Starting Treatment Early for Metastatic Prostate Cancer: Part I

Man at Doctor's Visit. Credit: LilliDay / Getty Images

Dr. Edward Messing tested this premise—that early treatment is superior to delayed treatment—in a study that was reported in The New England Journal of Medicine back in 1999.  One hundred men with cancer found in the lymph nodes after surgery were randomly allocated to start hormone therapy with Lupron immediately after surgery or to wait until the cancer progressed. The 10-year prostate cancer survival rate was 88% in the men who started Lupron right away compared to only 58% in the men who had delayed treatment with Lupron (the average delay was 2 years).

Dr. Messing’s study confirmed that earlier treatment prolongs survival better than delayed treatment.

Most people are aware that prostate cancer exists in multiple forms and types. However, many are unaware that a single individual can harbor multiple types of prostate cancer. These different cancers in the same patient are called clones. The “clonality” of prostate cancer is illustrated by the commonly-used Gleason grading system, a scoring system that incorporates the two most common grades when a biopsy specimen is examined under the microscope. For example, the Gleason score reports the first and second most common clones in the following format: 4 + 3 = 7.  In this case the most common clone seen in the biopsy is reported as grade “4” and the second most common clone is reported as grade “3”.  

As cancer grows and progresses the number of clones also tends to increase because cancer cells are genetically unstable leading to more mutations.

The capacity to mutate means that over time untreated lower grade cancer cells can potentially transform into higher-grade, more aggressive clones. Mutations converting cells to more aggressive clones are random events that occur infrequently. However, if the number of cancer cells increases into the billions, the risk of mutation will increase.

  Treatment-resistant tumor clones become more common when the cancer is allowed to grow unchecked.   

Based on the mechanism of genetic instability described above, the general principle that immediate treatment will work better than delayed treatment should hold true for metastatic prostate cancer at any stage, even after hormone resistance occurs. As of 2016 there are five FDA-approved, life-prolonging therapies for Lupron-resistant prostate cancer. There is every indication, therefore, that these treatments should be started early, at the first sign that Lupron is becoming ineffective.

So what is the earliest signal of hormone resistance? The most widely-accepted indication is a rising PSA. Since Lupron functions by lowering testosterone in the blood, true resistance must be confirmed by a blood test to confirm that the testosterone levels are indeed low. Documenting a low testosterone in the setting of a rising PSA proves that Lupron resistance is present. However, a rising PSA with a low testosterone is not the earliest indication of resistance.

  An article in the September 2005 issue of the Journal of Clinical Oncology highlighted a more sensitive indicator called “PSA nadir.” Nadir means, “The lowest level of PSA achieved within the first 6-8 months of starting Lupron. The authors reported that 75% of men whose PSA stabilized above 0.2 ng/ml typically developed a rapidly rising PSA in a short time.

Men starting on Lupron, therefore, should follow the policy of checking their PSA monthly for the first six months.  If their PSA fails to decline below 0.2, they should continue checking their PSA levels monthly as they are at high risk for the immediate development of a rising PSA-for example, Lupron resistance. Part II of this article will discuss how to sequence the five new FDA-approved treatments for Lupron resistance. This is Part I of a IV part article.

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