**7. How to implement the changes in clinical development paradigms for cancer vaccines?**

There are clear facts showing that the old paradigms for chemotherapeutics development, no longer apply to cancer vaccines. But paradigms not only differs in contents, but also are the source of methods and normative of solutions accepted by a mature scientific community in a given moment. As a result, receipt of a new paradigm often necessitates a redefinition of the corresponding science.

Moreover, an existing paradigm is shared by members of the scientific community who are engaged with the same. A paradigm shift requires a change not only in tools, but also in the visions of the problem by the related scientific community.

The question is: What is the process by which a new candidate for paradigm replaces its predecessor?

In this case, Axel Hoos et al (Hoos et al, 2007) have firstly described the needs of a paradigm shift for development of cancer vaccines and other related biologics. They have defined new terms or vocabulary according new needs and explained how to apply these new tools in further products development.

vaccine was very well tolerated, provoking only grade 1 or 2 of adverse events; the MTD

Secondly, after optimizing dose and schedule, a randomized trial was conducted to assess the preliminary efficacy in terms of survival and not response rate. Tumor shrinkage was rarely observed while all vaccinated patients had a trend toward SV benefit that was significant in those patients with 60 years old or younger. The Kaplan Meier survival curve showed a non-proportional hazard ratio, illustrating the delayed (not immediate) effect of the drug. CIMAVax EGF needed at least 3 months to induce a mature, neutralizing immune

Finally, vaccination was not stopped at the moment of clinically irrelevant, radiologic progression. Patients received chronic vaccination, which increased their probability of

Evidence Levels CIMAvax EGF trial

number

6 7

was never achieved.

Stages of clinical trials typically used for clinical development of new chemotherapeutic drugs

Phase I trials

**cancer vaccines?** 

predecessor?

redefinition of the corresponding science.

further products development.

visions of the problem by the related scientific community.

response and a consequent survival curve separation.

becoming good responders and long survivors (González et al, 2011)

Phase II trials PPT IIa

Phase III trials ET Ib

Table 5. Relation between clinical trials stages and Evidence Levels

**7. How to implement the changes in clinical development paradigms for** 

There are clear facts showing that the old paradigms for chemotherapeutics development, no longer apply to cancer vaccines. But paradigms not only differs in contents, but also are the source of methods and normative of solutions accepted by a mature scientific community in a given moment. As a result, receipt of a new paradigm often necessitates a

Moreover, an existing paradigm is shared by members of the scientific community who are engaged with the same. A paradigm shift requires a change not only in tools, but also in the

The question is: What is the process by which a new candidate for paradigm replaces its

In this case, Axel Hoos et al (Hoos et al, 2007) have firstly described the needs of a paradigm shift for development of cancer vaccines and other related biologics. They have defined new terms or vocabulary according new needs and explained how to apply these new tools in

Stages of clinical trials proposed for cancer vaccines development

Many people working in cancer vaccines development are facing the need of a change in clinical development paradigm as described by Axel Hoos et al and currently been being borne out in practice. As usual in the history of science, crises arise in different places at once, in this case, caused by the emergence of new therapies (cancer vaccines) that do not agree with the mechanism of action of these previously used (cytotoxic antitumor therapies). These people that faced firstly the needs of changes are the pioneers of the new paradigm and have the challenge of ¨converting¨ the rest of the scientific community to the new ideas. How to induce the conversion and how it resists? Probably the single most common

argument put forward by proponents of a new paradigm is that they can solve problems that have led to the old paradigm to crisis. As it has been extensively explained in this chapter, new paradigms proposed for cancer vaccines development solve the problems for which the old paradigms no longer work.

The challenge now is to persuade the whole medical community as well as the Regulatory bodies on the new conceptions, which will result in a more direct development of new drugs and a more rapid availability of the same for patients with cancer.

#### **8. Conclusion: A field of science in transition**

As Thomas Kuhn said in his book The Structure of Scientific Revolutions: ¨In science occurs as in manufacturing: a change of tools is an extravagance that is reserved for occasions that demand it. The significance of crises is that they provide an indication that it is time to change tools¨ .This is precisely what is going on in the field of cancer vaccines.

Cancer vaccines are, as other biological molecules, product of the development of Biotechnology, a tool of science which opened a new wave of opportunity for cancer immunotherapy. It created the possibility of finding and manufacturing biological molecules with the same purity, reproducibility and scalability of classic chemical pharmaceuticals. These novel therapeutical tools have the attribute of specificity, which means possibility of therapeutic effect with lack of toxicity. That property makes them very different to the cytotoxic tumor drugs approach for cancer treatment.

Because of that, biotechnology drugs claimed for a change in the paradigm through which antitumor drugs has been up to date investigated, developed, and finally approved. This is especially pertinent in the field of therapeutic cancer vaccines.

We are facing times of changes. As soon as new paradigms are implemented for new drugs development, the faster the profits of these new drugs will be available.

This is just the beginning. Cancer therapy is a field of Science in transition. The changes in the paradigm of product development come together with other changes also intrinsic to novel biotechnology drugs attributes.

There are other important differences between cancer vaccines and cytotoxic antitumor drugs: one is that they are intended to restrain tumor growth, not necessarily to reduce tumor mass, and the second is that they can be used long term.

These features connect with another paradigm shift which is going on in medical oncology, which is the transition of advanced cancer from a rapidly fatal disease into a chronic condition, compatible with years of quality life.

Such a transition is not new in the history of medicine. Diabetes Mellitus Type I was also a rapidly fatal disease until the introduction of Insulin in 1923. Now it is a chronic condition, which cannot be cured, but can be controlled long term.

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Biotechnology drugs and specially cancer vaccine have the potential to implement an analogous transition in oncology.

A new paradigm for accelerating the development of cancer vaccines should be embraced by the research community. With these therapeutic tools in hand, also a new paradigm for chronic management of advanced cancer should be embraced by the medical community and by Public Health Systems. Two field of Science which are evolving in parallel, and whose evolutions should merge in the near future, for the benefit of cancer patients and Society at large.

#### **9. References**


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**8**

**Brain Metastases: Biology and Comprehensive** 

Metastases to the brain is one of the most feared complication of systemic cancer and its incidence is rising for several reasons. The two most important reasons are the improvement in treatment, with a longer patient life; and the advance in diagnostic and imaging means Magnetic Resonance Image (MRI) and Computed Tomography (CT), Positron Emission Tomography [PET]) that have permitted to detect smaller lesions in asymptomatic patients. These improvement in radiology allows earlier diagnosis and result in better treatment management (Kamar et al., 2010, Rao et al, 2007, Patchell et al. 2003). Single metastases are detected in greater proportion. For example, in the case of ovarian tumors brain metastases are solitary in 43% of the cases (Pectasides et al. 2006). Single metastases appear approximately in one quarter of all patients with brain metastases (Rao et al. 2007). Norden et al. 2005 recently reported that breast, colon and renal cell carcinoma tend to produce single metastases, whereas melanoma and lung cancer have a greater tendency to produce multiple metastases. Single metastases can be treated surgically or by high precise radiotherapy modalities such as Gamma knife and StereoTactic Radiotherapy (SRT) or Conformal Radiotherapy (CRT). SRT was initially used for substituting surgical approach in patients with inaccessible tumor location or with comorbid medical conditions, now is used in many institutions as first approach, peculiarly from breast colon and renal carcinoma. Actually, many patients, refuse surgical approach so the use of SRT or CRT in combination with whole brain irradiation (WBRT) or SRT as a boosting method after WBRT is increasing. Associated to radiotherapy and chemotherapy we suggest and discuss the biological reasons for adding hyperthermia and glycolysis metabolic inhibitors with the aim to obtain a better

**1. Introduction** 

control of brain metastases.

**Strategy from Radiotherapy to Metabolic** 

**Inhibitors and Hyperthermia** 

Baronzio Gianfranco1, Fiorentini Giammaria2

Guais Adeline3 and Schwartz Laurent4 *1"Metabloc Cancer Center", c/o Centro Medico Kines* 

*2Oncology Unit, Hospital San Salvatore, Pesaro* 

*4Hôpital Raymond Poincaré, Garches* 

*Castano primo, (Mi)* 

*3Biorébus, Paris* 

*1.2Italy 3.4France* 

