9 januari 2018: lees ook dit artikel: 

https://kanker-actueel.nl/s-1-plus-irinotecan-plus-bevacizumab-versus-mfolfox6-of-capeox-plus-bevacizumab-voor-uitgezaaide-darmkanker-geeft-betere-overall-overleving-en-minder-bijwerkingen.html

9 oktober 2012: het lijkt toch interessant om de toevoeging van BCG aan een chemo behandeling van darmkanker eens nader te bekijken. Uit dit historisch overzicht blijkt dat de uiteindelijke 10 jaars overleving significant beter is met BCG dan zonder.

20 september 2004: Bron: JNCI-website

In onderstaand historisch overzicht van aanvullende chemotherapie voor darmkanker komt naar voren dat BCG wel eens voor een significant langere tienjaars overleving zou kunnen zorgen i.t.t. de onderzochte chemokuren - MOF. Terwijl BCG niet verhindert dat er significant minder recidieven voorkomen maar dus wel langere tienjaarsoverleving. Dit duidt erop dat BCG wel degelijk via de versterking van het immuunsysteem zorgt voor hogere kwaliteit van leven en ook langere levensduur. In de literatuurlijst van arts-bioloog drs. E. Valstar staan enkele tientallen studies waarin BCG voor aanmerkelijke verbeteringen zorgt bij verschillende soorten kanker zoals vooral bij blaaskanker, maar ook bij darmkanker. Onderstaand artikel heeft een zelfde teneur als artikel met als kop: chemo na operatie bij darmkankerpatiënten stadium II lijkt zinloos.

Adjuvant Therapy for Colon Cancer: A Historical Perspective
Jean Grem
Correspondence to: Jean Grem, MD, Section of Oncology/Hematology, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-7680 (e-mail: jgrem@unmc.edu)

In this issue, Smith et al. (1) present the 10-year results of the first National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol for colon cancer. The three-armed trial randomly assigned 1166 patients with Dukes’ stage B and C colon cancer to surgery alone; postoperative chemotherapy with eight 10-week cycles of semustine, 5-fluorouracil, and vincristine (MOF); or postoperative immunotherapy with bacillus Calmette-Guérin (BCG) given weekly for 12 weeks and then every other week for a total of 45 doses. When the initial results were published in 1988 (2), adjuvant MOF therapy was associated with a statistically significant improvement in disease-free survival (58% versus 51%; P = .02) and overall survival (67% versus 59%; P = .05) at 5 years compared with those receiving surgery alone. Adjuvant BCG therapy was associated with a trend toward improvement in disease-free survival (56% versus 51%; P = .09) and a statistically significant survival advantage in overall survival (67% versus 59%; P = .03). When deaths with no evidence of tumor recurrence were eliminated, BCG therapy had no statistically significant benefit in either disease-free survival or overall survival, whereas benefit from chemotherapy was retained. These results led to the adoption of MOF as the reference arm in a subsequent trial (C-03). At 10 years, however, MOF therapy showed no benefit compared with surgery alone in terms of disease-free survival, relapse-free survival, or overall survival. Although BCG therapy did not prevent tumor relapse, it was associated with a statistically significant improvement in overall survival (approximately 53% versus 47%); of note, the survival curves diverged only after 4 years.

What can we make of these results, as neither of the experimental arms is currently in clinical use? When this trial was begun, results of three randomized trials (3–5) had been published that demonstrated an improved response rate with MOF or semustine and 5-fluorouracil (MF) compared with 5-fluorouracil alone in advanced colorectal cancer, and one trial reported a higher response rate with MF versus semustine alone (6) (Table 1). Interest in using nonspecific agents, such as BCG, to stimulate the immune system in the adjuvant setting was spurred by data from preclinical studies and nonrandomized clinical trials in colorectal cancer.

NSABP C-03 demonstrated that weekly bolus leucovorin-modulated 5-fluorouracil was superior to MOF in terms of disease-free survival (73% versus 64%; P<.001) and overall survival (84% versus 77%; P<.01) at 3 years (6); thus, bolus 5-fluorouracil–leucovorin became the new reference arm for later NSABP studies (7).
Analysis of baseline variables in Smith’s report indicated that male sex, age of 65 years or older, tumor location (sites other than right colon), and increasing number of involved lymph nodes were associated with a poorer survival. However, only the number of involved lymph nodes had prognostic importance for relapse-free survival. The discrepancy between lack of adverse prognosis conferred by male sex and older age on relapse-free survival and disease-free survival suggests that the adverse prognosis for overall survival is not caused by inherent differences in the tumor biology in these subsets. Because most relapses or recurrences from colon cancer occur within the first 2–3 years after diagnosis, it is unlikely that late disease recurrence accounts for this observation. There appeared to be no difference in the number of patients who died after recurrence of colon cancer among the three arms, whereas about half the number of patients (n = 9) receiving BCG died after a second primary cancer compared with surgery alone or MOF (n = 18 and 21, respectively). Acute myeloid leukemia and myelodysplasia occurred only in MOF-treated patients. Six percent of patients randomly assigned to surgery alone died of a cardiac cause as the first event compared with about 3% in patients receiving either BCG or MOF. It is hard to believe that MOF confers a cardioprotective effect; therefore, the result with BCG may also be a chance observation. About 5% of patients receiving BCG died of noncancer-, noncardiac-related causes as their first event compared with 7%–8% of patients with surgery or MOF therapy. Death from other non–cancer-related illness is the most likely explanation; among patients who do not have cancer relapse, younger subjects are expected to have a longer life expectancy than older patients, and females have a longer life expectancy than males. The lower limit of the 95% confidence interval for the survival hazard ratio for right colon versus other sites was 1.00; this association is not persuasive despite a P value of .05.

There is debate concerning end points for adjuvant colon cancer trials. Sargent et al. (8) recently presented an analysis of 3-year disease-free survival as a surrogate end point to replace overall survival in adjuvant therapy. The analysis included individual data on more than 17 000 patients enrolled on 17 randomized adjuvant colon trials conducted between 1978 and 1996 that evaluated the worth of 5-fluorouracil–based regimens; 34% of patients had stage II disease and 65% had stage III disease. A pertinent finding was that recurrences peaked within the first 2 years. Furthermore, 74% occurred within the first 3 years, and the median survival after recurrence was 1.1 years. A very close association was noted between 3-year disease-free survival and 5-year overall survival. When the treatment arm was compared with the control arm in each study, a very close association between the hazard ratios for 3-year disease-free survival and 5-year overall survival was observed. There are several advantages to adopting 3-year disease-free survival as the major end point for adjuvant trials: decreasing the time needed for follow-up before definitive data analysis and reporting, allowing more timely completion of trials, and more rapid implementation of new trials testing promising new therapies. In Sargent's analyzed population, the ratio of patients with lymph node–positive disease to patients with lymph node–negative disease was about two to one. In more recent studies, the proportion of stage II patients is increasing, which implies that the overall prognosis of the subject population enrolled onto current adjuvant studies will be better. During the time over which these 17 trials were conducted, effective salvage therapies were not generally available (irinotecan was first approved by the U.S. Food and Drug Administration in 1996). With the availability of newer agents and regimens, the expected median survival after recurrence will be longer. As more effective combinations are introduced into the adjuvant setting, it is possible that the time to disease recurrence will be delayed. Nevertheless, 3-year disease-free survival appears to be an appropriate surrogate end point.

REFERENCES

(1) 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;96:1128–32.
(2) Wolmark N, Fisher B, Rockette H, Redmond C, Wickerham DL, Fisher ED, et al. Postoperative adjuvant chemotherapy of BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988;80:30–6.
(3) Moertel CG, .Schutt AJ, Hahn RG, Reitemeier RJ. Therapy of advanced colorectal cancer with a combination of 5-fluorouracil, methyl-1,3-cis(2-chlorethyl)-1-nitrosourea, and vincristine. J Natl Cancer Inst 1975;54:69–71.
(4) Baker LH, Vaitkevicious VK, Gehan E. Randomized prospective trial comparing 5-fluorouracil (NSC-19893) to 5-fluorouracil and methyl-CCNU (NSC-95441) in advanced gastrointestinal cancer. Cancer Treat Rep 1976;60:733–7.
(5) Falkson G, Falkson HC. Fluorouracil, methyl-CCNA and vincristine in cancer of the colon. Cancer 1976;38:1468–70.
(6) Posey LE, Morgan LR. Methyl-CCNU versus methyl-CCNU and 5-fluorouracil in carcinoma of the large bowel. Cancer Treat Rep 1977;61:1453–8.
(7) Womark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Risher ER, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03. J Clin Oncol 1993;11:1879–87.
(8) Sargent DJ, Wieand S, Benedetti J, Labianca R, Haller DG, Shepherd LE, et al. Disease-free survival vs. overall survival (O) as a primary endpoint for adjuvant colon cancer studies: individual patient data from 12915 patients on 15 randomized trials. Proc ASCO 2004;23.


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