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128 Kaneko H, Otsuka Y, Tsuchiay M, et al Application of
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133 Cho JY, Han HS, Yoon YS, et al Feasibility of laparoscopic
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134 Cho JY, Han HS, Yoon YS, et al Experiences of laparoscopic
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135 Lesurtel M, Belghiti J Open hepatic parenchymal
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136 Rau HG, Duessel AP, Wurzbacher S The use of water-jet
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138 Gold JS, Are C, Kornprat P, et al Increased use of
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139 Fong Y Hepatic colorectal metastasis: current surgical
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140 Fong Y, Salo J Surgical therapy of hepatic colorectal
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141 Ahmad A, Chen SL, Bilchik AJ Role of repeated
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147 Kattan MW, Gonen M, Jarnagin WR, et al A nomogram for predicting disease-specific survival after hepatic resection for metastatic colorectal cancer Ann Surg 2008; 247(2): 282–7
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158 Irshad K, Ahmad F, Morin JE, et al Pulmonary metastases from colorectal cancer: 25 years of experience Can J Surg 2001; 44(3): 217–21
159 Hendriks JM, van Putte B, Romjin S, et al Pneumonectomy for lung metastases: report of ten cases Thorac Cardiovasc Surg 2003; 51(1): 38–41
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Trang 3Liliana Bordeianou and Judith L Trudel
Challenging Case
A 56-year-old man presented with a 5 cm rectal cancer It was
located posteriorally at 8 cm from the anal verge The preop
ultrasound suggested a T3N1 tumor The patient received
pre-operative chemoradiotherapy He had a superb clinical response
with tumor shrinkage Six weeks after completing the therapy,
the patient underwent a low anterior resection with a diverting
loop ileostomy The final pathology was a T1N0 with five negative
lymph nodes identified All margins were negative Should the
patient receive postoperative chemotherapy?
Case ManageMent
There is little data on which to base this clinical decision Most
practioneers lean toward recommendations for postoptherapy
based on the pretreatment clinical stage if the patient receives
neoadjuvant therapy In a good risk patient, most would
recom-mend 6 months of postoperative adjuvant chemotherapy
introduCtion
Colorectal cancer (CRC) is the third most common cancer
diag-nosed in men and women in the United States Approximately
148,810 new cases of colon and rectal cancer were reported in
2007, with an estimated 49,960 deaths attributed to it.(1) This is
higher than the number of deaths attributed to pancreatic cancer,
liver and intrahepatic bile duct cancer or esophageal cancer
While surgery remains the mainstay of treatment for this
com-mon disease, it is the recent noteworthy changes in the indications
for chemotherapy, the timing strategy as far as chemotherapy
administration and the actual therapeutic regimens used to treat
advanced colon and rectum cancers that may provide the next step
toward the improvement in the survival rates of these patients
CheMotherapy agents or CoMbinations Most
CoMMonly used against ColoreCtal CanCer
5-FU with Either Leucovorin or Levamisole
Since its original use in the 1950s, 5-FU remains one the oldest
chemotherapeutic agents used today to target colorectal cancer
5-FU inhibits DNA synthesis via blockage of thymidylate
syn-thase At first used alone, and then in combination with
levami-sole, 5-FU/levamisole combination was noted to significantly
decrease recurrence rates and improve overall survival,
particu-larly in Dukes’C patients.(2) This observation was subsequently
confirmed in a large study of 971 patients with stage III and IV
disease (intergroup 0035) which in 1990 showed that this drug
combination reduced the risk of cancer recurrence by 41% and
the overall death by 33 % in this group of patients.(3) Given
these results, this drug combination was regarded as gold
stand-ard therapy for CRC till 1996, when an even more effective
regi-men using 5-FU in combination with leucovorin (folinic acid)
was described
Leucovorin is a 5-FU biomodulator Leucovorin and 5-FU form a stable ternary complex with thymydylate synthetase, per-mitting prolonged inhibition of the enzyme by 5-FU Its appli-cability to stage II and stage II disease was confirmed by the IMPACT (International Multicenter Pooled Analyses of Colon Cancer Trials) study of 1,526 patients in 1995, which showed that 5-FU/leucovorin increased the 3-year disease free survival from 62% to 71% while overall survival increased from 78%
to 83%.(4) The NSAPB C-03 randomized trial of 1,081 stage
II and stage III patients comparing MOF (semustine, vincris-tine and 5-FU) to 5-FU/leucovorin had documented a similar advantage of 5-FU/leucovorin, with a 3 year disease-free sur-vival increase from 64% to 73% and an overall sursur-vival increase from 77% to 84%.(5)
The relative merits of levamisole and leucovorin as modulators
of 5-FU-based adjuvant chemotherapy, and the optimal duration of treatment were documented in several studies between 1998 and 2000 The NCCTG/NCIC (National Cancer Institute of Canada) study of
915 patients compared 6 months 5-FU/leucovorin; 6 months 5-FU/ leucovorin/levamisole; 1 year 5-FU/levamisole; and 1 year 5-FU/leu-covorin/levamisole.(6) Triple therapy for 6 months was as effective
as 12 months; and 6-month triple therapy provided superior 5-year overall survival and disease-free survival compared to 5-FU/levami-sole.(6) The Intergroup trial 0089 of 3,759 patients compared 1 year 5-FU/levamisole; 5-FU/high-dose leucovorin for 32 weeks; 5-FU/ low-dose leucovorin for 6 cycles; and 5-FU/low-dose leucovorin/ levamisole for 6 cycles.(7) There were no differences between the four treatment arms with regards to 5-year disease-free and overall survival The NSABP CO-4 study essentially confirmed these results (8) The QUASAR Collaborative Group study confirmed the survival advantage provided by leucovorin modulation over levamisole.(9) Based on the results of these studies, the new standard for treatment was changed to 6 months of adjuvant chemotherapy with 5-FU/ leucovorin for stage III, node-positive disease
Until recently, this course of therapy was the standard of care for patients with advanced colorectal cancer However, with increas-ing understandincreas-ing of the molecular basis of cancer and the devel-opment of biologic-based therapy, chemotherapy for CRC has evolved once more and a variety of new agents are now available
to treat this disease
Oxaliplatin-Containing Regimens (FOLFOX, XELOX)
Oxaliplatin inhibits DNA replication through creation of bulky DNA adducts It was first introduced to treat patients with recurrent or meta-static colorectal cancer that was otherwise unresectable A study of 795 patients enrolled by Intergroup N9741 compared FOLFOX (oxalipla-tin and infused fluorouracil plus leucovorin) to either IFL (irinotecan and bolus fluorouracil plus leucovorin) or IROX (irinotecan and oxali-platin) to show that patients treated with FOLFOX had an increased median survival of 19.5 months (compared to 15 and 17.4 months in
Trang 4chemotherapy for colon and rectal cancer
the control arms) and an increased time to progression: 8.7 months as
compared to 6.9 and 6.5 months in the two control arms.(10) Given
the improved response rates with FOLFOX in metastatic disease, the
MOSAIC trial of 2,246 patients compared this regimen to the
stand-ard 5-FU leucovorin regimen in the adjuvant setting of resected colon
cancer After a median follow-up of 56.2 months, the 3 year
disease-free survival in the FOLFOX group was 76.4% (compared to 69.8%
observed in 5-FU/leucovorin group).(11)
On the strength of these results, FOLFOX is now the most
popular first-line therapy for the adjuvant treatment of resected
CRC and for metastatic CRC In patients interested in avoiding
IV infusions, the combination of capecitabine and oxaliplatin
(XELOX) may be used Capecitabine is the prodrug to 5-FU, and
is administered orally
Irinotecan-Containing Regimens (FOLFIRI, IFL, IROX)
Irinotecan inhibits DNA replication and transcription via
topoi-someraze blockade Irinotecan has been shown to have activity
against CRC, though its effects are less pronounced than those
of oxaliplatin IFL therapy (5-FU, leucovorin and irinotecan) has
been shown to be superior to 5FU/leucovorin therapy alone in
patients with metastatic colorectal cancer.(12) However, the N9741
Intergroup trial described above showed that patients treated with
FOLFOX had superior results to those treated with FOLFIRI (5-FU
and irinotecan), or IROX(irinotecan and oxaliplatin).(10) Based
on the results of this and other studies irinotecan containing
com-binations are now mostly used as second line therapy.(13)
Bevacizumab (AVASTIN®)
Bevacizumab (a monoclonal antibody that binds to the vascular
endothelial growth factor (VEGF) ligand) is one of the first biologic
therapy agents shown to be effective against CRC Bevacizumab, which blocks angiogenesis, was first found to improve efficacy of FOLFOX alone in patients with metastatic disease: the median dura-tion of survival for the group treated with FOLFOX and bevacizu-mab was 12.9 months compared with 10.8 months for the group treated with FOLFOX alone.(14, 15) Additional information on the feasibility and efficacy of bevacizumab in combination with FOLFOX
or other oxaliplatin combinations was gleaned in the TREE-2 trial, where the percentages of patients with progressive disease decreased substantially in all arms when bevacizumab was added.(16)
Cetuximab (ERBITUX®)
Cetuximab (a monoclonal antibody blocking epidermal growth factor (EGFR) is currently approved only as therapy as a single agent or in combination with irinotecan for patients with previ-ously treated advanced colorectal cancer A number of recently published trials suggested that patients treated with cetuximab have a longer time to disease progression, and this effect is aug-mented with addition of bevacizumab.(17)
indiCations and tiMing of CheMotherapy for ColoreCtal CanCer
Adjuvant Chemotherapy for Stage III and Stage IV Colon Cancer
While surgical resection is the only curative treatment for local-ized colon cancer, the 5-year survival rates vary from 93% in the patients with Stage I disease to 44% in patients with Stage III disease (Table 29.1) For the patients who have undergone potentially curative resection, disease recurrence is thought
to derive from clinically occult micrometastases The goal of
Table 29.1 American Joint Committee on Cancer (AJCC) colon cancer staging versus survival (37).
I T1
(tumor invades submucosa)
T2
(tumor invades muscularis propria)
N0
(no regional lymph nodes metastasis)
M0
(no evidence of distant metastasis)
93%
IIA T3
(tumor invades through muscularis propria into subserosa or nonperitonealized pericolic tissues)
IIB T4
(tumor directly invades into other organs and/or perforates visceral peritoneum)
IIIA T1
T2
N1
(metastasis to 1–3 regional lymph nodes)
IIIB T3
T4
(metastasis to four or more regional lymph nodes)
(distant metastasis)
8%
Trang 5improved outcomes in colon and rectal surgery
postoperative (adjuvant) chemotherapy is to eradicate these
micrometastases
Adjuvant chemotherapy for colon cancer has been studied for
at least 40 years Interestingly, 5-FU monotherapy did not improve
5-year survival following curative resection.(18) However, the
discovery of modulators of 5-FU activity and of the effects of
combination regimens on survival reignited the interest in
adju-vant chemotherapy The first large-scale trial to demonstrate a
sur-vival benefit for adjuvant chemotherapy in colon cancer, National
Surgical Adjuvant Breast and Bowel project (NSABP) C-01 included
1,166 patients with Dukes’ B or C colon cancer.(19) The patients
randomized to adjuvant MOF chemotherapy instead of surgery
alone had significant improvement in their 5-year overall survival
These improvements became even more pronounced as advances
in chemotherapy described earlier and postoperative (adjuvant)
systemic therapy has become routine and standard for node
posi-tive or metastatic disease Clinical data indicates that access to a
multidrug regimen consisting of two or more of the agents
dis-cussed earlier (in addition to 5-FU therapy) has almost doubled
median survival in the patients with advanced colorectal cancer
from 10–12 months to more than 20 months
Adjuvant Chemotherapy for Stage II Colon Cancer
In contrast to the clear benefit of adjuvant chemotherapy for patients
with node-positive disease, its role in resected stage II colon cancer
remains controversial While a number of clinical trials have included
stage II patients and have suggested a benefit from adjuvant therapy,
none of these have reached statistical significance Several
meta-analyses have been performed to evaluate this question further An
NSABP analysis of the data pooled from the adjuvant C-01, C-02,
C-03 and C-04 trials of 3,820 patients (1,556 with T3N0 disease)
suggested that the relative reduction in recurrence and mortality
from adjuvant therapy for patients with resected T3N0 colon cancer
was comparable to that seen in patients with node-positive disease
(20) In contrast, a 2004 systematic review by the Ontario Cancer
Care Program did not find a statistically significant improvement in
survival in the T3N0 patients treated with at least one 5-FU
chemo-therapy regimen after surgery.(21) In hopes of settling this debate, a
panel of the American Society of Clinical Oncology reviewed all the
pertinent information in regards to this issue.(22) This panel
con-cluded that routine use of adjuvant chemotherapy for medically fit
patients with stage II colon cancer is not recommended
Parenthetically, the panel also felt that selected patients with
stage II disease—such as patients with inadequately sampled
nodes, T4 lesions, perforation, or poorly differentiated
histol-ogy—could still be considered for adjuvant therapy.(22, 23) The
identification of patients with stage II colon cancer who might
benefit from adjuvant chemotherapy is an area of ongoing
research The prognostic value of additional molecular markers,
such as microsatellite instability and loss of 18Q allele is being
investigated (http://cancer.gov)
Neoadjuvant Chemoradiotherapy for T3
or Node-Positive Rectal Cancer
The management of rectal cancer is radically different from the
management of colon cancer While recommendations for
adju-vant postoperative therapy for advanced colon cancer are based
on the pathological stage revealed by the surgical specimen, rectal cancer staging determines initial management This, after much debate, is based on conclusive evidence that has clearly shown neo-adjuvant preoperative therapy to improve local control, disease-free survival, and overall survival compared to surgery alone or
to postoperative adjuvant therapy
The Swedish Rectal Cancer Trial examined whether neoad-juvant preoperative radiation therapy was of benefit to patients with advanced rectal cancer The study randomly assigned 1,168 patients to receive or not receive radiation therapy prior to sur-gery After 5 years, preoperative radiation therapy was associated with significant improvements in both local control (89% vs 73%) and overall survival (58% vs 48%).(24)
The German Rectal Cancer Trial examined whether radiation
is more beneficial before or after surgery The study randomly assigned 823 patients with clinically staged T3/T4 or node-positive rectal cancer to either neoadjuvant or adjuvant chemoradiotherapy With a 46 month median follow-up, preoperative chemoradiother-apy was associated with a significantly lower local recurrence rate (6% vs 13%), though the 5-year disease-free and overall survival rates were similar.(25) These two studies made preoperative radio-therapy for advanced rectal cancer the standard of care
At least two randomized trials have directly assessed the poten-tial benefits of concurrent chemotherapy with neoadjuvant radi-otherapy A European trial randomly assigned 762 patients with T3/4 rectal cancer within reach of the digital rectal exam to either preoperative radiotherapy alone or preoperative chemoradio-therapy At a median 69 month follow-up, the combined modality group had lower local recurrence rates (8.1% vs 16.5 %), but the rate of sphincter preservation surgery and 5-year overall survival rates were similar.(26) Another study, EORTC 22921 showed a similar benefit with chemoradiotherapy enhancing local control
in comparison to radiotherapy alone.(27) Based on these studies, neoadjuvant chemoradiotherapy is generally considered in all patients with T3 N0 and node positive tumors of any T stage Stage of the disease determines the need for neoadjuvant therapy Because of this, the importance of pre-treatment staging of rectal tumors becomes paramount and can-not be overemphasized The standard of care now dictates that all patients with rectal cancer should undergo a staging endorec-tal ultrasound or pelvic MRI to determine initial management Tumors penetrating into perirectal fat and/or lymph nodes should undergo neoadjuvant chemoradiotherapy Tumors that do not penetrate through muscularis propria (T1-2, N0) are candidates for initial surgical resection If the final pathological stage con-firms the stage suspected on imaging, no further chemotherapy (and/or radiation) is indicated However, if the final pathology reveals penetration into perirectal fat or into the lymph nodes, postoperative chemoradiotherapy is indicated
Adjuvant Chemotherapy Alone for T3
or Node-Positive Rectal Cancer
The benefit of 5-FU based postoperative chemotherapy in patients undergoing chemoradiotherapy has not been studied in prospec-tive randomized trials However, in EORTC trial 22921, patients who had received preoperative radiotherapy with or without chemotherapy were then further randomized to postoperative
Trang 6chemotherapy for colon and rectal cancer
chemotherapy versus no further therapy.(27) In the entire group,
there were trends favoring adjuvant chemotherapy in both 5-year
progression free survival (58% vs 52%), and overall survival
(67% vs 63%), but the trends were not statistically significant,
Nevertheless, these results are frequently quoted as justification of
adjuvant chemotherapy for patients treated with or without
preop-erative chemoradiotherapy Further information of the benefits of
postoperative chemotherapy are expected from the multicentre
British CHRONICLE trial.(28)
side effeCts of CheMotherapy
The benefits of modern chemotherapy with regards to its
abil-ity to delay disease progression and improve survival in patients
with advanced colon and rectal cancer are unquestionable
Nonetheless, these benefits should be balanced against individual
patient tolerance to the side effects of chemotherapy (Table 29.2),
as this may impact therapeutic effectiveness The elderly and the
medically compromised patients represent a group at particular
risk Very few elderly patients or patients with renal/hepatic
fail-ure or other major comorbidities have been enrolled in clinical
trials; the choices of therapeutic regimens in these subgroups
should be tailored to individual patients
5-FU/leucovorin alone is fairly well tolerated, and the
most commonly described side effects are those of diarrhea,
stomatitis, vomiting and nasea These side effects become much more pronounced when mutidrug chemotherapy regimens are used For example, addition of oxaliplatin to 5-FU, which is the most common first line chemotherapy regimen currently used in the US to treat colorectal cancer (FOLFOX), leads to an increased rate of diarrhea, nausea and vomiting, as well as alopecia In addition, the rates of significant neutropenia become relatively high One of the clinically relevant side effect of oxaliplatin-based chemotherapy is a late-onset predominantly sensory neuropathy with may require drug discontinuation despite ongoing tumor response Ultimately, more than 50 percent of patients receiving FOLFOX discontinue treatment for reasons other than disease progression.(29)
Multidrug combinations adding irinotecan, or bevacizumab to the standard 5-FU can cause serious toxic events, mainly severe hematological toxicity, diarrhea, thrombotic events, and neu-rosensory disorders.(30) The 5-FU, leucovorin, irinotecan, plus bevacuzimab regimen especially, while having the highest proba-bility of improving survival, might also lead to significant adverse effects to as many as 84.9% of patients, including a 1.5% chance
of gastrointestinal perforation.(30) While these side effects are temporary in patients undergo-ing adjuvant treatment for nonmetastatic disease, their effect on quality of life becomes quite important when the treatments are continuous and indefinite, as is the current practice in the patients with metastatic disease One potential way of reducing treatment-related side effects in this cohort is via a “chemotherapy holiday”, but the impact of a completely chemo-free interval on long term survival is of significant concern Two European phase II trials, OPTIMOX1 (which compared continuous FOLFOX versus main-tenance chemotherapy with 5-FU/leucovorin) and OPTIMOX2 (which compared maintenance chemotherapy using a nonoxali-platin regimen versus a totally chemotherapy free interval) were designed to address some of these concerns.(31, 32) Their results unfortunately suggested that a full break in therapy resulted in a decrease in overall survival and that some form of maintenance treatment is preferable to chemotherapy-free intervals
future direCtions
One of the major drawbacks of the current chemotherapy regimens for colorectal cancer is our inability to identify before treatment which patient will respond to a particular combination of chemotherapy drugs Knowledge of tumor gene expression and other biomarkers will hopefully provide clues and inroads in this direction Microarray profiling of gene expression in colorectal cancer patients has already been shown to stratify risk and predict lymph node involvement.(33) Just like in patients with breast cancer, patients with CRC might soon be screened in a prospective fashion to determine those with stage III disease that are unlikely to recur or those who may be resistant to a particular drug regimen
A promising area for colorectal cancer treatment is immuno-therapy The goal of cancer immmunotherapy is to stimulate the body’s immune system in order to improve host defense mecha-nisms against growing tumors, through either cell mediated or humoral immunity pathways Over 25 different vaccines, virus-modified tumor cells, gene-virus-modified tumor cells, tumor-antigen derived peptides, tumor lysates, proteins or carbohydrates have
Table 29.2 Side Effects and Mechanism of Action of Commonly
Used Chemotherapeutic Agents
Chemotherapy
agent Mechanism of action Common side-effects
5-FU Inhibits DNA synthesis via
blockage of thymidylate synthase
Heartburn, nausea, vomiting, anorexia, stomatitis, esophagitis, diarrhea, myelosuppression, cardiac toxicity
Oxaliplatin Inhibits DNA replication
through creation of bulky DNA adducts
Peripheral neuropathy, anemia,
thrombocytopenia, neutropenia, nausea, diarrhea, vomiting, abdominal pain, fatigue Irinotecan Inhibits DNA replication
and transcription via topoisomeraze blockade
Alopecia, diarrhea, nausea, emesis, severe myelosupression, colitis, gastrointestinal ulceration, gastrointestinal bleeding, ileus
Bevacizumab
(Avastin®)
A monoclonal antibody
that binds to the vascular endothelial growth factor (VEGF) ligand and inhibits tumor blood supply growth
Alopecia, thrombosis, bleeding, hyperkalemia, hypertension, abdominal pain, anorexia, vomiting, diarrhea, neutropenia, delayed wound healing and wound dehiscence, bowel perforation Cetuximab
(Erbitux®)
A monoclonal antibody
that blocks epidermal growth factor (EGFR) and decreases tumor growth
Fatigue, confusion, pruritis, insomnia, abdominal pain, nausea, vomiting, diarrhea,weakness, lung disease, dyspepsia
Trang 7improved outcomes in colon and rectal surgery
been studied in Phase I and II studies Three large studies
look-ing at the immune stimulation with autologous irradiated tumor
vaccine plus BCG in colorectal cancer patients suggest that this
approach may have merits For example, one study randomized 98
patients with colon or rectal cancer treated surgically to vaccination
with autologous irradiated tumor plus BCG versus placebo While
the study did not find a significant difference in the outcomes
between the two arms, a subset analysis of the colon cancer patients
did show an improvement in disease-free survival.(34) Similarly,
Eastern Cooperative Oncology Group (ECOG) randomized stage
II and II colon cancer patients to surgery alone versus surgery and
vaccine and found that patients with a marked delayed cutaneous
hypersensitivity response had a trend toward better disease-free
and overall survival.(35) Finally a study of 244 patients with colon
cancer randomized to receive a postoperative vaccine showed that
the overall risk for recurrence was decreased by 44% in all
vacci-nated patients, with a 61% reduction in stage II patients.(36)
ConClusion
In the past 20 years, advances in the adjuvant treatment of colon
and rectal cancer have significantly increased the rates of
disease-free and overall survival, increased survival rates in metastatic
disease, and decreased the rates of recurrence Ongoing research
focuses on developing more potent chemotherapeutic agents and
on identifying patients who may best benefit from those advances
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13 Hriesik C, Ramanathan RK, Hughes SJ Update for surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum J Am Coll Surg 2007; 205(3): 468–478
14 Giantonio BJ, Levy DE, O’Dwyer PJ et al A phase II study
of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced col-orectal cancer: results from the Eastern Cooperative Oncology Group study E2200 Ann Oncol 2006; 17(9): 1399–403
15 Giantonio BJ, Catalano PJ, Meropol NJ et al Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal can-cer: results from the Eastern Cooperative Oncology Group Study E3200 J Clin Oncol 2007; 25(12): 1539–44
16 Hochster HS Bevacizumab in combination with chemother-apy: first-line treatment of patients with metastatic colorec-tal cancer Semin Oncol 2006; 33(5 Suppl 10): S8–14
17 Saltz LB, Lenz HJ, Kindler HL et al Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refrac-tory colorectal cancer: the BOND-2 study J Clin Oncol 2007; 25(29): 4557–61
18 Buyse M, Zeleniuch-Jacquotte A, Chalmers TC Adjuvant therapy of colorectal cancer Why we still don’t know JAMA 1988; 259(24): 3571–78
19 Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01 J Natl Cancer Inst 2004; 96(15): 1128–32
20 Mamounas E, Wieand S, Wolmark N et al Comparative efficacy of adjuvant chemotherapy in patients with Dukes’
B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant stud-ies (C-01, C-02, C-03, and C-04) J Clin Oncol 1999; 17(5): 1349–55
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radio-therapy with or without concurrent fluorouracil and
leu-covorin in T3-4 rectal cancers: results of FFCD 9203 J Clin
Oncol 2006; 24(28): 4620–5
27 Bosset JF, Calais G, Mineur L et al Enhanced tumorocidal
effect of chemotherapy with preoperative radiotherapy for
rectal cancer: preliminary results–EORTC 22921 J Clin Oncol
2005; 23(24): 5620–7
28 Glynne-Jones R, Meadows H, Wood W Chemotherapy or
no chemotherapy in clear margins after neoadjuvant
chemo-radiation in locally advanced rectal cancer: CHRONICLE
A randomised phase III trial of control vs capecitabine
plus oxaliplatin Clin Oncol (R Coll Radiol) 2007; 19(5):
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29 Seymour MT, Maughan TS, Ledermann JA et al Different
strategies of sequential and combination chemotherapy for
patients with poor prognosis advanced colorectal cancer
(MRC FOCUS): a randomised controlled trial Lancet 2007; 370(9582): 143–52
30 Hurwitz H, Fehrenbacher L, Novotny W et al Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 2004; 350(23): 2335–42
31 Tournigand C, Cervantes A, Figer A et al OPTIMOX1: a ran-OPTIMOX1: a ran-domized study of FOLFOX4 or FOLFOX7 with oxaliplatin
in a stop-and-Go fashion in advanced colorectal cancer–a GERCOR study J Clin Oncol 2006; 24(3): 394–400
32 Andre T, Tournigand C, Mineur L et al Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study Ann Oncol 2007; 18(1): 77–81
33 Croner RS, Peters A, Brueckl WM et al Microarray versus conventional prediction of lymph node metastasis in col-orectal carcinoma Cancer 2005; 104(2): 395–404
34 Hoover HC Jr, Brandhorst JS, Peters LC et al Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively random-ized trial J Clin Oncol 1993; 11(3): 390–9
35 Harris JE, Ryan L, Hoover HC Jr et al Adjuvant active spe-Adjuvant active spe-cific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283 J Clin Oncol 2000; 18(1): 148–57
36 Vermorken JB, Claessen AM, van Tinteren H et al Active spe-Active spe-cific immunotherapy for stage II and stage III human colon cancer: a randomised trial Lancet 1999; 353(9150): 345–50
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Trang 9Roland Hawkins
ChAllenging CAse
A 62-year-old man presents with blood per rectum He has mild
rectal discomfort with bowel movements and a feeling of
incom-plete evacuation Two years previously he received external beam
radiotherapy for prostate cancer His rectal examination is normal
except for some blood on the gloved finger A flexible
sigmoidos-copy demonstrates friable mucosa with neovascularity of the
distal 4 cm of rectum The mucosa is friable with telangectasia
ChAllenging CAse MAnAgeMent
The history and endoscopic exam is suggestive of radiation proctitis
Management includes fiber and topical therapy The friable areas of
the rectum can be treated with topical application of a large swab
soaked with 10% formalin passed through an anoscope or
proctos-cope Argon plasma coagulation is also effective treatment.
intRoduCtion
Apart from a few exceptional circumstances, radiation treatment
is used as an adjunct to surgical resection in the potentially
cura-tive treatment of adenocarcinoma of the rectum As such, it is
employed to reduce the tumor burden and eradicate deposits of
cancer in pelvic lymph nodes and soft tissue not removed, or not
expected to be removed, by the surgeon In this setting, radiation
treatment is administered either before or following en bloc
resec-tion of the involved length of large bowel by low anterior (LAR) or
abdominal perineal resection (APR) that is intended to remove all
evident disease, i.e., to be an R0 resection Preoperative treatment
is referred to as neoadjuvant or adjuvant, and postoperative
treat-ment as adjuvant These are usually administered to patients with
locally advanced but resectable stage II or III disease (Table 30.1)
Less often adjuvant radiation treatment is administered following
local excision of less advanced disease Local excision is elected in
patients with small distal rectal tumors to avoid APR or LAR
Recurrence after apparently curative surgery for rectal cancer
may develop in structures adjacent to the margin of resection or
regional nodes in the pelvis (local recurrence), or as metastasis
to the peritoneal surface or distant organs (distant recurrence) Treatment with radiation and/or chemotherapy added to sur-gery is judged as beneficial in so far as it increases overall patient survival and reduces the incidence of local and distant recur-rence Overall survival is the most important outcome in judging benefit It is unambiguously evaluable and reflects the balance of benefit and potentially lethal adverse effects of treatment Local
recurrence is not often salvagable Its prevention is important, if
not a requirement, for achieving cure of the disease It may itself
be life threatening and may act as a source of distant metastasis Further, uncontrolled recurrence in the pelvis is particularly det-rimental to the quality of life of patients who are not cured by the treatment by causing pain, bleeding, infection, obstruction and incontinence affecting bowel and urogenital organs Distant recurrence is important because it is the most unsalvageable life threatening form of treatment failure
Evolution of the method of radiation treatment over the past
30 years has produced what are now two more or less standard regimens, referred to here as the short and long treatment courses The short course has been used only for preoperative treatment
It typically consists of a dose of 25 Gy in fractions of 5 Gy each over a period of 5 to 7 days with surgery following within a week The long course has been used for both pre and postoperative treatment It typically consists of 45 to 54 Gy in fractions of 1.8
to 2 Gy over a period of 5 to 6 weeks When used preoperatively the long course is usually followed by about 6 weeks rest before surgery and may include concurrent chemotherapy
There are several ways to compare the intensity of radiation treatment courses that differ in fractionation of dose and are given over different time intervals One in current use consists of
calculating a biologically equivalent dose (BED) for each
treat-ment course using the relation: (1)
BED = nd
1 + da/b
- g a(T - T k)
Wherein n is the number of fractions, d is the dose per
frac-tion, a/b is a ratio characteristic of cell type or tissue and ranging from about 2 to 20 or more For meta-analysis overview of the effect of radiation in the treatment of rectal cancer a/b has been assumed to be about 10.(2, 3) The value of the g/a ratio corrects for the repopulation of cells during the length of the treatment course and has been assumed to be 0.6 Gy per day The value of
T is the time from first to last radiation fraction in days and T k is
a lag time taken to be 7 days With these parameters the BED of the short course of 5 fractions of 5 Gy each is 37.5 Gy and that of
a long course consisting of 50.4 Gy in 28 fractions of 1.8 Gy each
is 40.9 Gy, implying they are roughly equivalent The validity of equation 1 in establishing equivalency with respect to the chance
Table 30.1 Staging of rectal carcinoma.
dukes tnM group
tnM (AJCC and uiCC) description
A I T1N0M0
T2N0M0
Tumor limited to submucosa, Tumor into, not through, muscularis propria
B II T3N0M0
T4N0M0
Tumor through muscularis propria
Tumor invades other organs or through peritoneal serosa
C III N1 or N2, any T N1 (1 to 3 nodes +), N2 (>3
nodes +)
D IV M1, any T or N Distant metastasis
Trang 10radiation therapy: acute and late toxicity
of eliminating pelvic cancer or causing any specific organ injury
is dependent on the appropriateness to the specific endpoint in
question and of the values chosen for a/b, g/a and Tk
The physiologic death, disintegration, and disappearance of
nearly all cells lethally injured by radiation takes place only after
they and/or their descendents go through one or more, often
aberrant, mitotic cell divisions An exception to this is some
lym-phocyte subsets that die within hours of irradiation As a result
there is a time lag between irradiation and response of a cancer
that is variable and dependent on the mitotic activity of the
can-cer cells This lag ranges from a few days up to a year or more
for the various carcinomas A typical time to manifest the
maxi-mal response of a carcinoma to radiation is the order of a month
or two The same phenomenon is in part responsible for delay
of up to a year or more in the development of some forms of
radiation injury With short course preoperative radiation there
is little time for tumor response before surgery There is evidence
that at surgery after short course irradiation the average tumor
size and average number of nodes with metastatic carcinoma has
decreased slightly but this is not sufficient to produce a change in
the distribution of tumor or nodal stage in a study population.(4)
With long course preoperative irradiation more time is allowed
for response of the disease and down staging to occur This is
evident in some of the trials listed in tables 30.3 and 30.4 and was
demonstrated in a trial in which all patients were treated with 13
daily fractions of 3 Gy each and randomly assigned to surgery
within 2 weeks after the end of radiation or surgery 6 to 8 weeks
after radiation.(5)
With both the long and short course, radiation treatment is
directed at the pelvis with the superior border placed at about
the L5S1 interspace The inferior border is placed at least 3 to 5
cm below the most distal extent of tumor or below the obdura-tor foramen For distal tumors it may include all or part of the anal canal In earlier studies treatment was restricted to anterior-posterior directed beams.(6) More recently, laterally directed beams that exclude bowel in the anterior part of the pelvis are a standard part of treatment plans Only the volume in which the beams overlap is exposed to the full prescribed dose This usually includes, in addition to the rectum, small and large bowel in the posterior pelvis, the posterior part of bladder and prostate, the soft tissue in the ischiorectal fossa and presacral areas, the sac-rum and the lymph nodes of the internal iliac and most distal part of the common iliac chains If there is extension of tumor to invade urogenital organs the external iliac nodes are sometimes included After APR, the perineal incision, which tends to be a site
of recurrence, is included in the treatment volume.(7, 8) Tables 30.2, 30.3 and 30.4 summarize several trials in which ran-domization was between arms composed of various combinations
of pre and postoperative radiation and chemotherapy.(9–26) The radiation treatment plans in each are similar to either the short or long course described above and can be gleaned from the table by noting the dose shown When the dose is about 25 Gy it is a short course and when 40 to 60 Gy it is similar to the long course The benefits and adverse effects of preoperative and postoperative radia-tion treatment reported in these studies will be examined and com-pared Adjuvant treatment after local excision is also discussed
Benefit of AdJuvAnt And neoAdJuvAnt RAdiAtion tReAtMent
Several randomized trials of postoperative adjuvant therapy in the late 1970s and 1980s listed in Table 30.2 indicate that post-operative radiation and chemotherapy can lead to statistically
Table 30.2 Postoperative adjuvant radiation studies.
Study Open/Closed
number
of Pts therapy Arms
local (Pelvic) Recurrence % at 5 years
overall survival
% at 5 years Comments
GITSG (9) 202 S
S–C S–44Gy S–44Gy-C
24 27 20 11
46 56 52
59 (p = 0.07)
T3,T4 or N+
Semustine and 5Fu
NCCTG (10)
794751
204 S–50.4Gy S–50.4Gy+C
25
13 (p = 0.036)
47
57 (p = 0.02)
Semustine and 5Fu.
NSABP (11)
R-01
11/77 to 10/86
555 S S–46Gy S–C
25
16 (p = 0.06)
21.4
43 41
53 (p = 0.01)
Semustine, 5Fu, vincristine
Norway (12, 13) 144 S
S–46Gy+C
30
12 (p = 0.01)
50
64 (p = 0.05)
Bolus 5Fu on 6 days during radiation
NSABP (14)
R-02
694 S–C S–50.4Gy+C
14
8 (p = 0.02)
58 58
Semustine, 5Fu, vincristine
in 10 week cycles or 5Fu and leukovorin in 8 week cycles
Retrospective
Study of Trans
anal excision (15)
MGH/Emory
99 LE (T1) LE–xrt (T1) LE–(T2) LE–xrt (T2)
11 0.0 67
15 (p = 0.004)
Concurrent chemotherapy for some patients
RTOG 8902 (16) 65 LE (T1, fav)
LE-xrt (T1,2,3)
14.3 17.6
86 72
fav = favorable features, see text
S indicates LAR or APR, LE is local excision, C is chemotherapy A dose in Gy indicates irradiation The dash line shows time sequence.