Background : Treatments : Radiation Therapy : Surgery

BACKGROUND

Brain metastases, unfortunately are very common and grave condition in the natural history of patients with cancer. It is estimated that approximately 250,000 patients with cancer will develop brain metastasis in the United States each years. Autopsy data have shown that up to 50% of patients who die with cancer have evidence of spread to the central nervous system, with approximately 40% of these patients having a solitary or single metastasis . (Solitary means that this metastasis is the only evidence of cancer in the whole body, whereas single means that there are other deposits of cancer outside the brain).

·        Tumors more prone to brain dissemination are: Lung, breast, melanoma, renal cell carcinoma, colorectal, sarcoma.

·        The temporal pattern of presentation is of interest:

1.      Preccocious (occult primary). Some authors state that up to one-third of patients who present with brain metastasis do not have previous cancer history, and in 16-35% of these patients a systemic cancer is never found

2.      Synchronous

3.      Metachronous (81%) Usually tertiary event: Short intervals (Lung, melanoma, renal CC). Long intervals (Breast, Colon, Sarcomas)

STAGING

Clinical Presentation: (the percentages vary largely with the published series)

Headaches 53%, usually caused by edema, CSF (Cerebral spinal fluid) flow compromise, traction of pain sensitive obstruction like sinuses, duramatter, blood vessels, or cranial nerves. These headaches are typically worse in the morning, and increase progressively in duration and intensity.

Focal weakness (40%), mental disturbance (31%), gait disorder (20%) visual problems (12%)

TREATMENT OPTIONS

OBSERVATION: Data from the early 1970s showed that with observation alone the median survival for patients with multiple metastases was four weeks, with the cause of death being uncontrollable edema. If patients were treated symptomatically with steroids alone, the median survival was doubled to eight weeks.

CHEMOTHERAPY: in general, it can be said that chemotherapy treatment does not work. Only few agents cross the BBB (VP16, VM26, Vinblastine). The biodistribution CSF-tumor is highly variable, as well as the intra-metastatic drug concentration. In 81% of the cases, brain metastasis are metachronous, often after chemotherapy, which probably represents a widespread drug-resistant systemic relapse

WHOLE BRAIN RADIATION THERAPY

Over the past several decades, whole brain external beam radiotherapy (WBXRT) has become the treatment of choice for patients with metastatic brain disease. From 1971 to 1976, the Radiation Therapy Oncology Group (RTOG) conducted two Phase III prospective randomized trials, in an attempt to evaluate several treatment schedules. The results were published together, showing an equivalent response to the treatment in all areas, with no differences in duration of improvement or time to progression within the various treatment schedules. The median survival in these studies was 15-18 weeks, with the degree of palliation being the same in the two studies. From those studies, 30 Gy in 10 fractions emerged as the standard treatment for patients with brain metastasis. In a subsequent RTOG study carried out between 1979 and 1983, 30 Gy in 10 fractions was compared in a randomized fashion with the same treatment schedule plus Misonidazole, a hypoxic cell sensitizer. Both were equally effective, with an overall median survival of 3.9 months. In these studies, a group of patients with favorable prognostic factors was identified. More precisely, those with a Karnofsky Performance Status (KPS)>70, primary tumor systemically controlled, and age less than 60 years, with the brain as the only metastatic site, had the best outcome.

Accelerated fractionation and dose escalation have also been evaluated by RTOG in a phase I/II trial for patients with controlled systemic disease. The whole brain received 32 Gy given as 1.6 Gy bid (two fractions a day), with boosts to the area of gross disease from 16 Gy to 22.4 Gy, 32 Gy and 42.2 Gy, at 1.6 Gy per fraction, bid. The median survival was increasingly higher, with no changes in toxicity. The best results were in the 70.4 Gy group (Whole brain 32 Gy, plus 42.4 Gy boost), with a median survival of 6.4 months. Survival was significantly increased in the subgroup of patients with solitary brain metastases treated with a higher dose (6).

The Radiation Therapy Oncology Group (RTOG) has reported the results of a prospective randomized trial testing the potential role of bromodeoxyuridine as a radiosensitizer. Bromodeoxyuridine did not enhance the efficacy of the radiotherapeutic schedule tested (37.5 Gy in 15 fractions of 2.5 Gy), despite the fact that brain metastases have shown high labeling indices.

MORBIDITY OF WHOLE BRAIN IRRADIATION

Acute: erythema in scalp, dry desquamation, hair loss, otitis media, HA, nausea and visual disturbances, due to increased ICP.

Early delayed: Somnolence syndrome (1-4 mo after XRT), due to interference in the metabolic turnover of the myelin.

Long-term effects: The literature of the early and mid-80s is flooded with papers reporting long-term side effects, such as dementia, memory loss, radiation-induced necrosis, leukoencephalopathy, in up to 50% of two year survivors. It is now known that WBXRT below 60 Gy@2 Gy/fx very seldom produces radionecrosis, although there is a strong dependency on the fraction size.

Very few patients survive longer than a year, so in general, long-term effects are not a concern, with the exception of patients with solitary brain metastasis. Because of the relationship between large fraction size and long-term side effects, the so called standard of 30 Gy/10 fractions is being challenged; in modern research protocols that include whole brain irradiation, the recommended treatment is 37.50 Gy in 15 fractions.

SURGERY

Potential indications for surgery (mostly true for solitary brain metastasis):

·        Diagnosis (When we do not have tissue evidence of cancer);

·        Solitary metastasis;

·        Life threatening situations, or metastasis critically located within the brain;.

·        Recurrent or persistent symptoms after non-surgical treatment;

·        Treatment of complications (infection, bleeding);

·        Placement of chemotherapy or isotope delivery devices (Ommaya).

COMBINATION OF SURGERY PLUS WBXRT

The potential role of more aggressive approaches such as surgery and WBXRT have been the subject of several prospective randomized trials. The first one, carried out at the University of Kentucky and reported by Patchell, showed that patients who underwent WBXRT and surgical resection of a solitary brain metastasis did better than those who received WBXRT only. In patients treated with both modalities, the median survival was 40 weeks with an actuarial local control at 70 weeks of 57%, compared to 15 weeks and 13%, respectively, for the WBXRT alone area.  More recently, in a Dutch trial reported by Noordjik, 66 patients were randomized to 40 Gy at 2 Gy bid of whole brain irradiation plus or minus surgical debulking . The results from these trials showed that several prognostic factors for increased survival were again identified, such as aggressive treatment, controlled systemic disease and young age. Little over a year ago, in a second trial the University of Kentucky evaluated in a prospective randomized fashion, the role of whole brain radiotherapy in patients with solitary brain metastasis that had been completely resected was studied. The question was to evaluate if whole brain radiotherapy was really necessary. The results of the trial were very interesting because it was seen that even though radiation therapy did not increased survival, it did increase local control. When the data on local control were evaluated closely it was found that the local control offered by radiation was mostly in the tumor bed and its vicinity. This has raised the question of local radiation after surgical resection with three dimensional conformal radiotherapy. 

TREATMENT OF PATIENTS WITH SOLITARY BRAIN METASTASIS OR OLIGOMETASTATIC BRAIN DISEASE (UP TO FOUR METASTASIS): STEREOTACTIC RADIOSURGERY

The most appropriate treatment for patients with solitary brain metastases has been a source of controversy for nearly two decades, and still needs to be defined. Recently, stereotactic radiosurgery, an elegant, sophisticated and non-invasive modality, has provided local intensification of dosage for well-defined intracranial targets with relative sparing of the surrounding normal brain. Stereotactic radiosurgery delivers a high dose of radiation to a relatively small volume of disease, secondary to the sharp dose gradients. Brain metastasis are considered ideal targets for stereotactic radiosurgery since they 1) take up the iodized contrast or the gadolinium so they can be easily identified on contrast enhanced CT or MRI; 2) are almost always spherical in shape, and 3) grow with minimal or no infiltration into the adjacent brain parenchyma. Also, with modern technology, they can be detected earlier, when the volume of the metastatic deposit is still relatively small. This has represented an attractive alternative to surgical resection, and possibly Whole Brain Radiotherapy for patients with oligometastatic brain disease. Stereotactic radiosurgery appears to offer several advantages over surgery, such as the treatment of surgically inaccessible lesions and decreased acute morbidity, as well as the decreased cost of the procedure.

DESCRIPTION OF THE STEREOTACTIC RADIOSURGERY PROCEDURE

Prior to the procedure, informed consent is obtained from all patients. All patients are placed on steroids prior to and following the procedure. On the day of the stereotactic radiosurgery, the Brown-Robert-Wells Stereotactic frame (Radionics. Inc., Burlington. Mass.) Is placed by the neurosurgeon. After frame placement, 5 millimeter thick cuts at 5 millimeter intervals are taken throughout the cranium. After delineation of the tumor volume and administration of Intravenous contrast, 2-3 millemeter cuts at 2-3 millimeter intervals were taken throughout the tumor. These images are transferred to the radiation oncology department via Intranet, with a DICOM-RT format. The tumor volume and treatment plans are performed by the radiation physicist, neurosurgeon and radiation oncologist, using the radiosurgical planning system by Scandiplan (Scanditronix, Ann Arbor, MI). Consideration is given to proximity of critical structures (i.e., brain stem and optic apparatus), previous radiotherapy, size and volume of lesion. At the end of the regularly scheduled treatment day, the linear accelerator is modified to accommodate the base plate and the floor stand. Appropriate quality assurance checks are performed to verify isocentricity and accuracy of set-up prior to beginning treatment. Once all the verifications have been done successfully, the patient is transferred to the treatment suite and placed on the treatment table that has been modified to have the stereotactic frame attached to it. The treatment machine will describe arcs around the patient while delivering a high dose of radiation specifically focused on the tumor. The procedure takes less than 20 minutes. The frame is then removed and the patient can be sent home soon afterward.