Active specific immunotherapy for stage II and stage III human colon cancer:
a randomised trial
||Vermorken J, Claessen A, van Tinteren H, Gall H, Ezinga
R, Meijer S, Scheper R, et al
||Lancet. 353:345-50. January 30, 1999.
||University Hospital, Amsterdam, Netherlands; University
Hospital, Antwerp, Belgium; Comprehensive Cancer Centre Amsterdam; INTRACEL
Active specific immunotherapy with vaccines prepared from the patient's
own tumor has shown some success in patients with melanoma and renal cell
cancer. Two trials of tumor vaccines in colon cancer failed to reveal a
significant benefit, but subgroup analyses suggested some benefit, particularly
among patients who had a substantial immune response.
This trial was designed to further study active immunotherapy in patients
with stage II or III colon cancer, using an enhanced vaccination schedule
(with four instead of three doses of vaccine) and with the vaccine prepared
by a central laboratory to assure quality control.
Patients were eligible if they had undergone curative resection of stage
II or III adenocarcinoma of the colon.
Patients were excluded if there was intestinal perforation or peritoneal
seeding, if patients had inflammatory bowel disease, if the cancer
was rectal, if the CEA level did not normalize within 21 days, if there
was a prior history of cancer or if they were being treated with steroids
or cytotoxic agents.
Surgery was performed at one of 12 hospitals. Tumor samples were processed
at one central site. The tumor was minced, dissociated with collagenase
and DNase and frozen. About 60% of vaccines prepared in this fashion contained
normal GI flora, but none were declared unsafe for use. Prior to
administration, the vaccine was thawed and irradiated with 200 Gy. Each
vaccine contained approximately 107 cells. The first two vaccinations
administered to each patient also contained 107 BCG microorganisms.
Randomization and vaccine administration
The specifics of randomization are not described in the article. Patients
were randomized to either receive or not receive the vaccine, and were
stratified by institution, tumor location and pathological stage.
Patients who were randomized to receive the vaccine were given a series
of four intradermal injections, starting 4-5 weeks after surgery.
The first two vaccinations were given one week apart, were injected in
the anterior thighs and included BCG organisms. Vaccines three and four
were administered at 3 weeks and 6 months (booster), were injected into
the upper arms and did not include the BCG.
Follow-up and analysis
Patients were followed up every three months for the first two years,
every 6 months for the next three years and annually thereafter. CEA was
measured at each follow-up, chest x-rays were performed regularly and CT
scan and colonoscopy were performed annually.
The primary endpoints were recurrence-free interval and recurrence-free
survival (time to first occurrence of any malignant disease and time to
occurrence of malignancy or death from any cause). Subgroup analysis
by pathological stage was also prespecified. Secondary endpoints included
deaths from recurrence of colon cancer and all-cause mortality.
There were 480 samples with adequate tumor cells. 161 patients declined
to participate and 65 were ineligible, leaving 254 patients randomized
(128 to vaccine, 126 to no vaccine).
Patient and disease characteristics were well matched, and included
(for both groups combined, unless otherwise indicated):
Vaccine and vaccine reactions
Median age: 65-66 years; male: 68%
Right colon 40%; left colon 54%
Greater than 4 positive lymph nodes: 25 in control group, 20 in vaccine
Stage II disease: 62%; stage III disease 32%
The mean time from tumor resection to the start of vaccine preparation
was 2.98 hours. Based on average specimen size and number of cells
per gram of specimen, the authors estimated that their approach would yield
enough tumor cells to prepare four vaccine doses in 88% of patients overall.
Local reactions to the vaccines were more intense with the first two
vaccinations, which contained BCG. These included induration in all
patients and some degree of ulceration in 93%. Eight patients did
not receive BCG in the second vaccination because of local reaction to
the first. Mild systemic reactions occurred in 22% of patients, severe
reactions in 5%.
Local reactions to the third and fourth vaccinations, which did not
contain BCG, were less intense but did occur in most patients. Induration
greater than 10 mm occurred in 87% of patients with the third vaccination
and 92% with the fourth. Ulceration only occurred in 7% and 4% of
patients with these vaccinations. Mild and severe systemic reactions were
only present in 7% and 0.5% of patients.
Median follow-up time was 5 years 4 months.
Among all patients, recurrence of (any) malignant disease occurred in
31.7% of unvaccinated patients and in 19.5% of vaccinated patients. This
was statistically significant. This effect was not seen in stage
III patients (41.4% vs. 34.9%). Thus, the reduced overall recurrence rate
was due to a particularly significant effect among stage II patients (27.1%
There was a trend towards reduction in the combined endpoint of
malignancy or death, which reached significance for stage II patients (36.5%
vs. 23.5%). Overall mortality was not affected, but there were trends
in reduction of disease-related mortality, particularly for stage II patients
(16.5% vs. 8.2%).
The authors conclude from their study that active specific immunotherapy
significantly lowers the recurrence rate of stage II and III colon cancer,
mainly through an impact on stage II disease. They speculate that
the reason for the preferential effect on stage II disease is the lesser
The authors argue that there are two reasons why this study showed a
benefit, whereas two other trials did not. The first is the addition of
a fourth vaccination at 6 months, and the second is greater quality control
in the preparation of the vaccine by the centralized laboratory.
Adequacy of vaccine preparation facilities is thus an important issue.
The authors note that adjuvant chemotherapy, which is effective for
stage III patients, has not been shown to benefit stage II patients. Thus,
immunotherapy would be a logical choice for stage II patients. Whether
or not it would benefit stage III patients in addition to chemotherapy
is an issue that they intend to assess in future trials.
This study, which examined the effect of four doses of a colon cancer vaccine
prepared from the patient's own tumor specimen, found a significant reduction
in disease recurrence among vaccinated patients. Although mortality was
not reduced, there was a trend towards reduction of disease related mortality,
particularly in stage II patients.
This was not a blinded study. Also, the details of randomization were
not provided and it is unclear at what point in the process consent was
obtained and at what point randomization actually took place. It
is also unclear how the study dealt with the withholding of adjuvant chemotherapy
from stage III patients who received no vaccine.
The results are promising, but one obstacle to the immediate applicability
of this approach will be the necessity of vaccine preparation by a highly
specialized and presumably centralized laboratory. This represents
a significant effort and cost, particularly for stage II disease which
has a relatively favorable prognosis to begin with. Furthermore,
no significant effect on overall mortality has yet been demonstrated, although
consistent trends were there.
Further studies to improve the vaccine efficacy even further, to standardize
and facilitate its production and to evaluate it in conjunction with adjuvant
chemotherapy will be needed.
February 21, 1998
related to this article from the NLM's PubMed
The following comments are from the corresponding author of the paper:
Date: Wed, 3 Mar 1999
From: "Eertwegh, A.J.M..van.den" <email@example.com>
Thank you for your letter and for discussing our paper in the journalclub.
Below are my comments on your summary of our paper.
1) the first three vaccinations were weekly and the fourth vaccination
was six months after operation. (The third was not after three months!).
2) patients were asked for informed consent after the tumor was dissociated
and provided that there were enough viable cells for four vaccinations.
3) randomization was performed after the patient fulfilled all the inclusion
criteria and after informed consent.
If you have more questions, don't hesitate and E-mail me.
With kind regards,
On behalf of Prof. G.M. Pinedo
A.J.M. van den Eertwegh, M.D. Ph. D.
I originally wrote that vaccine number three was given at three
months. This error has been rectified. I appreciate this correction and
the clarification of randomization and consent. -- mj
From: samim celebi (chalabi) [firstname.lastname@example.org]
In regard of using vaccination in colon cancer patients, we are basically
trying to increase tumor cell destruction by patient's own immune system
(bcg helping), assuming this is confirmed. Stage iii patients do
not have a favorable response most probably because the immune system is
like a tired horse, it cannot run anymore.
So in that line of thinking we have to look at tests to determine
the improvement in immunity in survivors and in those who improved and
if that is the case, first we can identify people who can benefit and next
we can look at specific as well as non-specific therapies to intervene
in the immune system.
samim celebi (chalabi) md
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