 months *No obvious early disadvantages

Adequacy of Resection Randomized Colectomy Trials Study LAP vs. Open Nelson* NSD + Milsom ** NSD Lacy*** NSD *N.C.I. / C.O.S.T. Trial, 1996 ** Cleveland Clinic Trial, 1996 *** Barcelona Trial, 1995 + NSD= no significant difference Bowel margins, # of lymph nodes similar

First Randomized Colectomy Trial Preliminary Report Cleveland Clinic Foundation n=109 (55 LAP vs. 54 Open) Median FU: 17 months (range 1.5 –46) No port site recurrences Similar number of cancer-related deaths *Milsom, JACS 1998

Cleveland Clinic Trial Short term advantages to LAP Less narcotic use * Earlier return of flatus (3.0 vs. 4.0 days) * Earlier return of FEV1 and FVC to 80% of pre-op (3.0 vs. 6.0 days) * * p < 0.05

The Barcelona Trial Lacy et al, 1993 – 1998 Single institution, two surgeons All non-metastatic colon cancer n=219 (111 LAP vs. 108 Open) Intention to treat analysis Median FU: 43 months (range 27 - 85)

Tumor Recurrence and Mortality LAP Open Tumor recurrence Time to recurrence (mo) Overall mortality Cancer-related mortality * 18 (17%) 15 (14) 19 (18%) 10 (9%) 28 (27%) 17 (12) 27 (26%) 21 (21%) : p < 0.05 * Lacy AM, Lancet 2002

COST* Study Group Randomized Prospective Study Nelson, et al. Non-inferiority randomized trial 48 institutions, USA and Canada n=872 (1994 – 2001) Median FU: 4.4 years Primary endpoint: Time to tumor recurrence *Clinical Outcomes of Surgical Therapy Study Group Nelson, NEJM, May 2004

Inclusion Criteria Exclusion Criteria > Age 18 Adenocarcinoma of the colon Exclusion Criteria Prohibitive abdominal incisions Advanced or metastatic disease Transverse colon or rectal cancer Acute obstruction or perforation Severe medical illness

Credentialing 66 surgeons at 48 institutions > 20 LAP colectomies Video to review oncologic technique Random audit of videotapes* Assessment of bowel margins* * Reviewed by external monitoring committee

Randomization Stratification variables Tumor site ASA classification Right, left, sigmoid ASA classification I, II, or III Surgeon

Survival and Recurrence Cost Trial LAP (n=435) Open (n=428) P value Tumor recurrence 76 (17 %) 84 (19 %) NS* Overall survival 79% 78% Disease-free survival 73% Time to recurrence Wound recurrences 2 (0.5 %) 1 (0.2 %) NS * True for any stage

Short Term Results Cost Trial LAP Open P value Hospital stay (days) 5 6 <0.001 IV narcotics (days) 3 4 Oral narcotics (days) 1 2 OR time (min) 150 95 Incision length (cm) 18 Overall complications (%) 92 (21) 85 (20) 0.64 Intraop complications (%) 16 (4) 8 (2) 0.10 Surgical margins, # of LN’s similar

COST Trial Conclusions LAP is not oncologically inferior to Open Marginal short term benefits seen with LAP in post-operative recovery Similar complications rates (LAP vs. Open) “… it is safe to proceed with laparoscopically assisted colectomy in patients with cancer.”

However… Study was not powered to detect whether LAP was oncologically superior Conversion rate 21% (n=90) excessive LAP (n=435) / 48 institutions / 7 years Only 1.3 laparoscopic cases / institution / year!!!

Results COST trial results substantiate results found in other trials LAP for colon CA is oncologically safe Small benefits are seen in post-operative recovery with LAP With good surgical technique, the rate of port site recurrences is minimal

Summary Whether LAP is oncologically superior to open surgery is still controversial… In 2007: LAP is here to stay Patients will demand it.. Anticipate more and more cases of colon CA will be resected laparoscopically

Cleveland Clinic Trial Longterm Results It is the only prospectively randomized study with 10 year or more follow -up There were no differences between the Lap versus open groups stage by stage in cancer specific survival or recurrence Geissler ASCRS Seattle 2006

COLOR Trial 1997-2003, 29 centers in Europe Over 600 patients in each group Less pain, blood loss, earlier recovery of bowel function and shorter hospital stay in Lx group 17 % conversion rates Equivalent morbidity and mortality Lancet 2005

CLASICC Trial 1996-2002, 27 UK centers 794 patients Less pain and shorter hospital stay in Lx group 29 % conversion rates Equivalent morbidity and mortality Increase positive radial margins in LX group Converted patients had raised complication rates Lancet 2005

Summary Surgeons participating in the COST study were experienced in LAP colectomies The results of the COST trial is not a license to start LAP colectomies for malignancy “Proceed with caution…” We owe it to our patients to exercise good oncologic technique and COMMON SENSE to avoid unwanted results!!!

Rectum

Laparoscopic Learning Curve 461 cases among 3 surgeons Operative time evaluated Conclusion: 30 case learning curve Schlachta – DC&R 2001

Learning Curve of Laparoscopic Resection for Rectal Cancer Li-China 105 cases Divided into 3 groups by time Learning curve for experienced laparoscopic surgeons is 35 cases doing 2.1 cases a month

How Much Colorectal Surgery to General Surgeons Do? Hyman-JACS 2002 ABS recertification database 2434 general surgeons (’95-97) Mean 33 colon cases 75% do less than 17 cases per year Mean 12.3 anal cases 75% do less than 16 cases per year

Minilap vs. Laparoscopy 52 patients 173 minutes Discharge=6d BM=3.9 d Incision 8 cm Minilap 35 patients 69 minutes Discharge=6.9d BM = 4 d Incision 12 cm Fleshman, Fry – DC&R 1997

Surgeon - Technique Heald 4% local recurrence - 87% survival Quirke - Lancet 1986 positive margines in 14/52 specimens positive correlation with recurrence

Discussion Biases of self-designated interests Better technique Better approach to patients Better follow-up Superior psychological support

Surgeon Procedure Volume and Outcome 2815 rectal cancers 30 day mortality not influenced by doing more that 21 cases 2 year mortality was very significantly influenced (34 vs 24% mortality) Schrag-Ann Surg 2002

Influence of Hospital and Surgeon Volume on In-Hospital mortality Hannan, Brennan-Surgery 2002 NY Statewide database Top quartile and bottom quartile differ by 50% (overall mortality 3.5%)

Conclusion Patients operated upon by members of ASCRS have 13% decreased death rate with a minimum of 3 years follow-up

Conclusion The surgeon is the most significant variable we can influence in the treatment of patients with colorectal cancer

Surgeon’s Influence The surgeon is the most significant variable we can influence in the treatment of patients with colorectal cancer Breast Cardiac Pancreas Esophagus ? Lung

We must accept the fact that surgical technique is important to outcome and that change in technique cannot be accepted without validation.

CLASICC Trial Guillou Lancet 2005 LAR Radial Margin Positive Open = 4/64 (6%) Laparoscopic = 16/129 (12%) NS Converted = 29% Increased TME achieved with laparoscopy Concern raised about the risk of increased local recurrence

Laparoscopic vs Open Surgery for Rectal Cancer: a meta-analysis 20 studies 2071 patients; 909 LX, versus 1162 open Short term outcomes may be improved Laparoscopic rectal cancer surgery results in an earlier postoperative recovery and a resected specimen that is oncologically comparable to open surgery Aziz 2006 Ann Surg Oncol

Stage I, II similar 3 yr survival Laparoscopic and Open Anterior Resection for Upper and Mid Rectal Cancer 265 patients Stage I, II similar 3 yr survival Open = 89.8% Lap = 88.6% Stage III 3 yr survival of concern Open = 65.6% Lap = 55.5% Law-DC&R 2006

There is no short term advantage that can outweigh increased long term cancer recurrence

Laparoscopic vs. Open total Mesorectal Excision for Rectal Cancer Cochrane Database 2006 80 studies identified 48 met inclusion, 4224 patients Methodological quality of most of the included studies was poor. There is evidence that LX TME results in less blood loss, quicker return to normal diet, less pain, less narcotic use and less immune response. It seems likely that LX TME is associated with longer operative time and higher costs. No results of quality of life were reported.

Ethical Issues Offering experimental ? surgery outside of a research environment A Marketing tool

Conclusion Surgical technique is important New techniques must be validated Laparoscopic LAR has increased CRM Laparoscopic proctectomy remains unproven and certainly not the standard

With the ethical values we have in the United States, how can a surgeon even consider performing a laparoscopic proctectomy outside of a study environment?

Conclusions Safe Return of early bowel function Less postoperative pain Better pulmonary postoperative function Shorter hospital stay Smaller incision Its application in rectal cancer needs to be determined

Conclusions Selection Early conversion Do not compromise for the sake smaller incision No short cuts and do not change your routine Patients come first

Preoperative Rectal Cancer Staging