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Dr. Ali Al-Bayati

 
Most of the site will reflect the ongoing surgical activity of Prof. Munir Elias MD., PhD. with brief slides and weekly activity. For reference to the academic and theoretical part, you are welcome to visit  neurosurgery.me

 

Metastases to the brain make up more than half of all intracranial tumors and occur in 20 to 40 percent of patients with systemic cancer.  Brain metastases are single in about one-third of cases. The term single brain metastasis is applied to patients with one metastasis in the brain but makes no inference about the presence or absence of cancer elsewhere in the body. The term solitary brain metastasis describes the relatively rare occurrence of a single brain metastasis that is the only known cancer in the body. The occurrence of brain metastasis is usually associated with a poor prognosis regardless of therapy. Untreated patients with brain metastases have a median survival of only about 1 month. Virtually all untreated patients die as a direct result of the brain tumor. With corticosteroid treatment alone, the median survival is increased to approximately 2 months. As is true for untreated patients, most patients treated with corticosteroids alone die as a direct result of the brain metastases.

The Role of Radiotherapy

Whole-brain radiation therapy (WBRT) increases median survival to 3 to 6 months. Large retrospective studies have shown that most patients treated with WBRT ultimately die from progressive systemic cancer and not as a direct result of the brain metastases. However, the WBRT survival data were derived from studies containing large numbers of patients with extensive systemic disease and relatively short expected survivals. In the subgroup of patients whose only metastases are to the brain, death is more likely to be due to the brain metastasis than to progressive systemic disease Therefore, in patients with controlled systemic cancer who develop brain metastases, the treatment of the brain lesion or lesions is the factor that will most likely determine length of survival.
A controversy remains regarding whether postoperative radiotherapy should be given as WBRT (as opposed to focal radiation) or whether radiotherapy is necessary at all after complete resection of a single metastasis. Postoperative WBRT is believed by some to be beneficial for treating residual tumor in the operative site or at other contiguous sites in the brain. However, brain metastases tend to be discrete masses that can be removed totally with high frequency. Although other undetected microscopic metastases may exist elsewhere in the brain, this contention has never been proved either by autopsy analysis or by clinical studies (retrospective or prospective).
From a theoretical standpoint, the combination of surgery followed by postoperative radiotherapy should be more effective at eradicating brain metastases than radiation or surgery alone. For larger tumors, radiotherapy is most effective at the periphery of the tumor, where cells are relatively small in number and well oxygenated. In the center of the tumor, where tumor cells are more numerous and hypoxic conditions usually exist, radiation may fail to completely destroy tumor cells. Although sterilization of brain metastases by radiotherapy alone is documented, in most cases residual tumor remains despite irradiation. Surgery can completely remove all tumor cells; however, residual tumor remains in about one-third of patients, even after "complete" surgical resection. Rational treatment plan's combining surgical debulking and radiotherapy have been developed to overcome the deficiencies of both types of treatment, and combined therapy has shown promise in patients with a variety of tumor types.
Five nonrandomized retrospective studies have compared surgery plus postoperative WBRT to surgery alone in the management of single brain metastases. These retrospective studies do not establish firmly the efficacy of postoperative WBRT in the treatment of single metastases, although they suggest that WBRT may decrease the recurrence rate. Little evidence exists to suggest that any improvement in overall survival times is achieved by the addition of WBRT. Current practice is to use WBRT postoperatively.

The Role of Surgery

Despite the theoretical advantages of combined surgical and radiation treatment, until recently the role of surgery was unclear because of an absence of any prospective randomized trials showing the efficacy of surgical treatment. Many uncontrolled surgical series showed longer survival rates for surgically treated patients than for historical patient controls treated with WBRT alone. Retrospective or nonrandomized uncontrolled studies of patients treated with WBRT (and containing small numbers treated with surgery plus postoperative WBRT) also generally showed increased survival rates for the surgically treated patients. However, neither historical controls nor controls consisting of concurrent unselected patients treated with WBRT alone are appropriate for comparing the efficacy of surgery plus WBRT versus WBRT alone. Patients who receive surgical treatment are usually selected from among patients with controlled or no known systemic disease (and consequently longer expected survivals), whereas patients treated with WBRT alone include patients with more extensive disease and generally much poorer prognoses. Patchell et al. used matched control groups to compare surgery plus WBRT with WBRT alone. Although this study suggested that surgery was effective, the study was retrospective and did not use randomized assignment to treatment groups.
Two randomized prospective studies have been performed to determine the effectiveness of surgery. Patchell et al. randomly assigned patients with single brain metastases to one of two treatment groups: (1) the surgical group had complete surgical removal of the brain metastasis followed by WBRT, and (2) the radiation-alone group had a stereotactic needle biopsy of the brain lesion followed by WBRT. All patients received 3600 cGy WBRT. Fifty-four patients were entered into the study; however, six (11 percent) were found not to have metastatic brain tumors after resection or biopsy. Local recurrence of the brain metastasis was more common in the radiation-alone group, 52 percent versus 20 percent (P < .02). Overall survival was significantly longer (P < .03) in the surgical group (median 40 weeks versus 15 weeks). Quality of life (based on the time that the Karnofsky score remained (70 percent) was also significantly (P < .006) better in the surgical group. The 30-day mortality rates were 4 percent in both the surgical group and the radiation-alone group.

A second randomized study, conducted as a multi-institutional trial in the Netherlands, randomized 63 patients either to complete surgical resection plus WBRT or to WBRT alone. WBRT schedules were the same for both treatment arms, consisting of 4000 cGy given in a nonstandard fractionation scheme of 200 cGy twice per day for 2 weeks (10 treatment days). Survival times were significantly longer for the surgical group (10 months vs. 6 months), and this patient group also demonstrated a nonsignificant trend toward longer duration of functional independence.

The results of these two well-controlled prospective trials clearly show that surgical resection is beneficial for selected patients. Surgical therapy plus postoperative WBRT is now the treatment of choice for patients with surgically accessible single brain metastases.

With any surgical procedure, operative mortality must be weighed against any possible benefit from surgery. In older series of patients with single brain metastases who were treated with surgery, operative mortality rates were in the range of 10 to 34 percent. However, with improvement in surgical technique (particularly the introduction of microsurgery), computer-assisted stereotactic surgery, intraoperative ultrasonography, and the widespread use of steroids, mortality rates in most series reported during the last 10 years have been below 10 percent. Kelly et al. reported no mortality in a series of 45 patients, using computer-assisted stereotactic techniques.  Sundaresan et al. reported a 3 percent mortality.

Standard practice has been to assume that patients with systemic cancer developing an intracranial lesion have a brain metastasis. An interesting finding is the high percentage of patients who proved not to have metastatic brain tumors after surgery or biopsy. All patients had tissue-proven primary tumors diagnosed before their entry into the study. Despite having computed tomography (CT) and magnetic resonance imaging (MRI) findings consistent with single brain metastases, 11 percent of the total (6/54) did not have metastatic tumors. Because of the relatively high rate of misdiagnosis of metastatic lesions with CT scans, even when surgical resection is not recommended, a stereotactic needle biopsy should usually be done to confirm the diagnosis. This practice should especially be followed in patients with controlled systemic cancer whose survival is likely to be dependent on the treatment of the brain lesion. Half of the patients who were proved not to have brain metastases had potentially treatable intracranial infectious or inflammatory processes.

Despite the demonstrated advantage of surgical intervention, however, WBRT alone remains the treatment of choice for most patients with brain metastases. Single metastases occur in approximately one-third of patients. Unfortunately, nearly half of the patients in this group are not candidates for surgery because of the inaccessibility of the tumor, extensive systemic disease, and other factors. At most, only 15 to 20 percent of all patients with brain metastases will benefit from surgical resection. The rest should usually be treated with radiotherapy.

Chemotherapy

Chemotherapy has been used in the treatment of brain metastases from a variety of primary tumors; however, the results have generally been unimpressive, although some small, controlled series of patients with certain highly chemosensitive tumors (breast, small cell lung cancer, and germ cell tumors) have been published. At present, chemotherapy should be used only to treat those metastatic brain tumors that are known to be chemosensitive, such as lymphoma or small cell carcinoma.

Stereotactic Radiosurgery

The development of stereotactic radiosurgery, a method of delivering intense focal irradiation by using a linear accelerator (LINAC) or multiple cobalt-60 sources (gamma knife), has again raised the question of the best treatment for both single- and multiple-metastatic disease. No definitive conclusion can be drawn regarding its efficacy in the treatment of brain metastases. Several uncontrolled series of highly preselected patients have been published. These studies suggest that the local control rate for radiosurgery in the treatment of single metastases may be similar to that achieved by conventional surgery. The combined results of several reports indicate that radiosurgery locally controls the growth of 80 to 90 percent of cerebral metastases with a low risk of radiation necrosis or new neurological deficits. At this time, the proven conventional therapy for single metastasis is still surgical excision followed by WBRT. The early reports of series using radiosurgery indicate that this may be an acceptable method of treatment for both surgically accessible and inaccessible lesions. To date, however, no well-controlled randomized trial has been reported comparing radiosurgery with conventional surgery for the treatment of cerebral metastases.

Surgical Indications

The best results with surgery are seen in those patients with a single surgically accessible lesion and either no remaining systemic disease (true solitary metastasis) or with controlled systemic cancer limited to the primary site only. A study from the Memorial Sloan-Kettering Cancer Center suggested that survival rates are significantly increased for patients undergoing resection of brain metastases from non-small cell lung carcinoma if the primary lung disease is also resected completely. No correlation was demonstrated between survival rates and initial cancer stage per se. Also, surgical treatment may be indicated for those patients without known systemic cancer (to obtain a tissue diagnosis) and for patients for whom death is imminent because of the effects of pressure on the brain stem.

Because the median time that Karnofsky scores remain 70 percent is about 2 months in patients treated with WBRT alone, patients with life expectancies less than that receive adequate palliation from radiation alone and are unlikely to gain any benefit from surgery.

Patients with metastasis from systemic lesions that are highly radiosensitive, such as lymphoma, germ cell tumors, or leukaemia, should have WBRT as the primary treatment. However, even those patients with very radiosensitive cancers with a single brain lesion should be offered diagnostic stereotactic biopsy before treatment of the brain lesion. Between 5 and 10 percent of brain lesions in patients with known systemic cancer are not metastases, so tissue confirmation of cerebral metastasis is necessary for accurate treatment planning.

Surgical Treatment

The microsurgical removal of a cerebral metastasis is performed following the same general techniques of craniotomy and microsurgery that are used for the removal of other intracranial lesions. However, in planning the surgical procedure, two features of a cerebral metastasis must be anticipated: (1) the propensity of a cerebral metastasis to cause substantial cerebral oedema, and (2) the small size of many metastatic lesions at the time of surgical resection. Administering corticosteroids preoperatively for at least 48 h to patients with considerable mass effect will help prevent transdural herniation at the time of tumor exposure. However, preparatory steroid administration can also cause the overlying cortical surface to appear normal and can make the safe localization of a small tumor even more difficult.

Metastatic lesions are often removed when they are quite small because the extensive cerebral oedema associated with the lesion rather than the lesion per se has caused early neurologic symptoms. Likewise, asymptomatic tumors discovered as part of the survey evaluation of patients with a newly discovered systemic cancer may be very small. These small lesions, if not superficial, may be quite difficult to locate under a normal-appearing cortical surface. Computer-assisted stereotactic techniques are very helpful to place the bone flap precisely over the tumor. Because most of the patients will receive postoperative radiotherapy, a linear scalp incision is preferred to decrease the chance of complications caused by poor wound healing. To lessen the possibility of a postoperative deficit, stereotactic or intraoperative ultrasound techniques should be used to locate small subcortical tumors precisely before making any cortical incision. Intraoperative ultrasound or direct localization of the lesion with the stereotactic probe or needle should be used during exposure of the lesion through a small cortical incision; these techniques provide a direct route to the tumor and a means of avoiding eloquent areas of the brain. These measures prevent the prolonged exploration for an elusive small lesion, which is the major cause of postoperative neurological deficits. Meticulous haemostasis is critical for preserving visualization in the plane of demarcation between tumor and compressed or oedematous normal brain. Self-retaining brain retractors should be used to minimize the manipulation of tissues necessary for exposing the tumor.

Microsurgical, laser, and ultrasonic aspiration techniques are invaluable adjuncts to localizing devices for the safe removal of small metastatic lesions that are deep-seated or adjacent to elo­quent areas of the brain. Complication rates of less than 5 percent are reported in recent series. Very small lesions « 1 cm in diameter) are better localized stereotactically than with ultrasound. Subcortical tumors should be approached by a dissection plane through the sulcus. An approach through the sylvian fissure is often preferred for tumors deep and medial to the middle cerebral artery. Only the most superficial tumors should be removed through an opening in the gyrus. When the lesion is in the speech area, consideration should be given to performing the surgery with the patient awake, using cortical mapping and cortical stimulation to identify speech and motor areas. If the decision is made to remove a deeply located lesion, stereotactic localization and careful planning of the surgical approach are essential. For deep midline lesions, a computer-assisted system is helpful in planning trajectory so as to avoid important vascular and neural structures.

Every effort should be made to excise the lesion completely, because complete removal seems to be related to both the length and the quality of postoperative survival. Metastatic lesions are usually very well circumscribed; in most cases, therefore, complete excision should be achievable. Some series report that complete excision is obtained in only about two-thirds of cases. Other series show that complete excision is possible in almost 100 percent of cases, as judged by early postoperative CT scanning or MRI. If there is any question of residual metastatic tumor at the end of the resection, a frozen section analysis of the tumor bed should be performed so that an intraoperative decision can be made about the completeness of the resection. Complete resection with tumor-free margins should be attempted rigorously by using the above-mentioned techniques, including microscopic visualization of the tumor bed. However, recurrences will occasionally result even when intraoperative tumor margin biopsies are negative and postoperative CT scanning or MRI shows no residual tumor.

Recurrent Metastases

Complete tumor resection is accomplished in about two-thirds of cases. In one randomized study,49 contrast CT scans done 1 to 5 days postoperatively showed removal in all cases. However, late local recurrence appeared in 20 percent of these patients. The potential for late local recurrence is the basis for administering radiotherapy after surgical resection. Kelly et al reported no local recurrences in their series of 44 patients using very sophisticated computer-assisted stereotactic resection techniques. They pointed out, however, that the postoperative radiotherapy that most of their patients received may have contributed to their excellent results. On the basis of currently available data, postoperative radiation should be administered even after apparently "complete" surgical resection.

Commonly, patients with recurrences have already been treated with radiotherapy to the brain, which limits the amount of subsequent radiation that can be given safely. Several uncontrolled studies have found no meaningful increase in survival or control of neurological symptoms in patients who underwent further radiotherapy after the recurrence of brain metastases. Conventional surgery for recurrent tumors is an option for patients who have a single recurrence and controlled systemic disease. Sundaresan et al. reported a series of 21 patients who were treated with craniotomy for the initial brain lesion and who underwent a second craniotomy for recurrence. After the second operation, two-thirds of the patients experienced neurological improvement, and the median survival time after operation for the recurrence was 9 months. If the lesion is presumed to be radioresistant (such as a metastasis of kidney, melanoma, or lung origin), and the recurrent lesion remains a single metastasis, repeat surgical resection is the best option when the patient's Karnofsky rating is > 60 percent and the systemic disease is controlled. The efficacy of interstitial brachytherapy in this circumstance is being determined in clinical trials.

Stereotactic radiosurgery has been used to treat recurrent brain metastases. Radiosurgery has the theoretical advantage of being able to deliver large doses of additional radiation to small areas of the brain, Further studies are needed to determine the true value of stereotactic radiosurgery in the management of recurrent brain metastases.

Multiple Lesions

The value of surgery in the management of multiple metastases remains to be demonstrated. Two published retrospective studies reached opposite conclusions regarding the safety and efficacy of surgical removal of more than one brain metastasis. Bindal et al. compared patients with multiple metastases who underwent resection of all of their brain metastases to patients with multiple metastases who underwent resection of some but not all of their brain tumors. A further comparison was made with patients with single metastases who were treated with complete resection plus WBRT. The authors found that the group with completely resected multiple metastases did relatively well (median survival 14 months); their survival rates were similar to those of the group treated by resection of a single metastasis (median survival 15 months). The patients who did not undergo excision of all of their brain tumors did less well (median survival 6 months). Hazuka et al. reported a retrospective surgical series containing 18 patients with multiple metastases and 28 patients with single metastases. The group with multiple metastases had a median survival of 5 months; those with single metastases had a median survival of 12 months.

Current standard practice is to treat multiple metastases with WBRT alone. It is logical to operate on patients with multiple metastases who have one life-threatening brain lesion. The intent of surgery in these cases is to remove the single life-threatening lesion without removing the other lesions. Additionally, resect a lesion too large to be treated with radiosurgery (diameter> 3.5 cm) when other lesions can be treated by radiosurgery.


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