Modern Taxotere Chemotherapy for Prostate Cancer

BY MARK SCHOLZ, MD


In prostate cancer, the word “chemotherapy” is essentially synonymous with Taxotere (docetaxel). Taxotere is by far the most common chemotherapy medicine for prostate cancer. Taxotere is an active agent that is also employed for the treatment of breast cancer and lung cancer.  Jevtana, which has many similarities to Taxotere, more than any differences, is the second most commonly used type of chemotherapy. Taxotere (and Jevtana) are administered intravenously every three weeks in a cyclical fashion.

These agents are typically used to treat advanced metastatic prostate cancer. Men with preexisting bone pain usually notice significant improvement within a week or two of starting therapy.  Another sign that the Taxotere is working is PSA levels decline.  If the PSA does not decline immediately, Taxotere should still be continued for at least two or three cycles before concluding the treatment is not working. An initial increase in PSA for 30-60 days is not an indication to stop Taxotere because on occasion men have a bump upward in the PSA, a “flare” from the dying cancer cells.  However, if the PSA continues to rise after three cycles, it indicates that the Taxotere is not working.

Cancer response rates can be further improved by using Taxotere in combination with Carboplatin.  Carboplatin is also administered intravenously and can be conveniently administered at the same time as the Taxotere. In patients who have normally functioning bone marrow and normal kidney function, a small dose of Carboplatin, say 200 mg, can be safely administered along with full-dose Taxotere.  Carboplatin is well-tolerated though occasional side effects include low-grade nausea, numbness in the hands or feet and tiredness.

Taxotere administered in combination is with Avastin and Revlimid is another very active combination that will induce a cancer response in most men. Avastin, which is FDA-approved for colon cancer but not prostate cancer, is an angiogenesis inhibitor given intravenously every two weeks.  It is generally well-tolerated but requires concomitant blood thinners due to a higher risk of blood clots.  Avastin can also cause slow wound healing and can't be used before or after surgery. Revlimid oral agent that is FDA-approved for a type of bone cancer called myeloma.  Like Avastin, it also functions by blocking new blood vessel growth. When using Revlimid in combination with Taxotere and Avastin we typically limit the Revlimid dosage to 5 mg daily.  Side effects at this dose range are rare though occasionally platelet counts can be suppressed.

A study using these three agents in combination that showed very high response rates was published by Dr. Figg from the National Cancer Institute.  This same study also reported a high frequency of fairly notable side effects including numbness of the hands and feet as well occasional cases of jaw damage, a condition called osteonecrosis.  Despite these significant problem, Dr. Figg reported that the vast majority of the men achieved significant remissions and that the remissions tended to be quite long lasting.  

Aggressive combination protocols like these require various supportive measures to be successful.  Defending against low white blood cell counts with an immune stimulator such as Neulasta should be considered routine. Neulasta is a powerful medicine that stimulates the bone marrow to manufacture white blood cells more quickly and in greater numbers. Side effects are rare but occasionally, serious but transient episodes of lower back pain can occur.

Another bone marrow stimulator, Aranesp, can defend against the development of progressive anemia. Anemia is a common in men with prostate cancer and can be due to hormone therapy, chemotherapy, or even from the prostate cancer invading the bone marrow. Symptoms of anemia are shortness of breath and fatigue. Timely and appropriate use of Aranesp helps to maintain normal red blood cell counts and can reduce the need for blood transfusions.

Taxotere usage has been greatly postponed in men with metastatic prostate cancer ever since the FDA approval of Xtandi and Zytiga. These agents induce meaningful remissions with far fewer side effect than Taxotere.  However, patient tend to have a rapid and virulent progression of the cancer after Zytiga and Xtandi stop working.  Taxotere, possibly in combination with Carboplatin should probably be implemented quickly in most cases. 

A Xofigo Update

BY MARK SCHOLZ, MD

Since Xofigo was FDA approved two years ago, the doctors at Prostate Oncology—Dr. Richard Lam, Dr. Jeffrey Turner and I—have been avid users.  So this seems to be a good time to provide an informal update of our experience with Xofigo to the present time.

The clinical trial that led to Xofigo’s approval by the FDA was a prospective, placebo-controlled study demonstrating improved survival in Xofigo-treated men compared to men treated with placebo alone.  The trial showed a very low incidence of side effects and good relief for men who were suffering from bone pain.

Xofigo is made out of radium, a radioactive element. After it is injected into the blood stream it concentrates near the cancer and delivers a potent dose of radiation.  So after Xofigo is injected into the patient, it travels through the blood stream and concentrates in the irritated areas of the bone and emits radiation where the cancer is most active.  Since prostate cancer spreads almost exclusively to bone, an injection of Xofigo ends up targeting most if not all of the cancer. Radiation consists of high energy, subatomic particles that blast cellular DNA. Once the DNA of the cancer cell has been hit, the cell is rendered incapable of reproduction.  If you stop cancer reproduction you basically stop the cancer.

To almost everyone, radiation conjures up horrible visions of toxicity. Fortunately, bone marrow toxicity is rare in men because Xofigo emits a different type of radiation, “alpha particles,” rather than the standard “photon type” of external beam radiation. Alpha particles dissipate their energy over a very short distance, only a couple of millimeters. External beam radiation therapy, the type of radiation that has traditionally been relied on to kill cancer cells in the bone, needs to be used very judiciously because the radiation is “beamed” through the body to hit the target in the bone. Typically it causes irreversible damage to the surrounding bone marrow.

Over the last two years at Prostate Oncology, we have treated over 50 patients with Xofigo.  The treatment has been very well tolerated.  Occasionally, we have seen a few patients with mild diarrhea or nausea that has been easily managed with common medications. Men experiencing pain from cancer usually see either partial improvement or total resolution of their pain after one to three of the monthly treatments.

As reported from the original study that led to FDA approval, even though pain relief occurs and alkaline phosphatase (ALP) levels in the blood decline, PSA may continue to rise.  This “disconnect” between PSA and other clinical parameters such as pain and ALP can be disconcerting to doctors and patients alike.  The reason that it occurs is unclear. A similar phenomenon has been observed with another FDA-approved cancer therapy called Provenge.

Experts hypothesize that the survival advantage from Xofigo and Provenge is due to a slowing of cancer progression rather than an actual regression of the cancer. This “slowing” is powerful enough to extend patients’ lives but insufficiently powerful to consistently induce a decline in PSA.  However, in our practice at Prostate Oncology notable declines in PSA have been observed in a few patients treated with Xofigo.  One patient dropped his PSA from 50 down to zero and his PSA still remains at undetectable levels.  Another recent patient has dropped his PSA from 150 down to 8.

For the patients on Xofigo who have rising PSA levels, it is logical to consider adding another effective anticancer agent such as Xtandi, Zytiga or Taxotere.  It is encouraging to know that several studies now show that Xofigo can be safely combined with these other effective therapies.

Xofigo has been a very welcome addition to our anticancer armamentarium.  The standard FDA approved protocol consists of a course of monthly treatments continued for a total of six months.  Further trials are in progress to study the potential advantages of continuing Xofigo for longer than six months.  Our experience to date suggests that longer therapy would indeed be advantageous in some instances.

Xtandi and Zytiga, The Future is Now

MARK SCHOLZ, MD

There are two new kids on the block, Xtandi and Zytiga. Both medications are real game changers. They are special because they can induce cancer remissions in men whose prostate cancer has become resistant to Lupron.  These pills are so effective that protocols for managing hormone resistant prostate cancer have been completely revamped.  Previously, men with hormone resistance were first treated with Taxotere chemotherapy, typically with undesirable side effects and frequent doctor’s visits.  When men on Xtandi and Zytiga are responding well, since they no longer need an intravenous infusion of Taxotere every three weeks, they only have to come in for a doctor’s visit every three months.

While Xtandi and Zytiga are now FDA approved for hormone resistant prostate cancer, there is no reason to believe they won’t also show enhanced effectiveness against earlier-stage, hormone-sensitive disease as well.  This rationale is based on a long established fact about anticancer treatments in general: “Any treatment that is effective against advanced cancer generally proves to be more effective against earlier-stage cancer.”  This assumption is so logical one might wonder why the academic medical world insists on doing studies to prove it.  Honestly, the biggest barrier is probably cost.  Insurance companies that pay for these expensive medications demand ironclad proof of a beneficial effect before being willing to cover their expanded use.

Physicians, particularly urologists, who are unfamiliar with these potent new agents, are another barrier to the expanded use of Xtandi and Zytiga in earlier-stage prostate cancer.  Urologists, the surgeons who over the last 20 years have only slowly become familiar with how the standard medications Lupron and Casodex function, are often uncomfortable using new agents that can be associated with rare side effects such as high blood pressure, seizures, liver problems and potassium depletion.  To urologists, the doctors who are managing the men with early-stage prostate cancer, Xtandi and Zytiga are relative unknowns.

In spite of all these barriers, the logical place to consider using Xtandi and Zytiga is in earlier-stage, “high-risk” situations which have suboptimal cure rates with Lupron alone.  The situations where this might apply are listed below:

·         Newly-diagnosed men with a PSA over 20 and a Gleason score over 8

·         Newly-diagnosed men with seminal vesicle invasion or pelvic lymph node metastases

·         Relapsed men after surgery with a PSA doubling < 3 months having salvage radiation

·         Newly-diagnosed oligometastatic disease undergoing radiation to all sites of disease

In all these situations, Lupron is known to be beneficial.  In some cases, the addition of Casodex to Lupron further increases the anticancer effect over Lupron alone. This is an important observation because compared to Xtandi or Zytiga, Casodex is a very weak anticancer agent.  Substituting these far more potent agents for Casodex is very likely to result in substantial improvement of the anticancer benefit and is a logical consideration for men who want to optimize their cure rates.        

INDIGO: Relapsed Prostate Cancer

MARK SCHOLZ, MD

Those dreaded words, “relapsed cancer,” shake you to the core. They mean that surgery or radiation has failed to “get it all.”  However, while with most cancers “relapse” is a fatal pronouncement.  However, prostate cancer has its own distinct reality. Most men who relapse don’t die from the disease.  The outlook is good because relapses are usually detected by a rising PSA when the cancer is still microscopic. Visible, scan-detected metastases may not appear for ten or more years after the PSA relapse occurs.

Multiple Treatment Options for a Rising PSA
The list of potential treatment options for INDIGO is extensive: observation, radiation, hormone therapy with Lupron and Casodex, salvage seed implant, salvage cryotherapy, Zytiga, Xtandi and Taxotere. However, combinations of these treatments are most commonly employed. Some of these combinations are listed below in order of increasing treatment intensity:  

1.     Observation

2.     Mild hormone therapy consisting of continuous or intermittent Casodex

3.     Monotherapy with fossa radiation, seed implant or cryotherapy for persistent local disease

4.     Combination hormone therapy with Lupron and Casodex given intermittently

5.     Same as #4 but with the addition of pelvic radiation and 4 months of hormone therapy

6.     Same as #5 but with hormone therapy extended for 18 months

7.     Same as #6 but with the addition of Taxotere or Zytiga or Xtandi

Defining Different Types of Relapses
Just as PSA, cancer grade, scan findings and stage were instrumental for assigning a SHADE in newly-diagnosed men; SHADES are important for putting a relapsed in perspective. Ultimately, how to treat INDIGO is guided by a combination of four factors— the SHADE before treatment, the PSA doubling time, individual patient factors such as age, sexual functionality and urinary control, and last, but not least, the cancer location.

The Original Shade before Treatment
In general, treatment should be more aggressive (combined therapy with Lupron and pelvic lymph node radiation) if the original SHADE was unfavorable (AZURE for example).  Treatment should lean toward a less aggressive approach—cryotherapy alone, seed implant alone or Casodex alone—if the original SHADE was SKY.

The PSA Doubling Time
Treatment is heavily influenced by the rate of PSA rise. For example, if the PSA is doubling in less than six months, aggressive combination treatment with Lupron and Casodex plus radiation (or cryosurgery in men previously treated with radiation) is probably required.  If the PSA doubling rate is between six and twelve months, a less aggressive treatment approach with radiation alone, cryosurgery alone or intermittent Lupron and Casodex is reasonable.  When more than a year is required for the PSA to double, observation without immediate treatment may be considered.

Patient Factors that Affect Treatment Selection
A patient’s age needs to be factored into the treatment decision-making process. Men who are more elderly can “step down” the intensity of their treatment by temporizing with milder hormone therapy such as Casodex with Avodart. Younger men, who, prior to relapse, were in the High-Risk (AZURE) category may want to consider upgrading the intensity of treatment by using prophylactic pelvic lymph node radiation plus a more intensive hormone therapy such as Zytiga or Xtandi and/or chemotherapy with Taxotere.

Searching for the Location of the Cancer
Men with rising PSA should undergo standard imaging studies (listed below) in an attempt to determine the location of the cancer. Unfortunately, these scans are often unable detect recurrent cancer unless the PSA is over 20. However, improved PET scans that utilize C11 choline or acetate have the potential to detect recurrent disease with much lower PSA levels. Unfortunately, the PET scans are so new that insurance coverage is often limited.

Sometime even the best scans can’t detect where the cancer is. When this occurs after surgery, particularly when the PSA doubling time is slow, residual cancer in prostate fossa is often suspected and radiation to the prostate fosse is often administered. Cure rates are better when radiation is initiated at a lower level of PSA. 

Standard Imaging Studies for INDIGO

• Color Doppler Ultrasound or Multiparametric 3 Tesla MRI can be used to look for residual cancer in the surgical fossa or in the prostate gland in men previously treated with radiation. 
• Pelvic MRI or CT scans are used to check for spread to pelvic lymph nodes. (Carbon 11 acetate PET scan, however, is far more accurate than CT or MRI but some centers still consider them investigational/experimental)
• Technetium bone scans are standard. New F18 PET bone scans, however, are preferable because they can detect much smaller cancers than technetium bone scans.

Apparent Locally Recurrent Disease

Scans done in a man with a rising PSA after radiation that indicate a recurrence localized inside the prostate, may be curable with cryosurgery alone or possibly with a seed implant alone.  Similarly, an isolated local relapse in the prostate fossa after surgery may be curable with radiation alone. Even though scans show no metastases outside the prostate or the fossa, microscopic metastases in the pelvic nodes may be present, especially in men who have fast PSA doubling times or whose SHADE was originally AZURE.  In these higher risk situations, the addition of prophylactic pelvic lymph node radiation with intensity modulated radiation (IMRT) combined with hormone therapy may be advisable.

Regional Spread to Lymph Nodes

When cancerous nodes are detected in the pelvis, the idea of doing node-directed IMRT is even more compelling. Since overt cancer in the lymph nodes is an indication of potentially life threatening disease, an extended course of hormone therapy, possibly with the addition of second generation hormones such as Zytiga or Xtandi, can be contemplated. Taxotere chemotherapy is an additional consideration.

Hormone Therapy Alone

When the location of the relapse is unclear, or if the risks of side effects from radiation appear too high, relapsed disease can be effectively suppressed for many years with hormone therapy alone. The side effects of hormone therapy tend to increase with longer use so intermittent therapy is very popular. A typical intermittent protocol is to begin with an initial course of treatment for six to twelve month followed by treatment holiday. After hormone therapy is stopped, testosterone starts to recover and the PSA begins to rise. Treatment is restarted when the PSA rises back to the original PSA baseline, or up to five, whichever is lower.

Putting It All Together

Treatment selection for INDIGO can be complex. Constructing a cancer “profile” using the original SHADE, the PSA doubling time, and scan finding, is the first step. Unfortunately, the location of the recurrent cancer may remain uncertain, even after doing the best scans.  When this is the case the extent of disease may require a professional “guesstimate” based on the PSA doubling time and the original SHADE.  Despite all these difficulties and uncertainties, the good news is that a wide variety of treatment options are available and treatment is usually very effective. For the majority of men the disease can be controlled on a long-term basis, and some cases it can even cured. 

CALENDAR ALERT TO THOSE WHO LIVE AROUND LONG BEACH, CA Learn more about prostate cancer treatments as Mark Scholz, MD, discusses treating PSA relapsed disease at UsTOO Long Beach Prostate Cancer Support Group July 22, 2014 - 6:30 PM to 8:30 PM, at Long Beach Memorial Medical Center. For more information follow this link: http://goo.gl/HMojNV

 

Xtandi (enzalutamide), the Star of the 10th Annual Genitourinary Meeting

BY MARK SCHOLZ, MD

The GU-ASCO meeting kicks off the first of five annual prostate cancer meetings that are on my calendar to attend every year. The other four meetings are hosted by the American Urological Association (AUA) in May, the PCRI meeting in September, the American Society of Therapeutic Radiation Oncology (ASTRO) that is also in September and the Prostate Cancer Foundation retreat (PCF) that occurs in November.  
 
Since GU-ASCO is the first meeting of the year, the new scientific research presented sets the tone for the whole Year.  This year’s meeting was dominated by the release of a report showing that Xtandi, a potent oral anti-cancer agent, prolongs life compared to placebo when administered prior to the chemotherapy drug Taxotere (a previously published study has already shown that Xtandi prolongs survival when used after Taxotere).
 
It’s exciting to see an effective pharmaceutical agent get expanded access. This will lead to a greater number of men benefiting with prolonged survival and better quality of life. The bare bones of this groundbreaking report are summarized here:
 
Abstract #1: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer. Results of the phase III PREVAIL study.
 
In this randomized, double-blind, placebo-controlled, multinational phase 3 study, chemotherapy-naive patients with metastatic hormone-resistant disease were treated with either enzalutamide or placebo.
 
Results: A total of 1,717 men were enrolled. Final results showed a significant benefit of enzalutamide over placebo with a 30% reduction in risk of death and an 81% reduction in risk of radiographic progression or death. At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died.
 
The findings of this study almost certainly indicate that the FDA will approve Xtandi for use prior to Taxotere and in the near future,  Xtandi will compete head to head with Zytiga and Provenge, both of which are already FDA-approved for men in the pre-chemo category.
 
The fact that FDA approval is almost guaranteed means that doctors are going to start asking a very important question:  What is the optimal way to sequence these three medications?
 
Presently there is no clear answer about whether Zytiga should be before Xtandi or vice versa. However, there are several very strong arguments that Dendreon’s product, Provenge, a medication that works by stimulating the immune system, should go first:

1.   Provenge only takes 6 weeks to administer, so there is no problem adding other anticancer agents after Provenge administration is complete.

2.   Immune treatments in general are thought to work better when initiated at an earlier stage, before the cancer becomes more entrenched and starts to suppress immune function.

3.   Provenge changes the immune system in a fashion that keeps working indefinitely after the initial 6-week treatment period is passed.

4.   Because insurance only pays for Provenge in men with rising PSA levels, starting Xtandi or Zytiga, both effective in lowering PSA, can substantially delay the initiation of Provenge.   

 

There seems to be broad consensus that Provenge should be first in line.  The real question then is, “What should come second, Xtandi or Zytiga?”

At the GU-ASCO meeting there were a number of reports, including a report from our office, that show reduced anticancer effects of Xtandi when used after Zytiga.  This is hardly surprising since the phenomena of progressively increasing cancer resistance with each cycle of therapy have been known about for 30 years. Preliminary reports also show a reduced Zytiga response-rate when it is used after Xtandi.

While these reports document that the first agent selected is likely to be used for a much longer time period than the agent that follows, so far there are no studies evaluating whether sequencing  affects overall survival.  Xtandi clearly has reduced anticancer activity after Zytiga. The same, however, has also been observed in reports evaluating Zytiga in men who have previously failed Xtandi.

The jury is still out. Until further comparative studies are performed, no one knows if there is an advantage to using Zytiga first or Xtandi first.  Presently however, I think most experts are assuming that Xtandi and Zytiga seem to have similar overall anti-cancer potency, the preference of sequencing one agent over the other to be first in line is unlikely to have a major impact on overall longevity.

The ROYAL Shade of Blue

BY MARK SCHOLZ, MD

Men in the ROYAL shade have metastatic prostate cancer that has spread to bone, or, to lymph nodes outside the pelvis, or, they have a PSA over 100, or, they have a rising PSA with a low testosterone level. Metastases are typically detected by doing a body scan or a bone scan.

Men with advanced prostate cancer tend to live longer than men with other types of cancer. One major reason is because prostate cancer doesn’t usually spread to critical organs like the brain, the liver or lungs.  Another reason is the availability of so many effective treatments. Standard hormonal treatment with Lupron and Casodex, for example, can induce long remissions. And just recently, the FDA approved two new types of hormone therapy—Xtandi and Zytiga. These medications are so powerful they can induce remissions in men who have become resistant to Lupron and Casodex. In addition to Xtandi and Zytiga, two non-hormonal treatments—Provenge and Xofigo—have also been recently approved by the FDA.

Since so many effective treatments are available, wasting time on a treatment that has stopped working is a terrible crime. Therefore, after initiating a new treatment close monitoring of disease status is essential. Monthly blood tests and PET scans with sodium fluoride or carbon 11 acetate help to determine when a specific treatment stops working. Ineffective treatment should be stopped as soon as disease progression occurs so that a more effective therapy can be started in a timely fashion.

Treatment for ROYAL
Men in the ROYAL category who have never had hormone therapy should start testosterone inactivating pharmaceuticals (TIP).  The standard approach is to begin with Lupron and Casodex in combination.

Men who have become resistant to Lupron, but have fewer metastases and a slower PSA doubling time, should take Provenge to boost their immune system. Studies show that Provenge works better when treatment is started earlier. Preliminary research has also suggested that Provenge might be more potent if it is combined with spot radiation directed at a site of metastatic cancer. Studies to evaluate this possibility are ongoing.

With or without Provenge, radiation to cancer metastases has historically been reserved for controlling bone pain, a use for which it is quite effective. However, newer thinking suggests that radiation directed to all known sites of metastases—when the numbers of metastases is relatively small, say less than five—may occasionally lead to longer remissions.

Potent medications to strengthen the bones—Xgeva and Zometa—are routinely recommended when bone metastases are present. These medications have three potential benefits: They inhibit cancer growth in the bones; they reduce bone pain; and they help counteract calcium loss that hormonal therapies commonly cause.

If men in ROYAL have the type of prostate cancer that progress quickly while on Lupron and Casodex, the first step should be to stop Casodex and start one of the following three options:

1.    Second-line TIP such as Zytiga or Xtandi

2.    Chemotherapy with Taxotere or Jevtana

3.     Xofigo, a form of injectable radiation

Three additional treatment options can be considered if these first three options are no longer effective in controlling the disease:

1.       Combination chemotherapy using Carboplatin or Xeloda with a Taxane or the combination of both Revlimid and Avastin added to a Taxane. 

2.       The “off-label” use of Cabozantinib (XL-184), a medication being researched for prostate cancer but already FDA-approved to treat thyroid cancer

3.       Other investigational medications

Investigational trials represent an opportunity for patients to get medications prior to FDA approval.  A patient’s enthusiasm for embarking on a study that uses an investigational medication, however, needs to be tempered by what is actually known about the effectiveness of the specific medication.  Some medications are so new that even the investigators performing the trial don’t know if they are going to work or not.

While on treatment men need to have their blood monitored monthly by checking PSA, PAP, ALP and CTC levels. Medication side effects and cancer-related problems also need to be screened for with monthly blood tests such as CBC, a metabolic panel and a hepatic panel.  A periodic bone scan and body scan should be performed to track the disease status.  Two to three months after starting a new treatment, if the blood markers are not improving, a change in therapy needs to be considered.    

Reducing the Side Effects of Treatment
Fatigue is one of the biggest challenges faced by men in ROYAL. First, both chemotherapy and radiation can cause tiredness. Second, muscle loss is a frequent occurrence from TIP-induced, low testosterone.  Stimulants such as Provigil or Nuvigil may be helpful, but the most important priority is to counteract muscle loss with consistent, diligent exercise. Resistance training with weight lifting is only known effective method for restoring muscle mass.

Xgeva and Zometa cause gum recession and infections of the jaw bone, a condition called osteonecrosis.  This phenomenon is much more likely to occur after a tooth extraction so men on this therapy are advised to avoid extractions as much as possible.  Osteonecrosis, when it occurs, generally resolves, albeit slowly, after Xgeva or Zometa are stopped.

A variety of different medications can be useful for reducing side effects from hormone therapy. Low-dose estrogen skin patches can control hot flashes. Excessive mood swings can be stabilized with low doses of antidepressant pills. Breast enlargement can be prevented with Femara. 

Final Thoughts

In this blog I have outlined a traditional, sequential approach to treatment selection.  Strong consideration, however, should be given to using these active new agents in combination and at an early stage.  Men in ROYAL have a potentially life-threatening type of prostate cancer. An aggressive and imaginative treatment plan should be designed that has the specific goal of attaining and maintaining a complete remission, i.e. a PSA less than 0.1. In my opinion, the standard “one treatment at a time” approach that is so popular at academic centers, it is a grave disservice to the men fighting aggressive prostate cancer. 

Technology to the Rescue

BY MARK SCHOLZ, MD

My dad always told me that good ideas are a dime a dozen. The trick is to put the good ideas into motion so that by perseverance and hard work they come to fruition.  This is true of the pharmaceutical industry. Massive investment in basic research has yielded a much better understanding of how cancer “works,” creating opportunities for biochemists to design specific pharmaceuticals that will inhibit cancer growth and spread. However, the fact remains that multi-million dollar clinical trials must be performed before a new medicine can be approved and released by the FDA.

One pharmaceutical company that is making fast progress is OncoGenex.  They have developed an elegant solution for blocking an overactive enzymatic pathway that cancer cells use to protect themselves from chemotherapy. For example, blocking the effectiveness of one popular type of chemotherapy commonly used to treat prostate cancer is called Taxotere. The specific overactive enzyme the scientists at OncoGenex have identified is called clusterin. Cancer cells over-produce clusterin to protect themselves from chemotherapy.

OncoGenex has designed a medicine that accurately targets clusterin.  This new medicine, called Custirsen, sharply reduces the amount of clusterin inside the cancer cells. A preliminary trial, using Custirsen was added to the regimen of 82 men with advanced metastatic prostate cancer being treated with Taxotere (a chemotherapy drug that is commonly used to treat prostate cancer), showed a 40% improvement in survival rate when Custirsen was added to Taxotere--compared to the survival in men receiving Taxotere alone.

Clinicaltrials.gov reports that 141 centers around the country are currently participating in a larger trial combining Custirsen and Taxotere.  This larger trial, involving hundreds of men with advanced prostate cancer, is aimed at proving the effectiveness of Custirsen and getting approval by the FDA for commercial availability. Custirsen is administered as a weekly intravenous infusion.      

Over the course of my 20 years as an oncologist many of the common cancer medicines have proven to be  major disappointments—not very effective and overly toxic.  These earlier agents were discovered and developed through a slow and cumbersome process of trial and error. In that era we had only a vague idea of how the new treatments actually worked.  Most of those agents were broad spectrum inhibitors of cellular growth that resulted in considerable collateral damage on the faster growing normal cells of our body like the hair follicles and the white blood cells.  

Research leading to the discovery and development of newer agents like Custirsen is completely different. These agents are rationally designed and targeted to attack and destroy a very specific part of the cancer cells. As a result, they are not only more effective, they also have fewer side effects.

At last, it appears to be technology to the rescue.

MDV-3100—An Embarrassment of Blessings

BY MARK SCHOLZ

Every day in the office, as a practicing prostate oncologist, I confront serious problems:  PSA levels that are rising, treatments causing too many side effects, patients desperately worried about their future. And sometimes, given our limited tools, the solutions we can offer are only partial. However, every time the FDA approves a new treatment there is an excitement akin to opening gifts on Christmas morning. All of a sudden we have a shiny new tool in the tool chest to help us do a better job.

I’ve repeatedly gone on record criticizing the FDA for the inflexible format they use to approve any new drug.  They insist on survival as the only important measure of effectiveness. There has to be a better way to study new drugs than giving a placebo—an inert substance containing no active ingredient—to unfortunate people who already have a life-threatening illness. But this is the format our government demands—forcing pharmaceutical companies to prove that their new anti-cancer drug works by comparing them with sugar pills. And so the human sacrifices continue.

However, back to the good news, the spirit of Christmas morning. Medivation, the manufacturer of MDV-3100, a new drug that is estimated to be twenty times more potent than Casodex, recently reported a significant survival advantage in their study comparing MDV to  the of unfortunate souls who got placebos. In other words, Medivation cleanly jumped over the bar set by the FDA. Since MDV-3100 was not associated with any unexpected side effects, the FDA will be essentially forced to hold up its end of the bargain and release it soon for commercial use.

Some are saying that MDV is just a copycat of Zytiga, one more expensive testosterone blocking pill in an already busy marketplace. I disagree completely:

1.       Since MDV has few side effects, it can be easily combined with other popular treatments like Provenge and Taxotere.

2.       Since the mechanism of testosterone blockade is completely different from Zytiga, it’s possibly that the anticancer effects of Zytiga and MDV will multiplied if they are given together.

3.       Due to its ease of use, it will be popular with the urologists, the surgeons who are charged with managing most men with prostate cancer.

My “Christmases” seem to get better every year.  Last year the tool chest was expanded to include Zytiga, Provenge and Jevtana. And there are also some amazing new drugs waiting in the wings—Ipilimumab, Dasatinib, XL-184, Revlimid and more. We finally seem to be entering a new, hopeful era for prostate oncologists—and, most important, for their patients.

FDA Roulette

BY MARK SCHOLZ

The notoriously stingy and demanding FDA gave the go ahead for two new treatments for prostate cancer in 2010.  New approvals are rare because of the hundreds of millions of dollars required to undertake the type of studies that the FDA requires. The FDA wants studies that randomly allocate men into two comparison groups. One group gets the new medicine. The other group gets an ineffective fake called a placebo. FDA approval comes when men getting the new medicine live longer than those given the placebo.

Finding volunteers willing to participate in these types of studies is difficult. The men know there is a 50% chance they will get an ineffective placebo. Who wants to take the chance of getting a sugar pill as their treatment? Even so, some men are so desperate, they sign up, hoping to be among the lucky ones who receive the real McCoy.

These studies often run for years because the study ends when the study participants die from progressive cancer.  To find men willing to participate, the supervising companies that organize and run these studies need contractual relationships with a hundred or more study centers. Just keeping track of all these different patients, at so many different locations, over a period of several years, is in itself very costly.

Provenge is the first FDA approved treatment for prostate cancer that works by strengthening the immune system. Dendreon is the name of the company that has patented a process of harvesting immune cells out of the blood by means of a technique known as “plasmapharesis.” Plasmapharesis is a three hour process similar to dialysis that extracts immune cells from the blood. The harvested cells are then taken to a special laboratory and mixed with substances that enhance their aggressiveness against cancer.  The cells are then re-infused back into the same patient. 

Provenge’s primary appeal is the low incidence of side effects. The treatment, which does not rely on chemotherapy, is so revolutionary that at first the FDA was very skeptical. They dragged their feet for years, forcing the company to run their studies over and over.  Lo and behold, additional studies again demonstrated that Provenge-treated men were 30% more likely to be three years after their treatment with Provenge compared to the men who received a placebo. Dendreon should be commended for patiently persevering time after time when the FDA kept turning them down. Now men with prostate cancer have access to an effective treatment that has very few side effects.

The other new treatment recently approved by the FDA, Jevtana, falls into the more familiar category of chemotherapy.  Jevtana was approved in July 2010 based on a randomized survival study evaluating Jevtana compared to an older, ineffective type of chemotherapy called Mitoxantrone. 755 men were treated with either Jevtana or Mitoxantrone. The survival of men receiving Jevtana was 30% better then the men treated with Mitoxantrone.  

This remarkable achievement took some industry experts by surprise because the participants in the trial had all been treated previously and become resistant to another type of chemotherapy called Taxotere.  Historically, resistance to Taxotere has been a bad sign predicting resistance to all types of chemotherapy. Jevtana, unlike Provenge has the traditional side effects of chemotherapy such as tiredness, hair loss and increased risk for infection. Even so, reversing cancer in men with Taxotere-resistant disease is quite an accomplishment. 

The FDA finally agrees that both Jevtana and Provenge are proven to make men live longer. Studies are ongoing with these newly-approved medicines to see if combining them with other drugs can further enhance their effectiveness. In the meantime, men with prostate cancer need to be aware that these new and effective tools are available.