15-30: Conventional Cancer Treatments

p.17 New developments in interventional radiology for cancer Cryoablation is not new and dates from 20 years ago but this started out with an open (surgery) approach and used a large bore 24 French device which led to complications such as liver fractures leaving many radiologists wary of its use.  New developments now allows for a much smaller 17 gauge French approach and metastatic lung/pleura/liver tumors can all be treated this way.  The recent reporting of the ECLIPSE trial (De Baere T, et al. Society of Interventional Radiology. Abstract 33, Presented April 14, 2013) enrolled 40 patients with pulmonary metastatic lesions up to 5 lesions of < 3.5cm each and yielded a disease control rate of 95% at 6 months. Complication rates are still high but minor and recovery was swift.  Another interesting approach is with a new technology called Irreversible Electroporation (IE) which uses electrical pulses to create permanent holes in the membranes of cancer cells, killng the tumors. Sloan-Kettering doctors reported using this approach in liver, lung and pancrease lesions. 28 patients with tumors up to 4 cm treated were 92% without recurrence at 6 months (some patients up to 2 years) (Silk M, et al. Society of Interventional Radiology. Abstract 29. Presented April 14, 2013)

p. 23 Potential and significance of cocktailed immunotherapy for cancer The complexity of the immune system lends itself particularly well for a cocktail approach.  This concept has been recently summarized by a review “Cancer Immunotherapy Comes of Age” by Drs. Topalian, Weiner, and Pardoll of Johns Hopkins (J. Clin Onc 29:4828, ’11.  In their conclusion, they wrote “The complexity of successful immune responses with coordinated recruitment of innate and adaptive immunity, including soluble and cellular factors, has been established … and applies to antitumor immunity as well. This review … barely scratches the surface of potential potency achievable by combinatorial strategies targeting distinct effector arms and both early activation and late execution stages of immune response.  For example, combinations of vaccines with blocking monoclonal [antibodies] mAbs against immune checkpoint receptors such as CTLA-4 and PD-1 demonstrate dramatic synergy in murine tumor models, in which the individual components offer little or no therapeutic efficacy.  Another therapeutic opportunity involves the rational combination of distinct checkpoint inhibitors based on their biologic properties. For example, the CTLA-4 checkpoint plays a major role in dampening initial T-cell activation, whereas PD-1 inhibits effector T-cell responses within tissues. Thus, anti-CTLA-4 and anti-PD-1 have demonstrated synergy in animal tumor models, and this combination is in clinical testing. Although such combinations may significantly enhance anti-tumor immunity, they may also generate additive or synergistic immune toxicities, requiring careful dose titrations to define windows of clinical efficacy. Finally, preclinical models suggest that certain chemotherapies and targeted kinase inhibitors induce an immunologic cell death resulting from rapid release of tumor antigens and self molecules from dying cancer cells, activating toll-like receptor pathways in [dendritic cells] DCs and promoting inflammation and heightened antitumor immunity. These and many other potentially synergistic treatment combinations are under active exploration and will be required to achieve the true potential of cancer immunotherapy.” Very eloquently stated indeed, interested readers should peruse the entire article  !

p.26 Expanding the concept of anti-angiogenesis as a therapeutic approach to targeting the tumor microenviroment to treat cancer. This was expounded by a very eloquent lecture presented by Rakesh Jain of Harvard as the Oncology Award Lecture at the 50th Annual Meeting of ASCO, Chicago, Jun 2-6, 2012 (published as a special article: Jain RK, J Clin Onco 31:17, pp 2205-2218). Instead of simply targeting the cancer and considering the cancer cell in a vacuum, here it is useful to consider the cancer cell in its microenviromental context, and the aim is to also treat the context.  The original hypothesis is that abnormal tumor microenviroment characterized by hypoxia and high interstitial fluid pressure fuels cancer cell progression and sets the cells up for resistance to treatments.  The tumor microenviroment is broadly considered under 3 parts: a) Blood Supply, b) Lymphatics, and c) Extracellular Matrix.  Angiogenesis and its treatment thus covers only the blood supply, and attention should be focused on b and c as well.  There are exciting advances made in the study of lymphatics and the extracellular matrix’s role in cancer therapy, as for example with the use of agents that “soften” the collagen matrix which may hamper deliver of certain large molecular therapeutics (e.g. liposomal doxorubicin, or Doxil) to tumor targets.   The use of such anti-fibrotics  that could deplete collagen  or agents that degrade collagen led to the finding that drugs which reduce collagen production such as the widely prescribed angiotensin II receptor blockers used for hypertension  (e.g. Losartan) could also increase the efficacy of large molecule chemotherapies such as Doxil. Indeed, pancreas cancer patients on these medications survive longer than those who are not (J Clin Onco 31:17, pp 2205-2211).  The importance of treating the context of the cancer as well as the cancer highlights the logical conclusion that a multi-targeted approach treating both the tumor and its contexts (blood supply + lymphatics + collagen matrix) simultaneously should lead to better results.

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  1. John Madara
    March 20, 2012 at 11:54 pm

    Dr. Chang,

    I was recently been diagnosed with an Anaplastic-AstroCytoma Grade III and am seeking alternative or homeopathic approached to treatment. I completed surgery in January and was able to remove 100% of the malignant tumor but I still have several benign tumors. I agreed to low-dose radiation but have waived Chemo. Would I be able learn these approaches by reading the book, or would I be better served meeting in person – I live in Ct?

    Thanks in advance – John

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