Most of us with late-stage prostate cancer have few survival options except continuance of hormonal blockade (HB), sequential chemotherapy protocols, and radiation therapy (RT) to palliate pain. In general, HB is ineffective as we are hormone refactory, have predominantly androgen-independent cancer cells, and thus, HB does not affect continued cancer growth. All chemotherapy protocols have a median duration of response (MDR) and a median duration of survival (MDS), thus they all exhaust themselves---such treatment exhaustion is reflected as increasing PSA and disease progression measured by CT/bone scans, symptoms, pain, and general deterioration of QOL. All chemotherapy trials and reports clearly designate the treatment as not extending survival.

Most of us resort to continued chemotherapy and RT for pain relief and symptom improvement. RT can be external beam (EBRT) as ‘spot welding’ to specific sites for pain relief, or systemic infusions of radiolabled drugs like SR⁸⁹ or SM¹⁵³. But, all of us know that any RT can adversely affect bone marrow and result in decreased platelets and white blood counts---these blood markers can be so adversely affected that any further treatment (such as chemotherapy) cannot be re-commenced until the blood markers recover. And, the only ‘treatment’ for blood markers to recover are blood transfusions or specific drugs to improve WBC/RBC, which are not always effective. Moreover, most cytotoxic treatments are ceased during RT because they are likewise myleotoxic (destructive to bone marrow components).

Therefore, most of us with late-stage disease must rely on what is considered to be standard treatments of chemotherapy and added RT for pain. These treatments modalities are practiced by two completely different medical disciplines---oncologists administer chemotherapy and radiation oncologists administer RT. During late-stage disease we are bounced between these different disciplines as we carefully watch our blood markers to see whether we can receive the next treatment.

But, is this standard of treatment extending quality survival time?---or, is it hastening our death? A considerable amount of medical literature indicates that this bouncing between chemotherapy and RT hastens our death as the RT greatly stimulates VEGF (2 to 10 times increase) and provides a milieu wherein the cancer proliferates at a much greater rate. During this enhanced VEGF and cancer growth time, we must wait for our blood markers to recover (if they ever do so) before we can return to cytotoxic therapy. Moreover, studies reflect that RT and resultant VEGF growth makes the cancer impervious to RT and chemotherapy agents; and, chemotherapy following RT might enhance cancer growth and thus, hasten death.

Again, are we accelerating our death by bouncing between RT and cytotoxic therapies, or could we extend quality survival by remaining with cytotoxic treatments for palliation of pain while moving up the scale of pain medications?

Recently, a woman on the Internet reported that her father is now in hospice care after 18 months of HB and chemotherapy while maintaining platelets of 130. He was recently treated with 7 courses of RT as ‘spot welding’ for painful bone metastastases; his platelets immediately fell to 30, multiple blood transfusions did not return it to levels that allow treatment, and she questions whether the RT did more harm than good and hastened her father’s impending death, since his pain at those exact ‘spot welded’ places immediately increased in severity. She questions whether the different medical disciplines tried to ‘fix one part while breaking another’?

If I may make the treatment matrix dilemma personal to clarify the issue--- In August ‘97 I presented with a PSA of 323, Gleason 5+4=9, D2 (multiple bone scan tracer uptakes)---I have been heavily-treated with CHT, AAWR, SR ⁸⁹ (for pain), HDK, PC SPES, RT ‘spot welding’ for pain, and 15 months of chemotherapy. I am faced with progressing disease as reflected by an unacceptable PSA nadir and slope, additional tracer uptake on bone scans, increasing pain, and the resultant ratcheting-up of pain medications. I can elect to continue with chemotherapy and increase pain medications as needed; or, I can elect to palliate pain with SM¹⁵³ in accordance with ASCO 2001 # 1036 wherein Sartor et al successfully repeated SM¹⁵³ infusions on recurrence of pain; median interval between doses was 133 days (55-395); median time to nadir for WBC and platelets was 4-5 weeks, regardless of number of infusions; the transient decrease in WBC and platelets was approximately 50%, with recovery usually by week 8; and, there was no trend toward increasing marrow toxicity with increasing numbers of infusions.

But, this is an ASCO abstract ---there is no full-text to reveal details of response rates or probability analysis that blood markers will not recover. Also, there is no indication that the patients returned to chemotherapy upon blood marker recovery. I have had friends that embarked on aggressive RT for pain, their blood markers deteriorated below accepted treatment levels, never to recover and thus, additional therapy was not available. They unsuccessfully received multiple blood transfusions---and they died.

PERSONAL DATA TO CONSIDER IN A RISK ANALYSIS: My platelets fluctuated between 150 and 200 (140-440) and WBC nadired at 3.4 (4.2-10.0) during 15 months of chemotherapy. If I now elect SM¹⁵³ for pain relief and my WBC and platelets deteriorate 50% and do not recover for 8 weeks (see Sartor, above ), and then do recover, I will have been exposed to 8 weeks of unfettered cancer growth and possibly 700% enhanced VEGF proteins which further encourage cancer proliferation. Moreover, in addition to the possible explosive cancer growth for 8 weeks, the SM¹⁵³ and resultant enhanced VEGF could make my cancer resistant to further chemotherapy. Should my platelets and WBC not recover sufficiently for additional therapy, the inevitable death spiral commences. This is the proverbial slippery slope.

When a man’s blood markers are not strong, there is fear that RT could deteriorate them to the point that the markers might not ever recover and thus, never allow additional therapy. Then, as with my friends, the inevitable death spiral begins. Is SM¹⁵³ worth the risk? Or, should our choice be to continue manipulating sequential chemotherapy protocols and increase pain medications as needed? Which treatment might allow more quality time and conversely, which one might hasten death? I have discussed this decision tree with several doctors and I assure you that they have no recommendation. This is the ultimate game of Russian Roulette .

Perhaps oncologists and radiation oncologists should consider this possibility and inform us thereof before sending us bouncing between ‘spot welding’ or SM¹⁵³ for pain and then return to chemotherapy for both palliation and an attempt at disease control?

angiogenesis - development of new blood vessels

apoptosis - programmed cell death

RBC - red blood count

cytotoxic - treatment that kills cancer

cytokines - protein that regulate intensity and duration of immune response

and mediate cell communication

cytothesis - repair of injury, restoration

endothelial - layer of fat cells lining blood and lymphatic vessels

neuroendocrine - (NE) - cells that release a hormone into the blood system

tyrosine - amino acid present in most proteins

kinase - an enzyme catalyzing the conversion of a proenzyme to an active

enzyme, thus catalyzing the transfer of phosphate groups

mitogens - stimulate mitosis

mitosis - process of cell reproduction

WBC - white blood count

VEGF - vascular endothelial growth factor

Obviously, death is caused by vital body organs ceasing to function. This, in turn, is the result of a cascade of other component functions ceasing to function. Many of my friends who have died from prostate cancer have done so by virtue of blood markers (platelets, WBC, RBC) falling below those acceptable for continued treatments, thus allowing the cancer to progress unabated and commence destroying vital body functions and organs. A common scenario is for sequential treatments of chemotherapy and RT to systematically deteriorate blood markers to levels below those acceptable for treatments;--followed by ‘treatments’ of blood transfusions, Neupogen™, Epogen™, or Procrit™ in an attempt to return the markers to levels that will allow cytotoxic treatments as an attack on the cancer. But, often the blood markers are so damaged by previous treatments that they will not recover and thus, the death spiral is inevitable.

During my most recent (12 September 2001) weekly chemotherapy treatment and after completion of this paper, I had a meaningful discussion concerning this issue with the oncology group who treats me . While they confirm that this is a very significant element in our decision process, the reasons for death from bone tumors is very complex, not the least is the fact that aggressive bone cancer is unpredictable. Again, the question of RT resulting in enhanced VEGF and possible cancer rapid progression is significant to consider regarding treatment decisions, but the matrix of death from cancer includes many additional treatment decision factors and each of us must discuss the entirety of the matrix variables with our medical team as many other interlocking factors can cause continued deterioration, notwithstanding therapy decisions.

Without detailing it, I believe that we all know that interrupting angiogenesis (the making of new blood vessels) is an important factor in arresting cancer. Multiple reports establish that VEGF proteins include potent mitogens (stimulate blood vessel growth) that enhance and promote angiogenesis and is one of the molecules responsible for metastasis of cancer cells. Furthermore, multiple reports establish that RT induces VEGF enhancement, renders the RT less effective, and contributes to the protection of blood vessels from RT and chemotherapy cytotoxicity.

Langer et al (1.) found that VEGF is a specific endothelial cell mitogen that stimulates angiogenesis and plays a crucial role in tumor growth. Arii et al (2.) found that the VEGF gene induces neovascularization in and around the tumors and augments metastatic potential by accelerating activity after reaching the organ. Ando et al (3.) found that VEGF is a multipotent cytokine contributing to tumor growth; X-ray irradiation significantly increased (by 2.5-fold) its expression---but, such over-expression can be blocked by pre-treatment with Genistein (a tyrosine kinase inhibitor). Gorski et al (4.) reports that VEGF proteins include potent and specific mitogens that are enhanced and induced by radiation and this enhancement contributes to the protection of tumor blood vessels from RT cytotoxicity and thereby render them RT-resistant. Castilla et al (5.) found that the VEGF protein possesses a protective mechanism of endothelial cells against injury; and upon injury, a significant increase in VEGF is noted. In an inverse analysis, Gridley et al (6.) injected VEGF into prostate cancer tumors and subjected the tumors to RT; the result was significant growth of PC-3 prostate cancer cells and a 700% tumor progression in 60 days.

What about VEGF and chemotherapy? Johansson et al (7.) found that tumor angiogenesis is essential for tumor progression and is a target for therapy; but, impaired tumor blood supply might also be an obstacle for treatment by RT and chemotherapy; RT decreased tumor microvascular density (MVD) by 30%, but Emcyt counteracted this by increasing the blood vessel size and after 5 days VEGF was significantly enhanced in the center of the tumors. Katoh et al (8.) earlier reported (9.) that RT induced VEGF enhancement inhibits apoptotic death and here again, finds that RT induces proliferation of VEGF and it, in turn, inhibits apoptotic death anticipated by exposure to VP-16 and Adriamycin; after RT, exposure of the cells to chemotherapy agents increased the viability of the cells. Klement et al (10.) found that antivascular effects of low-dose vinblastine were selectively enhanced by blocking survival signals mediated by VEGF with a monoclonal neutralizing antibody, DC101; results were diminished tumor vascularity and direct inhibition of angiogenesis; the combination therapy resulted in full and sustained regressions of large established tumors. This was in April 2000; where is DC101 now?

What about VEGF in prostate cancer? Haggerstrom et al (11.) state that tumor angiogenesis is important in progressive tumor growth and metastasis and found increasingly high levels of microvessel density and VEGF protein levels in androgen-insensitive and metastasizing prostate cancer cells. Mazzucchelli et al (12.) found that all prostate cancer cells stain strongly for VEGF; significant levels of VEGF exist in prostate cancer cells and in populations of PIN (prostatic intraepithelial neoplasia) lesions, expression being the highest in NE (neuroendocrine) cells; the VEGF intensity correlates with Gleason Score; and hormonal ablation before RP (radical prostatectomy) down-regulates the expression of VEGF, except in those cells with NE (neuroendocrine) features.

What can be done to down-regulate VEGF? Borgstrom et al (13.) found that VEGF is essential for growth of tumors and a neutralizing anti-VEGF antibody A4.6.1 completely suppressed prostate cancer angiogenesis and prevented tumor growth beyond the initial prevascular growth phase. What ever happened to A4.6.1? I can find no information about it. Hanna et al (14.) found that in vitro endostatin and simultaneous RT produced significant tumor growth inhibition and reduced tumor size by 47% compared to RT alone, indicating that endostatin down-regulated endothelial cell survival---but, endostatin has been found to inhibit angiogenesis only in cancer implanted in rabbit’s eyes---so, this might not be an answer to down-regulating VEGF. Lee et al (15.) states that an ‘anti-VEGF, which is a known to target human VEGF’ monoclonal antibody (MoAB) can compensate for the resistance to RT induced by hypoxia (oxygen levels below normal in blood)---this is pretty narrow and the ‘anti-VEGF’ MoAB is not identified. Huang/Harari (16.) successfully used C225 (Cetuximab) as an anti-VEGF MoAB and found that it enhanced radiosensitivity by inhibiting VEGF. This agent is active in several on-going trials. Melnyk et al (17.) state that tumor growth is dependent on new blood vessel formation and inhibition of VEGF alone with unidentified anti-VEGF antibodies prevented mitosis (cell reproduction) and dissemination in mice. Gately S (18.) reports that the contributions of COX-2 in tumor angiogenesis include increased expression of VEGF, stimulation of endothelial cell migration, and the inhibition of endothelial apoptosis (death) by stimulating Bcl-2; pharmacological inhibitors of COX-2 can have therapeutic value---thus, Viiox and Celebrex seem to be the only agents that have current efficacy to inhibit VEGF.

NOTE : I am not a doctor and cannot render medical advice. I am not a medical researcher. I am a prostate cancer patient and I performed this layman’s analysis for my own decision-making purposes. I make no claim that this analysis is definitive or complete. In conjunction with a medical team, every cancer patient must make their own decision regarding treatment options. I invite any and all contributions/critiques that will improve this layman’s analysis.

(1.) Langer et al. Expression of VEGF and VEGF receptors in human neuroblastomas; Med Pediatr Oncol 2000 Jun;34(6):386-393.

(6.) Gridley et al. Enhancement of prostate cancer xenograph growth with whole-body radiation and vascular endothelial growth factor; Anticancer Res 1997 Mar;17(2A):923-928.