from Leadership Medica n. 10/2007

Abstract

In Italy, there are currently approximately 1 million persons living with cancer; of these about half can be considered to be cured but in a few years it is estimated that this number may reach 2 million persons. Survival, after a cancer diagnosis, varies greatly on the basis of the tumor considered; if for certain types of tumors the possibility of being cured have greatly increased in the last 10 years, for certain other types the survival data have remained significantly low. Therefore, especially in this last group of patients, much still needs to be done to arrive at better (more efficacious) forms of therapy. The best means for reaching higher levels of survival (%), besides a rapid diagnosis utilizing sophisticated diagnostic techniques, is also possible through improvement of therapeutic regimens especially by means of new, more efficient drug discovery rather than those products that are currently available. This would be available through phase I-III clinical trials. In this review, we will evaluate in particular the processes of phase I-III trials and how patients and physicians can be informed about clinical trials currently ongoing in Italy.

Article

Approximately one and a half million persons in Italy live with cancer and nearly half can be considered cured; that is have the same probability of survival as the population not affected by cancer. Every working day in Italy about 1,000 new cases of cancer are diagnosed and these augment the already high number of persons living with cancer.
In just a few years, it is foreseen that this number can quickly reach 2 million persons; given on the one hand to the improved survival of patients and, on the other, to the higher number of cancer diagnoses that will result due to the ageing of the population and to the precocious diagnosis of disease. Overall, survival after a cancer diagnosis varies greatly on the basis of the type of tumor considered, and while in certain types of cancer percentages of cured patients have increased significantly in the last decades (i.e., lymphomas, testicle tumors) in other types the percentages have remained low or have not significantly increased (i.e., lung cancer, metastatic cancer, the majority of solid tumors).  Therefore, especially in this last patient group a lot remains to be done in the search for more efficacious therapies: especially chemotherapy and biological therapy, searching for tumor biomarkers on which to tailor therapeutic interventions (new molecules with therapeutic ability). The best way to be able to increase percent survival data, beyond a precocious diagnosis with sophisticated diagnostic ability, is that of improving therapeutic processes also and especially by means of better new drug discovery. The best way to achieve results is through implementation of clinical trials.
Phase I studies represent the first experimental step in testing a new drug in man. In these studies, researchers work to determine a secure profile and the best means of administering the new drug. In particular, the most appropriate dose with respect to possible toxicity is studied.
Phase II studies aim at establishing whether the new drug is active on the tumor (for example if it reduces its size) and at which dosage this is possible. At the same time, side effects are studied. There are various types of phase II studies, even very different ones: these range from studies on drugs that have just emerged from phase I, of which we know relatively little and attempt to find the best dosage, to studies on thoroughly tested drugs, for which the main objective is study the effect on a particular type of tumor or on select patient groups.
Phase III studies are expected to verify the efficacy of the new drug. In fact, the tumor’s activity evaluated in phase II trials does not guarantee that the drug is also efficacious; meaning that it can be ultimately useful to the patient within his/her treatment regimen, survival status or quality of life. In general, phase III studies compare two (or more) treatment regimens: one experimental and the other conventional, each one administered to a group of patients. After an adequate follow-up period, the comparison between those that received the new drug and those that received the conventional drug allows an objective evaluation of the efficacy of the new treatment expressing this as a function of lengthening of survival and better quality of life for patients.
In the majority of cases, new drugs pass to phase III only after appropriate documented dose, administration requirements, toxicity, and anti-cancer activity have been determined in phase I and II trials.  Hundreds or thousands of patients can participate in phase III trials which are enrolled by numerous research institutes at the national or international level. This method allows the distribution in a casual (random) manner of patients between the case and control arms of the trial, those that will be receiving the conventional form of treatment. Trials that follow this method of patient distribution are named “randomized” trials. The randomization has the objective of avoiding that the results of the study be conditioned by choices made by humans or other interfering factors. Only avoiding a programmed selection of patients can we be sure that we are comparing groups of patients in which the only variable is the different type of treatment regimen. In some randomized clinical trials, we do not reveal to the patients or even to the physicians, if the drug administered is conventional or experimental. This occurs especially when the effects of the treatment could determine a high level of subjectivity and knowledge of the type of treatment on the part of patients and physicians that could influence their evaluation. This is the case of “blind” trials when only the patient is not told if he/she is receiving the conventional or new drug and “double blind” when neither patient nor physician know which drugs are being administered. If the patient expresses consent to participate in a clinical trial, physicians and nurses will keep the patient under rigorous observation for the entire duration of the study so as to check his/her response to treatment and to evaluate possible side effects that may result.  If the principal investigators of the study determine that the treatment regimen is giving adverse effects, the patient will be immediately taken out of the trial and an alternative treatment will be proposed.
The patient has a right to abandon the study at any time. One of the fundamental rights regards informed consent, recognized by State laws. Informed consent foresees that physicians and healthcare personnel be able to treat a person only if he/she is in agreement: the patient must be able to decide if he/she wants to be treated with a certain regimen and, specifically in this case, if he/she wishes to participate in a clinical trial and has the right/responsibility to know all the information available; including potential risks and benefits. The most important information will be reported in an appropriate form that the patient will be required to undersign if he/she wishes to participate in the study.  In clinical trials, informed consent continues during the entire duration of the trial. For example, the patient will be informed concerning any new issue that emerges from the trial itself and in case new potential risks are found, he/she may be asked to undersign a new form to continue in the trial.  Signing the form that gives patient consent for participation in the study does not mean that he/she must remain in the trial until it is completed.  He/She may abandon the study at any time and will have the opportunity to examine other therapeutic options.
The reasons for which potential drugs do not become marketed drugs are linked to an excessive toxicity that occurs in passing from animal experimentation to human experimentation. Certain false myths must be dispelled: that patients participating in clinical trials are guinea pigs, in other words that they are objects for experimentation. Whereas their participation in clinical trials means that they receive better treatment and more controlled regimens with respect to other patients that do not participate.
How does one get information on clinical trials?  Notwithstanding numerous debates including patients and patients’ associations and significant results reached with respect to transparency, participation in project development and organization of clinical trials, unfortunately there are still complex and relevant problems with regard to access to information, especially for phase I trials which impact patients for which there are no useful therapies for their practically irreversible phase of disease.
According to Italian legislation all clinical trials for experimental drugs are required to be included in the National Observatory for Clinical Experimentation of Drugs (OsSC) coordinated by the Italian Pharmaceutical Agency (AIFA)-Italian Health Ministry.  From the beginning of December 2005, the Observatory is able to offer the public a relevant standard selection of information concerning phase II and III clinical trials; this information is provided under the responsibility of the promoters, their delegates, and the Ethical Committees involved.
Such information can be found online at the Observatory’s site; user-friendly site graphics will lead one to a series of data pertaining to current clinical trials ongoing in Italy and in real time it will be possible to know if the study is still recruiting or in a subsequent phase (defined as “open” or “closed”). These are the steps suggested:

1. go to the site  http://oss-sper-clin.agenziafarmaco.it/ click on Data (Dati)
2. then choose Search for Clinical Experimentation (Ricerca Sperimentazioni Cliniche) (registration is not compulsory)
3. if you do not wish to register, choose Search for Clinical Experimentation again
4. search by choosing between Guided Search within Therapeutic/Pathological Area (Ricerca Guidata per Area terapeutica/ patologica), Geographic Area (Area geografica) and Free Search (Ricerca Libera).

For each trial or protocol the following information is available:

• EudraCT code
• protocol code
• protocol title
• registration date
• sponsor
• trial status (Open or Closed)
• therapeutic area (ex. Oncology or Gynecology)
• indication of coordinator and participating Centers

Owing to collaboration with AIFA, the AImaC (Italian association of cancer patients), will be able to retrieve any useful information concerning data found in the Observatory and may be assisted further by the helpline, phone n. 840 503579 (free of charge); This email address is being protected from spambots. You need JavaScript enabled to view it. ).
The progress that occurs in oncology and in particular the continuous increase of survivors or patients whose survival is prolonged derives directly from the impact that clinical trials have had on patient management. Several examples of this can be given in the following: in breast cancer, clinical trials have demonstrated that surgical interventions limited to removal of the tumor tissue (quandrantectomy) followed by radiotherapy guarantee the same survival chances than other more radical interventions performed in the past (mastectomy) that destroy the organ and are invalidating; the former have also provided a better quality of life for the patient. Always in breast cancer, chemotherapy after surgery in patients with positive axillary lymph nodes has demonstrated an increase in their survival with respect to those that received surgery alone.  These two breast cancer trials were performed at the Istituto Tumori in Milan with reference to both Umberto Veronesi and Gianni Buonadonna and their collaborators; they have had a significative worldwide impact such that millions of patients have benefitted from these results and the outcome of said clinical trials.
Dissemination of information concerning clinical trials for cancer patients cannot preclude the “sacred alliance” established between medical oncologists and Associations of cancer patients; in Italy in particular there is FAVO (Italian Cancer Volunteer Associations), directed by Prof. Francesco De Lorenzo, which is fundamental to the dissemination of all the information that can be given to patients from medical oncologists.  An international conference, ”Clinical trials for new therapies against cancer: a patient’s guide”, organized with the auspices of a joint project between ISS (Italian National Institute of Health) and AIMaC (Italian cancer patients Association) was held on April 20^th 2007 in Rome with the objective of informing cancer patients about clinical trials.  Participants included, among others, the representatives of the major institutions involved in the study and therapy of tumors; i.e. AIFA, EMEA, NIH, WHO. They have co-authored a booklet edited by AIMaC entitled Clinical trials in cancer: patient’s information which is easily viewed by downloading from the site: www.aimac.it.
Clinical trials in oncology are important because they allow a rapid transferral of results obtained from biomedical research (first in the lab then to animal testing) to clinical practice. It must be clear that this can occur only after the appropriate ethical committees have approved the individual clinical trial related to the specific pathology and that informed consent be obtained from the patient.  Let us give a pertinent example: 16,000 new lymphoma patients diagnosed every year are recruited in trials in  about 10% of cases, that is in 1,600 prospective clinical controlled trials (often randomized) within the Italian Lymphoma Intergroup, a cooperative group which is responsible in Italy for associating different study groups for lymphoma therapy. It can be estimated that concerning breast cancer or gastrointestinal cancer, a smaller number of patients participates in clinical controlled trials. Obviously those that aren’t included in clinical controlled trials will be treated with the best conventional forms of treatment. 
Elderly patients, in particular those that are older than 70 years, and constitute more than half of cancer patients are rarely treated with the latest knowledge on cancer. Not only are elderly cancer patients rarely recruited in clinical trials but even conventional treatments are poorly defined and many of the patients risk being treated less or more than necessary. Therefore, in the context of geriatric oncology, there is a wide margin of improvement possible for both conventional regimens and experimental clinical regimens. For example, within the GOL Cooperative Group (under the auspices of a collaboration between National Cancer Institute in Aviano and Humanitas Institute in Milan) 100 consecutive patients affected by large cell diffuse NHLs aged over 70 have been treated based on a prospective protocol that indicated a treatment regimen resulting from a multidimensional geriatric evaluation process.  All patients were treated with a chemotherapeutic regimen that was appropriate to their general conditions based on whether they were fit, unfit, or frail. In this way, exceptional results were obtained in the 100 patients with advanced stage large cell diffuse NHLs; comparable to adult patients with complete remission, whose survival and cure were similar to adult patients undergoing treatment with conventional regimens or available ones with entirely acceptable toxicity. This example shows just how much space there is for conventional treatments both in clinically controlled trials of elderly oncological patients and in lymphomas but also other types of cancers that mainly affect this patient age group; as described above these represent nearly 50% of all cancer patients.
In what way is research conducted and how are patients protected? Each clinical trial is supported by a protocol that explains the way in which the trial will be conducted in detail, the reasons for which the research was undertaken, the objectives of experimentation and the criteria by which results will be evaluated, the number of patients to be recruited, and especially describes the therapeutic plan. All physicians participating in the trial must adhere to the protocol even if clinical considerations pertaining to an individual patient may, at any time, justify a deviation from the protocol if necessary until suspension of treatment, meaning exclusion of the patient from the trial.
In order to guarantee patient safety, each clinical trial protocol must be approved by the Scientific Committee and Ethical Committee of the Center in which the trial is being administered. The former must express a scientific, methodological and clinical evaluation which tends to verify the scientific validity of the trial; the latter must instead express an ethical evaluation that tends to verify how the interests of the individual patient are guaranteed.  In reality the two types of evaluations intersect since a trial that is not scientifically valid would also not be ethical. The Ethical Committee is composed of physicians but also non-medical staff to include patient representatives, experts in ethics and legal matters, religious figures but also pharmacologists, statisticians and other professionals. The Committee carefully evaluates every aspect of the protocol also to ascertain that research activity does not expose patients to unacceptable risks.
The eligibility criteria detail the characteristics that patients must have to be admitted to the study. The eligibility criteria are described in the protocol and vary in function of the trial’s final objectives.  Normally these include age, sex, type and stage of disease, previous acceptable treatment regimens, and other accepted concomitant diseases. The application of eligibility criteria is an important principle for medical research, which contributes to guaranteeing security in research outcomes. The criteria ensure, among other issues, the safety of patients so as not to expose individuals to clinical trial regimens which could be detrimental and have negative effects. (for example, a new treatment could give good results for a certain type of tumor but not for another, or it could be more effective in males but not in females, etc.).

Professor Umberto Tirelli
Dipartimento di Oncologia Medica

Bibliografia

1. AiMaC 2007 Gli studi clinici sul cancro: informazioni per il malato.
2. Bonadonna, G. Robustelli Della Cuna, P. Valagussa: Medicina Oncologica. VIII ed., Elsevier Masson S.r.l. Milano, 2007.