Adenovirus: Bewerkt adenovirus rechtstreeks ingebracht in tumorweefsel zorgt voor opmerkelijke resultaten
4 juni 2004: bron DOW en Yahoonews

Onderzoekers van Cancer Research UK aan de universiteit van Londen maken melding van een succesvolle trial met het inbrengen van een genbewerkt virus in kankercellen. Het zogenoemde adenovirus is dusdanig bewerkt dat het zich razendsnel verspreid in de kankercellen zelf maar de gezonde cellen ongemoeid laat omdat deze tijdig het virus herkennen en onschadelijk maken. Kankercellen lukt het echter niet dit virus onschadelijk te maken en het virus zorgt ervoor dat de kankercellen als het ware 'exploderen' zoals de onderzoekers dat omschrijven. Hier twee persberichten over dit toch wel opzienbarende nieuws.

Genetically-modified virus explodes cancer cells
By Shaoni Bhattacharya

A genetically-modified virus that exploits the selfish behaviour of cancer cells may offer a powerful and selective way of killing tumours.

Deleting a key gene from the virus enabled it to infect and burst cancer cells while leaving normal tissues unharmed, reveals a study by researchers at Cancer Research UK and Queen Mary's School of Medicine and Dentistry, University of London.

Viruses spread by infiltrating the cells of their host. Normally, the detection of an intruder by a cell triggers a process called apoptosis, which causes the cell to commit suicide and prevents the virus spreading further. However, viruses can carry genes that allow them to slip past this cell death process in normal cells, causing infection.

The UK researchers deleted one such gene in an adenovirus. This meant that the virus was immediately detected by normal cells and was unable to spread. But in cancer cells, which grow uncontrollably and ignore the cell death process, the virus was able to thrive and spread rapidly. It then multiplied so vigorously that it killed the cancer cells by making them explode.

"The great thing about this strategy is that the cancer cell does all the hard work," says Nick Lemoine, director of the Cancer Research UK Clinical Centre at Bart's Medical School, who led the team. "It makes more and more virus to infect its neighbouring cancer cells. But if a normal cell is infected, it commits suicide before it can make new virus and spread of the virus is contained."

Unexpected benefit

The gene the team deleted from the adenovirus is called E1B-19kD. But, as well as removing the cloak the viruses normally use to evade detection by cells, it had another "unexpected" effect, says Lemoine.

This was enabling the viruses to replicate much faster than normal, which in turn helped burst the cancer cells. Previous GM viruses have not shown this effect.

The team examined the effects of the GM virus on pancreatic, lung, ovarian, liver and colorectal cancers in the test tube, as well as on live tumour-bearing mice. The team plans to test the GM virus in clinical trials in people in 2005.

"In tests so far it has proven both potent and selective, although only clinical trials will tell us whether the approach can be an effective treatment in people, "comments Robert Souhami, Cancer Research UK's director of clinical and external affairs.

Lemoine adds that the GM virus could also be armed with additional anti-cancer weapons, in the form of genes producing toxic compounds. "The fact that we have taken a gene out of the viral backbone means we could arm the virus with something that deliberately kills cancer," he told New Scientist .

Journal reference: Molecular Therapy (DOI: 10.1016/j.ymthe.2004.03.017)

Ook het DOW journaal maakt melding van deze studiepublicaties:

-- =WSJ.COM/The Daily Scan: Genetically Altered Viruses --


By Mark Ingebretsen
Of THE WALL STREET JOURNAL ONLINE

NEW YORK (Dow Jones)--Researchers in the U.K. may have found one of the
closest things yet to a magic bullet in the battle against cancer.
By removing a genetic component from a virus, the scientists prompted "it to
infect and burst cancer cells while leaving normal tissues unharmed," according
to the New Scientist.
The modified virus is able to destroy cancer cells by taking advantage of
their so-called "selfish behavior." As a news release from the group, Cancer
Research UK, explained, the body's normal cells will self-destruct if infected
with a virus, and this suicidal behavior helps to prevent the virus from
spreading. Cancer cells, by contrast, "refuse to stop for anything - allowing
the virus to thrive." Thus, the selfish behavior on the part of the cancer cells
- that is their abject refusal to self-destruct on cue - allows "the
(genetically modified) virus to replicate and spread through tumor tissue," the
release said.
The news from Britain follows a Dow Jones Newswires story that reported: "New
cancer drugs that target tumors and leave healthy cells alone are changing the
face of cancer treatment."
"Unlike traditional chemotherapy, which often debilitates patients with severe
nausea, diarrhea or opportunistic infections, these targeted drugs attack tumor
cells directly and with fewer side effects."

Alimta goedgekeurd door FDA voor niet-klein-cellige longkanker in plaats van taxol en taxotere na uitstekende studieresultaten met veel minder bijwerkingen dan traditionele chemokuren.
27 augustus 2004: Bron: DOW: De FDA heeft afgelopen week goedkeuring gegeven aan Alimta, een medicijn tegen niet-klein-cellige longkanker, dat in studies minimaal zelfde resultaten gaf als taxol maar met veel minder bijwerkingen. Opvallend is dat in dit korte persbericht ook aanvullend B12 en foliumzuur wordt aanbevolen voor verminderen van bijwerkingen bij de behandeling van Alimta , maar ook andere chemokuren. we zullen proberen wat meer studieresultaten van Alimta te pakken te krijgen en hier te plaatsen.

WASHINGTON (AP)--The Food and Drug Administration on Thursday approved a cancer drug made by pharmaceutical giant Eli Lilly & Co. (LLY) to treat advanced non-small cell lung cancer in patients who have undergone chemotherapy. According to the American Cancer Society, non-small cell lung cancer is the leading cause of cancer-related deaths in the nation. Eighty percent of 174,000 new lung cancer cases diagnosed each year are non-small cell lung cancer. By the time most patients arrive for treatment, the cancer is widespread. The drug, Alimta, in clinical trials was found to shrink tumors as effectively as another cancer-fighting drug, Taxotere. But Alimta did so with fewer troubling side effects, which include hair loss, tingling fingers and toes, depressed blood count, and hospitalizations for subsequent infection. "Lung cancer is a very devastating disease and the therapies can be hard on patients," said Roy Herbst, chief of thoracic oncology at MD Anderson Cancer Center. The Houston facility sees nearly 1,500 new lung cancer patients per year and treated at least 20 in the Alimta versus Taxotere study. One in 50 patients taking Alimta had side effects. That benefit came without any lessening of the drug's effectiveness. That's significant as cancer care moves toward more combination drug or sequential therapies, Herbst said. "We can only do that if the drugs we give (patients) leave them in a state ... where they're still strong. You can kill the cancer, but leave the patient feeling well," he said. The Alimta treatment, 500 mg every 21 days, costs patients $3,900 per month, according to the company. The anti-cancer drug works by interfering with three enzymes on which tumors depend. "There's no question, the survival was comparable to the survival with the best drugs we have," said Dr. Paul Bunn, director of the University of Colorado Cancer Center and principal investigator for the clinical trial. "This drug is as good as anything else we have. It does benefit patients." Dr. Richard Gralla, president of the New York Lung Cancer Alliance, estimated tens of thousands of lung-cancer patients per year would be eligible to take Alimta. The trial tested a simple way to reduce side effects: Taking Alimta in concert with folate pills and B-12 injections. "When you take those special B vitamins, it further reduces the side effects of the chemotherapy," Gralla said.

BBBD-behandeling (Blood Brain Barrier Disruption) bij lymfomen (tumoren) van centrale zenuwstelsel succesvol en hoog significant aldus fase II studie gepubliceerd in Pubmed
BBBD-behandeling (Blood Brain Barrier Disruption) bij lymfomen (tumoren) van centrale zenuwstelsel succesvol en hoog significant aldus fase II studie gepublicerd in Pubmed d.d. 28 april 2004: Bron Pubmed De BBBD behandeling - Blood Brain Barrier Disruption - (Bloed-hersenblokkade onderbrekers behandeling noemen we het maar vrij vertaald) De BBBD-behandeling doorbreekt de natuurlijk ingebouwde beschermende barriëre (BBBD) van de hersenen die is samengesteld uit een net van endothelial cellen, die als het ware de muren van het bloedvat in de hersenen vormen. Dit netwerk van cellen creërt een barrière die de toegang van diverse substanties/stoffen, met inbegrip van vele therapeutische middelen, blokkeert. Door deze cellen met een geconcentreerde suikeroplossing tijdelijk te krimpen, wordt de blokkade tijdelijk geopend, daarmee toestaande dat de chemo de tumor in de hersenen bereikt. Vergeleken met standaardchemotherapie, verhoogt de BBBD-behandeling door de ophef van de blokkade de levering van de chemomedicijnen aan de tumor en het omringende gebied met tien tot het honderdvoudige (Neuwelt 1998). De producent claimt en staaft dat met klinische studies dat zij hoog significante resultaten hebben met deze manier van behandelen van hersentumoren maar ook succes hebben bij de behandeling van lymfomen van het centraal zenuwstelsel Voor OPS-leden hebben we directe adresgegevens enz. beschikbaar van ziekenhuizen die met deze BBBD techniek werken. Hier het abstract uit Pubmed van de resultaten van een BBBD-behandeling van lymfomen in het centrale zenuwstelsel: (LD McAllister et al, Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma, Neurosurgery 46:51-61, 2000). Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, Crossen JR, Neuwelt EA. Department of Neurology, Oregon Health Sciences University, Portland 97201, USA. OBJECTIVE: Patients with non-acquired immunodeficiency syndrome-related primary central nervous system lymphomas have the potential to achieve durable complete responses without radiotherapy, with treatment using enhanced chemotherapy delivery with blood-brain barrier disruption (BBBD). Reported 5-year survival rates with combined chemotherapy and radiotherapy were generally only 9 to 22% and were associated, in one study, with an overall 32% incidence of overt dementia and ataxia, which are dramatically increased among patients more than 60 years of age. METHODS: At the Oregon Health Sciences University, 111 consecutive patients with non-acquired immunodeficiency syndrome-related central nervous system lymphomas were prospectively treated with methotrexate-based, BBBD-enhanced chemotherapy and underwent formal neuropsychological evaluations. Of those, 74 patients had no systemic lymphoma and had received no prior irradiation; those 74 patients are described in this report. RESULTS: The estimated 5-year survival rate for this group was 42%, and the median survival time was 40.7 months. Overall, 48 patients (65%) exhibited complete responses and 36 patients continued to exhibit complete responses after 1 year of BBBD-enhanced chemotherapy. Of those 36 patients, none demonstrated evidence of cognitive loss in neuropsychological tests and/or clinical examinations. CONCLUSION: BBBD-enhanced chemotherapy delivery, without subsequent radiotherapy, resulted in favorable survival and cognitive outcomes for patients with primary central nervous system lymphomas who had not previously undergone irradiation. A cooperative multicenter study of intravenous chemotherapy without radiotherapy versus BBBD-enhanced chemotherapy would address the feasibility and necessity of performing a Phase III study for these rare central nervous system malignancies.

Bestraling met 70 GY 1x per dag bij niet-klein-cellige longkanker net zo effectief als chemo, aldus fase II studie met 63 patiënten.
2 september 2004: Bron Pubmed Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):460-8.

Een fase II studie wijst uit dat een dagelijkse bestraling met 70GY bij niet-klein-cellige longkanker met zo effectief en met minder bijwerkingen op korte termijn is dan de chemokuren paclitaxel en topotecan en carboplatin en etoposide. we schrijven hier nadrukkelijk op korte termijn want de effecten van bestraling komen vaak pas jaren later aan de oppervlakte door o.a. hogere kans op leukemie door de bestralingen. Voor aanvullende ondersteuning door voeding en extra voedingssupplementen van bestraling en de bijwerkingen lees ook eens onder bestraling en voeding. Bij 92% van de patiënten - 57 van de 63 deelnemende patiënten - sloeg deze dagelijkse behandeling met 70 GY bestraling aan en de gemiddelde overlevingstijd was 22,4 maanden. 28 patiënten overleefden met een gemiddelde follow-up van 24,7 maanden. De onderzoekers bevelen een fase III studie aan omdat zij vinden dat de resultaten hoopgevend zijn. Hieronder het abstract zoals vermeld in Pubmed.

70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808.

Bogart JA, Herndon JE 2nd, Lyss AP, Watson D, Miller AA, Lee ME, Turrisi AT, Green MR; Cancer and Leukemia Group B study 39808.

Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Bogart@Upstate.edu

PURPOSE: To prospectively evaluate the feasibility of delivering 70 Gy once-daily thoracic radiotherapy (TRT), concurrent with chemotherapy, in the treatment of limited-stage small-cell lung cancer (L-SCLC).

MATERIALS AND METHODS: Eligible patients received two cycles of induction paclitaxel (175 mg/m(2) on Day 1) and topotecan (1 mg/m(2) on Days 1-5) with granulocyte colony stimulating factor support, followed by three cycles of carboplatin (area under the curve = 5 on Day 1) and etoposide (100 mg/m(2) on Days 1-3). TRT (70 Gy, 2 Gy/fx/7 weeks) was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered to patients achieving a complete response or good partial response.

RESULTS: Ninety percent of patients (57 of 63) proceeded to protocol TRT. There was one treatment-related fatality. Nonhematologic Grade 3/4 toxicities affecting more than 10% of patients, during or after TRT, were dysphagia (16%/5%) and febrile neutropenia (12%/4%). The response rate to all therapy was 92% and the median overall survival is 22.4 months (95% confidence interval 16.1, infinity ). Twenty-eight patients remain alive with a median follow-up of 24.7 months.

CONCLUSION: 70 Gy once-daily TRT can be delivered safely in the cooperative group setting for patients with L-SCLC. Initial efficacy data are encouraging. The hypothesis that high-dose once-daily TRT results in comparable or improved survival compared with twice-daily accelerated TRT warrants testing in a Phase III trial. .

BCG - Bacillus Calmette-Gue´rin: Hier een mini overzicht gepubliceerd van wetenschappelijke studies en bewijzen over het gebruik van BCG - Bacillus Calmette-Gue´rin - als succesvolle immuuntherapie bij blaaskanker.
13 september 2004: Bron: Pubmed: Ann Oncol. 2003 Mar;14(3):414-20.

13 juli 2004 werd in the British Journal of Cancer een mini overzicht gepubliceerd van het gebruik van BCG - Bacillus Calmette-Gue´rin - bij blaaskanker, als immuuntherapie. Met name in het LUMC - Leiden wordt veel gewerkt en onderzoek gedaan naar BCG bij blaaskanker. Ook in de literatuurlijst van arts-bioloog drs. E. Valstar is deze aanpak van BCG - Bacillus Calmette-Gue´rin - bij blaaskanker in vele fase III studies bewezen als effectief en hoopgevend. Voor alle duidelijkheid BCG is een vorm van immuuntherapie gebruikmakend van een bepaalde bacterie die een immunologisch proces op gang brengt. BCG wordt ook bij andere vormen van kanker toegepast. Hieronder het volledige Engelstalige rapport zoals gepubliceerd in the British Journal of Cancer, juli 2004.

Minireview
Role of urothelial cells in BCG immunotherapy for superficial bladder cancer
RFM Bevers*,1, K-H Kurth2 and DHJ Schamhart2 1Department of Urology, Leiden University Medical Center J3-P, PB 9600, 2300 RC Leiden, The Netherlands; 2Department of Urology, Academic Medical Center G-4, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Intravesical instillation of Bacillus Calmette-Gue´rin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been directed to decipher the exact mechanism of action of the BCG-associated antitumour effect.

Bacillus Calmette-Gue´rin causes an extensive local inflammatory reaction in the bladder wall. Of this, the massive appearance of cytokines in the urine of BCG-treated patients stands out. Activated lymphocytes and macrophages are the most likely sources of these cytokines, but at present other cellular sources such as urothelial tumour cells cannot be ruled out. Bacillus Calmette-Gue´rin is internalised and processed both by professional antigen-presenting cells and urothelial tumour cells, resulting in an altered gene expression of these cells that accumulates in the presentation of BCG antigens and secretion of particular cytokines.
British Journal of Cancer (2004) 91, 607–612. doi:10.1038/sj.bjc.6602026 www.bjcancer.com Published online 13 July 2004 & 2004 Cancer Research UK

Bladder cancer is detected in 75% of patients at an early, superficial stage. The majority of the superficial urothelial cell carcinomas (TCCs) consists of papillary bladder carcinomas (Figure 1A), while the remaining (10%) is called carcinoma in situ (CIS), a high-grade diffuse surface-spreading lesions. The standard treatment is trans-urethral resection (TUR) followed by intravesical instillation with adjuvant, chemo- or immunotherapeutic drugs (Kurth et al, 2000). For treatment of the surgically nonaccessible CIS, these latter modalities are the only bladder sparing options available. Although the therapeutic efficacy is well recognised, a high recurrence rate of 60–70% and a progression rate of 15% dictate the need for lifelong follow-up and treatment. Adjuvant agents were introduced to reduce the risk for recurrence and progression of TCC. Recent, comparative trials indicate that immunotherapy with Bacillus Calmette-Gue´rin (BCG; Figure 1B) is superior to chemotherapy in patients with intermediate to high risk for recurrence. In these patients, the benefits of treatment outweigh the burden of side effects. Moreover, BCG seems to exert a better antitumour effect in CIS and high-grade cancer (Melekos et al, 1993; Kurth et al, 2000). Bacillus Calmette-Gue´rin, an attenuated strain of Mycobacterium bovis, was developed by Calmette and Gue´rin with the intention to generate a vaccine against tuberculosis. The clinical efficacy of the commercially available strains of BCG, such as Connaught and Tice, appears to be comparable (Witjes et al, 1996; Champetier et al, 2000).

Since the first report of intravesical use of BCG in 1976, investigators try to understand the working mechanism of BCG as an antitumour modality. Both BCG treatment regimen and dose are historically determined. Arbitrarily, BCG therapy consists of a single course of six weekly intravesical instillations. Extension of BCG treatment (maintenance immunotherapy) is used to increase efficacy. Despite its success, 30–50% of patients either fail to respond or relapse within the first 5 years of treatment. Unfortunately, BCG, a viable, living organism, can cause infections resulting in side effects ranging from bothersome cystitis in the majority of patients to sepsis eventually leading to death in rare cases.

In order to reduce the side effects of BCG and to improve efficacy, interesting approaches are developed, such as the application of a cell wall–DNA complex (MCC) of Mycobacterium phlei, which was effective in patients who failed BCG therapy (Morales et al, 2001), genetically engineered BCG secreting relevant cytokines such as human lL-2 (Yamada et al, 2000), or treatment schedules consisting of three times viable BCG and three subsequent instillations with killed BCG (De Boer et al, 2003).
This review presents an overview of the current state of ‘BCG research’. Special attention will be paid to the role of the urothelial cells in the cascade of events leading to BCG-associated tumour cell clearance. As an underdeveloped field of research, the significance of an interaction between potentially hostile bacteria and epithelial cells is a relatively unknown aspect of the host immune-defense system. Better knowledge about this interaction might open new avenues for improvement of the BCG immunotherapy. Received 15 March 2004; revised 17 May 2004; accepted 26 May 2004; published online 13 July 2004 *Correspondence: Dr RFM Bevers; E-mail: R.F.M.Bevers@lumc.nl This review is devoted to the role of the urothelial cell in the mechanism of BCG action British Journal of Cancer (2004) 91, 607 – 612 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $30.00 www.bjcancer.com

For an actual overview on the practical, clinical aspects of the immunotherapy for TCC with BCG, the reader is referred to various, recently published papers (Kurth et al, 2000). DETAILS OF THE MODE OF ACTION OF BCG Nowadays, it is generally assumed that the BCG-induced antitumour activity is critically dominated by a local nonspecific immunological reaction reflecting the activity of immunocompetent cells (Alexandroff et al, 1999). It should be realised however that preceding the activation of the local immune system, some possibly rate-limiting events need to be executed. The sequential order of these initial events has been addressed only to a limited extent.

Interaction of BCG with the bladder wall
Interaction of BCG with the luminal surface of the bladder is the first step for BCG to accomplish. Accumulation of BCG near the bladder wall and adherence may be limiting processes for an adequate, clinical response. Suboptimal binding of BCG may explain the absence of clinical response in a subgroup of patients (Ratliff et al, 1987; Schamhart et al, 1994). Experimental modulation of BCG attachment affects BCG-induced response in animal models (Hudson et al, 1991). Systematic analysis of the interaction of BCG with the bladder wall has not been accomplished, probably due to poor recognition of the biological and physicochemical processes involved. The process of interaction should be divided into nonspecific, physicochemical and specific, receptor–ligand-mediated events.

Physicochemical interaction The luminal side of the bladder is covered with a layer of hydrophilic, highly sulphated glycosaminoglycans (GAGs). This GAG layer protects the bladder from toxic compounds and microorganisms. Both the GAG layer and the BCG cell wall are highly negatively charged (the zeta potentials). These conditions prescribe that BCG bacteria accumulate without adherence, at a close docking distance (70–100 A° ) to the bladder wall (Figure 1C) (Schamhart et al, 1994). In addition to this reversible adsorption, physicochemical considerations predict a low probability of irreversible adherence of BCG to the bladder wall, due to the high electrostatic, repellent force between the respective surfaces. The observed, in animals, low abundance of BCG adherence to the uninjured bladder wall and the dependency of BCG adherence to diluent properties (pH, salt concentration) seem to be in accord with these theoretical considerations (Ratliff et al, 1987; Hudson et al, 1991; Teppema et al, 1992). Damage of the GAG layer and urothelium may lower the negative charge of the bladder wall, leading to an increased BCG docking and adherence, as observed in a murine BCG model after electrocautery damage of the bladder (Ratliff et al, 1987).

Specific, receptor–ligand-mediated events In addition to nonspecific interaction, more specific mechanisms seem to be involved in BCG adherence. A crucial binding of BCG to fibronectin (FN) in the bladder mucosa has been postulated (Kavoussi et al, 1990). Fibronectin is part of the extracellular matrix, is equally distributed on normal and malignant urothelium, and a soluble form can be found in urine. Binding of BCG to the murine bladder was impaired with anti-FN antibodies or addition of soluble FN (Kavoussi et al, 1990). Furthermore, BCG bacteria possess a receptor with high affinity for the collagen domain of FN, the fibronectin attachment protein (FAP). These data and the observation that the clinical effect of BCG therapy is related to the degree of FN expression on normal mucosa suggest a specific FN-mediated adherence of BCG to the bladder wall. However, these experimental, animal data were largely obtained with preinjured bladders, contradictory to the clinical situation, and a fortuitous relationship between the efficacy of BCG therapy and fibronectin has been suggested (Bevers et al, 1998, 2000).

Internalisation of BCG and phenotypical alterations of urothelial cells Internalisation of BCG in urothelial cells Several reports show that urothelial cells are capable of internalisation of BCG (Bevers et al, 1998, 2000; Durek et al, 1999). Bacillus Calmette-Gue´rin internalisation in vitro is time and dose dependent and can already be demonstrated after a 15-min incubation period. In a spheroid 3- D model, internalised BCG was found four cell layers deep, whereas normal urothelial cells in this system did not internalise BCG (Durek et al, 1999). Guinea pig studies showed no adherent or internalised BCG in normal urothelial cells (Teppema et al, 1992). In malignant cells, BCG internalisation appeared to be cell differentiation dependent. Contrary to well-differentiated (G1) bladder tumour cell lines, poorly differentiated (G3) cell lines exhibit significant internalisation of BCG (Bevers et al, 1998). Clinically, these data relate well to observations that show a better response to BCG treatment of high-grade compared to low-grade tumours (Table 1) (Melekos et al, 1993).

Knowledge about the mechanism of BCG internalisation is scarce. Fibronectin is suggested to act as a bridging molecule, binding both to urothelial cells and BCG. Urothelial cells express an integrin (a5b1 receptor) with affinity for FN (Zhao et al, 2000). Pretreatment of T24 cells, a human TCC cell line, with anti-FN or anti-a5b1-receptor antibodies resulted in an impaired BCG attachment to and internalisation in these cells. However, other investigators could not inhibit BCG internalisation with anti-FN antibodies (Schneider et al, 1994; Bevers et al, 2000). The current available data do not suggest a mandatory role of FN in BCG internalisation. It seems that BCG internalisation is mediated by additional molecule(s), possibly coexpressed with FN, such as heparan sulphate-containing proteoglycans interacting with the mycobacterial heparin-binding haemagglutinin adhesin (HBHA) (Schneider et al, 1994; Bevers et al, 2000).

Regardless of the exact mechanism of internalisation, intracellular BCG is transported within phagosomes. These fuse with lysosomes to form phagolysosomes. Recent evidence shows that intracellular, live BCG can interfere with this phagolysosome formation (Maksymowych and Kane, 2000). However, only a small fraction of commercially available BCG preparations consists of live BCG. Therefore, most BCG particles will be degraded, and mycobacterial glycoproteins and lipoproteins are transported to the cell surface (Neyrolles et al, 2001).

Patient studies, analysing bladder washings after BCG instillations, revealed vigorous phagocytosis of BCG by leucocytes. However, concerning internalised BCG in urothelial cells, conflicting results are reported (Teppema et al, 1992). Accepting the inability of normal urothelial cells to internalise BCG, these conflicting observations may be explained by the presence or absence of residual urinary tumour cells in the limited number of patients included in both studies.

In summary, BCG particles can be internalised and processed by residual, especially high-grade tumour cells. As a consequence, the possibility that BCG introduces phenotypical alterations of TCC Table 1 Recurrence rate/100 patients-months in patients with superficial bladder cancer, following TUR with and without adjuvant intravesical BCG instillationsa

Treatment Grade 1 Grade 2 Grade 3 TUR 1.5 NS 3.67 Po0.01 20.83 Po0.002 TUR+BCG 1.18 1.02 1.26 aData from Melekos et al (1993); NS¼not significant. BCG therapy for bladder cancer RFM Bevers et al 608

British Journal of Cancer (2004) 91(4), 607 – 612 & 2004 Cancer Research UK cells that affect tumoricidal effector mechanisms has been a subject of study. Several effects, ranging from a direct antiproliferative/ cytotoxic effect of BCG, to a role in the initiation and/or modulation of the host immune response, and to an increase of susceptibility of tumour cells, have been proposed.

Cytotoxic effects of BCG on BCG-internalising urothelial cells
In vitro studies with human TCC cell lines show that BCG exerts cytolytic, antiproliferative and antimotility effects. The inhibitory effects on cell proliferation were most pronounced in highly dedifferentiated cell lines. Today, the causal mechanisms are unknown. Internalised BCG increased the production of cytotoxic nitric oxide (NO) in TCC cells. Patients treated with BCG showed an augmented bladder NO production and an upregulation of urothelial-associated nitric oxide synthase (Jansson et al, 1998). NO, at high concentration, may cause DNA damage, and cytostatic and cytotoxic effects. Possible accumulation of DNA damage may be related to the observation that, contrary to nontreated patients, urothelial cells of BCG-treated patients express regulatory genes related to DNA repair, knowingly wild-type p53 and P21waf1/cip1 (Fontana et al, 1999). Whether these observations represent an indirect or direct cytotoxic effect of BCG in situ remains unclear. Bacillus Calmette-Gue´rin-internalising urothelial cells and the initiation/modulation of the immune response

Activation of the host immune system has been considered an exclusive characteristic of professional antigen-presenting cells (APCs), like dendritic cells and macrophages. New insights support a role for the interaction of (airway)epithelial cells and bacteria in the initiation of the immunological cascade (Levine, 1995; Neyrolles et al, 2001). Bacillus Calmette-Gue´rin-treated urothelial tumour cells are now considered as active participants in the cytokine-mediated initiation and/or regulation of the early immune response (Alexandroff et al, 1999).

The initial immune response to BCG
The local immune response to bacteria, including live BCG, is complex, but the presentation of bacterial antigens by APC to T-helper cells is the pivotal interaction (Alexandroff et al, 1999). Derived from an extensive series of papers, it appears that, after internalisation and processing by professional APC, processed BCG antigen(s) become associated with MHC class II molecules (Figure 1D). The antigen– MHC class II complex is expressed at the cell surface to be recognised by CD4þ T-helper lymphocytes via the T-cell receptor (TCR) molecule (Figure 1E). Along with this binding, the interaction between the APC and CD4þ T cell is only fully accomplished by an additional series of costimulatory, but essential, interacting molecules. Among others, binding of CD4 to MHC class II, lymphocyte function-associated antigen-3 (LFA- 3) to intercellular adhesion molecule-1 (ICAM-1) and CD28 (CD4þ cell) to B7 enhances the conjugation of the cells and promotes T-cell activation signals. Soluble cytokines, such as IL-2, IL-6 and IFN-g, provide generation of APC and T cells and ‘finetuning’. Depending on many nonspecific factors, including antigen dose, type of APC and the expression of the mentioned membranebound costimulatory signals of the T-helper cells, a so-called Th1- type, and to some degree a Th2-type, response develops during BCG treatment. The Th1 or cell-mediated immune response and the Th2 or humoral immune response are characterised by the patterns of cytokines, secreted by the CD4þ T-helper cells following antigen-specific stimulation. In mouse models, the Th1 response is primarily characterised by IL-2, IL-12, IFN-g and TNF-b, and the Th2 response by IL-4, IL-5, IL-6 and IL-10. The recognition that this description of two types of responses reflects the human immune response and that they are regulated in a reciprocal fashion, critically regulated by the cytokines, represent a major advance in the field of antitumour cytotoxicity mechanisms. Knowledge concerning the APC–T-helper cell interaction and development of Th1 and Th2 responses has been used to study the BCG-induced role of the urothelium in antigen presentation and initiation of the immune response.

Uroepithelial tumour cells and antigen-presenting properties Immunocompetence of the host is essential for BCG therapy. Dendritic cells, macrophages and CD4þ T lymphocytes play a crucial role in the antitumour effect. In addition, evidence exists for an important role of epithelial, TCC cancer cells. Mouse bladder tumour cells present BCG antigen to CD4þ T cells, via MHC class II molecules (Lattime et al, 1992). The initial observations were extended for another murine cell line and a panel of human cell lines. Constitutive and BCG-induced expres- A B C E F H G D Antigen presenting cells APC BCG + Bladder Adherence and phagocytosis Processing and antigen presentation Cytokine production Cytokine production Th1-type response or cell-mediated immune response Cell-mediated tumour cell eradication CD4+ T cell cell G1 Th1 response IL-2, IL-12, IFN-_, TNF-_ Th2 response IL-5, IL-6, IL-10 Inflammation Side-effects Natural killer cell Bladder cancer cell Macrophage Cytotoxic T cell Cell-mediated Immune Response G2 G3 Grade APC properties TCC

Figure 1 Simplified scheme of the supposed mechanism of action of BCG in tumour cell eradication. After its instillation in the bladder (A), BCG (B) accumulates near the bladder wall, followed by adherence and passage through the GAG layer of the bladder wall (C). Bacillus Calmette-Gue´rin is internalised and processed by professional antigen-presenting cells (APCs) and (high-grade) tumour cells (D), and BCG antigens are presented to CD4þ T cells (E). Depending on various conditions, this results in the local synthesis of a particular set of cytokines, known as the Th1-type or cellmediated immune response (F, G). The Th1 cytokine profile enables recruitment and maturation of cytotoxic effector cells. No definite statements can be made yet about the actual effector cell(s), but a key role for NK cells in tumour cell killing has been proposed (H). BCG therapy for bladder cancer RFM Bevers et al 609 British Journal of Cancer (2004) 91(4), 607 – 612 & 2004 Cancer Research UK

sion of MHC class II and the major costimulatory molecules ICAM-1 and B7-1 was observed. The antigen presentation factors are enhanced in high-grade TCC cell lines only (Figure 1D) (Ikeda et al, 2002). Quantitative immunohistochemistry has confirmed the in vitro findings. Serial bladder biopsies and urinary cytospins, taken before and after BCG therapy, revealed an upregulation of MHC class II and ICAM-1 expression of urothelial tumour cells (Jackson et al, 1994).
Interestingly and likely of uttermost importance, recently non- MHC-encoded, CD1-restricted presentation of (glyco)lipid antigens has been recognised (Maksymowych and Kane, 2000). Although for BCG no data are available yet, CD4þ CD1-restricted T cells were observed in patients suffering from Mycobacterium leprae (Sieling et al, 2000). These cells produce IFN-g, but not IL-4. Bacillus Calmette-Gue´rin therapy-related research has revealed an increased CD1 expression of TCC cell lines in the presence of live BCG (Ikeda et al, 2002) and a virtual absence of urinary IL-4 during BCG treatment (Nadler et al, 2003). Accordingly, it is tempting to hypothesise that CD1-facilitated BCG antigen presentation contributes to the development of BCG immunity.

In summary, epithelial TCC cells gain the phenotypical characteristics and functioning of APCs in the presence of BCG. These functions strongly suggest that the BCG–high-grade tumour cell interaction acts in cohort with the BCG–professional APC interaction. Clinical observations seem to confirm this conclusion, since BCG therapy seems to exert a better antitumour effect in high-grade bladder cancer (Table 1).

Secretion of cytokines by urothelial tumour cells Multiple studies have reported on cytokine production as a result of BCG therapy. Following intravesical BCG instillations, there is an increase in the urinary level of several cytokines, such as IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-a and IFN-g. Undoubtedly, the major cell sources are the immunocompetent cells, but urothelial cells contribute to a significant degree. In vitro studies with human TCC cells revealed a BCG-induced upregulation of the cytokines IL-6, IL-8, IL-10, GM-CSF, TNF-a and IFN-a, but not IFN-g, IL-2, IL-4 and IL-12 (Figure 1F and G) (Boer de et al, 1997; Bevers et al, 1998). Of all cytokines produced by TCC cell lines, the cytokines IL-6 and IL-8 are highly prominent and their role will be discussed here in some detail.

Interleukin-6 Within the challenged immune system, several cell types including APC produce IL-6. This multifunctional cytokine is critically involved in the acute phase response, T-cell proliferation, B-cell maturation, macrophage maturation and cytotoxic T-cell differentiation. In combination with IL-1, IL-2 and IFN-g, IL-6 induces expression of the IL-2 receptor (IL-2R), thus participating in the activation of resting T cells (Lauta, 2003). Furthermore, Il-6 seems to contribute to MHC-nonrestricted cytotoxic activity by inducing natural killer (NK) cell proliferation. Nowadays, NK cells are considered as essential, cytotoxic effector cells during BCG therapy (Figure 1H) (Brandau et al, 2001).

High-grade TCC cell lines show a high constitutive and BCGinduced production of IL-6. However, the importance of IL-6 produced by bladder cancer cells in the BCG-induced immune response remains to be established. In vitro studies revealed that IL-6 mRNA upregulation and IL-6 production depend on BCG dose, incubation period, BCG internalisation and TCC cell grade (Bevers et al, 1998). Interleukin-6 production requires a minimal BCG exposure time of 0.5–1 h, which is in accordance with clinical practice.

Interleukin-6 is considered a major source of early Th1/Th2 control during CD4þ T-cell activation as it attributes to the promotion of the Th2 response and simultaneously inhibition of Th1 polarisation (Figure 1G). Interleukin-6 activates the production of IL-4 by CD4þ T cells and their differentiation into Th2 effector cells. Moreover, it inhibits Th1 differentiation by interference with IFN-g signalling and the development of Th1 cells (Diehl and Rincon, 2002). The abundant IL-6 response during BCG therapy and virtually the absence of urinary IL-4 seem to be however in conflict with the recognition that the presence of BCG primarily induces a Th1 response. The absence of IL-4 and a high production of IFN-g may prevent or contradict the Th2-promoting effect of IL-6. Moreover, this finding suggests an important role of the CD1-restricted presentation of (glyco)lipid antigens of live BCG , since CD4þ CD1-restricted T cells produce IFN-g but not IL-4 (Sieling et al, 2000; Ikeda et al, 2002).

Interleukin-8 Interleukin-8 is a proinflammatory cytokine with strong chemotactic properties, attracting T lymphocytes and neutrophils. Interleukin-8 is induced rapidly, already after the first instillation, during BCG therapy (Boer de et al, 1997). Dendritic cells, macrophages and a number of other cells, including TCC cell lines, produce IL-8. The early urinary IL-8 production in vivo may indicate the significance of an interaction of BCG bacilli with (residual) bladder cancer cells in the initiation of the host immune response.

Cell-mediated antitumour effects: the effector cells The final step in the eradication of tumour cells consists of mobilisation and activation of cytotoxic effector cells (Figure 1H). Several in vitro studies show evidence for several nonspecific cytolytic cells like NK cells, BCG-activated killer cells (BAKs), macrophageactivated killer cells (MAKs), lymphokine-activated killer cells (LAKs) and cytotoxic T lymphocytes (Kawashima et al, 2003).

A key role is supposed for NK cells (Brandau et al, 2001). NK cells, a special population of mononuclear cells, recognise ‘self’- peptides presented by MHC class I molecules on the surface of cells. A cell not displaying these peptides in a correct way is attacked and killed by NK cells (Ka¨rre, 1995). In untreated bladder cancer patients, a loss or alteration of MHC class I expression is seen in tumour cells (Saint et al, 2001). Bacillus Calmette-Gue´rin-infected cells present BCG glycoprotein and lipoprotein antigens on their MHC class I molecule (Neyrolles et al, 2001). This may be a trigger for NK cells to attack BCG-infected urothelial tumour cells. Bacillus Calmette-Gue´rin therapy in the murine model, using NK celldeficient mice, is ineffective (Brandau et al, 2001).

However, in studies regarding the presence of NK cells after BCG therapy, relatively few NK cells were seen 3 weeks after the last instillation of a 6-week course (Lattime et al, 1992; Saint et al, 2001). It would be interesting to know if NK cells are more abundant earlier, during the BCG course. Strong direct evidence for NK cell or other effector cell(s) is still lacking. The recent acknowledgement of effector cells that recognise mycobacterial (glyco)lipid antigens through nonpolymorphic MHC molecules, such as CD1, may provide new insights into the true nature of the cytolytic effector cells involved in tumour cell eradication during BCG treatment (Maksymowych and Kane, 2000; Kawashima et al, 2003).

SUMMARY AND CONCLUSIONS Current insight of the mode of action of BCG, ranging from its introduction into the bladder to killing of residual tumour cells, has revealed a complex sequence of processes. Bacillus Calmette- Gue´rin accumulates near, and adheres to, the bladder wall. After passage through the GAG layer, BCG is internalised and processed by professional APC and tumour cells. The modified gene expression of these cells accumulates in the secretion of particular cytokines and presentation of BCG antigens. Bacillus Calmette- Gue´rin antigens are presented via MHC class II molecules to CD4þ T cells and via MHC class I molecules to CD8þ T cells. Lipid and glycolipid BCG antigens can be presented to CD4þ and CD8þ T BCG therapy for bladder cancer RFM Bevers et al 610 British Journal of Cancer (2004) 91(4), 607 – 612 & 2004 Cancer Research UK cells in a non-MHC-restricted, CD1-restricted fashion. Production of chemokines, such as IL-8, secreted partly by BCG-internalised tumour cells, contributes to the local activation of the immune system. Consequently, activated leucocytes and mononuclear cells invade the bladder wall. These developments provide the condition for a Th1 response, associated with particular cytokines (IFN-g, IL- 2, IL-12 and TNF-b). This cytokines profile promotes delayed-type hypersensitivity response, cytotoxic cell response, and macrophage activation or cellular immune inflammatory reaction. Depending on bacterial and host components, an upregulation of the Th2 response, associated with cytokines IL-6 and IL-10, may occur to some degree and adversely affect the functioning of the Th1 response. The Th1 cytokine profile enables recruitment and maturation of cytotoxic effector cells.
No definite statements can be made yet about the actual effector cell(s), but a crucial, cytotoxic role of NK cells has been proposed. In addition, some of the cytokines, and BCG itself, may exhibit a direct cytotoxic effect on tumour cells.

In 28 years of major research efforts, understanding of the mode of action underlying BCG therapy for bladder carcinoma is obviously much improved. Yet the jigsaw is not complete and many details wait unraveling. However, if successful, the reward might be a better, evidence-based BCG immunotherapy with optimal clinical efficacy and minimal occurrence of side effects in the form of an optimal BCG dose and treatment schedule, genetically engineered BCG, or particular antigenic molecule(s) that trigger immunological antitumour activity in a well-controlled manner.

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Bestraling - inwendig: Hoge dosis radioactief jodium verlengt leven van patiënten met uitgezaaide carcinoid significant, 5,75 jaren tegenover 2,09 jaren, aldus 15 jarige studie bij 96 patiënten, waarbij andere medicijnen en aanpak niets meer hielp
30 september 2004: Bron: Pubmed: Cancer. 2004 Sep 28

Hoge dosis radioactief jodium - ook wel bekend als inwendige bestraling - als aanvulling gegeven aan patiënten met uitgezaaide carcinoid, waarbij alle andere medicijnen en aanpak niets hielp geeft significant betere resultaten op langere overlevingstijd. De studie bij 98 patiënten en gevolgd over 15 jaar is opgezet om te meten wat het effect zou zijn van toevoeging van een bepaalde dosis radioactief gelabeld jodium - 401 +/- 202 millicuries (mCi) (131)I-MIBG. De patiënten die daarop reageerden met een symptomatische respons - wat dat precies is durven we niet te zeggen, maar weet uw arts beslist wel - overleefden gemiddeld 5,75 jaren tegenover 2,09 jaren in controlegroep. (5.76 years vs. 2.09 years; P < 0.01), een hoog significant resultaat dus. Bij 56 patienten waarvan de 5-HIAA waarden werden gevolgd - gemonitored, zakten de gemiddelde urine 5-HIAA waarden significant na (131)I-MIBG behandeling (126 +/- 122 ng/mL vs. 91 +/- 125 ng/mL; P < 0.01); echter, de patiënten met gereduceerde 5-HIAA waarden bij aanvang hadden geen verbeterde overleving (4.11 years vs. 3.42 years; P = 0.2). Patiënten die een initiële (131)I-MIBG dosis van meer dan 400 mCi kregen leefden weer wel significant langer dan patiënten die minder dan 400 mCi (4.69 years vs. 1.86 years; P = 0.05) kregen toegediend. Toxische bijwerkingen van deze aanpak zijn - pancytopenia, thrombocytopenia, nausea, and emesis.
Met dank aan Maud die deze bijwerkingen in het Nederlands aan ons uitlegt:

Gemcitabine: Chemokuren gemcitabine en cisplatin bij niet-klein-cellige longkanker ter overbrugging van tijd naar radiotherapie zorgt voor erg slecht resultaat aldus Nederlandse studie. Na de chemokuur verdubbelde de groei van de tumoren ten opzichte van controlegroep die geen chemo kregen.

GVAX: Vaccin - een GVAX-vaccin - tegen alvleesklierkanker en reagerend op de molecuul mesothelin geeft hoop in fase I trial bij 14 patiënten.
27 augustus: Bron Dow: Een vaccin uit de GVAX groep van Cellgenesys tegen alvleesklierkanker geeft hoop aldus resultaten uit een fase I trial. 14 patiënten kregen dit vaccin na de reguliere behandelingen als operatie en chemo c.q. bestraling. Alle patiënten hadden door aanwezigheid van uitgezaaide kankercellen in de lymfeklieren en bloed een sterk verhoogd risico op een recidief. Drie patiënten bleven kankervrij voor een periode nu al van 6,5 jaar en tonen alle drie in hun bloed sterke groei van specifieke T-immuuncellen. In 2005 worden de resultaten verwacht van een fase II trial bij 60 patiënten. Voor OPS-leden hebben we het adres van een contactpersoon bij Cellgenesys beschikbaar. Hier het persbericht via de DOW verkregen.

SOUTH SAN FRANCISCO, Calif., Aug. 19 /PRNewswire-FirstCall/ -- Cell Genesys, Inc. (Nasdaq: CEGE) today announced the publication of encouraging immunologic data for GVAX(R) pancreatic cancer vaccine, a non patient-specific vaccine which is being developed as an "off-the-shelf" pharmaceutical product. In a previously reported Phase 1 trial of this product, 14 patients received the vaccine after pancreatic cancer surgery and standard adjuvant therapy. Three patients remain alive and disease-free at their most recent follow-up of at least 6.5 years. The newly published article describes a detailed analysis of the immune response to the vaccine product in these patients. Of particular note is that all three long-term survivors demonstrated strong T cell responses to mesothelin, a tumor-associated molecule found on GVAX(R) pancreatic cancer vaccine cells, and that the specificity of the T cell response to mesothelin was unique to each responding patient. In contrast, only one of the 11 patients who progressed and died from pancreatic cancer mounted a detectable immune response to mesothelin and the level of response in this patient was minimal by comparison. These findings provide evidence that patient-specific immune responses can be generated following vaccination with a non patient-specific GVAX(R) cancer vaccine product and that such responses may correlate with clinical outcome. The results were published in an August issue of the Journal of Experimental Medicine by Elizabeth Jaffee, M.D., professor of Oncology, and colleagues at the Johns Hopkins Kimmel Cancer Center.
"These newly published results provide compelling evidence in humans that a non patient-specific GVAX(R) vaccine product can be used to generate antitumor immunity, with a profile specific to each vaccinated patient," said Joseph J. Vallner, Ph.D., president and chief operating officer of Cell Genesys. "Such findings are important because they provide further scientific proof-of-concept for our GVAX cancer vaccine strategy, which is focused on non patient-specific, "off-the-shelf" products. For example, our GVAX(R) prostate cancer vaccine, which is currently in Phase 3 clinical trials, is a non patient-specific vaccine product."

The initial Phase 1 trial of GVAX(R) pancreatic cancer vaccine was conducted at the Johns Hopkins Kimmel Cancer Center in 14 patients who received the vaccine following surgical resection of their tumor and standard adjuvant radiation and chemotherapy. As first reported in the Journal of Clinical Oncology in January 2001, three of eight patients who received the higher dose levels of the vaccine had prolonged disease-free survival and this continues to be true at their most recent follow-up of at least 6.5 years. This outcome is considered particularly significant since all three long-term survivors were judged to be at high risk for recurrent cancer due to microscopic evidence of pancreatic tumor following surgery and/or metastatic tumor in pancreatic lymph nodes. In addition, the three patients with prolonged disease-free survival had biopsy-proven vaccine-induced antitumor immunity as well as delayed type sensitivity (DTH) reactions against their own tumor cells, findings not seen in the patients whose cancer progressed. This observed relationship between evidence of an immune response to the vaccine and clinical outcome is further supported by T cell responses to mesothelin described in the Journal of Experimental Medicine article. As with other GVAX(R) clinical trials, vaccine treatment was generally well tolerated.

A follow-on Phase 2 clinical trial of GVAX(R) pancreatic cancer vaccine in patients with operable pancreatic cancer who receive the vaccine after surgical resection of tumor and adjuvant radiation chemotherapy is currently being conducted at the Johns Hopkins Kimmel Cancer Center. To date, the study has enrolled approximately 50 out of a projected 60 patients. Enrollment is expected to be completed this year, in which case preliminary data may be available during 2005.

Clinical trials of GVAX(R) cancer vaccines are under way for multiple types of cancer in addition to pancreatic cancer, including prostate cancer, lung cancer, leukemia and myeloma. GVAX(R) vaccines are whole-cell vaccines that are designed to stimulate an immune response against the patient's tumor. The vaccines are comprised of tumor cells that have been genetically modified to secrete GM-CSF, an immune stimulatory hormone that plays a key role in stimulating the body's immune response to vaccines. Currently, Cell Genesys is developing non patient-specific, "off-the-shelf" GVAX(R) vaccines for prostate cancer, pancreatic cancer, leukemia and myeloma, and a patient-specific, individualized vaccine for lung cancer. GVAX(R) cancer vaccines have demonstrated a favorable side effect profile in over 600 patients treated in clinical trials to date.

Cell Genesys is focused on the development and commercialization of novel biological therapies for patients with cancer. The company is pursuing three cancer product platforms -- GVAX(R) cancer vaccines, oncolytic virus therapies and antiangiogenesis therapies. Clinical trials of GVAX(R) cancer vaccines include an ongoing Phase 3 trial of GVAX(R) prostate cancer vaccine as well as trials of GVAX(R) vaccines for lung cancer, pancreatic cancer, leukemia and myeloma. Clinical programs of oncolytic virus therapies include CG7870 for prostate cancer. Preclinical studies are in progress for additional GVAX(R) cancer vaccines, oncolytic virus therapies and antiangiogenesis therapies for multiple types of cancer. Cell Genesys' minority-owned subsidiary, Ceregene, Inc., is focused on gene therapies for neurologic disorders. Cell Genesys also continues to hold an equity interest in its former subsidiary, Abgenix, Inc., an antibody products company. Cell Genesys is headquartered in South San Francisco, CA and has manufacturing operations in San Diego, CA, Hayward, CA and Memphis, TN. For additional information, please visit the company's website.

Tamoxifen en bestraling: Aanpak van borstkanker na operatie met tamoxifen en bestraling bij vrouwen ouder dan 70 jaar lijkt zinloos. Voor vrouwen vanaf 50 jaar lijkt deze aanpak wel zinvol voor lokale uitzaaiïngen, al is ook hier geen verschil in krijgen van uitzaaiingen op afstand en op overleven tussen beide groepen, blijkt uit recent gepubliceerde gerandomiseerde studies.
9 september 2004: Bron: Pubmed: N Engl J Med. 2004 Sep 2;351(10):971-7.

Gerandomiseerde studies hebben uitgewezen dat voor vrouwen met borstkanker boven de 70 jaar operatie en tamoxifen net zo effectief is als operatie en bestraling en tamoxifen en daarmee lijkt extra bestraling geen enkel postief effect te geven bij vrouwen ouder dan 70 jaar. Een andere gerandomiseerde studie laat door deze aanpak bij vrouwen boven de 50 jaar wel een significant positief effect zien op lokaal recidief. Extra bestraling geeft uiteraard veel meer bijwerkingen en is intensiever voor de patiënt.

In de studie bij vrouwen boven de 70 jaar die vijf jaar liep is geen verschil geconstateerd tussen de twee groepen. In de studie bij vrouwen vanaf 50 jaar blijkt het verschil significant beter op het wel of niet krijgen van lokale uitzaaiingen. In beide studies is overigens geen sprake van verschil in wel of niet krijgen van uitzaaiingen op afstand en geen verschil in overleven. Ook in de studie bij vrouwen vanaf 50 jaar was er dus geen verschil in borstkanker overleven tussen vrouwen die wel en vrouwen die niet extra werden bestraald. Overigens hebben verschillende studies bewezen dat andere hormoonkuren beter en efectiever zijn dan Tamoxifen. Zie meer informatie daarover onder kankersoorten-borstkanker. Wellicht is met goede voeding en bepaalde extra vitamines en mineralen en anti-oxidanten het effect van deze behandelingen wel te verbeteren, maar daarvoor zult u een consult moeten doen bij een goed gekwalificeerde orthomoleculaire arts. Zo heeft bv. een studie uitgewezen dat GLA, zit veel in teunisbloemolie als aanvulling het effect van bestralen lijkt te vergroten en de bijwerkingen aanzienlijk te verminderen. Lees studie verslag van GLA onder tamoxifen

Hier de abstracts van beide studies uit Pubmed gehaald en gepubliceerd met toelichting enz. in New England Journal of Medicin september 2004.

Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.

Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, Wheeler J, Champion LA, Smith TJ, Smith BL, Shapiro C, Muss HB, Winer E, Hudis C, Wood W, Sugarbaker D, Henderson IC, Norton L; Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group.

Avon Comprehensive Breast Evaluation Center, Breast/Ovarian Cancer Genetics and Risk Assessment Program, Massachusetts General Hospital, Division of Surgical Oncology, Boston 02114, USA. kshughes@partners.org

BACKGROUND: In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy.

METHODS: Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival.

RESULTS: The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone.

CONCLUSIONS: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer. Copyright 2004 Massachusetts Medical Society

Bron: Pubmed: N Engl J Med. 2004 Sep 2;351(10):963-70.

Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.>br>
Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, Weir LM, Olivotto IA.

Department of Radiation Oncology, Princess Margaret Hospital,, Toronto, ON, Canada. kankersoorten-borstkanker. Opvallend is wel dat deze studie al uitgevoerd is van 1987 tot 1992 en pas in 2003 is gepubliceerd. Wat voor belangen zouden hier nu weer achter zitten. Hieronder het abstract van de studie.

Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial.
Mustacchi G, Ceccherini R, Milani S, Pluchinotta A, De Matteis A, Maiorino L, Farris A, Scanni A, Sasso F; Italian Cooperative Group GRETA.

Oncology Center, University of Trieste, Napoli, Italy. mustacchi@fmc.univ.trieste.it

BACKGROUND: To evaluate the efficacy of tamoxifen as primary treatment in women aged over 70 years with operable breast cancer versus surgery followed by adjuvant tamoxifen.

PATIENTS AND METHODS: Patients randomly received tamoxifen alone (160 mg day 1, then 20 mg/day) for 5 years or surgery followed by tamoxifen (20 mg/day) for 5 years. Overall survival was the main study end point; secondary objectives included breast cancer survival and local control of the disease.

RESULTS: Between 1987 and 1992, 239 patients were assigned to surgery plus tamoxifen and 235 to tamoxifen alone. Treatment arms were comparable for tumor size, clinical nodal status and performance status. At a median follow-up of 80 months 274 patients had died. No difference between groups had emerged in overall and breast cancer survival. There were 27 local progressions in the surgery plus tamoxifen group and 106 in the tamoxifen-alone group (P = 0.0001). In the surgery plus tamoxifen group, no difference in overall survival had emerged according to the extension of operation.

CONCLUSIONS: The long-term results of the study confirm the 3-year interim analysis already reported. Surgery (radical or minimal) followed by adjuvant tamoxifen does not modify overall and breast cancer survival as compared with tamoxifen alone in early breast cancer of older women. Because of the high rate of local progressions with tamoxifen alone, minimal surgery followed by tamoxifen appears to be the appropriate treatment in such patients. More extensive surgery is not useful. Tamoxifen alone is an adequate alternative treatment in very old or frail patients.

Uracil-tagafur (UFT) vergroot kans op vijfsjaaroverleving van 74% naar 85% bij niet-kleincellige longkankerpatiënten na operatie.
Uracil-tegafur (UFT) vergroot kans op vijfjaarsoverleving bij longkankerpatiënten met niet-kleincellige kankercellen van 74% naar 85%.

d.d. 25 april 2004:

Bron: CNN, onderstaande artikel vrij vertaald met hulp van een freetranslater.

Uracil-tegafur (UFT) een chemo in pilvorm vergroot kans op vijfjaarsoverleving van 74% naar 85% bij longkankerpatiënten met niet-kleincellige kankercellen na operatie, aldus Japanse onderzoekers.

Een Japanse studie heeft gevonden/bewezen dat een drugscombinatie die als een kanker behandeling bij darmkanker in de Verenigde Staten is afgekeurd jaren kan toevoegen aan het leven van mensen met longkanker zonder uitzaaiingen buiten de longen.

Longkanker is een van de meest voorkomende en dodelijkste soort kanker en 85 procent sterft aan longkanker. Enkel een andere chemo, cisplatin, kan de overlevingstijd in vroege stadiums van longkanker verbeteren en het voegt enkel maanden toe aan de levensverwachting.
"Dit is een grote verrassing voor Amerikaanse oncologen," zegt Dr. Herman Kattlove of Los Angeles, medical editor for the American Cancer Society.
Bovendien de twee-drugscombinatie, genaamd uracil-tegafur of UFT, is een pil, in plaats van iets dat in een ader ingebracht moet worden en bovendien heeft UFT weinig neveneffecten/bijwerkingen, zoals Dr. Yukito Ichinose and others verbonden aan Japanse ziekenhuizen rapporteerden in de New England Journal of Medicine.
Nochtans, zou UFT schijnbaar nuttig zijn voor een klein percentage van de 174,000 mensen gediagnosticeerd met long kanker in de Verenigde Staten elk jaar -- minder dan 10.000, ruwwweg geschat. UFT werkt alleen tegen adenomas, ook wel niet--kleine-celkanker genoemd en enkel bij patiënten met kleine tumoren die zich nog niet buiten de longen verspreid hebben.
Overlevingsbijzonderheden: De Japanse onderzoekers keken naar 979 patiënten. Bij alle patiënten waren via chirurgie de tumoren verwijderd. De helft -- 482 -- kreeg ook de pillen Uracil-tegafur (UFT), die tweemaal per dag gedurende twee jaren werden genomen.
Na vijf jaar was er geen verschil in lichameljke conditie en tumrogroei onder de 412 patiënten met de kleinste tumors, die minder dan acht-tiende van een inch waren (ca. 2 cm. doorsnee).
Maar patiënten met grotere tumoren bleken langer met deze chemo UFT te leven. Na vijf jaar was 85 procent van de UFT patiënten met tumoren groter dan 2,5 cm. nog steeds in leven, tegen 74 procenten van degenen die geen aanvullende chemotherapie kregen.
Het resultaatsverschil op overleven na vijf jaar voor mensen met tumoren die kleiner waren dan 2,5 cm. doorsnee was niet significant: 89 procent van de UFT patiënten tegen 86 procenten van de vergelijkingsgroep.
"Hoe gevorderder uw kanker hoe waarschijnljker het is dat u eraan sterft , maar hoe beter zal een behandeling u helpen," zegt Kattlove.
De Uracil-tegafur (UFT) werd voor longkanker in de Verenigde Staten niet in trials getest. Bristol Myers Squibb and Taiho Pharmaceutical Co. onderzochten in trials UFT tegen uitgezaaide darmkanker, maar de FDA weigerde hun onderzoeksresultaten toestemming te geven. UFT wordt wel in Azië, Europa, en Latijns-Amerika gegeven.
Kathy Baum, een woordvoerster voor farmaceutisch bedrijf Bristol Myers Squibb, wilde niet zeggen of deze nieuwe vondsten een nieuwe toepassing voor UFT als een longkanker behandeling zou stimuleren.
Kattlove zegt dat de meeste oncologen meer studies willen zien. "Het vinden van een medicijn dat zo eenvoudig kan worden toegediend, en bijna zonder neveneffecten werkt, is eenvoudig te goed om juist te zijn," zegt hij.
Dr. Alfred Munzer, voorbije president van de American Lung Association zegt dat het medicijn aan patiënten die de beste kansen hebben enige hoop zou kunnen geven ermee te beginnen.
", Maar de boodschap voor longkanker is nog steeds dat preventie veel belangrijker is dan behandeling en veel doeltreffender," zegt hij. "Dat wil zeggen stoppen met roken."
d.d. 25 april 2004:

Hieronder het CNN bericht dat hierboven is vertaald:

(AP) -- Surprising U.S. experts, a Japanese study has found that a drug combination rejected as a cancer treatment in the United States can add years to the lives of people with early lung cancer.
Lung cancer is one of the most common and lethal types of cancer, killing 85 percent of its sufferers. Only one other drug, cisplatin, has been shown to improve survival in early stages, and it adds only months.
"This is a big surprise to American oncologists," said Dr. Herman Kattlove of Los Angeles, medical editor for the American Cancer Society.
In addition, the two-drug combination, called uracil-tegafur, or UFT, is a pill, rather than something which must be dripped into a vein, and it has few side effects, Dr. Yukito Ichinose and others at hospitals around Japan reported in Thursday's New England Journal of Medicine.
However, UFT apparently would be useful for only a small percentage of the 174,000 people diagnosed with lung cancer each year in the United States -- as few as 10,000, by some estimates. It works only against adenomas, also called non-small-cell cancers, and only among patients with small tumors that have not spread out of the lung.
Survival specifics
The Japanese researchers looked at 979 such patients. All had surgery to remove the tumor. Half -- 482 -- also got the pills, which were taken twice a day for two years.
After five years, there was no difference among the 412 patients with the smallest tumors, those less than eight-tenths of an inch across.
But patients with larger tumors were more likely to live longer with the drug. After five years, 85 percent of the UFT patients with tumors more than 1.2 inches across were still alive, versus 74 percent of those who got no chemotherapy.
The effect on survival after five years was much less marked for people with tumors in between those two sizes: Eighty-nine percent of the UFT patients versus 86 percent of the comparison group.
"The more advanced the cancer the more likely it is to kill you, so the more likely a treatment is to help you," Kattlove said.
Uracil-tegafur was not tested for lung cancer in the United States. Bristol Myers Squibb and Taiho Pharmaceutical Co. did test it against colon cancer, but the Food and Drug Administration rejected their application for approval. However, it is used in Asia, Europe, and Latin America.
Kathy Baum, a spokeswoman for drug-maker Bristol Myers Squibb, would not say whether the findings would prompt a new application for UFT as a lung cancer treatment.
Kattlove said most cancer doctors would want to see more studies. "Finding a drug as simple as this, as free of side effects, that works is just too good to be true," he said.
Dr. Alfred Munzer, past president of the American Lung Association, said the drug could offer some hope to patients who have the best chances to start with.
"But the message for lung cancer still is that prevention is far more important than cure, and far more effective," he said. "That's, of course, to stop smoking."

Uracil-tegafur (UFT) geeft zelfde resultaat bij uitgezaaide darmkanker als intraveneuze chemo (5-FU en leucovorin) maar veel minder bijwerkingen en veel gemakkelijker in te nemen
Uracil-tegafur (UFT) geeft zelfde resultaat bij uitgezaaide darmkanker als intraveneuze chemo (5-FU en leucovorin) maar veel minder bijwerkingen en veel gemakkelijker in te nemen

d.d. 25 april 2004: Bron: Pubmed, J Clin Oncol. 2002 Sep 1;20(17):3605-16

. Onderstaande dubbelblinde gerandomiseerde studie suggereert en bewijst dat Uracil-tagafur (UFT) in vergelijking met 5-FU en leucorin een even goed resultaat geeft bij uitgezaaide darmkanker maar met veel minder bijwerkingen en veel gemakkelijker in te nemen. Wie op internet zoekt ziet dat deze oral chemo in tabletvorm net als Xeloda bv. bij veel verschillende vaste tumoren nu wordt uitgeprobeerd in fase II en fase III trials. Een interessante ontwikkeling.

Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.

Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, Vincent MD, Lembersky BC, Thompson S, Maniero A, Benner SE.

Centre Rene Gauducheau, Nantes, France. jy-douillard@nantes.fnclcc.fr PURPOSE: This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared.

PATIENTS AND METHODS: Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d) for 5 days every 28 days.

RESULTS: UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P =.630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P =.232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P =.011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P <.001) and documented infections (P <.05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P <.001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics.

CONCLUSION: UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.

Virus als medicijn: MediGene start Phase I/II Trial met inbreng van kankerdodend virus bij niet te opereren leveruitzaaiïngen onder de naam NV1020, een herpes simplex virus.
3 september 2004: Bron -- Persbericht van Medigene

Na alle mooie nieuws over bv. het Newcastle virus en inbreng van virus door engelse onderzoekers, zie elders onder deze artikelen onder actueel regulier onderzoek, een mooi nieuw initiatief met inbrengen van een kankerdodend virus. Deze week maakte het Amerikaans-Duitse farmaceutisch bedrijf Medigene bekend dat zij een fase I - II trial starten om het effect te testen van het inbrengen van een kankerdodend virus, een herpes simplex virus, in niet operabele tumoren in de lever van darmkankerpatiënten met het adenocarcinoom. Het kankerdodende virus wordt onder de codenaam NV1020 getest. Allereerst op effect, tolerantie en veiligheid. Er wordt zowel getest met het virus alleen als wel in combinatie met chemo bij ca. 30 patienten in 7 verschillende ziekenhuizen in de USA. De patiënten krijgen vier keer het virus teogeeind en daarna nog een chemokuur erachteraan. De uitslagen van deze trial worden medio 2006 verwacht.

MediGene Initiates Clinical Phase I/II Trial of Cancer-Killing Virus NV1020 for the Treatment of Liver Metastases.

MARTINSRIED, Germany and SAN DIEGO, Sept. 2 /PRNewswire-FirstCall/ --
Today the German-American biotech company MediGene AG (Frankfurt, Prime Standard: MDG) announced the initiation of a clinical phase I/II trial of the drug candidate NV1020 for the treatment of liver metastases developing from colorectal cancer. NV1020 is currently developed as a cancer-killing (oncolytic) virus. It is a herpes simplex virus, genetically modified for the specific destruction of tumor cells without harming healthy tissue. The trial will evaluate safety, tolerability and efficacy of NV1020 as well as its synergies with chemotherapy. In this trial, about 30 patients will be treated in up to 7 clinical centres in the USA. The positive results obtained in a clinical phase I trial of NV1020 form the basis for this trial. MediGene expects the results of the phase I/II study by mid 2006. The sales potential for NV1020 is estimated at over 200 million Euros, provided that the three- step clinical development is successful and marketing authorization is granted.
Dr. Peter Heinrich, Chief Executive Officer of MediGene AG, comments: "Cancer-killing viruses like NV1020 are among the most innovative products of today's drug development. If the development of NV1020 proceeds as successfully in the future as it has up to now, MediGene may become the first company wordwide to develop a virus mutant cancer drug to market maturity. This could be a very valuable contribution to improvement in cancer therapy."

NV1020: MediGene's oncolytic herpes simplex virus (HSV) NV1020 is designed to selectively multiply in tumor cells, thus destroying the tumor (oncolysis). The technology is based on the assumption that oncolytic HSV act more selectively and efficiently than conventional cancer therapies, without leading to severe adverse events. They could provide a therapeutic alternative against tumors that are inoperable or have developed a resistance to chemotherapy or radiotherapy. There may be also a synergistic effect of combining oncolytic HSV and standard therapies such as chemotherapy.

Study design: The trial will be composed of a part to determine the appropriate dosage, followed by a phase 2 part investigating tolerability and efficacy utilizing the optimal dose of NV1020. The patients participating in the trial suffer from colorectal adenocarcinoma which cannot be removed by surgery. In the course of the trial, NV1020 is administered to these patients four times, followed by standard chemotherapy. The first study center has been initiated and the first patient has been evaluated for study eligibility.

This press release contains forward-looking statements that involve risks and uncertainties. The forward-looking statements contained herein represent the judgement of MediGene as of the date of this release. These forward- looking statements are no guarantees for future performance, and the forward- looking events discussed in this press release may not occur. MediGene disclaims any intent or obligation to update any of these forward-looking statements.

MediGene(TM) is a trademark of MediGene AG. About MediGene: MediGene AG is a publicly quoted (Frankfurt: Prime Standard), German- American biotechnology company located in Martinsried, Germany and San Diego, USA. MediGene is the first German biotech company with a drug on the market. The company has the most mature drug development pipeline in the German biotech industry (drug candidates undergoing clinical phase I - III trials). In addition, MediGene possesses innovative platform technologies with its HSV technology and the newly acquired EndoTAG(TM) technology. MediGene's core competence lies in research and development of novel approaches for the treatment of various tumor diseases. Thus MediGene focuses on indications of high medical need and economic opportunities.

SOURCE MediGene AG /CONTACT: Julia Hofmann, Public Relations, +49-89-85-65-3324, or Dr. Michael Nettersheim, Investor Relations, +49-89-85-65-2946, both of MediGene AG, fax, +49-89-85-65-2920, or investor@medigene.com

Xeloda - capecitabine geeft 14% beter resultaat in overleving en tijd tot recidief bij darmkankerpatiënten na operatie in vergelijking met 5FU. Xeloda lijkt nu eerste lijns te gaan worden bij darmkankerpatiënten, ook in Europa
24 augustus 2004: Bron: Dow

De orale chemo Xeloda - Capecitabine zorgt in gerandomiseerde fase III trial voor 14% beter resultaat dan 5FU/LV bij darmkanker na operatie. Daarnaast geeft Xeloda veel minder bijwerkingen en is minder ziekenhuisbezoek nodig. Op basis van deze studieresultaten ljikt nu ook in Europa Xeloda - capecitabine als eerste lijns voorgesteld en geaccepteerd te gaan worden bij uitgezaaide darmkanker. Lees hier het persbericht zoals dat vandaag door de DOW werd vrijgegeven. Pikant en ook iets om toch even met trots op terug te kijken, al drie jaar geleden kwamen wij als eerste in Nederland op deze website met aandacht voor Xeloda in vergelijking met 5FU. In het begin moesten patiënten enorm knokken en praten om Xeloda te kunnen krijgen van hun oncoloog, maar nu lijkt het veel minder moeite te kosten. Deze studie en aanvraag tot acceptatie als eerste lijns bevestigt dat we toen al terecht hier aandacht aan hebben besteed. Als u dan ook nog eens gezond erbij eet en bepaalde voedingsuppletie gebruikt kan dat een enorme verbetering en misschien zelfs wel volledige genezing van uw darmkanker betekenen. In ieder geval lijkt de kwaliteit van leven met sprongen vooruit te gaan door de combinatie Xeloda en extra dieet zoals bv. Moermandieet en bepaalde extra voedimgsuppletie. Wacht nu eens niet tot u echt ongeneeslijk wordt verklaard of een recidief krijgt. Bij darmkanker is juist die periode na operatie zo ontzettend belangrijk. besteed aandacht aan uw eten en leefstijl. Echt het is de moeite waard. Overigens lijkt Xeloda - capecitabine ook zeer interessant voor borstkankerpatiënten na operatie.

-- DJ Roche Files Additional Xeloda Indication In Europe, US --

Edited Press Release
BASEL (Dow Jones)--Swiss pharmaceutical company Roche Holding AG (RHHBY) said Tuesday it has has filed an additional indication in Europe and the U.S. for its cancer drug Xeloda to treat colon cancer patients after surgery Adjuvant therapy, or after surgery therpay, is one of the most common treatment approaches in colon cancer patients. The submission to the European and the U.S. regulatory authorities is based on results from the successful X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) which demonstrated that Xeloda, an oral chemotherapy treatment, could replace commonly used intravenous 5-FU/LV based therapy. William M. Burns, Head of Roche's Pharmaceuticals Division said, "Our endeavour is to constantly improve treatment options in cancer. We are therefore pleased to be able to work with the regulatory authorities to also improve the therapy of patients with early stage colon cancer, encouraged by the outstanding results of the X-ACT study."
The global study involved almost 2,000 patients and has first been presented at this year's American Society of Clinical Oncology (ASCO) conference in New Orleans. The X-ACT trial successfully met its primary endpoint of demonstrating at least equivalent disease free survival compared to intravenous 5-FU/LV. Moreover, it proved that Xeloda reduced the risk of tumours coming back (relapse-free survival) by an impressive 14%. This means that, each year, if treated with Xeloda, nearly 4,000 additional colon cancer patients worldwide would not suffer a recurrence of their cancer.
As further presented at ASCO, Xeloda also saved medical resources compared to intravenous chemotherapy. On average, a patient only needed about 8 hospital visits if treated with Xeloda compared to about 30 visits if treated with intravenous chemotherapy and Xeloda treatment resulted in fewer drug costs to treat chemotherapy side effects. Roche will present a full pharmacoeconomic analysis of Xeloda at this years European Society of Medical Oncology congress in Vienna, Austria.
The lead investigator Professor Jim Cassidy concluded his oral presentation at ASCO by stating: "Capecitabine (Xeloda) should replace 5-FU/LV in adjuvant treatment of colon cancer". Professor Cassidy is the Cancer Research UK Professor of Oncology and Chair of Medical Oncology, Beatson Oncology Centre, at the University of Glasgow in Scotland. The results of the X-ACT trial further support the ongoing and planned adjuvant studies of Xeloda in combination with other chemotherapies and targeted therapy such as Avastin, enrolling over 6000 patients on a global level. Company Web Site: www.Roche.com