COLORECTAL CANCER: PART 2
Educational Objectives
| The goal of this program is to improve management of colorectal cancer. After hearing and assimilating this program, the
clinician will be better able to:
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 | 1. Define the probability of a pathologic complete response (pCR) after neoadjuvant CRT and identify some of the factors
that contribute to achieving pCR.
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| 2. Detail the methods used to predict pCR and explain how this information can be used to help select potential candidates
for nonoperative treatment.
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| 3. Describe new cancer staging strategies included in and planned for the sixth and seventh editions of the American
Joint Committee on Cancer (AJCC) Cancer Staging Manual.
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| 4. Explain the potential benefits and limitations of sentinel lymph node mapping in the management of patients with
colorectal cancer.
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| 5. Review the current options in chemotherapy and biologic therapy for advanced colorectal cancer and choose the best
regimen for patients.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgements
Drs. Roberts, Greene, and Caushaj were recorded at the 19th Annual International Colorectal Disease Symposium,
held February 14-16, 2008, in Fort Lauderdale, FL, and sponsored by the Cleveland Clinic Florida. Dr. Greeno spoke
at 70th Annual Colon and Rectal Surgery: Current Principles and Practice 2007, held October 24-27, 2007, in Minneapolis,
MN, and sponsored by the Division of Colon and Rectal Surgery at the University of Minnesota Medical
School, Colon and Rectal Surgery Associates, Ltd, and the Minnesota Colon and Rectal Foundation. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| RECTAL CANCER: CHEMORADIOTHERAPY FOLLOWED BY LOCAL EXCISION FOR T1 LESIONS —Patricia
Roberts, MD, Professor of Surgery, Tufts University School of Medicine, Boston, MA, and Chair, Department of Colon and
Rectal Surgery, Lahey Clinic Medical Center, Burlington, MA
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| Case: woman, 27 yr of age, with rectal lesion, undergoes transanal excision of lesion; pathology reveals T3 cancer with
positive microscopic margins; no visible tumor found on follow-up after chemoradiation; patient undergoes total mesorectal
excision, coloanal anastomosis, and ileoanal reservoir procedure (J-pouch); patient had complete clinical and
pathologic response and no recurrence at 5 yr; question—example of optimal treatment or unnecessary surgery?
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| Nonoperative management after chemoradiation therapy (CRT): advantages—improve function; avoid low
anterior resection syndrome; reduce need for fecal diversion; decrease morbidity and mortality; disadvantages—questions
about follow-up protocols and certainty about disease-free status; study—34% of patients with rectal cancer had complete
clinical response after neoadjuvant CRT (81% of these had sustained clinical response; ≈13% recurred within 5 yr)
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| Frequency of pathologic complete response (pCR): review of >3000 patients in phase 2 and phase 3 trials completed
before 2004 found 13% incidence after neoadjuvant CRT (factors associated with pCR were use of 2 chemotherapeutic
agents, continuous infusion of fluorouracil [5-FU], and radiotherapy dose ≥45 Gy); in studies after 2004, incidence
>20%; other factors affecting pCR—interval between radiotherapy and definitive surgery (interval of 6-8 wk improves outcome,
compared to 2-wk interval); interval between CRT and tumor assessment (longer interval) may improve rate of tumor
response
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| Complete clinical response as predictor of pCR: since pCR determined by pathologic examination of resected
specimen after radical surgery, key consideration whether clinical complete response predicts pCR; in Memorial Sloan-
Kettering study of 488 patients who underwent neoadjuvant treatment for rectal cancer, complete clinical response rate
did not predict pCR
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| Transanal excision for rectal cancer: during late 1980s to late 1990s, use of local excision increased from 22% to
46% for T1 lesions and from 6% to 17% for T2 lesions; recent data show high risk for local recurrence after local excision
for T1 lesions (and even higher risk after excision for T2 lesions), when compared to radical resection; however, local
excision may be useful in patients after CRT to assess for residual disease and as predictor of nodal status
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| Prediction of nodal status after neoadjuvant CRT: by assessment of T category—studies have shown that patients
whose primary tumor T0 or T1 at time of surgery had only 3% risk for lymph node involvement (suggests that patients
whose lesions downstage to T0 or T1 after neoadjuvant CRT have very small risk for residual disease, and may be
cohort in whom surgery can be omitted)
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| Diagnosis of pCR: imaging studies—increasing evidence supporting use of positron emission tomography (PET) and
computed tomography (CT) in assessment of complete clinical response; magnetic resonance imaging (MRI) has had increasing
role in staging of rectal cancer and in follow-up; certain molecular markers (eg, pretreatment expression of p53
tumor-suppressor gene) may be potential predictors of response to radiotherapy
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| Grading tumor regression: pathologic grading system based on histologic degree of tumor regression and fibrosis; regression
correlates with stage and size of tumors
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| Identification of candidates for nonoperative treatment: probably best done in setting of clinical trial; complete
clinical assessment required after preoperative CRT, following rigorous program of clinical examination, imaging studies
(eg, MRI), and meticulous endoscopic follow-up; determine optimal neoadjuvant regimen
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| Conclusion: unlikely that significant number of rectal cancer patients can be treated with chemoradiation only; some patients
may be effectively treated in this manner; if clinicians identify this subset and adequately predict response to therapy, possible
to safely follow these patients without compromising outcome
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| STRATEGIES IN STAGING —Frederick Greene, MD, Chair, Department of Surgery, Carolinas Medical Center, Charlotte,
NC
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| Introductory remarks: all physicians should use common language of cancer; worldwide language of cancer, at least
since mid 1980s, is tumor node metastasis (TNM) staging system; TNM system provides framework for discussion, stratifies
patients for clinical trials, and facilitates comparison along lines of individual practices; aids in planning treatment,
assessing prognosis, and evaluating results of treatment
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| Residual tumor (R) classification: whether residual tumor present strongest predictor of outcome; forthcoming
change in R classification system—R1 resection to be defined as negative margin within 1 to 2 mm of primary tumor;
change will be incorporated into seventh edition of American Joint Committee on Cancer (AJCC) Cancer Staging Manual
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| Cancer staging strategy of AJCC: looks at TNM status, R classification, and multiple prognostic factors (new prognostic
factor included in sixth edition of AJCC manual was presence or absence of isolated tumor cells; in future, staging
strategies will include use of molecular techniques such as transcriptase polymerase chain reaction (RT-PCR; included in
sixth edition of manual [classified as mol-/mol+], and will be carried over into seventh edition)
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| Change in classification of stage III colon cancer: in past, all cases of stage III colon cancer grouped into one
common entity (ie, any cancer with positive regional lymph nodes); however, in late 1990s to early 2000s, some (including
speaker) started suggesting that patients with node positive disease be stratified rather than placed into single category;
analysis of 50,000 patients with stage III colon cancer from National Cancer Data Base (NCDB) identified 3
distinct subcategories within traditional stage III cohort of colon cancer (stages IIIA, IIIB, and IIIC); data show significant
differences among subgroups; all 3 subgroups included in sixth edition of AJCC staging manual; importance of
subcategories—implication that not every patient with stage III disease should receive same treatment with adjuvant
therapy
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| Change in classification of stage II colon cancer: to be included in seventh edition of AJCC Cancer Staging Manual
; stage II disease previously subdivided into IIA and IIB (depending on whether primary tumor classified as T3 or T4);
now evident that T4 disease should be further split into T4A (defined as tumors that have penetrated serosa of bowel and
gotten free peritoneum) and T4B (tumors infiltrating into adjacent organ); subdivision of T4 classification will result in
new category of stage II disease (IIC, defined as patients with T4B lesions); speaker suggests that this change will be important
for medical oncologists, and that stage IIC lesions will be routinely treated with chemotherapy
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| Concluding comments: future staging strategies will deal with mitotic measurements (such as mitotic rate), and include
grading of colon cancer (nonexistent to date); this will lead to more precise diagnosis and improved ability to tailor
treatment; important to look not only at prognostic factors but also at predictive factors; newer drugs based on TNM staging
strategies anticipated; new techniques, ie, use of molecular markers (eg, P53 gene expression) and screening for microsatellite
instability will be routinely incorporated into the evaluation and management of patients
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| THE ROLE OF SENTINEL NODE MAPPING —Philip J. Caushaj, MD, Professor of Surgery, Temple University School
of Medicine, Philadelphia, PA, and Colorectal Surgeon, Western Pennsylvania Hospital, Pittsburgh
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| Introductory remarks: histologic status of regional lymph nodes most important prognostic factor for malignant colorectal
tumors; nodal status determines stage of tumor and need for adjuvant chemotherapy; pathologic methods that have
increased detection of nodal micrometastases (eg, serial sectioning, immunohistochemistry, RT-PCR) add burden to pathologist
in terms of time, cost, and intensity of labor (thus, cannot be routinely ordered for every resected specimen)
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| Technical aspects of sentinel lymph node (SLN) mapping: using 25- to 30-gauge needle, peritumor injection of
isosulfan blue dye made circumferentially into subserosal surface of bowel; be careful to avoid spillage and intraluminal
injection of dye; narrow window of opportunity from time of injection to time of sentinel node identification; types of
tracers used; injection can be done in vivo or ex vivo
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| Contraindications to SLN mapping: previous colon surgery; neoadjuvant CRT; large tumor invading adjacent organs;
perforated carcinoma; multiple primary tumors
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| Applicability to colorectal cancer: gold standard in treatment of colorectal cancer en block primary tumor resection
and regional lymphadenectomy (in majority of patients, information obtained by SLN mapping does not alter extent of
operation); aberrant lymph node drainage (SLN mapping should alter extent of operation)
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| Role and importance of SLN mapping: more accurately identifies node most likely to harbor metastasis; enables
focused evaluation (provides more precise prognostic information); helps identify those patients who may benefit from
new and different forms of adjuvant therapy
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| Results of published studies of colorectal lymph node mapping: in all but one study using isosulfan blue dye,
time between injection of tracer and labeling of SLN ranged from 1 to 60 min (in studies that used radioactive tracers,
time ranged from 26 min to 20 hr); results widely varied (SLN mapping with isosulfan blue dye alone has success rate of
58%-100% in studies with 30-99 cases, and 97%-100% in studies with >100 cases); false-negative rates range from 0% to
63%; conflicting results (when compared to immunohistochemical techniques) seen in patient outcomes
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| Fundamental questions: does SLN mapping significantly upstage or increase staging accuracy? do patients with negative
nodes on hematoxylin and eosin (H and E) staining, who have nodal micrometastases, have significantly worse oncologic
outcome than those without micrometastases? does treatment of nodal micrometastatic disease with adjuvant
chemotherapy translate into meaningful survival benefit?
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| CHEMOTHERAPY AND BIOLOGIC OPTIONS FOR ADVANCED COLORECTAL CANCER —Edward W. Greeno,
MD, Associate Professor of Medicine, University of Minnesota, Minneapolis, Medical School, and Medical Director, Masonic
Cancer Center, Minneapolis, MN
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| Introductory remarks: median survival 8 mo in patients with unresectable disease ; small subset of patients curable
with surgical resection; medical therapy improves quality of life (QOL) and can double median survival time; for 30 to 40
yr, only available therapy for treatment of colon cancer was 5-FU; chemotherapy developed in last decade—oral 5-FU
analogues; irinotecan; oxaliplatin
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| Oral 5-FU analogues: capecitabine—prodrug; selectively activated in tumor cells; survival equivalent to and response
rate better than intravenous (IV) 5-FU and leucovorin; similar toxicity; greater convenience for patients; possible reimbursement
issues
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| Irinotecan: principal toxicities include diarrhea, bone marrow suppression, and hair loss; administered once weekly or
once monthly; 20% to 30% response rate when given as second-line agent after failure of 5-FU; increases median survival
by 1 to 3 mo and improves QOL (compared to best supportive care); can be combined with 5-FU (combination therapy
more toxic but effective)
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| Oxaliplatin: platinum analogue; synergistic with 5-FU (inhibits upregulation of thymidilate synthase); no renal and minimal
hematologic toxicity; some neurotoxicity (markedly exacerbated by cold); given by IV bolus monthly or biweekly;
when used as first-line agent, slightly improves response rates and increases median survival by 1 mo (compared to 5-
FU); slightly worse toxicity; overall QOL similar; recent study showed adding oxaliplatin to 5-FU achieves median survival
of 19 mo
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| State-of-the-art chemotherapy with cytotoxins: choose either irinotecan or oxaliplatin with 5-FU initially, if failure
occurs, switch to other; achieves median survival of >20 mo
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| Triplet vs doublet therapy: recent study found that giving combination of 5-FU plus oxaliplatin and irinotecan initially
produces greater benefits than giving 5-FU and irinotecan initially and then switching to 5-FU plus oxaliplatin;
however, many patients in study did not receive second-line treatment (so were never exposed to oxaliplatin)
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| Sequential vs combination therapy: study comparing sequential to combination therapy found no significant difference
in outcomes as long as patients exposed to all 3 drugs (capecitabine, irinotecan, and oxaliplatin) during course of
treatment
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| Angiogenesis inhibitors: underlying concept that tumor must grow blood supply; several angiogenesis inhibitors and
activators; vascular endothelial growth factor (VEGF) important to vasculogenesis; many human tumors make VEGF;
animal models have shown tumor inhibition by multiple strategies that inhibit VEGF (marked synergism when given in
conjunction with chemotherapy); bevacizumab—approved by Food and Drug Administration (FDA; many other VEGF
inhibitors currently in development); landmark study led to approval; side effects include hypertension, proteinuria, increased
risk for bleeding and clotting, bowel perforation, and impaired wound healing (do not give 1 mo before or after
surgery); studies show that addition of bevacizumab to various chemotherapy agents can improve median survival by 2 to
>4 mo
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| Epidermal growth factor receptor (EGFR) inhibitors: cetuximab—EGFR inhibitor most recently approved by
FDA; exhibits in vitro synergy with chemotherapy; approval based on study in which cetuximab increased response rate
to 22% in patients with disease refractory to chemotherapy when added to irinotecan; more recent data show that adding
cetuximab to treatment in patients who have failed conventional chemotherapy can improve survival
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| Immunotherapy: still fairly ineffective; interleukin (IL)-2-expressing Salmonella vaccine that seems to control liver
metastases in development
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| Cost of therapy: 60,000 patients per year expected to need bevacizumab for treatment of metastatic disease; treatment
lasts 10 mo at cost of $4000/mo (total cost $2.4 billion/yr); cost of drugs has risen dramatically (10 yr ago, 5-FU alone
cost few hundred dollars for 2 mo of treatment; 3-drug chemotherapy regimen costs $10,000; adding biologic treatments
raises price to $20,000-$30,000); significant cost associated with added benefit
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Suggested Reading
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data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic
colorectal cancer. Clin Colorectal Cancer 7 Suppl 1:S21, 2007; Comella P et al: Capecitabine, alone and in combination,
in the management of patients with colorectal cancer: a review of the evidence. Drugs 68:949, 2008; Das P et al:
Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer
109:1750, 2007; Dionigi G et al: The application of sentinel lymph node mapping in colon cancer. Surg Oncol 16 Suppl
1:S129, 2007; Eng C, Shalan N: Biological agents versus chemotherapy in the treatment of colorectal cancer. Expert
Opin Pharmacother 7:1251, 2006; Greene FL, Sobin LH: The staging of cancer: a retrospective and prospective appraisal.
CA Cancer J Clin 58:180, 2008; Habr-Gama A: Assessment and management of the complete clinical response
of rectal cancer to chemoradiotherapy. Colorectal Dis 8 Suppl 3:21, 2006; Habr-Gama A et al: Operative versus nonoperative
treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 240:711,
2004; Hartley A et al: Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis
of phase II/III trials. Br J Radiol 78:934, 2005; Hurwitz H et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin
for metastatic colorectal cancer. N Engl J Med 350:2335, 2004; Labianca R et al: The role of adjuvant
chemotherapy in colon cancer. Surg Oncol 16 Suppl 1:S93, 2007; Lee JJ, Chu E: An update on treatment advances for
the first-line therapy of metastatic colorectal cancer. Cancer J 13:276, 2007; Pessino A et al: First-line single-agent cetuximab
in patients with advanced colorectal cancer. Ann Oncol 19:711, 2008; Read TE et al: Sentinel lymph node mapping
for adenocarcinoma of the colon does not improve staging accuracy. Dis Colon Rectum 48:80, 2005; Saha S et al: Sentinel
lymph node mapping in colon and rectal cancer: its impact on staging, limitations, and pitfalls. Cancer Treat Res 127:105,
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results from the United States Military Cancer Institute Clinical Trials Group Study GI-01. Ann Surg 245:846, 2007; Verhoef
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