Treating Oligometastatic Disease in Prostate Cancer

Treating Oligometastatic Disease in Prostate Cancer

Few guidelines exist for treating oligometastatic prostate cancer (OPC), with little consensus even on the criteria that define the disease. Yet consideration of clinical trial data and anecdotal patient information can help oncologists weigh available treatment options, including the potential use of ablative techniques like surgery and stereotactic ablative radiation therapy, to either help delay disease progression or avoid hormone therapy for patients with OPC, according to speakers at an Education Session on Friday, June 3.

Biologic theories of prostate cancer metastases have evolved but presently a multidisciplinary perspective suggests OPC involves a limited number of metastases that develop early from monoclonal expansion that can seed other sites over time, said Session Chair Neha Vapiwala, MD, of the University of Pennsylvania. “This offers both an attractive target and a potential window of time.”

The session, “Oligometastatic Disease in Prostate Cancer: Treating the Patient or the Scan?,” featured discussions of the definition of OPC and effective management strategies, if and when surgery may be a useful treatment, and if radiation therapy has a role in ablation therapy for OPC.

Dr. Christopher Sweeney

A Metastatic, Hormone-Sensitive State

“There is no harmonized definition of OPC, nor good data to quantify its frequency,” said Christopher Sweeney, MBBS, of Dana-Farber Cancer Institute. “It presents either as de novo metastatic disease or as relapsed after local therapy, but there is an increasing appreciation that it should be considered a unique entity.” During prostate cancer disease progression, OPC presents early as a hormone-sensitive state with rising prostate-specific antigen (PSA) levels and low burden of metastatic disease. Dr. Sweeney suggested that approximately 9,000 patients present with de novo metastatic OPC each year in the United States.

Clinical trial groups have different definitions of OPC based on conventional imaging CT and bone scan to define subgroups. All agree that OPC lacks visceral disease and involves nodal disease. A general consensus also includes the presence of three or fewer vertebral or pelvic bone metastases. “In all of the phase III studies, OPC patients with a low tumor burden treated only with androgen deprivation therapy [ADT], have a median overall survival [OS] of about 7 years,” Dr. Sweeney explained. OS is reduced to approximately 3 years in metastatic prostate cancer with a higher tumor burden.

As new imaging modalities emerge, such as prostate-specific membrane antigen (PSMA)-based PET and gallium scanning, choline PET imaging, whole-body MRI, and sodium fluoride PET, studies will reveal micrometastatic lesions that were invisible to conventional imaging. Dr. Sweeney explained that the patient with micrometastatic diseases is possibly cured with early androgen inhibition.

A definitive treatment strategy for OPC remains uncertain, ranging from ADT alone to comprehensive therapy with ADT, systemic chemotherapy, and ablative techniques. After presenting several case studies, Dr. Sweeney suggested that “we can do better than just ADT alone” by adding radiation therapy to ADT. He concluded by offering his preference to use ablative local therapy to all disease plus ADT for 2 years, stopping if PSA levels are higher than 0.2, and then assessing degree of control.

Surgery Appropriate for Low-Volume Nodal Disease

Traditional thought has been that radical prostatectomy (RP) is historically reserved for low-stage/low-risk disease, explained R. Jeffrey Karnes, MD, of Mayo Clinic. But does it benefit men with metastatic disease? “Metastasis can lead to further metastasis and does not always have to come from the primary,” he said of the importance of treating both the primary tumor and the metastasis.

Dr. R. Jeffrey Karnes

Referencing several studies, Dr. Karnes showed that RP in addition to hormone therapy improves OS at 10 years to 65%, compared with 30% for hormone therapy alone. “This is fairly suggestive, favoring treating the primary even in the face of positive pelvic nodes, which are usually occult micrometastatic nodes,” he said. Another study showed that surgery can cure low-volume metastasis with favorable characteristics such as a Gleason score (GS) of 7, negative margins, and two or fewer positive nodes.

Approximately one-third of patients who have already undergone RP will have a biochemical recurrence. For these patients, salvage lymph node dissection (sLND) has been shown to delay further progression/recurrence and postpone hormone therapy. “This is what drives our men to seek other therapies,” says Dr. Karnes. “They want to avoid hormone therapy, usually at all costs.” Optimal candidates for sLND are those with PSA lower than 4, pelvic lesion(s), GS of 7 and T2 on RP, and non–castration-resistant prostate cancer.

“Patients are looking to us for alternatives to hormone therapy,” said Dr. Karnes. “Surgery in the local metastatic prostate cancer state does make sense, especially for nodal disease, often as a part of a multimodal therapy package.”

Radiation Therapy for Metastatic Prostate Lesions

Similar to Dr. Karnes’ recommendation for surgery in some patients with OPC, Dr. Vapiwala outlined suggestions for appropriate local radiation therapy (RT) of metastatic lesions in this population.

She noted that stereotactic ablative radiotherapy (SABR or SBRT) offers multiple advantages over standard conventional radiotherapy (1.8 to 2.0 Gy/day). She presented findings showing that high-dose SABR (over 21 Gy as a single dose or over 8 Gy per fraction) provide approximately 90% control of the local radiated metastatic site.

“We have come a long way in our techniques and capabilities in radiation therapy,” said Dr. Vapiwala. High precision and conformity to target are critical given the extreme dose gradient between the target lesion and organs at risk. She credits the availability of advanced imaging technologies, such as MRI for the spinal cord and choline-PET/CT for nodal metastases that provide real-time, image-guidance capabilities, together with precise stereotactic SABR tools, and improved immobilization techniques, for improving the safety and efficacy of SABR in the OPC population.

Dr. Vapiwala suggested radiation therapy may be an appropriate strategy for OPC in the presence of limited quantities and locations of metastases, after a largely effective systemic treatment to eradicate residual deposits, or with one or more distant metastases in one or more organs that are amenable to local treatment.

She cited better prostate cancer–specific survival in patients who received primary curative treatment who have a longer time from primary treatment to presentation of OPC. Other positive criteria are node or axial skeletal involvement and a lower number of metastases (recurrent disease with five or fewer metastases in bone, especially the spine.) “Perhaps this is the population in whom we should focus our efforts,” she said.

However, unlike in oligometastatic colorectal and lung cancers, the current guidelines for OPC do not include ablative radiation therapy, which is limited to a purely palliative role at best. “However, I believe there will hopefully be techniques that will allow us to identify subsets of these patients with oligometastatic disease that are appropriate for high-dose ablative radiation therapy in a way that can alter prognosis, not just palliate symptoms,” said Dr. Vapiwali. She cited studies supporting the idea that RT may be used to delay progression as well as to delay the onset of ADT.

To date, approximately 140 ongoing clinical trials are exploring the role of ablative RT in different locations. Of those, 53 are focused on oligometastatic disease. As the results from these and other prospective trials become available, Dr. Vapiwali believes the role of ablative local RT will become clearer. Until then, the most popular dose range for most of the completed SABR studies is one 20-Gy treatment or three 10-Gy doses.

“We know that ADT delays clinical progression and can prolong survival in asymptomatic patients with prostate cancer,” said Dr. Vapiwali. “And we know radiation is an excellent collaborator and works well with ADT.” But the question remains: How can radiation therapy be better incorporated?

—Alice McCarthy