Valacyclovir, een herpes medicijn plus een gemoduleerd virus naast radiotherapie en met of zonder hormoontherapie bij prostaatkankerpatienten geeft betere overleving (plus 20 procent) in vergelijking met historische statististische cijfers

Raadpleeg ook de lijst van niet-toxische ondersteuning bij prostaatkanker van arts-bioloog drs. Engelbert Valstar.

En als donateur kunt u ook korting krijgen bij verschillende bedrijven, waaronder bij Medpro voor o.a. prostasol een veelgebruikt natuurlijk middel bij prostaatkanker als alternatief voor hormoontherapie.

10 augustus 2022: Bron: Journal of Radiation Oncology 4, 377–386 (2015)

Zelfmoordgentherapie geeft uitstekende overall overleving voor prostaatkankerpatiënten.

Onderzoekers van het Houston Methodist Hospital (TX, VS) hebben al in 2015 opmerkelijk goede resultaten gepubliceerd van een langdurige studie naar radiotherapie - bestralingstherapie in combinatie met een zogeheten 'zelfmoordgentherapie' bij prostaatkankerpatiënten. De resultaten uit de studie laten een algehele 5-jaarsoverleving zien van 97% en 94% in twee patiëntengroepen, wat volgens deze onderzoekers een verbetering is van de mediane overall overleving (resp. met 20% in vergelijking met resultaten uit eerdere studies met radiotherapie en hormoontherapie bij dezelfde groep van patiënten. Geen aantoonbaar recidief na vijf jaar was 94 procent voor groep A en 91 procent voor groep B. De totale overleving na vijf jaar (OS) was 97 procent voor groep A en 94 procent voor groep B.

Wat hebben deze onderzoekers gedaan?

Tussen 1999 en 2003 namen 66 patiënten deel aan een fase II-studie en werden ze in twee groepen gesplitst: groep A bestond uit patiënten met niet uitgezaaide prostaatkanker (groep A; T1–T2a, Gleason score <7, pretreatment PSA <10)) en groep B bestond uit patiënten met een meer agressieve vorm van prostaatkanker, (T2b–T3, Gleason score ≥7, pretreatment PSA ≥10).

De lokaal toegediende gentherapie (GT) bestond uit een intraprostatische injectie van een adenovirale vector (adeno verkoudheidsvirus) die herpes simplex thymidinekinase (ADV/HSV-tk) bevat, gevolgd door valaciclovir, een veel gebruikt medicijn tegen herpes. Met als doel dat de valaciclovir het immuunsysteem van de patiënt zou stimuleren om actief de tumorcellen te vernietigen. Met de IMRT (intensiteit gemoduleerde radiotherapie) werd een gemiddelde dosis van 76 Gy de prostaat bestraald.

E Brian Butler, senior auteur en voorzitter van de afdeling Radiation Oncology van het Houston Methodist Hospital, legde eerder in een persbericht uit hoe deze zelfmoordgentherapie werkt: "We hebben strategisch een adenovirus gebruikt, vergelijkbaar met het virus dat verkoudheid veroorzaakt, om het therapiemiddel te dragen - een herpesvirusgen dat het enzym thymidinekinase (TK) direct in de tumorcellen produceert.
"Toen het herpesvirus-gen was afgeleverd en het TK begon te produceren, gaven we patiënten een veelgebruikt anti-herpesgeneesmiddel, valaciclovir. De combinatie viel het herpes-DNA aan en de TK-producerende tumorcellen vernietigden zichzelf, daarom wordt de procedure 'zelfmoordgentherapie' genoemd.

Patiënten met een laag risico (groep A; T1-T2a, Gleason-score <7, PSA vóór behandeling <10) werden behandeld met twee injecties met ADV/HSV-tk, elk gevolgd door valaciclovir en IMRT.
Patiënten met gemiddeld/hoog risico (groep B; T2b–T3, Gleason-score ≥7, PSA vóór de behandeling ≥10) werden behandeld met drie injecties met ADV/HSV-tk, elk gevolgd door valaciclovir, IMRT en hormonale therapie.

Aangezien het vaccin is gemaakt met de eigen kankercellen van de patiënt, heeft de behandeling het potentieel om de resultaten van standaardbestraling en hormonale therapieën aan te vullen en zelfs te verbeteren.
De onderzoeksresultaten rapporteerden opmerkelijk hoge recidiefvrije percentages op 5-jaars meting in beide groepen. Specifiek onthulden biochemische testen geen indicatie van terugkeer van kanker bij 62 patiënten.

Uit het abstract vertaald:

66 patiënten (33 patiënten in elke groep) werden in de studie opgenomen. De mediane follow-up was 100 maanden.
De percentages vrij van falen (FFF), dus geen aantoonbaar recidief na vijf jaar waren 94 procent voor groep A en 91 procent voor groep B.
De totale overleving na vijf jaar (OS) was 97 procent voor groep A en 94 procent voor groep B. Negatieve biopsiepercentages na 24 maanden waren 83 procent voor groep A en 79 % voor groep B.

Bijwerkingen waren minimaal: Eén patiënt in groep B ontwikkelde een graad 3 verhoging van het leverenzym. Er was geen hematologische toxiciteit van graad 3 of hoger. Eén patiënt had graad 3 urogenitale toxiciteit. Er was geen graad 3 of hoger van lagere gastro-intestinale toxiciteit.

Het volledige studierapport is tegen betaling aan te vragen. Of vraag het studierapport op bij de hoofdonderzoeker: Correspondence to E. Brian Butler.

Hier het persbericht en het abstract van de studie:

Suicide gene therapy demonstrates remarkable prostate cancer survival rates 16 DEC 2015

Researchers at Houston Methodist Hospital (TX, USA) have reported ground-breaking results from a long-term clinical trial investigating radiation therapy combined with suicide gene therapy in prostate cancer.

The findings, published in the Journal of Radiation Oncology, reveal 5-year overall survival rates of 97 % and 94 % in two patient arms, demonstrating a 20% improvement for survival over previous studies.

Between 1999 and 2003, 66 patients participated in the Phase II clinical trial and were split into two arms: Arm A consisted of patients with cancer cells confined to the prostate and Arm B consisted of patients with more aggressive prostate cancer.

An experimental gene therapy termed ‘suicide gene therapy’ was given to patients in Arm A twice during the study alongside radiotherapy treatment. Arm B patients received suicide gene therapy three times during the study, alongside radiation and hormonal therapy.

E Brian Butler, senior author and Chair of the Department of Radiation Oncology at Houston Methodist Hospital explained how this suicide gene therapy works: “We strategically used an adenovirus, similar to the one that causes the common cold, to carry the therapy agent – a herpes virus gene that produces the enzyme thymidine kinase, or TK – directly into the tumor cells.

“Once the herpes virus gene was delivered and it started manufacturing TK, we gave patients a commonly used anti-herpes drug, valacyclovir. The combination attacked the herpes DNA, and the TK-producing tumor cells self-destructed, which is why the procedure is called ‘suicide gene therapy.”

Once activated, valacyclovir kills tumor cells, and alerts the patient’s immune system to induce an attack on the cancer.

Since the vaccine has been created with patient’s own cancer cells, the therapy has the potential to complement and even enhance results from standard-of-care radiation and hormonal therapies.

The study findings reported remarkably high 5-year freedom from failure rates across both arms of the study. Specifically, biochemical testing revealed no indication of cancer recurrence in 62 patients.

Eighty three percent of Arm A patients and 79% of Arm B patients demonstrated negative prostate biopsies, which were performed 24 months after treatment completion. Compared with radiotherapy alone, all evaluative factors exhibited significantly higher outcomes.

Bin Teh, lead author and Vice Chair of Houston Methodist’s Department of Radiation Oncology, explained that the majority of patients in the trial also experienced little or no side effects.

Currently a Phase III trial is underway to evaluate the safety and efficacy of the in situ immunomodulatory gene therapy before it can be approved by the US FDA.

Teh shared his enthusiasm for the future: “We firmly believe this will be a viable treatment strategy.”

Sources: Teh BS, Ishiyama H, Mai WY. Thompson TC, Butler EB. Long-term outcome of a phase II trial using immunomodulatory in situ gene therapy in combination with intensity-modulated radiotherapy with or without hormonal therapy in the treatment of prostate cancer. J. Radiat. Oncol. DOI: 10.1007/s13566-015-0239-y (2015); Houston Methodist press release

Long-term outcome of a phase II trial using immunomodulatory in situ gene therapy in combination with intensity-modulated radiotherapy with or without hormonal therapy in the treatment of prostate cancer

Original Research
Published: 12 December 2015

Journal of Radiation Oncologyvolume 4, pages377–386 (2015)Cite this article

Abstract

Objective

The objective of this study is to report the long-term outcome of a phase II trial of immune-modulatory in situ gene therapy (GT) in combination with intensity-modulated radiotherapy (IMRT) with or without hormonal therapy for the treatment of prostate cancer.

Methods

GT was comprised of intraprostatic injection of adenoviral vector containing herpes simplex thymidine kinase (ADV/HSV-tk) followed by valacyclovir. A mean dose of 76 Gy was delivered to the prostate with IMRT. Low-risk patients (arm A; T1–T2a, Gleason score <7, pretreatment PSA <10) were treated with two injections of ADV/HSV-tk, each followed by valacyclovir, and IMRT. Intermediate/high-risk patients (arm B; T2b–T3, Gleason score ≥7, pretreatment PSA ≥10) were treated with three injections of ADV/HSV-tk, each followed by valacyclovir, IMRT, and hormonal therapy.

Results

Sixty-six patients (33 patients in each arm) were enrolled. The median follow-up was 100 months. Five-year freedom from failure (FFF) rates were 94 and 91 % for arms A and B, respectively. Five-year overall survival (OS) rates were 97 and 94 % for arms A and B. Negative biopsy rates at 24 months were 83 and 79 % for arms A and B. One patient in arm B developed grade 3 elevation in liver enzyme. There was no grade 3 or higher hematologic toxicity. One patient had grade 3 genitourinary toxicity. There was no grade 3 or higher lower gastrointestinal toxicity.

Conclusion

The combination of immunomodulatory in situ gene therapy and IMRT with or without hormonal therapy is feasible, safe, and effective in the treatment of prostate cancer. The effectiveness of this combined approach was likely through enhanced cytotoxicity, antitumor immune response, and abscopal effects. This approach with long term follow up appears to provide better clinical outcome over historical controls. A randomized trial of this strategy is currently ongoing.

This is a preview of subscription content, access via your institution.

References

Thompson TC (1999) In situ gene therapy for prostate cancer. Oncol Res 11(1):1–8

PubMed CAS Google Scholar
Hall SJ, Mutchnik SE, Chen SH, et al. (1997) Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer. Int J Cancer 70(2):183–187

Article PubMed CAS Google Scholar
Fujita T, Teh BS, Timme TL, et al. (2006) Sustained long-term immune responses after in situ gene therapy combined with radiotherapy and hormonal therapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 65(1):84–90

Article PubMed CAS Google Scholar
Satoh T, Teh BS, Timme TL, et al. (2004) Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 59(2):562–571

Article PubMed CAS Google Scholar
Ayala G, Satoh T, Li R, et al. (2006) Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Mol Ther 13(4):716–728

Article PubMed CAS Google Scholar
Ayala G, Wheeler TM, Shalev M, et al. (2000) Cytopathic effect of in situ gene therapy in prostate cancer. Hum Pathol 31(7):866–870

Article PubMed CAS Google Scholar
Miles BJ, Shalev M, Aguilar-Cordova E, et al. (2001) Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy. Hum Gene Ther 12(16):1955–1967

Article PubMed CAS Google Scholar
Finkelstein SE, Salenius S, Mantz CA, et al. (2015) Combining immunotherapy and radiation for prostate cancer. Clinical genitourinary cancer 13(1):1–9

Article PubMed Google Scholar
Timme TL, Hall SJ, Barrios R, et al. (1998) Local inflammatory response and vector spread after direct intraprostatic injection of a recombinant adenovirus containing the herpes simplex virus thymidine kinase gene and ganciclovir therapy in mice. Cancer Gene Ther 5(2):74–82

PubMed CAS Google Scholar
Teh BS, Aguilar-Cordova E, Vlachaki MT, et al. (2002) Combining radiotherapy with gene therapy (from the bench to the bedside): a novel treatment strategy for prostate cancer. Oncologist 7(5):458–466

Article PubMed CAS Google Scholar
Chen Y, DeWeese T, Dilley J, et al. (2001) CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res 61(14):5453–5460

PubMed CAS Google Scholar
Kaminski JM, Nguyen K, Buyyounouski M, et al. (2002) Prostate cancer gene therapy and the role of radiation. Cancer Treat Rev 28(1):49–64

Article PubMed CAS Google Scholar
Atkinson G, Hall SJ (1999) Prodrug activation gene therapy and external beam irradiation in the treatment of prostate cancer. Urology 54(6):1098–1104

Article PubMed CAS Google Scholar
Cowen D, Salem N, Ashoori F, et al. (2000) Prostate cancer radiosensitization in vivo with adenovirus-mediated p53 gene therapy. Clin Cancer Res 6(11):4402–4408

PubMed CAS Google Scholar
Colletier PJ, Ashoori F, Cowen D, et al. (2000) Adenoviral-mediated p53 transgene expression sensitizes both wild-type and null p53 prostate cancer cells in vitro to radiation. Int J Radiat Oncol Biol Phys 48(5):1507–1512

Article PubMed CAS Google Scholar
Freytag SO, Paielli D, Wing M, et al. (2002) Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model. Int J Radiat Oncol Biol Phys 54(3):873–885

Article PubMed CAS Google Scholar
Herman JR, Adler HL, Aguilar-Cordova E, et al. (1999) In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther 10(7):1239–1249

Article PubMed CAS Google Scholar
Chen SH, Shine HD, Goodman JC, et al. (1994) Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A 91(8):3054–3057

Article PubMed Central PubMed CAS Google Scholar
Hasenburg A, Tong XW, Rojas-Martinez A, et al. (2000) Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer. Cancer Gene Ther 7(6):839–844

Article PubMed CAS Google Scholar
Teh BS, Mai WY, Uhl BM, et al. (2001) Intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of a rectal balloon for prostate immobilization: acute toxicity and dose-volume analysis. Int J Radiat Oncol Biol Phys 49(3):705–712

Article PubMed CAS Google Scholar
Teh BS, Woo SY, Mai WY, et al. (2002) Clinical experience with intensity-modulated radiation therapy (IMRT) for prostate cancer with the use of rectal balloon for prostate immobilization. Med Dosim 27(2):105–113

Article PubMed Google Scholar
Roach 3rd M, Hanks G, Thames Jr H, et al. (2006) Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65(4):965–974

Article PubMed Google Scholar
Peeters ST, Heemsbergen WD, Koper PC, et al. (2006) Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 24(13):1990–1996

Article PubMed Google Scholar
Crook J, Ludgate C, Malone S, et al. (2009) Final report of multicenter Canadian phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 73(2):327–333

Article PubMed CAS Google Scholar
Dearnaley DP, Sydes MR, Graham JD, et al. (2007) Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 8(6):475–487

Article PubMed Google Scholar
Zelefsky MJ, Chan H, Hunt M, et al. (2006) Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 176(4 Pt 1):1415–1419

Article PubMed Google Scholar
Crook J, Malone S, Perry G, et al. (2000) Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients. Int J Radiat Oncol Biol Phys 48(2):355–367

Article PubMed CAS Google Scholar
Pollack A, Zagars GK, Antolak JA, et al. (2002) Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: analysis of a prostate cancer randomized radiation dose escalation trial. Int J Radiat Oncol Biol Phys 54(3):677–685

Article PubMed Google Scholar
Vance W, Tucker SL, de Crevoisier R, et al. (2007) The predictive value of 2-year post-treatment biopsy after prostate cancer radiotherapy for eventual biochemical outcome. Int J Radiat Oncol Biol Phys 67(3):828–833

Article PubMed Google Scholar
Kubo M, Satoh T, Tabata KI, et al. (2015) Enhanced central memory cluster of differentiation 8 and tumor antigen-specific T cells in prostate cancer patients receiving repeated adenovirus-mediated suicide gene therapy. Mol Clin Oncol 3(3):515–521

PubMed Central PubMed Google Scholar
Finkelstein S, Salenius S, Mantz C, et al. (2012) White blood cell counts remain stable following standard radiation approaches for high-risk adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 84(3 SUPPL. 1):S356–S357

Article Google Scholar
Dewan MZ, Galloway AE, Kawashima N, et al. (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15(17):5379–5388

Article PubMed Central PubMed CAS Google Scholar
Lee Y, Auh SL, Wang Y, et al. (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114(3):589–595

Article PubMed Central PubMed CAS Google Scholar
Schaue D, Ratikan JA, Iwamoto KS, et al. (2012) Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys 83(4):1306–1310

Article PubMed Central PubMed CAS Google Scholar
Chhikara M, Huang H, Vlachaki MT, et al. (2001) Enhanced therapeutic effect of HSV-tk + GCV gene therapy and ionizing radiation for prostate cancer. Molecular Ther 3:536–542

Article CAS Google Scholar
Teh BS, Mai WY, Augspurger ME, et al. (2001) Intensity modulated radiation therapy (IMRT) following prostatectomy: more favorable acute genitourinary toxicity profile compared to primary IMRT for prostate cancer. Int J Radiat Oncol Biol Phys 49(2):465–472

Article PubMed CAS Google Scholar
Rodriguez LV, Terris MK (1998) Risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. J Urol 160(6 Pt 1):2115–2120

PubMed CAS Google Scholar
Vora SA, Wong WW, Schild SE, et al. (2007) Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 68(4):1053–1058

Article PubMed CAS Google Scholar
Lips IM, Dehnad H, van Gils CH, et al. (2008) High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients. Radiat Oncol 3:15

Article PubMed Central PubMed Google Scholar

Download references

Acknowledgments

This work was supported by a specialized Program of Research Excellence (SPORE) grant (CA58204) from the National Cancer Institute, the Methodist Hospital Foundation, and the General Clinical Research Center (GCRC).

Author information

Authors and Affiliations

Department of Radiation Oncology, Houston Methodist Hospital, 1130 Earle St, AX 157, Houston, TX, 77030, USA

Bin S. Teh & E. Brian Butler
Department of Radiology and Radiation Oncology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

Hiromichi Ishiyama
Department of Radiation Oncology, Michael E. DeBakey Veteran Affairs Hospital, Houston, TX, USA

Wei-Yuan Mai
UT MD Anderson Cancer Center, Houston, TX, USA

Timothy C. Thompson

Corresponding author

Correspondence to E. Brian Butler.

Ethics declarations

Funding

This work was supported by NIH SPORE Grant P50-58,204. A specialized Program of Research Excellence (SPORE) grant (CA58204) from the National Cancer Institute, the Methodist Hospital Foundation, and the General Clinic Research Center (GCRC).

Conflicts of interest

The authors declare that they have no competing interests.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.