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430 R. Bleday and J. Garcia-Aguilar
respectively. These rates are equivalent to those seen for
transanal excision, but again comparison is difficult because
of the differences in patient population, adjuvant therapy, and
tumor characteristics (Table 30-5).
Recommendations
Patient selection is arguably the most important factor for
obtaining comparable oncologic results with local excision or
TEM versus APR in the treatment of low rectal cancers. All
patients should receive a thorough history and physical
including a digital rectal examination to assess the distance of
the tumor from the anal verge, as well as its size and mobility. Ideally, tumors should be <4 cm in diameter and occupy
<40% of the bowel circumference. Tumors within 5 cm from
the dentate are amenable to resection via a transanal procedure, whereas more proximal tumors may require a TEM or
transcoccygeal approach if an LAR is not feasible. Immobile
tumors are not candidates for local excision because they are
likely transmural. The overall health of the patient must be
taken into account, because medically unfit patients are often
good candidates for local excision. Even T2 and T3 lesions in
these patients can be locally excised, accepting a higher rate
of local recurrence for lower rates of morbidity and mortality.
In this setting, these patients should receive adjuvant
chemoradiotherapy and close follow-up.
After a thorough history and physical, all patients should
undergo preoperative ERUS or eMRI to assess for transmural
spread and regional lymphadenopathy. Tumors with evidence
of nodal involvement should be considered advanced disease,
and should be treated with a radical resection, either an APR
or LAR with low pelvic anastomosis. T1 lesions have a very
low probability of regional nodal involvement and are excellent candidates for local excision, whereas the opposite is true
for T3 and T4 lesions, which should be treated via radical
resection. The treatment of T2 lesions is somewhat controversial. Historically, better results have been seen with APR
for T2 lesions; however, local excision with postoperative
chemoradiation seems to be yielding similar results. If local
excisions is offered to patients with T2 lesions, either preoperative or postoperative chemoradiation therapy should be
part of the treatment plan.
CT scans of the abdomen and pelvis should be obtained in
order to look for any signs of distant spread. PA and lateral
TABLE 30-6. Treatment recommendations after initial resection
T stage Low risk
T1 No further treatment Adjuvant chemoradiation
T2 Adjuvant chemoradiation Radical resection
T3 Radical resection Radical resection
*
Low risk: well or moderately differentiated with no evidence of lymphatic or
vascular invasion.
†High risk: poorly differentiated or lymphatic invasion or vascular invasion.
*
High risk†
views of the chest are necessary for similar reasons. In the
presence of incurable distant metastases, there is a role for
local excision for small T2 and T3 lesions, because these
patients are likely to succumb to their distant disease before
local recurrence causes any major problems. A full
colonoscopy should also be performed preoperatively to
assess for any synchronous polyps or carcinomas.
After this thorough preoperative evaluation has been completed, patients may then undergo local excision. Surgical
margins should be 1 cm, although the key factor is a negative
margin regardless of size. These excisions must be full thickness and include some perirectal fat. Local excisions are still
considered total excisional biopsies, because final therapy
awaits pathologic evaluation. After excision, these tumors
should be evaluated for surgical margins, depth of invasion,
histologic grade, and vascular or lymphatic invasion. Tumors
with positive margins must be treated with additional therapy,
either via reexcision, chemoradiation, or radical resection.
Tumors are then categorized into low or high risk based on
their level of differentiation and the presence or absence of
vascular or lymphatic invasion. Patients with low-risk T1
lesions do not receive any additional therapy, whereas patients
with high-risk T1 lesions and low-risk T2 lesions are given
adjuvant chemoradiation. Patients with high-risk T2 and any
T3 lesions should undergo radical resection (Table 30-6).
Close follow-up is essential for all patients in order to detect
local recurrence as early as possible.
Other Local Techniques
Small rectal cancers can be treated definitively using electrocoagulation or endocavitary radiation (ecRT). Electrocoagulation uses standard electric cautery to ablate the tumor,
frequently with a specialized operating proctoscope. ecRT is
TABLE 30-5. Transanal endoscopic microsurgery
Author No. of patients Treatment arms Follow-up Local recurrence Survival
Lezoche 35 (All T2) All had preop 50 Gy Median 38 mo 1/35 (2.85%) Probability of survival
101
et al.
Farmer 49 (36 Tis, 10 T1, All TEM Median 33 mo 2/49 (5.6%) 1 patient 1 death from disseminated
102
et al.
Azimuddin 21 (7 Tis, 9 T1, 5 T2) All TEM Mean 15 mo 0% for T0 and T1 100% for all grades
de Graaf 76 (32 Tis, 21 T1, All TEM Median 10 mo, mean Tis = 0%, T1 = 10%, 1 patient died yielding
103
et al.
3 T2, 1 T3) (20–48 mo) had a salvage APR cancer. Survival = 97.9%
18 T2, 5 T3) 13.9 mo (1–52 mo) T2 = 33%, and T3 = 0% overall survival of 98.7%
XRT then TEM (24–96 mo) at 96 mo = 83%
20% for T2
30. Surgical Treatment of Rectal Cancer 431
a high-dose low-voltage technique applied to a smaller rectal
cancer through a special proctoscope. Both techniques have
the disadvantage of not providing an intact specimen for histologic analysis. Treatment results using each technique have
not been evaluated in any prospective trial; however, recent
retrospective reviews
104,105
conclude that these two techniques
are good treatment options in carefully selected patients.
Survival after Rectal Cancer Excision
Overall 5-year survival rates for colorectal cancer have shown
improvement over recent decades with the combination of
better surgery and adjuvant therapy. Reports from 20 years
previous have assured us that a sphincter-sparing surgical
approach does not sacrifice survival in selected patients where
an adequate margin can be achieved.
106–108
Overall, 5-year
survival rates after major surgery for rectal cancer are as follows: Stage I, 85%–100%; Stage II, 60%–80%; and Stage III,
30%–50%.
57,66,106,109–115
Local excision of cancers confined to the rectal wall without lymphatic or distant spread (T1 and T2N0) can achieve
cure rates of 80%–100% as discussed previously; however,
the results published in retrospective trials are extremely
unreliable because many studies span decades, have no standard entrance criteria, and no standard adjuvant therapy policy. In some retrospective studies, local recurrence seemed
high but overall survival was not different than a comparative
group of patients who underwent radical resection.
93
Future
emphasis on earlier diagnosis, accurate preoperative staging,
and appropriate choice of resection procedure, combined with
improved adjuvant therapy, should influence favorably overall survival using this conservative technique.
Laparoscopically Assisted Resections for
Rectal Cancer
The application of laparoscopy for the treatment of intraabdominal malignancies including proctectomy for rectal cancer
is now being performed. In these operations, part of the procedure is done using the laparoscope and completion of the procedure is in the traditional manner. In particular, exploration
and mobilization of the colon and rectum can be done with the
laparoscope and laparoscopic instruments. Ligation of the vascular pedicle is performed with laparoscopic clips, vascular
stapling devices, or radiofrequency coagulation devices. The
pelvic dissection can be performed and well visualized laparoscopically in many patients. Most often, however, the actual
resection of the bowel and an anastomosis are still more easily
performed in an extracorporeal manner.
The main questions about laparoscopically assisted proctectomy for colorectal cancer are whether it provides the same
TME specimen as traditional open techniques, and whether
there is any other unique biologic alteration in the laparoscopic procedure that leads to a change in survival or in recurrence patterns. Concerning the latter point, there have been
several reports of unusual wound recurrences at trocar sites
in patients undergoing laparoscopic-assisted colectomy.
However, a randomized trial of open versus laparoscopically
assisted colon resection found no statistically significant dif-
116
ferences in survival.
In a recent article from the United
Kingdom, laparoscopically assisted LAR for rectal cancer
revealed an increased risk of a positive circumferential margin compared with open surgery.
117
Going forward, the use of
laparoscopy will increase with rectal resection; however, its
use will need to be monitored and studied to make sure that
the standard principles of a TME are adhered to.
Synchronous Cancers
Synchronous cancers of the large intestine occur with an incidence of approximately 3.5%.
are common with a primary cancer. If one finds two cancers
within the colon and rectum, then one must plan an approach
to the surgical resection that depends on the location of the
two lesions. Certainly, two resections and two primary anastomoses can be performed in large bowel surgery with a complication rate that is similar to that of just one anastomosis.
If a patient has a small rectal cancer that is amenable to local
excision along with a synchronous cancer of the colon, one
can consider a local excision of the rectal lesion followed by
primary resection of the colon lesion. It is important, however, to realize that surveillance after local excision of a rectal cancer needs to be more aggressive in monitoring for local
recurrence and metachronous cancers or precancers than after
resection of single bowel cancer.
118
Also, synchronous polyps
119
Extended Resection for Locally Advanced
Colon or Rectal Cancer
Carcinoma of the colon and rectum will sometimes invade
adjacent organs or the abdominal wall. When this occurs, it
has been shown that extended resection of the cancer along
with the tissue or organ that it has adhered to can lead to a
5-year survival rate of >50%, provided the surgical margins
are tumor free.
120,121
Patients with inflammatory adhesions to
contiguous organs have a slightly higher survival rate than
patients with malignant infiltration, but the distinction
between malignant and inflammatory contiguity often cannot
be made until after en bloc resection. The organs that are usually involved with adhesions from colon or rectal cancer
include the uterus, small bowel, urinary bladder, and abdominal wall. In general, approximately 5% of patients will
present with locally advanced lesions.
121
Surgical Treatment of Recurrent Colorectal
Carcinoma
Recurrent colorectal cancer affects between 12% and 50% of
patients with Dukes B or C (TT2N0 through T3NN1) disease.
Although adjuvant treatment has some effect on survival,
432 R. Bleday and J. Garcia-Aguilar
surgery remains the mainstay in treatment of recurrent disease. Most often, the intent of surgery for recurrent disease is
not curative, but to improve survival or palliate symptoms.
There are three main patterns of recurrence after resection of a
primary colorectal cancer. The most common site of recurrence is
the liver. However, isolated recurrences can also be seen locoregionally or in the lung. Although 60%–70% of patients who die
of colorectal cancer have liver metastasis, the liver is an isolated
site of recurrence in <20% of patients. Of the latter group, only
5%–10% will be candidates for curative hepatic resection.
Locoregional recurrence of rectal cancer has been decreasing over the past 2 decades. With the use of adjuvant therapy
and the wider application of TME, local failure has been
reported as low as 3%. However, when a patient develops a
local recurrence, it is often not just a suture line recurrence
but a regional recurrence. The workup of these patients
requires extensive imaging to identify features of the tumor
which would make it unresectable.
Wanebo et al.
vival after abdominal sacral resection for recurrent colorectal
cancer. They concluded that patients presenting after a long disease-free interval could benefit from such a large procedure.
Noncurative surgery has only a small role in the treatment of
symptomatic pelvic recurrence, particularly with sacral
involvement. Newer approaches such as cryoablation of perineal recurrences may replace heroic procedures and may be
useful in symptomatic relief of nonresectable pelvic recurrence.
123
demonstrated a 25% actuarial 5-year sur-
122
penetration, MRI to evaluate perirectal tissue involvement,
and CT scan to identify hepatic or pulmonary metastasis.
Laboratory Studies
Laboratory studies should be obtained as indicated by the
patient’s general condition and anesthetic requirements. The
measurement of baseline CEA is useful if postoperative monitoring is planned.
Treatment Considerations
Where possible, the patient should participate in the treatment
selection. They should understand the risks and benefits of
therapy including short-term and long-term outcome and
treatment alternatives.
Abdominoperineal Resection
This procedure is generally indicated for lesions of the lower
one-third of the rectum or for higher lesions where tumor characteristics and anatomic factors favor such resection. Where
possible, preoperative colostomy counseling is recommended.
Appendix: Practice Parameters for the
Treatment of Rectal Carcinoma
Prepared by the American Society of Colon and Rectal Surgeons
Preoperative Evaluation
A patient with a newly diagnosed rectal cancer requires
preoperative assessment to identify tumor stage and operative
risk factors that may affect the choice of the surgical procedure.
Examination
Digital rectal examination and sigmoidoscopy allow for the
assessment of tumor location, size, and fixation.
Synchronous colon malignancies or coexisting adenomatous polyps should be identified preoperatively, if possible.
Colonoscopy is preferred over barium enema.
Imaging Studies
Identifying the extent of local, regional, or distant metastasis
may be useful if the findings would modify the approach
to treatment. ERUS may be preferred to assess rectal wall
Sphincter-preserving Resection
These procedures are possible for the majority of patients
with rectal carcinoma. The choice of the anastomotic technique should be left to the discretion of the surgeon.
Transanal Procedures
Such procedures may be performed for cure in highly selected
patients with favorable tumor characteristics or for patients in
need of palliative therapy. These procedures include local
excision, electrocoagulation, endocavitary irradiation, and
laser ablation.
Hartmann’s Procedure
This procedure may be indicated for patients who present
with obstructed or perforated carcinoma and for patients in
whom colorectal anastomosis is clinically inadvisable.
Abdominal Transsacral Resection
The indication for this procedure has been largely supplemented by other sphincter-preserving resections. It provides
adequate treatment for mid rectal cancers in the hands of
surgeons experienced with this approach.
30. Surgical Treatment of Rectal Cancer 433
Adjacent Organ Resection
Contiguous organ resection should be considered in the
absence of metastatic disease.
Palliative Surgical Procedures
Such procedures, which may include contiguous organ resection, may be indicated to alleviate or significantly reduce the
patient’s symptoms caused by primary or recurrent tumor.
Adjuvant Therapy
Adjuvant chemotherapy or radiation therapy, preoperatively
or postoperatively, may be used in combination with surgical resection to potentially improve results for cure or for
palliation.
Reprinted from Dis Colon Rectum 1993;36(11):989–1006.
Copyright © 1993. All rights reserved. American Society of
Colon and Rectal Surgeons.
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31
Adjuvant Therapy for Colorectal Cancer
Judith L. Trudel and Lars A. Påhlman
Colon Cancer
The stage of disease at presentation remains the most important prognostic factor for colon cancer patients.
ease carries an excellent prognosis of more than 95% 5-year
survival rate, and surgical treatment alone is considered sufficient; adjuvant treatment is not indicated. In contrast, adjuvant treatment has repeatedly been shown to improve survival
for Stage III disease. The role of adjuvant treatment for Stage
II (node-negative) disease remains controversial.
Adjuvant Chemotherapy for Node-positive
Disease (Stage III)
Overall 5-year survival from curative surgery for Stage III
colon cancer is 30%–60%.
hence the need for systemic adjuvant treatment in these highrisk patients. Adjuvant chemotherapy improves survival by
approximately 10%–15%.
5-Fluorouracil (5-FU)/leucovorin (LV)-based adjuvant
chemotherapy for Stage III disease is the standard of care in
the United States today.
chemotherapeutic agents such as thiotepa or fluoropyrimidines did not prove helpful as adjuvant treatment of colon
cancer. Progressively, several combination trials of
chemotherapy and immune modulators helped refine the recommendations made for adjuvant treatment. In 1988, the
NSABP (National Surgical Adjuvant Breast and Bowel
Project) CO-1 trial documented a significant 8% improvement in overall 5-year survival for Stage II and Stage III disease when adjuvant chemotherapy with MOF (semustine,
vincristine, and 5-FU) was used.
Central Cancer Treatment Group) published a three-arm
randomized study of 401 Dukes’ Stage B and C patients
comparing surgical resection alone to levamisole and to 5-FU
plus levamisole. 5-FU plus levamisole significantly decreased
the recurrence rates and improved overall survival, particularly in Dukes’ C patients.
1
Recurrences are often systemic,
2
Historically, single-agent
3
In 1989, the NCCTG (North
4
The large Intergroup 0035 study
1
Stage I dis-
confirmed the efficacy of 5-FU plus levamisole in 971
5
patients with Dukes’ Stage C cancer in 1990
; death rates
were reduced by 33% (P = .0007), and recurrence rates by
40% (P < .0001). In 1990, the NIH (National Institutes of
Health) published a consensus statement establishing 5-FU
plus levamisole as the standard adjuvant therapy for Stage III
colon cancer.
6
A recent European study has confirmed a significant reduction of 25% in the odds of cancer death in Stage
III patients receiving adjuvant 5-FU and levamisole.
7
While the usefulness of 5-FU/levamisole in Stage III disease was being confirmed, LV emerged as a beneficial agent
for the treatment of metastatic disease. Its applicability to
Stage II and Stage III disease was confirmed by the IMPACT
(International Multicenter Pooled Analyses of Colon Cancer
Trials) study of 1526 patients, published in 1995. In this
study, 3-year disease-free survival increased from 62% to
71% (P = .0001) whereas overall survival increased from 78%
to 83% (P = .029) in the 5-FU/LV group compared with surgical controls.
8
The NSAPB C-03 randomized trial of 1081
Stage II and Stage III patients comparing MOF to 5-FU/LV
had documented a similar advantage of 5-FU/LV, with a
3-year disease-free survival increase from 64% to 73%
(P = .0004) and an overall survival increase from 77% to
84% (P = .003) in the 5-FU/LV group compared with MOF.
9
The relative merits of levamisole and LV as modulators of
5-FU-based adjuvant chemotherapy, and the optimal duration
of treatment were investigated in several studies published
between 1998 and 2000. The NCCTG/NCIC (National
Cancer Institute of Canada)
10
study of 915 patients compared
6 months 5-FU/levamisole; 6 months 5-FU/LV/levamisole;
1 year 5-FU/levamisole; and 1 year 5-FU/LV/levamisole.
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 with 5-FU/levamisole. The Intergroup trial 0089 of 3759 patients compared
1 year 5-FU/levamisole; 5-FU/high-dose LV for 32 weeks; and
5-FU/low-dose LV with or without levamisole for six cycles.
11
There were no differences between the four treatment arms
437
438 J.L. Trudel and L.A. Påhlman
with regard to 5-year disease-free and overall survival. The
NSABP CO-4 study
13
study
have later confirmed the survival advantage provided
12
and the QUASAR Collaborative Group
by LV modulation over levamisole. Based on the results of
these studies, the new standard for treatment was changed to
6 months of adjuvant chemotherapy with 5-FU/LV for Stage
III, node-positive disease.
The newer chemotherapeutic agents currently under study
or in use for treatment of metastatic disease (e.g., irinotecan,
capecitabine, oxaliplatin) are undergoing evaluation for their
usefulness in the adjuvant treatment of patients with Stage II
and Stage III disease. Recent data from the multicenter international randomized MOSAIC trial have confirmed that the
addition of oxaliplatin to 5-FU/LV (FOLFOX) further
decreases the risk of recurrence in Stage II and Stage III disease by 23%, resulting in a significant improvement in 3-year
disease-free survival.
14
Another important trial, the PETACC
3 trial, will soon report the results. In that trial 5-FU/leucovourin is compared with irinotecan to 5-FU/LV (FOLFIRI) in
both Stage II and Stage III colon cancer.
Several tumor characteristics such as microsatellite instability and the expression of DNA synthesis-associated
enzymes have recently been found to predict chemoresistance
to 5-FU and irinotecan.
15,16
This is an area of research that is
evolving rapidly, and will certainly change the recommendations for adjuvant treatment in both node-positive and nodenegative disease.
Adjuvant Chemotherapy for Node-negative
Disease (Stage II)
Whereas the efficacy and benefits of adjuvant chemotherapy
for Stage III node-positive disease is unequivocally documented through numerous randomized trials, the role of adjuvant chemotherapy for Stage II node-negative disease is still
controversial. The data from the early studies that prompted the
NIH recommendation for adjuvant treatment in Stage III disease did not support a similar recommendation for Stage II dis-
4,5
ease.
The IMPACT-B
B
five trials conducted from 1982 to 1989 and regrouping 1016
patients with Stage B
death rates, 5-year event-free survival and overall survival were
similar in patients treated with adjuvant 5-FU/LV compared
with controls. Increasing age and poor tumor differentiation
were indicators of poor prognosis.
analysis of 3700 patients with resected Stage II colon cancer
did not reveal any improvement in 5-year survival in patients
having received adjuvant chemotherapy compared with controls (74% versus 72%).
NSABP trials (CO1, CO2, CO3, and CO4) with widely different treatment and control arms regrouping 1565 patients with
Dukes’ B disease (Stage II) and 2255 patients with Dukes’ C
disease (Stage III) concluded that patients with Dukes’ B
Recent metaanalyses have yielded conflicting results.
(International Multicenter Pooled Analysis of
Colon Cancer Trials) Group published a pooled analysis of
2
2
colon cancer.17Relapse rates, all-cause
2
17
A SEER-Medicare cohort
18
In contrast, a pooled analysis of four
disease (Stage II) should be offered adjuvant chemotherapy.
The authors calculated a 30% relative reduction in mortality for
Stage II patients having received adjuvant chemotherapy. That
metaanalysis has since been widely criticized for its methodologic flaws, and the controversy rages on. The likelihood of
reaching a resolution on this subject is remote: to detect a significant survival benefit among Stage II colon cancer patients
(who have an estimated 5-year survival of 80%), an adjuvant
trial with a no-treatment control arm would require a sample
size of 5000–8000 patients.
20
The recent data from the
MOSAIC trial showing a significant improvement of 3-year
disease-free survival and a 23% reduction of recurrence risk
using a combination of 5-FU/LV/oxaliplatin (FOLFOX) in
Stage II disease will undoubtedly spur renewed interest in this
14
debate.
At this time, the use of adjuvant chemotherapy for
Stage II node-negative disease remains an unanswered question, mainly because the prognosis for Stage II node-negative
disease is good overall, and many patients would face unnecessary treatment. For the time being, patients with Stage II colon
cancer at high risk for tumor recurrence might be considered
for adjuvant treatment on an individual basis, or might be
entered in a clinical trial.
Radiotherapy
Local recurrence of rectal cancer after surgery with curative
intent has always been recognized as a significant clinical
problem. Combined chemoradiotherapy has been shown to
increase both local control and survival for patients with
locally advanced and node-positive rectal cancer.
trast, although local failure and recurrence after surgery for
colon cancer had been described, there long existed an
unwritten consensus that treatment failures in colon cancer
surgery were primarily systemic rather than local. Thus, no
prospective, randomized study was devised to provide data on
the role of external beam radiotherapy in preventing local
recurrence or improving survival after colon surgery. The
recognition that selected individuals with colon cancer were
at a high risk for local recurrence eventually came from retrospective reviews of patterns of failure after surgery with curative intent. Two large retrospective reviews
the risk factors for local recurrence after surgery for colon
cancer. Locoregional failure was identified in 19%
of patients overall; at least half of local recurrences were in
the original tumor bed. Only 13% of the local recurrences
22
were salvageable surgically.
The most important risk factors
for local recurrence were: 1) pathologic staging, with local
recurrence rates of 35% in modified Astler-Coller Stages B3,
C2, or C3 versus 7% in Stages A, B1, and C1
tumor localization in a fixed, nonperitonealized segment of
the colon, with the highest failure rates in the cecum,
descending colon, hepatic or splenic flexures, and sigmoid
22,23
colon
; 3) colon carcinoma complicated by perforation or
obstruction, with a two- to three-fold increase in local recurrence for any given pathologic stage.
22
22,23
helped define
22
2
; 2) primary
21
In con-
to 46%
19
23
31. Adjuvant Therapy for Colorectal Cancer 439
Identification of individuals at high risk for local recurrence after curative surgery for colon cancer triggered a number of studies on the role of external beam radiotherapy in
preventing local recurrence or improving survival after colon
surgery. Several disparate single-institutional retrospective
studies suggested an improvement in local failure and recurrence rates with adjuvant radiotherapy compared with historical controls.
25–26
Wide variations in radiation techniques and
doses, concurrent use and choice of chemotherapy, and
patient selection criteria make comparison among studies difficult. Overall, local control rates ranged from 60% to 88%, a
significant improvement over controls treated by surgery
alone. A single randomized prospective study initiated jointly
by the NCCTG and RTOG, comparing chemotherapy alone
with F-FU/levamisole versus combined chemotherapy/radiotherapy closed prematurely because of poor accrual; although
no differences were observed in overall survival between
treatment arms, the study lacked sufficient statistical power to
draw valid conclusions.
27
At this time, the precise role of adjuvant radiotherapy in the
treatment of colon cancer remains undefined. There are no
data to support a systematic recommendation for therapy or a
well-recognized adjuvant regimen. The potential risks of
adjuvant radiotherapy for colon cancer, particularly radiation
damage to surrounding organs (e.g., small bowel) are significant. Treatment for individuals deemed at high risk for local
recurrence after curative surgery for colon cancer should be
individualized.
Immunotherapy, Tumor Vaccines, and
Gene Therapy
The goal of cancer immunotherapy treatments is to stimulate
the body’s immune system in order to improve host defense
mechanisms against growing tumors. Colorectal cancer
immunotherapy strategies have evolved dramatically over the
past 30 years. Nonspecific immune stimulation with bacterial
cell products (e.g., BCG) and cytokines (e.g., interleukin-2)
has recently been superseded by more specific immune stimulation targeted against colorectal tumor-expressed antigens.
Whereas some tumor antigens are present in normal tissues
but overexpressed in cancer, other tumor antigens are
restricted to cancer tissues. Vaccines stimulate the immune
system to recognize and act specifically against these tumorexpressed antigens, through either the humoral or cellular
pathway.
More than 25 Phase I and Phase II studies have explored a
variety of vaccines based on whole colorectal tumor cells,
virus-modified tumor cells, gene-modified tumor cells,
tumor antigen-derived peptides, tumor cell lysates, proteins
or carbohydrates, monoclonal antibodies, plasmid or viral
vectors encoding tumor antigens, and dendritic cell-based
vaccines. Promising results were observed in some animal
models and Phase I and II studies, prompting ongoing
research efforts.
A few Phase III studies have also yielded promising
28
results.
Three large studies have looked at the effect of
immune stimulation with autologous irradiated tumor vaccine
plus BCG in patients with colorectal cancer. Hoover et al.
randomized 98 patients with colon or rectal cancer to surgical
resection alone or surgical resection followed by vaccination
with autologous irradiated tumor plus BCG. There was no difference in disease-free or overall survival in the 80 eligible
patients, but subset analysis showed a significant improvement in disease-free survival for colon cancer patients. The
Eastern Cooperative Oncology Group (ECOG) randomized
Stage II and Stage III colon cancer patients to either observation or vaccination with autologous irradiated tumor plus
BCG. There was no survival difference between groups, but
patients with a marked delayed cutaneous hypersensitivity
showed a trend toward better disease-free and overall survival, suggesting that survival correlated with the patient’s
immune response to vaccination.
30
Vermoken et al.31randomized 254 patients operated for colon cancer to either observation or vaccination with autologous irradiated tumor plus
BCG immediately after operation, followed by a vaccine
booster 6 months after operation. The overall risk for recurrence was decreased by 44% in all vaccinated patients, with a
61% reduction in Stage II patients. Vaccination significantly
increased recurrence-free survival, and there was a trend
toward improved overall survival.
31
Because of its marginal
efficacy, the complexity in the preparation of the vaccine, and
the introduction of more effective chemotherapeutic agents,
tumor cell-based immunotherapy is not frequently used in
colon cancer patients.
Gene therapy is based on the concept of transferring
genetic material into target cells, which would allow for correction of genetic defects in tumor suppressor genes, inactivation of oncogenes, or insertion of treatment-sensitizing
genes (such as drug-converting enzymes) or “suicide genes”
into the colorectal cells. Correction of p53 mutations, inactivation of k-ras gene product p21, and the delivery of prodrug
converting enzymes are currently being studied. The longterm potential for clinical usefulness of these techniques
remains to be defined.
Rectal Cancer
Although surgery remains the central treatment of rectal cancer, the overall approach to treatment has changed dramatically over the last three decades. Surgical technique has been
refined to become more focused and precise, with specific
attention given to a locally more aggressive and meticulous
technique. The modern multimodal therapy approach individualizes rectal cancer care, thus offering the best and most
appropriate treatment to every single patient. Local and distant staging guides the decision for adjuvant radiotherapy
and/or chemoradiotherapy and for available surgical
approaches, i.e., local excision or an abdominal procedure.
29
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