In updating my Nanotechnology in Medicine page recently, I noticed that several efforts to use nanotechnology in medicine have moved from the realm of research papers to the pre-clinical or clinical testing stage. For example, CytImmune has published the preliminary results of a phase 1 clinical trial of a targeted chemotherapy treatment method. They use gold nanoparticles attached to a molecule of a tumor-killing agent called tumor necrosis factor alpha (TNF) as well as a molecule of Thiol-derivatized polyethylene glycol (PEG-THIOL), which hides the TNF bearing nanoparticle from the immune system. The PEG-THIOL allows the nanoparticle to flow through the blood stream without being attacked. The combination of a gold nanoparticle, TNF and PEG-THIOL is named Aurmine.
The nanoparticle carrying the TNF tends to accumulate in cancer tumors but does not appear to accumulate in other regions of the body, which limits the toxic effects of TNF on healthy cells. CytImmune uses a combination of two techniques to target the TNF-carrying nanoparticle to cancer tumors. First, the nanoparticle is designed to be too big to exit most healthy blood vessels, however some blood vessels located at the site of tumors are leaky, allowing the nanoparticle to exit the blood vessel at the tumor site. The second technique involves the TNF molecules binding to the tumor. The fact that they had to get all these details right, determine the right size, a way to hide the nanoparticle from the immune system as well as choosing a targeting molecule to bind to the cancer turmor, gives you some idea as to why it has taken a while to go from research concept to clinical testing.
TNF has been shown to be most effective when administered with other chemotherapy drugs. Therefore, now that the phase 1 trial involving 16 patients is over, CytImmune is planning a phase 2 trial with Aurmine combined with other chemotherapy drugs. They are also performing pre-clinical testing of another combination in which TNF, PEG-THIOL and a chemotherapy drug called paclitaxel is bound to the surface of the nanoparticle. Three other treatments are under development using nanoparticles combined with TNF and other chemotherapy drugs. It will take a while to bring these treatments through all the phases required for qualification with the FDA, however it is exciting that they have progressed from the realm of research papers to trials that will lead to targeted treatment for patients.
c or regional chemotherapy: does it matter and should surgeons be involved? F. 0. STEPHENS Sydney Melanoma and Surgical Oncology Unit, The Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia TNF (tumour necrosis factor) is a new immunological anti-cancer agent which is too toxic for systemic use and relatively ineffective when used alone, but remarkably effective when used in closed circuit perfusion techniques together with other anti-cancer agents. Several studies have shown that when TNF is used with melphalan in closed circuit perfusion treatment for multiple melanoma metastases confined to a limb, a response rate of 80% can be achieved compared to a best response rate of 40% with melphalan alone. These findings confirm the difference in tumour responses which can be achieved with the appropriate use of regional chemotherapy in treatment of locally advanced tumours and the importance of surgical oncologists and vascular radiologists in maintaining and developing skills in integrated regional cancer treatment.
Keywords: closed circuit infusion/perfusion, dose/concentration/safety, 'flow off' induction chemotherapy, osteosarcoma, regional chemotherapy, soft tissue sarcoma (breast, liver, pancreas, pelvis), TNF (tumour necrosis factor).
SystemiThe seventh International Congress on Regional Cancer Treatment and the second bi-annual congress of the officially constituted International Society for Regional Cancer Therapy was held in Wiesbaden, Germany, 11-13 September 1995. Those attending included leading oncologists from the USA, the UK and most European countries, Israel, Japan and Australia. About one-third of attendants were surgeons but many of those present were medical and radiation oncologists and clinicians or scientists from other disciplines. As a result it was a spirited and successful meeting both in the quality of papers delivered and the depth of the discussion. The most significant new treatment reported at this meeting was the regional use of TNF (tumour necrosis factor), a most promising immunological agent, in treatment of melanomas and soft tissue sarcomas. At last, after two decades of using so great a proportion of available cancer research funds, a clinically effective product of immunological research is now being produced.1-3
However, in using TNF one principle was acknowledged by all presenters. TNF is far too toxic to be used in effective doses in anything other than a closed circuit infusion or perfusion.* If the congress did nothing else it addressed and laid to rest the concerns expressed by those who adopt an attitude that regional chemotherapy is dangerous and achieves nothing more than can be achieved with systematic chemotherapy. The falsehood of such a statement has been evident for years, but is often ignored especially by those with no skills or experience in its use. The use of TNF with chemotherapy in regional treatment of melanomas and soft tissue sarcomas cannot be matched by any systemic manipulation of agents and exemplifies the need for and benefits of techniques of regional delivery.
It may have taken this demonstration of the advantages in dose/ concentration/safety of regional application of TNF in treating certain localized malignancies to prove to the satisfaction of all that there can be distinct advantages in the use of regional chemotherapy. The more subtle and less immediately apparent advantages of regional application of many anti-cancer agents by more simple and more easily obtainable techniques must surely now be further investigated and made available to all patients likely to benefit.4,5
Fundamental principles of the use of anti-cancer drugs and other agents are as follows. (1) The realization that cancer chemotherapy might be required equally in all parts of the body (i.e. systemic chemotherapy). This is necessary to treat, for example, leukaemias, widespread metastatic cancers or as adjuvant chemotherapy for breast cancer or osteosarcoma. This is the most common use of chemotherapy and for such treatments there is no special need of surgical or vascular radiology skills. (2)In treating some cancers, for some agents to have maximal anti-tumour advantage in safe doses, more concentrated chemotherapy may be required predominantly in the primary tumour region. However, systemic 'flow off' and systemic circulation of the agents may also be desirable for possible metastases. Examples are intra-arterial (i.a.) or intra-peritoneal (i.p.) chemotherapy as induction treatment for gastric cancer or i.a. chemotherapy for locally advanced breast cancers or for osteosarcoma or soft tissue sarcomas with a significant risk of metastatic spread. If not carried out by surgical oncologists, such treatment procedures at least require involvement of a surgeon and/or a skilled vascular radiologist.
Additional systemic chemotherapy at a lower, safer, concentration may also be desirable. (3)Chemotherapy may be required in one region only and systemic 'flow off' may be a disadvantage, possibly dose-limiting but acceptable. Such i.a. or i.p. techniques do deliver an increased concentration of chemotherapy to where it is most needed. An example is in using i.a. chemotherapy as initial (induction) treatment of locally advanced head and neck cancers unlikely to have spread further than the head and neck region, or as induction treatment for some large soft tissue sarcomas with low propensity for metastatic spread. Also, some soft tissue sarcomas are resistant to chemotherapy in doses and concentrations safe to give systematically so that systemic 'flow off' is unlikely to be of clinical value but may cause some toxicity at an acceptable level.
(4) Chemotherapy may be required in one region only, but to be effective must be given in doses so concentrated that it is too toxic to allow 'flow off' into systemic tissues. This is when closed circuit perfusion or infusion is required.6 For example, melanoma is unlikely to respond to concentrations of chemotherapy other than can be given safely only in a closed circuit system. It seems that to be effective TNF must be in concentrations that can be given safely only in a closed circuit system. It is also not effective unless given together with another highly concentrated cytotoxic agent. Until recently, 'closed circuit' really only referred to circulation in a limb, where the circulation can easily be isolated. However, more recent techniques have been developed which can achieve isolation of vascular circuits in the pelvis, liver and other abdominal organs including the pancreas.7 These have potential for expanding the application of isolation chemotherapy, possibly including the clinical use of TNF.8,9
Such i.a. or i.p. techniques in (2) and (3) above are relatively simple and safe to use, provided they are constantly monitored by experienced team members for maintenance of desirable distribution and desirable rates of flow for the agents being used. This ideally requires the skills of an experienced surgical oncologist. However, a highly skilled and experienced surgical oncologist with an equally skilled vascular radiologist are mandatory for any form of isolation perfusion.
In short, the skills of surgeons interested in comprehensive cancer care and interventional vascular radiologists are essential if patients are to benefit from local or regional application of anti-cancer agents in concentrations which are too toxic for systemic delivery. Decisions in these matters require surgical input and should not be left to clinicians with little experience and limited skills or interest in safe and effective arterial cannulation, infusion or perfusion.
It is also no longer defensible for cancer treatment teams to have any pretensions to being able to deliver most appropriate comprehensive cancer care unless the team includes a surgical oncologist and an experienced vascular radiologist.
* Papers on TNF in infusion chemotherapy given at the VII International Congress of the International Society For Regional Cancer Therapy held in Wiesbaden, Germany 11-13 September 1995. Papers were given by teams headed by Professors Eggermont, Schraffordt-Koops, Kroon (Holland); Hohenberger, Schlag (Germany); Lejeune, Lienard (Switzerland); BenAri, Klein, Klausner (Israel); Hafstrom (Sweden); Cavaliere and Vaglini (Italy). Abstracts are published in the congress handbook pages 84-98. Full texts of these papers will be published in the official journal of the society Regional Cancer Treatment.
REFERENCES
Paper accepted 17 June 1996
© 1998 The Royal College of Surgeons of Edinburgh, J. R. Coll. Surg. Edinb., 43, April, 80-81