New Hope in Kidney Cancer Treatment

AUTHOR'S NOTES: This article was published in The Big C Magazine.

* * * * * * * * *

NEW HOPE IN KIDNEY CANCER TREATMENT

While there has been a growing awareness among Filipinos of cancers of the breast, cervix, prostate and colon thanks to extensive media coverage, little interest has been generated with regards to kidney cancer. This is unfortunate because kidney cancer poses a major threat to health. It is quite difficult to determine the number of new cases that are diagnosed in the Philippines each year. Needless to say, a significant number of people suffer from kidney tumors. Majority of these diagnosed cases (85%) are renal cell carcinoma (RCC), with pelvic urothelial tumors as the remaining 15%.

Risk Factors

According to Dr. Jose Vicente "JV" Prodigalidad, Head of the Section of Laparoscopic Urology, Dept. of Urology of the National Kidney and Transplant Institute (NKTI), there are a number of factors that puts an individual at risk of developing kidney cancer.
"Genetics plays a very big role," says Dr. Prodigalidad. "Another risk factor is gender – men are more at risk of developing RCC than women by twice as much. Other acquired risk factors are smoking, obesity, a sedentary lifestyle, and exposure to chemicals such as asbestos.

Warning Signs

Most early cases of RCC are asymptomatic. A commonly encountered warning sign, if present, is blood on urinalysis (microscopic hematuria) or visible in the urine itself (gross hematuria). Both would warrant further investigation with ultrasound or contrast studies such as a KUB-IVP or CT scan with IV contrast. Occasionally, pain may be felt in the right flank. For larger tumors, a flank mass may be palpable.

In some cases, RCC is an incidental finding on CT scan when a patient is being examined for another condition or when having an executive check-up.

"CT scan with IV contrast remains the best diagnostic procedure for determining whether a patient has a renal mass or not," notes Dr. Prodigalidad.

Staging of Kidney Cancer

In his clinical practice, most of Dr. Prodigalidad's patients were diagnosed at Stage I. "This means the lesion is 7 cm or less. It was originally set at 4 cm, but researchers have decided to increase it to 7 cm because even a tumor of that size, when taken out completely, is good for cure."

The stages of kidney cancer are as follows…

• Stage I = tumor is 7 cm or less and localized within the kidney; 80% survival rate
  
• Stage II = tumor is no longer localized within the kidney and has extended to the fat around the kidney but within the fascia (known as the Gerota's fascia); 60% survival rate.
  
• Stage III = there is involvement of the vessels and lymph nodes in the area; 35-40% survival rate.
  
• Stage IV = there is metastasis to the adjacent organs, intestines, liver or lungs; 10% survival rate.
  

Treatment of Stage I-III Kidney Cancer

At present, the real cure for kidney cancer is total or radical nephrectomy, which involves the removal of the entire kidney together with its capsule. Radical nephrectomy can be performed as an open surgery or by laparoscopy.

Says Dr. Prodigalidad, "Most urologists are more comfortable doing open radical nephrectomy because it allows for better visualization of the tumor and blood vessels, especially in Stage III cancers. With laparoscopic radical nephrectomy, the success rate is the same as open surgery if done by a trained surgeon. There is less blood loss and the recuperation rates are faster. In centers abroad, lap nephrectomy is slowly becoming the treatment of choice for Stage I and II tumors.

Another procedure is partial nephrectomy (the removal of the affected part of the kidney). However, this procedure is done when there is a risk of rendering the patient anephric, such as in patients with only one functioning kidney and in those who have tumors in both kidneys.

"You can only do partial nephrectomy if the tumors are small, they are located in the upper or lower poles, or are exophytic (the mass is projecting outward)," Dr. Prodigalidad points out. "If the tumor occupies more than one-half of the kidney, preservation of the vascular supply will be difficult. Without the blood supply, the rest of the kidney will die. Better go for total nephrectomy and leave partial nephrectomy to selected cases."

Treatment for Stage IV Kidney Cancer

Unlike other forms of cancer wherein surgery is not done in Stage IV disease, for kidney cancer, radical nephrectomy has two goals – 1) palliative and 2) reduction of tumor bulk.
Palliative nephrectomy entails removal of the tumor itself to help relieve pain as the tumor enlarges because it stretches the renal capsule, and to prevent significant bleeding.
Reduction of the tumor bulk, on the other hand, would make it easier for other palliative measures, such as radiotherapy and the use of biologic therapies (like interferon and interleukin-2), to work.

Drug Treatment For Kidney Cancer

According to Dr. Prodigalidad, "Kidney cancer is not really responsive to chemotherapy and radiotherapy that's why we call them 'chemo- and radio-resistant'."
Still, researchers have not given up hope in finding that 'magic pill' that could aid in treating patients in the advanced stages of the disease. One form of treatment being explored is biologic therapy, most notable of which is cytokine treatment.

In an interview conducted by Big C's Marian Martin-Layug with visiting Korean kidney specialist Dr. Yoon Koo Kang last October 13, it was explained that cytokine treatment, which involves the use of Interferon Alpha and Interleukin-2, act upon the immune system by promoting better communication between the cells so that they could act promptly against the cancer.

However, there is a drawback to using cytokines in renal cell carcinoma. "Cytokine treatment was not effective for the treatment of renal cell carcinoma, especially if it is metastatic," explains Dr. Kang. "Both Interferon Alpha and Interleukin-2 are very, very toxic. They are not used in all stages."

Dr. Kang also emphasized that cytokine treatment is not a standard of treatment for renal cell carcinoma. "These treatments are not effective enough so they are not standard. When you say that a treatment is 'standard', it means that these drugs are better given to the patient than letting them have no treatment at all. However, in the case of cytokine treatment, they are not effective enough to show the benefits.

There is current interest in two new drugs that have recently approved by the U.S. Food And Drug Administration. Called targeted therapies, these drugs are Bayer's Nexavar (sorafenib) and Pfizer's Sutent (sunitinib).

According to Dr. Kang, Nexavar acts as an inhibitor of the receptors of tyrosine kinases that promote tumor cell proliferation and angiogenesis (or the formation of blood vessels that feed blood to the tumor). "Nexavar has a dual effect on the tumor cell by targeting these two pathways. First one is the direct effect through the interruption of the signal transduction pathway that increases proliferation of tumor cells. The other effect is the inhibition of angiogenesis."

Sutent, on the other hand, roughly has the same mechanism of action as Nexavar, but it targets different signal pathways that promote tumor cell proliferation and angiogenesis.
Both Nexavar and Sutent can be given to patients in all stages of renal cell carcinoma. "Tumor reduction is difficult to achieve so we call these kinds of agents as cytostatic agents, not cytocidal agents, which are common in conventional chemotherapy," explains Dr. Kang. "Usually these drugs rarely reduce the cancer cells so an objective response is 30 percent size reduction (or what is termed as 'partial response'). In less than ten percent of patients, the partial response was achieved with Nexavar, with 70 percent of patients achieving a stable state, meaning that there is no increase in the tumor size. Around 84 percent of patients achieved either disease stabilization or reduction of tumor size. That activity translated into survival of two months."

Dr. Kang mentioned that other forms of treatment are being explored. "One interesting strategy is to combine the targeted agents together. At present, a clinical trial involving a combination therapy of Nexavar and Roche's Avastin, which is a monoclonal antibody, is in its fourth phase. How does this work? In the blood vessel, there are endothelial cells, which contain receptors, the most notable of which is the vascular endothelial growth factor (VEGF). Both Nexavar and Avastin act on VEGF producing a synergistic effect that prevents tumor cell proliferation."
Dr. Prodigalidad, however, pointed out that only a handful of urologists in the country would use these drugs in treating kidney cancer, most preferring the surgical approach, which remains the standard of treatment for this dreaded disease. "The prognoses for those patients who receive these kinds of therapy are not very good. It was depressing to see the side effects."

Vaccine Therapy for Kidney Cancer

There are a number of new treatments for kidney cancer that are being developed, including cryotherapy (a procedure that involves freezing the tumor) and High
Intensity Focused Ultrasound or HIFU. The treatment, however, that is showing promise for advanced kidney cancer is vaccine therapy.

Dr. Dante P. Dator, Chairman of the Dept. of Urology of the NKTI, explains, "When you say 'vaccination', there is no such thing as a vaccine that is universally accepted at the moment for cancer in general, and kidney cancer in particular, because what is being developed are specific 'vaccines' targeted against specific types of cancer. It is still in the experimental stage and work is in progress on at least two dozen malignancies, majority of them concentrated on malignant melanoma, multiple myeloma, colorectal carcinoma, prostate cancer and renal cell carcinoma (hence the interest of us urologists). In fact, the trials in the U.S. are now in Phase III. At the NKTI and Asian Hospital, we are in Phase I/II, which means that we are testing the safety and secondarily the efficacy of the vaccine."

Generally, tumor vaccines follow a simple principle as the vaccines that are being given to combat viral infections in children. "These tumor vaccines educates the body's immune system so that the body will recognize the cancer cells as 'non-self'," Dr. Dator further explains. "The cancer in principle is supposed to be foreign to us, but we do not recognize them as such, and therefore it proliferates, multiplies and can spread all over. The main issue is how do we get these cancer cells to be recognized by our immune system such that they will be destroyed by our body's natural defenses the same way they reject transplants and destroy viruses and bacteria."

There are two ways in which a tumor vaccine is created and administered. As Dr. Dator explains, "First of all, we make use of dendritic cells, the body’s scavenger or antigen presenting cell which is harvested by leukapharesis from the patient himself. These are then cultured, propagated and allowed to mature in the lab until sufficient numbers are attained. They are then exposed to the tumor antigens, which they readily capture and process and deliver to the lymph nodes where the cytotoxic arm of the immune system is activated and now educate these cells to act upon any part of the body containing these antigens. One method is to 'injure' the tumor to produce an environment of damaged and dying cells where the antigens are now 'exposed'. Cryotherapy using very low temperature (-40 degrees) lyses the tumor and the dendritic cells are injected intratumorally. The other method is to create a hybrid of autologous tumor cells, previously harvested and cultured and fused with dendritic cells and subsequently injected as a vaccine. These dendritic cells then activate the killer T-lymphocytes and other immune cells into attacking the tumor and any part of the body containing the tumor antigens.

The tumor vaccine was initially tested in a patient with malignant pheochromocytoma in 2003. As of this writing, dendritic cell vaccine therapy has been administered in patients with prostate cancer, kidney cancer, breast cancer, colonic carcinoma and malignant melanoma.

The initial results are promising. Some patients have demonstrated tumor regression while others have slowed down progression of disease. Of course, there are disappointments and much of the focus of worldwide research is to identify the patients who will best benefit from these treatment. Unlike chemotherapeutic agents, the only adverse effects noted with vaccine therapy are the same as regular vaccines, namely fever, fatigue and the flu-like syndrome.
According to Dr. Dator, "Immunotherapy is essentially non-toxic and it can be added to other treatments and repeated time and again. The results in animals and humans are promising and it may become the only way to control cancer if it has spread to other sites. It is still in its developmental stage but it should be remembered that any beneficial effect that prolongs or improves quality of life, whether achieved by the vaccine alone or in association with other treatments, would be welcomed by patients suffering from cancer."

Kidney Cancer Prevention

The three keys to kidney cancer prevention are the reduction of one's risks of acquiring the disease, knowledge of one's family history, and early detection.

Says Dr. Prodigalidad, "Since kidney cancer has a genetic predisposition, every Filipino must strive to know their family health history and be aware of the different cancers that are present in the family. If you know that you have that risk, then you would be more vigilant with your health habits. Don't smoke. If you are smoking, stop now. Keep yourself physically fit. Don't be a couch potato; be active. Of course, eat healthy. If there is a risk of kidney cancer in your family, have a regular urinalysis done. It is very important to try and catch the cancer early. Most cancers, if detected early enough, can be cured."