The percutaneous approach is also “much cheaper, has a much quicker recovery time and a much shorter hospital stay” compared with laparoscopic surgery, Dr. J. Louis Hinshaw, of University of Wisconsin in Madison, said.

Dr. Hinshaw presented data for 19 cases of renal cryoablation performed percutaneously and 48 performed laparoscopically. The average patient age was about 68 years in both groups.

“When we first started treating kidney tumors with cryoablation, we were doing them all laparoscopically,” the radiologist noted. “The surgeon would get the kidney exposed, and then we would do the cryoablation through the laparoscopic ports.”

They soon found that some cases did not require laparoscopy. Instead, they used ultrasound and CT to locate the tumor and guide the cryoablation probe.

However, “there has never been a study published that compared the two approaches,” Dr. Hinshaw said.

They found that the percutaneous approach was at least as safe and effective as the laparoscopic approach. Major complications occurred in 6.3% of cases treated laparoscopically, whereas there were none in the percutaneous group. Local recurrence rates were 12.5% versus 10.5%, respectively.

The hospital stay was significantly shorter in the percutaneous group, at 1.1 day versus 2.5 days, and the cost was 59.5% lower.

In some ways, it is difficult to compare the two procedures, the physician noted. The approach used “was made on a patient-by-patient basis in conjunction with the urologist.”

Much has to do with size and location of the tumor, he added. Interventional radiologists can treat tumors up to about 3 centimeters in size. The approach is also more likely to be used with sicker patients who have multiple comorbidities – those who can not tolerate surgery and general anesthesia.

Patients are more likely to be treated laparoscopically if their tumors are larger, centrally located, or in close proximity to the bowel or the ureter, Dr. Hinshaw said.

“Just as with all evolving and changing technology and therapies, it takes a while to accrue sufficient long-term data to say with certainty that (percutaneous cryoablation) is what we should be doing,” he concluded.

“Gleevec was considered as a targeted anticancer drug which is specific for only certain types of malignancies,” senior investigator Dr. Hermann M. Schaetzl said, “and which acts in stopping cancer growth. We describe a much broader effect of this compound which might be beneficial for all kind of tumors.”

In previous studies, Dr. Schaetzl, of the Technical University of Munich, and colleagues found that imatinib increases the cellular clearance of intracellular protein aggregates by targeting the abl pathway and upregulating lysosomal activity.

In the current study, the team found that imatinib also activates the cellular autophagy machinery in mammalian cells in a dose-dependent fashion. Moreover, they observe that this happened “in all cell lines tested,” which strongly suggests this is not cell-type or species specific, but a generalized effect.

Autophagy, the investigators add, is a degradation mechanism mainly involved in the recycling and turnover of cytoplasmic constituents.

Autophagy may promote death in certain cancer cells, and the researchers point out that “this feature is in accordance with the anticancer potential of imatinib and may strengthen its pro-apoptotic function.”

They suggest further study in cancers that do not use autophagy as a protective mechanism. Under these circumstances, the investigators conclude, “the application of imatinib in combination with other autophagy-inducing drugs might not only inhibit tumour progression but even promote tumour regression.”

“This trial shows that it is not possible to interrupt a targeted treatment — here imatinib– of cancer in the advanced phase, without exposing a patient to a high risk of rapid relapse,” lead investigator Dr. Jean-Yves Blay said.

To investigate whether imatinib might be safely stopped in patients in whom disease were controlled, the researchers randomized 58 patients with advanced gastrointestinal stromal tumors who had responded or who had stable disease following a year of treatment, to continue with imatinib or to have their treatment interrupted.

After follow-up for as long as 2 years, 8 of 26 patients in the continuation group had disease progression. This was the case in 26 of 32 patients in the interruption group. However, 24 of these patients responded when imatinib was reintroduced.

“When efficacious, the standard strategy remains to give the treatment without stopping unless there is progression or intolerance,” Dr. Blay said.

A second randomization, this time at 3 years, is being performed and the results will be presented later this year at the annual meeting of the American Society of Clinical Oncology, he said.

“Cancers share more properties of normal developing tissues than we may have appreciated,” Dr. Richard J. Gilbertson from St. Jude Children’s Research Hospital, Memphis, Tennessee said. “This work opens up new avenues for treatments, but suggests also that we need to work hard to define truly how cancers and normal tissues differ.”

Dr. Gilbertson and associates investigated whether brain tumor stem cells develop within niche microenvironments in the brain vasculature. The majority of cancer stem cells in brain tumors were closely associated with tumor capillaries, the authors report in the January issue of Cancer Cell.

In vitro, brain tumor stem cells associated rapidly with endothelial vascular tubes, forming close contacts along their lengths, the results indicate. Further experiments showed that endothelial cells maintained self-renewing and undifferentiated brain tumor cells and promoted the propagation of brain tumors in vivo.

Depletion of brain tumor blood vessels effectively eradicated the population of self-renewing tumor cells, the report indicates. This led investigators to propose “that antiangiogenic drugs arrest brain tumor growth, at least in part, by disrupting a vascular niche microenvironment that is critical for the maintenance of cancer stem cells.”

“We are currently dissecting the various cellular and protein components of the niche to identify the critical parts that maintain cancer stem cells,” Dr. Gilbertson said. This may help identify new therapeutic targets.

This work “highlights the importance of the vascular microenvironment in brain tumor growth,” write Dr. Zeng-Jie Yang and Dr. Robert J. Wechsler-Reya from Duke University Medical Center, Durham, North Carolina, in a related commentary.

“Similarly, the finding that disruption of angiogenesis leads to a reduction in growth of fully formed tumors suggests that the vascular niche may also be critical for tumor maintenance.”

“The notion that antiangiogenic therapy targets cancer stem cells has important implications for evaluating and optimizing the use of antiangiogenic drugs in cancer,” they conclude.

Using murine osteoclastic tumor models, Dr. Katherine Weilbaecher and her colleagues in St. Louis, Missouri, administered G-CSF or saline daily for 8 days. On the fifth day of G-CSF treatment, the investigators injected tumor cells. Another group of animals received G-CSF after tumor cell injection.

Dr. Weilbaecher and colleagues report that “G-CSF administration increases osteoclast number and decreases trabecular bone area in vivo.” Bone tumor volume is also increased after G-CSF administration, but subcutaneous tumors are not increased.

The increase in bone tumor growth induced by G-CSF is independent of its effect on neutrophil proliferation, the investigators also report.

The magnitude of bone loss seen with the osteoclastogenesis induced by G-CSF “is similar to that which is seen in mouse models of oophorectomy,” Dr. Weilbaecher and colleagues comment.

The effect could be clinically significant, but Dr. Weilbaecher cautioned, in an interview with Reuters Health, that “our studies were conducted in mice and we do not yet know if they have any relevance for humans.”

“We do not think that these studies in mice should change the standard of care for patients with cancer” at this early stage of study, Dr. Weilbaecher continued. “However, our studies suggest that awareness of changes in bone health during cancer therapies could be important. Hopefully, clinical trials will be done to understand the effects of G-CSF in humans.”

By:Jan Koedam
Applied Clinical Trials

For a long time, drug development has been dominated by the urge to find yet a better drug to treat hypertension, hypercholesterolemia or heartburn. Big pharma companies were competing in the major primary care markets. And today, for every indication, more than a handful of blockbuster drugs are available. But now that reimbursement is more of an issue, with many generic products on the market featuring comparable effects, the industry has changed its focus toward more specialized care, like oncology.

Cancer is still a frightening thought for most people. The search for cancer medicines usually gains the support of the public, even with their rather hostile attitude toward pharmaceutical companies. Until recently, however, the number of drugs developed for cancer treatment was rather limited. Since the discovery of Nitrogen mustard derivates and the anthracyclines, it has been relatively quiet. This may be attributed to the suggestions that cancer drug development is complex.

Figure 1. Worldwide lung cancer incidence in men.

The question of whether oncologic drug development is truly different from the development of primary care medicines was discussed during a workshop at the European ACT Summit in the Fall of 2006. The reasons for the relative absence of new oncologic drugs was discussed, based on the statement: Cancer is a rare, lethal, and complex disease that is not profitable for the industry, as drugs require a different development approach.

A rare disease

The incidence of cancer varies enormously across the world. The age-adjusted incidence of breast cancer in China and India is 19 per 100,000 females; that number jumps to 101 in the United States. Similar differences across the world can be found for colorectal and lung cancer. Despite the numbers, incidences of cancer can be considered low when compared to hypertension, heartburn, COPD, and other diseases or conditions.

Figure 2. Worldwide female lung cancer incidence.

The incidence of hypertension is not always well documented, but it is at least 300 per 100,000 persons; the prevalence is thought to be much higher and may even reach 30% in elderly patients.1,2 Clearly, this condition is of a different magnitude than cancer when compared to the individual types of tumors. Even when adding up the major cancer types like breast, lung, and colon, the total incidence rate per 100,000 persons is below the rate of common diseases and, thus, relatively rare.3,4 However, when realizing that in many developed countries one in 10 women will be confronted with breast cancer, one cannot call this a rare disease.

In addition, most cancers have shown a gradual increase in incidence over the past few years, which implies that cancer is a growing problem.

A lethal disease

Cancer is still associated with death by the public. It is probably the most feared message from a physician. The question is whether this is realistic.

Worldwide, cancer is definitely not the most frequent cause of death. In developing countries infections are responsible for the vast majority of deaths. AIDS, malaria, and other more general infectious diseases kill almost 10 million people a year. In the industrialized world, cardiovascular diseases are the major cause of death. Myocardial infarctions, hypertension, cerebrovascular events, and heart failure kill over 7.5 million people a year.5 In this respect, cancer still plays a relatively minor role. Lung and stomach cancer together cause the death of about 1.5 million people, the other types of cancer considerably less. From a magnitude perspective, cancer is not a lethal disease—but what about the people who actually have it?

Over the past few decades, cancer survival rates have significantly increased. Overall, more than half of all patients survive more than five years. But there is considerable variation among the different types of cancer. Whereas more than 80% of all patients with skin cancer survive for more than five years, survival is only about 10% for those with esophagus cancer.

It is important to realize that the increase in cancer survival rates is largely attributable to a few relative frequent cancer types like breast and prostate cancer. For these cancer types, screening programs for early detection have been implemented and there are more treatment opportunities. Compared to other diseases, cancer is still a very serious deadly disease. Fortunately, recent improvements have dramatically improved patient outcomes.

An unprofitable disease?

Some claim that one reason for the relative absence of oncology drugs is that they are not profitable for pharmaceutical companies. But is this claim true?

In 2001, the best-selling oncology drug was the LHRH analog goserelin, with estimated sales of over $1 billion. It ranked 82 on the top 100 list of best selling drugs, along with docetaxel and oxaliplatin—the only other oncologic drugs on the list. In 2005, docetaxel was ranked 34, and three other oncologic blockbusters made the top 50 list. Many new oncology drugs have recently entered the market, which means increased revenues for the companies.6,7

So, oncology drugs have shown to be beneficial for both patients and industry. Clearly the industry has become aware of this. Almost all major pharmaceutical companies are now focused on oncology drug development. As a result, over 400 new oncology drugs are in clinical development. Still, the number of new oncology drugs that reach the market is relatively modest. This may have to do with the nature of the disease.

Complex and difficult

There is no such thing as one disease called cancer. Cancer is just a synonym for a large number of diseases characterized by uncontrolled cell growth. The cause of this loss of control can be very diverse, even within cancers of the same organ. Loss of cell growth control can be caused by loss of control mechanisms that suppress growth. Mutations in so-called tumor suppressor genes can result in loss of growth control, which in turn may result in cancer. On the other hand, cancer may be caused by excessive stimulation of certain pathways.

Although this may sound relatively easy, the truth is far more complex. Within one patient a tumor often carries cells with different types of deregulations, characterized by different mutations. This may explain why only a percentage of patients benefit from a treatment even though they all have the same cancer type. All this proves that cancer is complex. The question is whether this is the case for other diseases.

The fact that cancer therapies were toxic and often could not be tolerated forced science to better understand the background and cause of the disease. Molecular biology proved instrumental in this research, which revealed the different signaling pathways that we now know. But it would be naïve to assume that cancer is the only disease in which these genetic defects play a significant role. It was not until very recently, however, that researchers began looking at this correlation. That’s because as long as antihypertensive drugs work in the majority of patients without causing bad side effects, their underlying molecular mechanisms are not as interesting.

Also, in nononcologic therapeutic areas understanding the molecular biology of the disease increases; thus, the chances of developing specific targeted drugs increase.

Oncology drug development

All the previous hypotheses have lead to the discussion of drug development in oncology. As mentioned, classical chemotherapeutics require a different approach compared to conventional drugs, but there are more distinct differences.

Unlike conventional drugs, most oncology drugs cannot be tested in healthy humans. It simply would not be ethical to expose healthy people to highly toxic drugs that could potentially be lethal. Some drugs act on specific targets in cancer cells only or, like aromatase inhibitors, have different pharmacokinetics/pharmacodynamics in cancer patients compared to noncancer patients. This makes it very complicated and even impossible to first test these drugs in healthy volunteers. Therefore, first-in-man trials are usually performed with patients that have no other therapeutic option left. When all available conventional therapies fail, many patients are prepared to take a risk for a small chance of success.

To limit patients’ exposure to doses too low to be effective, only a very small number of patients per cohort are treated. It is always highly frustrating to realize that several patients will likely be exposed to doses too low to be effective; on the other hand, the recent Tegenero incident proves that one cannot be careful enough. That also is the reason why most Phase I and Phase II oncology trials are performed in highly specialized hospitals that are fully equipped and staffed and not in CRO research centers. Conventional drugs are usually tested in healthy volunteers, as toxicity is usually limited and predictable. Safety is still an issue, but treated subjects are in good condition and a specific treatment effect is expected.

In the era of new, targeted drugs there is yet another dilemma. Oncology drugs act primarily by inhibiting a deregulated pathway, which indirectly leads to cell death. These are the classical cytotoxic drugs. But what is the optimal dose for such drugs? The maximum tolerated dose? The minimum dose that leads to maximum inhibition of the target?

Drugs like imatinib and sunitinib inhibit their primary target in a nanomolar concentration. Increasing the dose often leads to inhibition of other targets for which these drugs do not as fit well. Sometimes this is favorable, as these targets can also be involved in tumor development. In other cases, increasing the dose only leads to an increase in side effects.8,9,10

Even though these types of drugs are relatively mild, side effects often do occur at higher doses. Relatively low doses, on the other hand, may lead to early resistance, as lower doses may allow relative insensitive clones of malignant cells to develop into fully resistant ones. Latest opinions tend to favor the minimum dose that maximally inhibits the target. Although not very toxic, these drugs often need to be tested in cancer patients, since the target of the drug is expressed only in these patients.

Another difference between oncology and conventional drugs is the endpoint of most Phase III trials. Obviously, the most important endpoint is overall survival. In many cases, however, patient prognosis is still rather good, like in early breast cancer. After completion of recruitment, it easily takes more than a decade before results on survival become available. This is unacceptable for patients, and hardly any progress can be made while waiting for the results.

In addition, survival is heavily influenced by the choice of treatment for recurrences. Relatively ineffective drugs will require effective salvage drugs, and this may obscure the true effects of a drug with regard to survival. Nevertheless, one cannot withhold effective therapy from a patient; so cross-over designs are often used, enabling patients randomized to control arms to switch to the more effective drug once they relapse. Thus, surrogate endpoints like response rate and progression-free survival are commonly accepted, although all parties involved realize the risk involved. The use of response rates is usually confined to Phase II, as it has been shown that the relation to overall survival is not always present.

Obviously, trials investigating prevention of cardiovascular aspects like myocardial infarction require a long time too, but it’s more or less accepted that these drugs are used to counter a symptom that in the end may result in a serious disease.

Therapeutic role model

The question is whether oncology drugs are really different than drugs used in other therapeutic areas. The answer is not a straightforward “yes” or “no.” It must be put in perspective.

Oncology drugs to a certain extent have served as a kind of role model for other therapeutic areas. It was first in oncology that therapy was aimed at the deregulated cell signaling that leads to the disease. Aromatase inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies have become commonplace in oncology, but in other therapeutic areas the same development paths have been chosen.

The same is happening with the use of molecular biology techniques. PCR has become an irreplaceable tool in determining the individual patient response, and micro-assays have revealed the diversity of disease subtypes within one type of cancer—which in the future will probably lead to patient tailored therapy. The same is happening in rheumatology, cardiology, and many other therapeutic areas.11,12,13,14

Therefore, it is fair to state that oncology has more or less been leading the way in the development of innovative drugs. There is no doubt, however, that within a few years the majority of the differences mentioned in this article will have disappeared, which most likely will be to the benefit of patients.

Jan Koedam is associate director of medical affairs at Celgene BV, Regus La Ligne, Utrechtsestraat 38F, 6811LZ Arnhem, The Netherlands, email: jkoedam@celgene.com

References

1. J. Staessen, “Epidemiology of Treated and Untreated Hypertension in the Elderly,” in Handbook of Hypertension Vol. 12, Hypertension in the Elderly, A. Amery and J. Staesen, eds. (Elsevier, New York, 1989) pp. 320–351.

2. C.J. Bulpitt, “Definition, Prevalence and Incidence of Hypertension in the Elderly,” in Handbook of Hypertension Vol. 12, Hypertension in the Elderly, A. Amery and J. Staesen, eds. (Elsevier, New York, 1989) pp. 53–69.

3. http://www-dep.iarc.fr/.

4. Dutch cancer registry: http://www.ikcnet.nl.

5. http://www.who.int/mediacentre/news/releases/2003/pr27/en/.

6. http://www.imshealth.com/ims/portal/front/indexC/0,2773,6599_5264_0,00.html.

7. Fixing the Drugs Pipeline, The Economist, March 11, 2004

8. E. Schering, “Current Stumbling Blocks in Oncology Drug Development,” Res. Found Workshop 2007 (59) 135–149.

9. Global Pharma Development, Medical Sciences, F. Hoffmann-La Roche Ltd, Basel, Switzerland. Claude.Gimmi@Roche.com

10. P. Workman, “How Much Gets There and What Does It Do? The Need for Better Pharmacokinetic and Pharmacodynamic Endpoints in Contemporary Drug Discovery and Development,” Current Pharmaceutical Design, 9 (11) 891–902 (2003).

11. N.C. Dracopoli, “Development of Oncology Drug Response Markers Using Transcription Profiling” Current Molecular Medicine, 5 (1) 103–110 (February 2005).

12. S.K. Gruvberger et al., “Expression Profiling to Predict Outcome in Breast Cancer: The Influence of Sample Selection,” Breast Cancer Research, 5 (1) 23–26 (2003).

13. L.J. van’t Veer et al., “Gene Expression Profiling Predicts Clinical Outcome of Breast Cancer,” Nature, 415 (6871) 530–536 (January 31, 2002).

14. C. Mathers, “Updated Projections of Global Mortality and Burden of Disease, 2002–2030: Data Sources, Methods and Results,” http://www.who.int/healthinfo/statistics/bod_projections2030_paper.pdf.