Brain and lung cancer

When a metastatic brain tumor is diagnosed, it means that cancer cells from another organ have spread to the brain.

Metastatic tumors are the most common type of brain cancer today—about 10 times more common than cancers that originate within the brain (such as gliomas or meningiomas). The prevalence of brain metastases is increasing because cancer treatment has advanced considerably; instead of living just months after cancer diagnosis, many people live years with the disease, or their cancers go into remission. An estimated 200,000 new cases of brain metastases are now diagnosed in the U.S. every year.

Just a decade ago, finding a brain metastasis meant a person’s average life expectancy was no more than six months, making aggressive treatment not worthwhile. That’s no longer the case. With longer survival rates, neurosurgery is increasingly used to treat brain metastases.

Our dedicated team of oncologists and neurosurgeons focus specifically on the management of brain metastases. At Yale Medicine our world-renowned experts use state-of-the-art equipment to provide patients the best possible multidisciplinary care.

Contents

Brain Metastases in Small Cell Lung Cancer

ABSTRACT: Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate earlier in the course of its natural history than non-small cell lung cancer and is clinically more aggressive. Approximately 10% of patients present with brain metastases at the time of initial diagnosis, and an additional 40% to 50% will develop brain metastases some time during the course of their disease. The prognosis of patients with brain metastases from SCLC is poor despite years of research. The standard of care remains appropriate medical management followed by whole brain radiation therapy. Current research is evaluating novel agents in an attempt to improve the survival and quality of life in these patients. However, the most effective treatment for brain metastases from SCLC is the prevention of the development of clinically detectable disease. For patients with a complete response to initial treatment, prophylactic cranial irradiation is an effective method of prevention.

Approximately 173,770 new cases of lung cancer will be diagnosed in the United States in 2004 with an estimated 160,440 deaths. Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate earlier in the course of its natural history than non-small cell lung cancer (NSCLC) and is clinically more aggressive.

Patients with SCLC are classified as having either limited- or extensive-stage disease according to the system developed by the Veteran’s Administration Lung Cancer Study Group. Patients with tumors that can easily be encompassed within an acceptable radiation portal (historically defined as a hemithorax) are classified as having limited disease, and they represent approximately one-third of all new SCLC cases. In contrast, two-thirds of patients with SCLC present with extensive-stage disease, with frank distant sites of involvement that cannot be incorporated into a safe and tolerable radiation portal. In that regard, metastases from SCLC have a particular predilection for the brain. Approximately 10% of patients present with brain metastases at the time of initial diagnosis, and an additional 40% to 50% will develop brain metastases some time during the course of their disease.

The purpose of this paper is to provide an overview of the clinical presentation, diagnosis, and treatment of brain metastases in patients with SCLC, with a focus on current trends and developments in the treatment of this disease.

Clinical Presentation

Brain metastases most frequently arise at the junction between the white and grey matter, or the so called “watershed area” of the brain. The signs and symptoms are not specific to the disease but rather reflect the location and number of metastatic lesions. Moreover, the severity of these symptoms may be a function of the degree of tumor-related vasogenic edema. The most common signs and symptoms include headache, focal weakness, mental disturbances, gait ataxia, seizures, speech difficulty, visual disturbance, sensory disturbance, and limb ataxia.

Diagnosis

The diagnosis of brain metastases is based on patient history, neurologic examination, and diagnostic imaging. Imaging of the brain is very important in patients with SCLC who are suspected of having brain metastases, because these patients often have metabolic abnormalities or paraneoplastic syndromes that can produce symptoms that mimic those caused by intracranial metastases.

In fact, SCLC is the most common histologic type of cancer associated with neurologic paraneoplastic syndromes. These syndromes are thought to be related to an autoimmune process in which the tumor produces substances that are similar to those normally expressed by the nervous system. These substances lead to the production of autoantibodies that crossreact with neuronal antigens and ultimately damage normal tissue. One such disorder, Eaton-Lambert myasthenic syndrome, is seen in up to 3% of patients with SCLC and causes proximal muscle weakness, autonomic dysfunction, and paresthesias. Other neurologic syndromes seen in patients with SCLC include sensory neuropathies and paraneoplastic cerebellar degeneration.

The most helpful imaging study is gadolinium-enhanced magnetic resonance imaging (MRI). When brain metastases from SCLC develop, they usually occur at multiple sites and tend to be located in the posterior cranial fossa. The posterior fossa is better visualized on MRI, which can also detect small lesions not seen on a computed tomography (CT) scan. Magnetic resonance imaging can also help identify leptomeningeal involvement-an uncommon finding in patients with SCLC. In addition to establishing a diagnosis, MRI can also be used in treatment planning and as a baseline for gauging response to treatment.

Prognostic Factors

TABLE 1
Classification of Brain Metastases

Although patients with brain metastases have a poor prognosis overall, certain factors have been identified that are predictive for an improved outcome. Gaspar et al performed a recursive partitioning analysis of 18 pretreatment characteristics and three treatment-related variables in three consecutive Radiation Therapy Oncology Group (RTOG) brain metastases trials conducted between 1979 and 1993. The analysis included 1,200 patients, over 50% of whom had NSCLC. Only 51 patients included in this analysis had brain metastases from SCLC. The small number of patients with SCLC did not allow for this histology to be evaluated separately from other primaries. Based on this analysis, age, performance status, control of the primary tumor, and the presence or absence of extracranial metastatic disease were found to significantly influence survival. These factors were grouped into three prognostic classes (Table 1).

Treatment

Initial Management

Brain metastases require prompt intervention to minimize progressive neurologic injury. The aim of initial management is to control increased intracranial pressure if it is present. This can be accomplished with the use of corticosteroids such as dexamethasone, which decreases the brain-to-tumor capillary permeability, thereby reducing edema of the brain. Patients are typically prescribed dexamethasone (8 to 16 mg) divided into two to four daily doses. Antiepileptic medications such as phenytoin are not used routinely in this setting unless the patient presents with seizures.

Radiation

TABLE 2
Median Survival of Patients After the Development of Brain Metastases From Small Cell Lung Cancer

• External Beam Radiation Therapy—Small cell lung cancer is very radiosensitive. In vitro, SCLC cell lines have lower survival rates than squamous-cell carcinomas in singlefraction clonogenic assays. Whole brain radiation therapy (WBRT) is the standard of care in managing brain metastases from SCLC because it is well tolerated and rapidly resolves symptoms. However, the prognosis of SCLC patients with brain metastases is poor. Reported median survival for these patients ranges from 1 to 14 months, but most survive only 3 to 4 months (Table 2.).

Although brain metastases from SCLC can cause significant morbidity, it is rarely the sole cause of death. Rather, the presence of brain metastases often heralds the development of systemic progression of disease. Between 60% and 95% of SCLC patients with brain metastases are found to have extracranial disease at the time of or shortly after diagnosis. Because of the aggressive systemic nature of SCLC, these patients have been historically excluded from participation in clinical trials that are exploring alternatives to conventional WBRT. As a result, few randomized trials have been conducted to guide the treatment evolution in this group of patients and to challenge the prevailing perspective that WBRT alone is the only effective treatment for brain metastases from SCLC.

TABLE 3
Response Rates of Brain Metastases From Small Cell Lung Cancer Treated With Whole Brain Radiation Therapy

The effectiveness of WBRT has been examined mainly in retrospective studies (Table 3). Interpreting the data from these studies, however, is difficult because different criteria were used to measure response rates. The response criteria used in the older studies were often based on symptomatic improvement rather than on objective measurements of tumor size on radiographic studies. In addition, many of the patients included in these studies were also treated with chemotherapy, either concurrently with radiation or shortly thereafter. Finally, the chemotherapy regimens varied widely from study to study.

Another confounding factor is the use of corticosteroids. Symptomatic improvement is frequently seen after the initiation of such medications. Thus, in patients treated with corticosteroids, it is not known whether the clinical response should be attributed to the medical treatment or to WBRT. Finally, some of these retrospective studies included patients presenting with brain metastases at the initial diagnosis as well as patients whose disease relapsed in the brain after initial treatment. Some studies have found that patients presenting with brain metastases at diagnosis may have a better prognosis than patients who develop brain metastases at a later date.

The largest series documenting the role of WBRT in SCLC was reported in 1988 by Carmichael et al, who performed a retrospective review of 59 patients with proven brain metastases from SCLC treated with therapeutic irradiation from 1977 through 1983. Although patients were treated with varying chemotherapy regimens, all those with brain metastases at presentation were given induction chemotherapy. However, the systemic treatment of patients with delayed presentation of brain metastases was individualized. The radiation dose and fractionation schedules depended on the patient’s performance and disease status and whether or not the patient had received previous prophylactic cranial irradiation (PCI).

A total of 19 patients (32.2%) achieved a complete response to WBRT, and an additional 18 patients (30.5%) had a partial response. However, of the 37 patients with an objective response, 24 (8/19 complete responders and 16/18 partial responders) developed recurrent or progressive intracranial disease prior to death. The median duration of the response was 10 months in patients with a complete response and 5 months in patients with a partial response. The median survival of patients presenting with brain metastases was 7 months, compared with 3 months in patients with delayed development of metastatic disease. Patients who received radiation doses of more than 40 Gy had longer response durations than those given lower doses. The authors concluded that the irradiation schedules customarily used to treat brain metastases in SCLC are unlikely to eradicate intracranial tumors in the occasional patient whose systemic cancer has a durable complete response. They suggested that it may be appropriate to consider treatment with doses greater that 40 Gy.

The European Organization for Research and Treatment of Cancer (EORTC) conducted a prospective, phase II study between 1989 and 1995 that accrued 22 patients with SCLC and brain-only metastases to evaluate the efficacy of WBRT as a single treatment modality. Radiation consisted of 30 Gy in 10 fractions to the whole brain. Six patients had a complete response, and five had a partial response. The median response duration in patients with an objective response was 5.4 months, and the median survival of all patients was 4.7 months. This trial confirmed a major finding from the previous retrospective studies-that a significant number of patients respond to WBRT, but the response duration and survival are short.

• Attempts to Improve WBRT Results—Investigators have attempted to improve the results of WBRT by increasing the total radiation dose using altered fractionation schedules. Bach et al performed a retrospective review of 101 patients with brain metastases from SCLC that compared extended-course with short-course brain irradiation. Extended-course irradiation consisted of > 45 Gy in > 4 weeks, with most patients receiving 50.4 Gy in 28 fractions. Shortcourse irradiation consisted of < 30 Gy in < 1 week, with most patients receiving 22 Gy in four fractions. Extended-course irradiation significantly improved median survival (5.3 vs 2.9 months, P = .00001). However, 40% of patients who received shortcourse brain irradiation had evidence of extracranial progressive disease at the time of treatment, whereas all patients who received extended-course brain irradiation were in partial or complete remission outside the brain.

Many prospective trials have been conducted to identify the optimal dose and fractionation schedule in the treatment of patients with brain metastases. Although these issues have not been addressed in a prospective fashion in the SCLC population alone, these patients were not specifically excluded from participation in these trials. The RTOG has been very active in exploring different fractionation schedules for WBRT. The first two trials evaluated different accelerated fractionation regimens, including 40 Gy in 4 weeks, 40 Gy in 3 weeks, 30 Gy in 3 weeks, 30 Gy in 2 weeks, 10 Gy in one fraction, and 12 Gy in two fractions over 3 days. The overall response to treatment was equivalent in all arms. However, the duration of neurologic improvement was shorter in patients treated with 10 or 12 Gy.

RTOG 9104 was a phase III study comparing accelerated hyperfractionation with standard accelerated fractionation in 429 patients with unresected brain metastases. In this study, 39 patients had SCLC. Standard accelerated fractionation consisted of 30 Gy in 10 fractions. For those receiving accelerated hyperfractionation, the entire brain was treated with 1.6 Gy bid to a total dose of 32 Gy in 20 fractions. This was followed by an additional 22.4 Gy in 14 fractions to clinically visible lesions with a 2-cm margin, for a total dose of 54.4 Gy in 34 fractions. Median survival was 4.5 months in both arms, with a 1-year overall survival rate of 19% in the accelerated fractionation arm and 16% in the accelerated hyperfractionation arm. Given that higher radiation doses and altered fractionation schedules have not been shown to improve outcome in prospective trials, 30 Gy in 10 fractions continues to be one of the most commonly used fractionation schedules in WBRT.

• Re-treatment With External Beam Radiation Therapy—Although many patients with brain metastases from SCLC experience a good initial response to WBRT, many develop recurrent or progressive intracranial disease prior to death. The treatment options for these patients are often limited, and some authors have advocated repeat WBRT for palliation of symptoms.

Wong et al reported on the Mayo Clinic experience with reirradiation for brain metastases. From 1975 through 1993, 86 patients were reirradiated because their neurologic function had deteriorated or findings on imaging studies were consistent with progressive disease after an initial course of WBRT, or both. The most common primary sites were the breasts and lung, but the proportion of patients with SCLC was not identified. The median time interval between the first and second courses of irradiation was 7.6 months. The median dose of the first course of WBRT was 30 Gy, which was usually given in 10 fractions. The median dose of the second course was 20 Gy, most commonly given in 10 fractions.

Neurologic symptoms were resolved in 27% of patients, 43% experienced a partial improvement, and 29% had either no change or their condition worsened after reirradiation. The median survival following reirradiation was 4 months. Most patients had no significant toxicity secondary to reirradiation. Radiographic abnormalities consistent with radiation changes appeared in five patients, and one patient developed symptoms of dementia, which was attributed to radiation therapy. From this review, the authors concluded that reirradiation should be offered to patients who develop progressive brain metastases.

Imanaka et al used reirradiation therapy in three patients with recurrent brain metastases from SCLC. The initial therapy varied among the three patients. Two patients were treated with 30 Gy in 10 fractions to the whole brain, followed by a boost consisting of 10 Gy in four fractions for one patient and 9 Gy in three fractions for the other patient. The third patient was initially treated with 38 Gy in 14 fractions. Re-treatment consisted of 20 Gy and was administered to two patients with hyperfractionation (20 fractions) and to one patient with conventional fractionation (10 fractions). The time interval between the two treatments ranged from 4 to 8 months. Of the re-treated patients, two achieved a partial response and the third had no response. The survival after reirradiation was 4 months for all patients. No radiation injury was observed during follow-up. Therefore, the authors suggested that whole brain reirradiation is useful and safe for brain recurrence of SCLC.

• Stereotactic Radiosurgery—With this external irradiation technique, multiple collimated beams of radiation are stereotactically aimed at a target to deliver a single, high dose of radiation to a small volume of tissue. Brain metastases are ideal targets for stereotactic radiosurgery because they are usually relatively small when they are diagnosed, and they are often spherical in shape. They are also minimally invasive and displace normal brain parenchyma, which reduces the risk of injury to healthy tissue.

Numerous retrospective studies have evaluated the effectiveness of stereotactic radiosurgery in the treatment of brain metastases. These studies have suggested that radiosurgery improves both control of intracranial metastases and survival. However, the survival benefit suggested by these studies may have been due to bias because patients with known favorable prognostic factors were selected.

Sanghavi et al performed a retrospective review of 502 patients with brain metastases treated with radiosurgery and external beam radiation therapy at 10 institutions from January 1988 through May 1998. Patients with brain metastases from any primary tumor treated with WBRT and a stereotactic radiosurgery boost to all visible lesions were included in this analysis. Patients in this study were stratified according to their recursive partitioning analysis classification based on the RTOG’s phase III brain metastases database reported by Gaspar et al (Table 1). With this stratification system, current results can be compared with prior RTOG results. In addition, the recursive partitioning analysis system attempts to remove the potential bias resulting from patient selection. The median external beam dose was 37.5 Gy, and 97% of patients received ≥ 30 Gy. Radiosurgery was delivered using a modified linear accelerator or via Gamma Knife. The dose and prescription line varied depending on each institution’s preference.Sanghavi et al performed a retrospective review of 502 patients with brain metastases treated with radiosurgery and external beam radiation therapy at 10 institutions from January 1988 through May 1998. Patients with brain metastases from any primary tumor treated with WBRT and a stereotactic radiosurgery boost to all visible lesions were included in this analysis. Patients in this study were stratified according to their recursive partitioning analysis classification based on the RTOG’s phase III brain metastases database reported by Gaspar et al (Table 1). With this stratification system, current results can be compared with prior RTOG results. In addition, the recursive partitioning analysis system attempts to remove the potential bias resulting from patient selection. The median external beam dose was 37.5 Gy, and 97% of patients received ≥ 30 Gy. Radiosurgery was delivered using a modified linear accelerator or via Gamma Knife. The dose and prescription line varied depending on each institution’s preference.

On multivariate analysis, performance status, controlled primary disease, and absence of extracranial metastases were significant predictors of improved survival. The median survival of all patients was 10.7 months. No specific comments were made regarding survival based on histology. Median survival for recursive partitioning analysis class I, II, and III patients was 16.1, 10.3, and 8.7 months, respectively. The median survival times were longer in this study for each recursive partitioning analysis class than they were in the RTOG studies. Therefore, this study suggested that radiosurgery may improve survival in all patients with brain metastases regardless of recursive partitioning analysis class.

Serizawa et al performed a retrospective review of 245 patients with brain metastases from either SCLC (34 patients) or NSCLC (211 patients) treated with Gamma Knife radiosurgery. The inclusion criteria included: (1) no prior brain tumor treatment; (2) 25 or fewer lesions; (3) a maximum of 3 tumors with a diameter of 20 mm or more; (4) no surgically inaccessible tumor ≥ 30 mm in diameter; and (5) a life expectancy > 3 months. Tumors > 30 mm in diameter were surgically resected. All other smaller brain metastases were treated using the Gamma Knife system, with a mean prescription dose of 21.3 Gy. New brain metastases detected on follow-up MRI scans were treated with repeat Gamma Knife radiosurgery. Chemotherapy was administered according to the referring physician’s protocol.

The tumor control rate was 94.5% in the SCLC group and 98% in the NSCLC group. The median survival was 9.1 months in the SCLC group and 8.6 months in the NSCLC group. There was no significant difference between the two groups for any type of survival. Therefore, the results of this study suggest that Gamma Knife radiosurgery appears to be as effective in treating brain metastases from SCLC as for those from NSCLC.

RTOG 9508 was a phase III trial comparing WBRT alone vs WBRT followed by stereotactic radiosurgery for patients with one to three unresected brain metastases ≤ 4 cm from any primary tumor except for leukemia or lymphoma. Patients were not stratified according to histology. Whole brain radiation therapy consisted of 37.5 Gy delivered in 15 fractions. The radiosurgery doses were based on a previous RTOG trial and depended on the size of the lesion. For lesions ≤ 2 cm, patients were treated with 24 Gy. Lesions measuring 2.1 to 3 cm were treated with 18 Gy, and lesions measuring 3.1 to 4 cm were treated with 15 Gy.

Patients treated with stereotactic radiosurgery were found to have a statistically significant improvement in the 1-year local control rate (82% vs 71%, P = .01). Furthermore, all subsets of patients treated with stereotactic radiosurgery were more likely to have a stable or improved performance status than those receiving WBRT alone. There was no improvement in survival overall, but it did improve for recursive partitioning analysis class I patients, patients < 50 years of age, and patients with SCLC, any squamous cell cancers, or solitary brain metastases. The authors concluded that stereotactic radiosurgery can prolong survival in select patients with brain metastases only by 1 to 2 months. Systemic disease remained the primary cause of death in more than two-thirds of the patients. Improved systemic therapies are needed to significantly lengthen survival.

• Brachytherapy—In this treatment, radioactive sources are used to deliver radiation at a short distance by interstitial, intracavitary, or surface application. With this technique, a high dose of radiation can be delivered locally to the tumor with rapid dose fall-off in the surrounding healthy tissue. Brachytherapy can be used as a primary treatment, as a means of delivering a boost in conjunction with conventional radiation therapy, or as a treatment for recurrent lesions.

Brachytherapy can be divided into two categories, low dose rate (LDR) and high dose rate (HDR). In LDR brachytherapy, the radioactive sources are typically placed in catheters that are spaced evenly within the tumor or in the center of the tumor to deliver 5 to 60 cGy/h. Another approach to LDR brachytherapy involves permanent interstitial implants in which iodine (I)-125 sources that are embedded in suture material are inserted or implanted directly into a tumor cavity. In HDR brachytherapy, a dose rate of 100 to 200 cGy/min is delivered through temporary catheters that are placed within the tumor; high-activity radioactive sources are inserted into the catheters.

The relatively discrete nature of brain metastases suits the physical dose parameters of brachytherapy. Nonetheless, it remains an invasive procedure. Patients with a single brain metastasis whose greatest dimension measures < 5 cm are candidates for brachytherapy. Because patients with SCLC rarely present with a single brain metastasis, experience with brachytherapy in these patients is limited.

McDermott et al reported on the University of California, San Francisco, experience in 30 patients with a single brain metastasis who underwent temporary I-125 implantation. One of the patients included in this study had SCLC. Of the 25 patients treated for recurrence of their metastasis, 4 received brachytherapy as a boost, and 1 had brachytherapy alone after resection without external irradiation. The median implant dose was 4,901 cGy delivered at a median dose rate of 45 cGy/h. The median survival for the entire group was 14.7 months. The median survival for patients treated at recurrence was 13.9 vs 68.2 months for those treated with a boost. The authors concluded that their experience with interstitial brachytherapy using I-125 implants was favorable and that interstitial brachytherapy is particularly useful in salvaging metastases that recur after prior therapies.

Treatment Choices for Small Cell Lung Cancer, by Stage

For practical reasons, small cell lung cancer (SCLC) is usually staged as either limited or extensive. In most cases, SCLC has already spread by the time it is found, so chemotherapy (chemo) is usually part of treatment.

If you smoke, one of the most important things you can do to be ready for treatment is to quit. Studies have shown that patients who stop smoking after a diagnosis of lung cancer tend to have better outcomes than those who don’t.

Treating limited stage SCLC

Stage I cancers

If you only have one small tumor in your lung and there is no evidence of cancer in lymph nodes or elsewhere, your doctors might recommend surgery to remove the tumor and the nearby lymph nodes.

Very few patients with SCLC are treated this way. This is only an option if you are in fairly good health and can withstand having all or part of a lung removed.

Before the operation, the lymph nodes in your chest will be checked for cancer with mediastinoscopy or other tests, because surgery is unlikely to be a good option if the cancer has spread there.

Surgery is generally followed by chemotherapy. If cancer is found in the lymph nodes that were removed, radiation therapy to the chest is also usually recommended. The radiation is often given at the same time as the chemo. Although this increases the side effects of treatment, it appears to be more effective than giving one treatment after the other. If you already have severe lung disease (in addition to your cancer) or other serious health problems, you might not be given radiation therapy.

In about half of people with SCLC, the cancer will eventually spread to the brain if no preventive measures are taken. For this reason, you may be given radiation therapy to the head (called prophylactic cranial irradiation, or PCI) to try to prevent this. The radiation is usually given in low doses. Still, some patients may have side effects.

Other limited stage cancers

For most people with limited stage SCLC, surgery is not an option because the tumor is too large, it’s in a place that can’t be removed easily, or it has spread to nearby lymph nodes or other lobes in the same lung. If you are in good health, the standard treatment is chemo plus radiation to the chest given at the same time (called concurrent chemoradiation). The chemo drugs used are usually etoposide plus either cisplatin or carboplatin.

Concurrent chemoradiation can help people with limited stage SCLC live longer and give them a better chance at a cure than giving one treatment (or one treatment at a time). The downside is that this combination has more side effects than either chemo or radiation alone.

People who aren’t healthy enough for chemoradiation are usually treated with chemo by itself. This may be followed by radiation to the chest.

If no measures are taken to prevent it, about half of people with SCLC will have cancer spread to their brain. If your cancer has responded well to initial treatment, you may be given radiation therapy to the head (prophylactic cranial irradiation, or PCI) to try to prevent this. The radiation is usually given in lower doses than what is used if the cancer had already spread to brain, but some patients may still have side effects.

In most people with limited stage SCLC, tumors treated with chemo (with or without radiation) will shrink significantly. In many, the tumor will shrink to the point where it can no longer be seen on imaging tests. Unfortunately, for most people, the cancer will return at some point.

Because these cancers are hard to cure, clinical trials of newer treatments may be a good option for some people. If you think you might want to take part in a clinical trial, talk to your doctor.

Treating extensive stage SCLC

Extensive stage SCLC has spread too far for surgery or radiation therapy to be useful as the initial treatment. If you have extensive SCLC and are in fairly good health, chemotherapy (chemo), possibly along with an immunotherapy drug, is typically the first treatment. This can often shrink the cancer, treat your symptoms, and help you live longer.

The most common combination of chemo drugs is etoposide plus either cisplatin or carboplatin. The immunotherapy drug atezolizumab (Tecentriq) can be used along with etoposide and carboplatin for initial treatment and can then be continued alone as maintenance therapy. The cancer will shrink significantly with treatment in most people, and in some the cancer might no longer be seen on imaging tests. Unfortunately, the cancer will still return at some point in almost all people with extensive stage SCLC.

If the cancer responds well to the initial treatment, radiation to the chest may be given. This can help people with extensive stage SCLC live longer. Radiation to the brain (prophylactic cranial irradiation, or PCI) may also be considered to help prevent cancer progression in the brain.

If cancer growth in the lungs is causing symptoms such as shortness of breath or bleeding, radiation therapy or other types of treatment, such as laser surgery, can sometimes be helpful. Radiation therapy can also be used to relieve symptoms if the cancer has spread to the bones, brain, or spinal cord.

If your overall health is poor, you might not be able to withstand the side effects of standard doses of chemo. If this is the case, your doctor may treat you with lower doses of chemo or palliative/supportive care alone. This would include treatment of any pain, breathing problems, or other symptoms you might have.

Because these cancers are hard to treat, clinical trials of newer chemo drugs and combinations, as well as other new treatments, could be a good option for some people. If you think you might be interested in taking part in a clinical trial, talk to your doctor.

SCLC that progresses or recurs after treatment

If the cancer continues to grow during treatment or comes back, any further treatment will depend on the location and extent of the cancer, what treatments you’ve had, and on your health and desire for further treatment. It’s always important to understand the goal of any further treatment before it starts. You should understand if it’s to try to cure the cancer, to slow its growth, or to help relieve symptoms. It is also important to understand the benefits and risks.

If a cancer continues to grow during the initial chemotherapy treatment or if a cancer starts to grow after chemo has been stopped for less than 6 months, another type of chemo, such as topotecan may be tried, although it may be less likely to help. For cancers that come back after initial treatment is finished, the choice of chemo drugs depends on how long the cancer was in remission (see Chemotherapy for Small Cell Lung Cancer). Another option for people whose cancer continues to grow after two or more lines of treatment (including chemo with either carboplatin or cisplatin) are the immunotherapy drugs nivolumab (Opdivo) or pembrolizumab (Keytruda).

For more on dealing with a recurrence, see Coping With Cancer Recurrence.

The treatment information in this document is not official policy of the American Cancer Society and is not intended as medical advice to replace the expertise and judgment of your cancer care team. It is intended to help you and your family make informed decisions, together with your doctor. Your doctor may have reasons for suggesting a treatment plan different from these general treatment options. Don’t hesitate to ask him or her questions about your treatment options.

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All About Brain Metastases

Key Takeaways:

  • Brain metastases are a cancer that has spread to the brain from another area of the body.
  • This occurs most commonly in lung, breast, colon and kidney cancer and melanoma.
  • Common symptoms can include changes in cognitive abilities, behavior changes, unsteady gait, visual changes, difficulty finding words, headache, and seizures.
  • Treatments can include surgery, radiation and some anti-cancer medications.

What are brain metastases?

Brain metastases happen when cancer cells from the primary site (where the cancer started) spread to the brain. This is different from a primary brain tumor. For example, a lung cancer is first formed in the lung tissue. These tumor cells can break off from the original mass in the lung and travel through the bloodstream or lymph system to other areas of the body, including the brain. This spreading of the tumor is known as “metastasis.” When lung cancer metastasizes to the brain, this “brain tumor” is actually lung cancer cells.

Primary malignant brain tumors are tumors that start in the brain. There are an estimated 23,820 new cases yearly. Brain metastases, commonly called “brain mets,” are far more common but the exact incidence of brain metastases is not known. Studies suggest brain metastases occur in about 10%-30% of patients with cancer.

It is important to understand the difference between primary brain tumors and brain metastases because they are treated differently. The media may refer to a person who died of lung cancer and brain cancer when it was lung cancer that had metastasized to the brain.

Lung cancers account for the highest number of brain metastases. Other cancers that commonly metastasize to the brain include melanoma, breast cancer, colon cancer, and renal cell (kidney) cancer. Although these are the most likely types to do so, any type of cancer can spread to the brain.

There has been a rise in the number of brain metastases in recent years. This may be due to better diagnosis of brain metastases using advanced imaging. People are also living longer with metastatic disease due to advances in cancer therapy.

Signs, Symptoms, and Diagnosis

Common signs and symptoms of brain metastases include changes in cognitive ability (memory, attention, reasoning), behavior changes, gait changes (unsteadiness), visual changes, aphasia (difficulty finding words), headache, weakness, and seizures. Report any of these to your care team immediately.

If brain metastases are suspected, your care team will order radiology studies (MRI, CT scan). A biopsy may be needed if the patient presents without a primary cancer or if there has been a long period of time between treatment for the initial primary cancer and the new symptoms.

Treatment Options

Treatment decisions for each patient are based on several factors, including tumor type, general health, age, presence/control of cancer outside of the brain, and number of brain metastases. Each cancer acts differently and this is important to consider when choosing treatments. For example, primary lung cancers are quite sensitive to radiation, but melanomas are not. This does not change once the tumor spreads to the brain. Treatment decisions vary based on the primary (original site) tumor type.

Symptom Management

A danger of brain metastases is the space they take up in the brain and the pressure they put on surrounding tissue. This pressure can cause symptoms such as headaches, speech difficulties, seizures, nausea/vomiting, weakness of a limb, or visual disturbances. The goal of initial therapy is to relieve some of this pressure by decreasing swelling using medications called corticosteroids (dexamethasone, prednisone). They can be given either orally (by mouth) or through an intravenous (IV) line. Some patients may see relief of symptoms quickly after starting steroids. However, this does not mean the tumor is gone. If patients experience seizures as a result of their brain metastases, they may also receive anti-seizure medications to prevent further seizures.

Surgery

For patients with a single brain lesion, surgery may be a good option, especially if the cancer is under control in the rest of the body. However, the lesion must be in an area of the brain where it is safe to operate. Studies have shown that patients with a single brain metastasis who had surgery followed by whole brain radiation therapy (WBRT) have fewer recurrences and better quality of life than patients treated with WBRT alone. Life expectancy in these patients has also been shown to increase. However, these results do not apply to patients with radiosensitive tumors such as lymphomas, small cell lung cancer, and germ cell tumors (where surgery is generally not recommended).

Whole Brain Radiation Therapy

Whole brain radiotherapy (WBRT) is just what it sounds like – giving radiation to the entire brain. This is generally given in 10 to 15 doses (also called fractions). WBRT is often used in patients who are not candidates for surgery, or patients with more than 3 brain lesions. Many patients may receive WBRT in combination with another therapy (surgery, radiosurgery). The motivation of treating the whole brain is that there may be cancer cells in the normal-appearing brain, but not enough of them yet to form a mass or be seen by radiology studies. Thus, treatment of the whole brain attempts to kill all the cancer cells.

WBRT has been reported to improve symptoms of brain metastases in 70-90% of patients, although some of this benefit is also a result of the corticosteroids. Despite this symptom improvement, recurrence is common, and control of brain metastases may only occur in half of the patients. Patients with tumors that are more sensitive to the effects of radiation respond better (lung and breast, for example) than those with tumors that are less sensitive to radiation (melanoma and renal cancers).

It is difficult to evaluate the long-term effects of WBRT, given the small number of patients that survive long-term. These effects could include dementia and a decline in cognitive and physical functioning.

Stereotactic Radiosurgery (SRS)

Stereotactic radiosurgery (SRS) is a confusing term. It is actually not surgery at all, but a highly precise administration of a large dose of radiation to the tumor site.

Unlike traditional external beam radiation, which is usually given daily over many weeks, SRS is administered in a single dose (Gamma Knife®) or up to five doses (Cyberknife®). More than one brain tumor can be treated during one session (for example, if a patient had 2 separate brain metastases, both could be treated on the same day). Treatments are administered by a traditional radiation machine called a linear accelerator, or a specialized machine such as Gamma Knife®, Cyberknife®, XKnife® and ExacTrac®.

Gamma Knife® delivers several hundred beams of radiation from a cobalt source. Cobalt is one of the elements in the periodic table. It is the radioactive source used in this technique. The radiation beams concentrate at the point where all the beams meet (see picture). The radiation beams travel through hundreds of holes in the helmet, allowing a high dose of radiation to be delivered to the tumor while sparing the surrounding tissue from the high dose. SRS is highly dependent on accuracy and requires that the patient’s head be securely stabilized using a helmet (head frame), so there is no movement during the treatment. Finally, there is a size limit for Gamma Knife; the metastases should be 3 cm or smaller.

XKnife® is a linear accelerator-based treatment. Like Gamma Knife, it requires a head frame, which will remain on the patient for the entire procedure, providing a reference for the patient’s anatomy.

Cyberknife® is a form of frameless SRS using a specialized miniature linear accelerator with a robotic arm. It gets around the issue of using a frame for immobilization by using a custom mask for each patient along with skull-based tracking, allowing the robot to follow a target. Cyberknife can accommodate lesions larger than 3 cm, and can also be used to treat other types of cancer outside the brain.

Proton therapy is a newer form of SRS. Instead of using photons to target a tumor, this form of SRS uses protons. A machine called a synchrotron or cyclotron speeds up the protons, which are positively charged particles. The high energy of these moving protons can kill cancer cells. During treatment, the protons can precisely target the tumor. Proton therapy is a growing field of radiation therapy and not every cancer center has this treatment.

Your care team will assess the best radiation option(s) for you and create a patient-specific care plan to best treat your brain metastasis and control your symptoms.

Chemotherapy

It is widely believed that most chemotherapy agents are not able to cross the blood-brain barrier. In other words, they move through the bloodstream, but cannot enter the brain. As a result, the brain allows cancer cells to “escape” the chemo and make their way there. However, there are exceptions. Researchers have found that brain metastases from tumor types that are particularly sensitive to chemotherapy (for example testicular cancer, lymphomas, and small cell lung cancer) are also sensitive to chemotherapy. Research has also shown that people who have not received a large amount of chemotherapy in the past may have a greater reduction in brain metastases with chemotherapy treatment. This leads researchers to believe that there is some penetration of the blood-brain barrier by chemotherapy, just not always in effective amounts. One chemotherapy agent, temozolomide (Temodar®), is an oral medication that is capable of crossing the blood-brain barrier. This medication is used to treat primary brain tumors and metastatic melanoma lesions.

More recently, studies show that chemotherapies such as targeted therapies and immunotherapies may be useful in treating brain metastases by way of treating the primary cancer. Targeted therapies include lapatinib, capecitabine, erlotinib, gefitinib, and vemurafenib. Ipilimumab, nivolumab, and pembrolizumab are immunotherapy medications used to treat various types of cancer.

Preventing Brain Metastases with WBRT: Prophylactic Cranial Irradiation

Whole brain radiation can be used as a way to prevent future brain metastases from developing. When whole brain radiation is given as a preventive measure, it is also known by the name “prophylactic cranial irradiation” or “PCI.” Studies of PCI have shown significant decreases in brain mets (from 55% to 19% at 2 years and from 56% to 35% at 3 years) and increases in overall survival. Some have suggested there may be long-term neurologic impairment from this treatment, but long-term neurotoxicity data is lacking.

Clinical Trials

Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your healthcare provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Use our Cancer Types menu to find more information about primary tumor types and their treatment.

Magnetic Resonance (MR) Patterns of Brain Metastasis in Lung Cancer Patients: Correlation of Imaging Findings with Symptom

Approximately 25 to 30% of patients with lung cancer develop brain metastasis at some stage and the incidence at the initial work up has been reported to be between 12% and 18%.5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References, 7x7Hooper, RG, Tenholder, MF, Underwood, GH, Beechler, CR, and Spratling, L. Computed tomograhpic scanning of the brain in initial staging of bronchogenic carcinoma. Chest. 1984; 85: 774–776
Crossref | PubMed | Scopus (52) | Google ScholarSee all References, 8x8Mintz, BJ, Tuhrim, S, Alexander, S, Alexander, S, Yang, WC, and Shanzer, S. Intracranial metastases in the initial staging of bronchogenic carcinoma. Chest. 1984; 86: 850–853
Crossref | PubMed | Scopus (62) | Google ScholarSee all References Hochstenbag et al.9x9Hochstenbag, MM, Twijnstra, A, Hofman, P, Wouters, EF, and ten Velde, GP. MR imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?. Lung Cancer. 2003; 42: 189–193
Abstract | Full Text | Full Text PDF | PubMed | Scopus (45) | Google ScholarSee all References in 2003, and Kim et al.5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References in 2005, have documented incidence of brain metastasis in patients with lung cancer to be 14% and 18.9%, respectively. In our study, 35.4% patients with newly diagnosed lung cancer had brain metastasis on MR imaging at the time of initial staging. This is probably because we had a large number of patients (68.5%) in stage IV. Although none of our patients with stages I and II had brain metastasis, only 6 of 38 patients with stage III disease had brain metastasis. It corroborates with the fact that the incidence of brain metastasis increases with advancing stage of the disease.5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References, 9x9Hochstenbag, MM, Twijnstra, A, Hofman, P, Wouters, EF, and ten Velde, GP. MR imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?. Lung Cancer. 2003; 42: 189–193
Abstract | Full Text | Full Text PDF | PubMed | Scopus (45) | Google ScholarSee all References

The prognosis for patients with brain metastasis who go untreated is extremely poor (about 1 month after diagnosis),2x2Sorensen, JB, Hansen, HH, Hansen, M, and Dombernowsky, P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol. 1988; 6: 1474–1480
PubMed | Google ScholarSee all References whereas patients with NSCLC who are treated with radiation therapy survive for about 8 months.10x10Zabel, A, Milker-Zabel, S, Thilmann, C et al. Treatment of brain metastasis in patients with non-small cell lung cancer(NSCLC) by stereotactic linac-based radiosurgery:prognostic factors. Lung Cancer. 2002; 37: 87–94
Abstract | Full Text | Full Text PDF | PubMed | Scopus (41) | Google ScholarSee all References Improvements in systemic and local therapies can improve the long-term survival of cancer patients, which means that early and accurate diagnosis of BM has become crucial to improving quality of life and poor survival rates of cancer patients.

In our study, asymptomatic brain metastasis was found in about 16.5% of lung cancer patients which was in agreement with previous studies.5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References, 9x9Hochstenbag, MM, Twijnstra, A, Hofman, P, Wouters, EF, and ten Velde, GP. MR imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment?. Lung Cancer. 2003; 42: 189–193
Abstract | Full Text | Full Text PDF | PubMed | Scopus (45) | Google ScholarSee all References Patients (44.6% of stage IV) and 66.6% of stage III patients with brain metastasis were asymptomatic at presentation. However, we did not find any statistically significant difference between symptom and stage of disease (p = 0.308). This is in concordance with the findings of Shi et al.11x11Shi, A, Subba, D, Jennifer, T, Elkan, H, Landon, K, and Suzanne, A. Does initial staging or tumor histology better identify asymptomatic brain metastasis in patients with non-small cell lung cancer?. J Thorac Oncol. 2006; 1: 205–210
Abstract | Full Text | Full Text PDF | PubMed | Scopus (55) | Google ScholarSee all References stating that the patient symptom is independent of the stage of disease at presentation.

The prognosis of patients with symptomatic brain metastasis is substantially worse than those in which metastasis are asymptomatic.4x4Demange, L, Tack, L, Morel, M et al. Single brain metastasis of non-small cell lung carcinoma: study of survival among 54 patients. Br J Neurosur. 1989; 3: 81–88
Crossref | PubMed | Scopus (18) | Google ScholarSee all References Several reports in the past have emphasized screening of the brain for early detection of brain metastasis with survival benefit in those who are in good neurologic condition at presentation. Kim et al.5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References in 2005, reported better survival in patients who had less than three metastatic foci with a statistically significant difference in the median survival in patients with 1 to 3 and >3 foci. However, their study does not mention the distribution of these metastatic foci in symptomatic and asymptomatic groups.

In our study, we found no statistically significant difference (p = 0.554) in the number of lesions in both groups of patients. Equal numbers of symptomatic and asymptomatic patients were found to harbor a sizeable metastatic load. Asymptomatic patients with a large metastatic load may not have survival benefit over those symptomatic patients with a smaller load. Kim et al.,5x5Sun-Young, Kim, Jae-Sung, Kim, Hee-Sun, Park et al. Screening of brain metastasis with limited magnetic resonance imaging (MRI): clinical implications of using limited brain MRI during initial staging for non-small cell lung cancer patients. J Korean Med Sci. 2005; 20: 121–126
Crossref | PubMed | Scopus (30) | Google ScholarSee all References also reported that there was no statistically significant difference in the survival rate in symptomatic and asymptomatic patients. They, however, reasoned it probably to be because of early and aggressive treatment in both groups of patients with and without symptoms.

In a follow-up study of brain with CT in patients with resected lung cancer, Kohei Yokoi et al.6x6Kohei, Yokoi, Naoto, Miyazawa, and Toshimoto, Arai. Brain metastasis in resected lung cancer: value of intensive follow up with computed tomography. Ann Thorac Surg. 1996; 61: 546–551
Abstract | Full Text PDF | PubMed | Scopus (33) | Google ScholarSee all References found asymptomatic metastasis in 63.6% of their cases and reported that the number of metastasis in all asymptomatic patients was small and maximum size of almost all lesions were less than 25 mm. We have found no statistically significant association between presence of symptom and size of the lesion (p = 0.282) with an overlap in lesion size between the two groups of patients. The disparity could be because of the modality used (CT instead of MR imaging) and limited number of patients in their study (n = 11). Moreover, the largest lesion in their study (lesion size 3.7 cm) was not associated with any symptoms and equal number of patients with and without symptoms (n = 2) harbored lesions measuring 2.5 cm. Also, no overall correlation was found between the site of lesion and symptoms (p = 0.344) though all three IT lesions were symptomatic in our study. Shi et al., also found similar observation as regards the number and distribution of brain metastasis.10x10Zabel, A, Milker-Zabel, S, Thilmann, C et al. Treatment of brain metastasis in patients with non-small cell lung cancer(NSCLC) by stereotactic linac-based radiosurgery:prognostic factors. Lung Cancer. 2002; 37: 87–94
Abstract | Full Text | Full Text PDF | PubMed | Scopus (41) | Google ScholarSee all References

We did not find any reported studies that mention influence of other contributory factors (viz presence of edema, hemorrhage, and necrosis within the lesions) on patients’ symptoms at presentation. We found no association between presence of perilesional edema and symptoms (p = 0.027) and 41.8% of patients with perilesional edema were silent at presentation. Although 63.1% of patients with intralesional hemorrhage were symptomatic at presentation, 24.1% of asymptomatic patients had associated hemorrhage (p = 0.09). We also did not find any statistically significant difference in the two groups as regards to nature of lesions with and without necrosis.

Secondary cancer

When a cancer has spread to the brain from where it started it is called a secondary cancer. Find out about symptoms and tests.

Where a cancer starts is called the primary cancer. If some cells break away from the primary cancer they can move through the bloodstream or lymph system to another part of the body, where they can form a new tumour. This is called a secondary cancer. Secondary cancers are also called metastases (pronounced met-ass-ta-sees).

The secondary cancer is made of the same type of cells as the primary cancer.

So, if your cancer started in your lung and has spread to your brain, the areas of cancer in the brain are made up of lung cancer cells.

This is different from having a cancer that first started in the brain (a primary brain cancer). In that case, the cancer is made up of brain cells that have become cancerous. This is important because the primary cancer tells your doctor which type of treatment you need.

Which cancers spread to the brain

Any cancer can spread to the brain. The most common cancers that do are:

  • lung cancer
  • breast cancer
  • kidney cancer
  • melanoma skin cancer
  • bowel cancer (colorectal cancer)

Symptoms of secondary brain tumours

Symptoms can include:

  • headaches
  • feeling sick
  • weakness of a part of the body
  • fits (seizures)
  • personality changes or mood changes
  • eyesight changes
  • confusion

Symptoms depend on where the tumour is in your brain. Tumours cause pressure on the surrounding brain tissue and the symptoms will depend on what this part of the brain does.

Remember other conditions can cause these symptoms. They don’t necessarily mean that you have cancer that has spread to the brain. But if you have any of these symptoms, tell your doctors so that they can check them out.

Tests

You may have one or more of the following tests:

  • physical examination by a doctor to test your muscle strength, eyes and reaction times
  • CT scan
  • MRI scan
  • biopsy (removing some or all of the tumour to see if it is cancer)

Your medical history and brain scans usually give a clear idea about whether you have a secondary cancer. So, you may not need to have a biopsy.

Survival

Most people worry about their outlook (prognosis) when they have a secondary cancer. Your individual outlook depends on many factors including whether the cancer has spread to more than one part of your body, how quickly it is growing and how it responds to treatment.

It is usually difficult to predict and this uncertainty can be hard to deal with.

Caring for a loved one who has a brain tumor or cancer that has spread to the brain from another part of the body can be a unique challenge. In addition to physical changes, people with a brain tumor or cancer that has spread to the brain can experience changes in their mood, personality, and thinking. As a result, caregivers often have a variety of responsibilities that can become overwhelming. Planning for this role will help you provide quality care while also taking care of your health and well-being.

Understanding the symptoms of a brain tumor or brain metastasis

A primary brain tumor is a tumor that starts in the brain. A secondary brain tumor is a cancerous tumor that starts in another part of the body and then spreads to the brain. The spread of cancer from the place where the cancer began to another part of the body is called metastasis, or metastases when there are multiple areas of spread. Brain metastases can develop from any type of cancer. The types of cancer most likely to spread to the brain are breast cancer, lung cancer, kidney cancer, and melanoma.

The symptoms of a brain tumor or brain metastases depend on where in the brain the tumor forms, the tumor’s size, and how fast the tumor spreads. Cancer treatment can also cause symptoms and side effects. Your loved one may have several symptoms or none at all.

Types of symptoms that may occur from cancer in the brain are:

  • Physical symptoms. These can include headaches, seizures, nausea, muscle weakness, vision problems, and bowel and bladder problems.

  • Cognitive symptoms. When the tumor affects how a person’s brain processes information, symptoms can include personality changes, confusion, impaired judgment, memory loss, and socially inappropriate behavior.

  • Emotional symptoms. Coping with a brain tumor or brain metastases can be very stressful, causing depression, anxiety, anger, and other emotional changes.

It is important for you to monitor these and other symptoms. Relieving a person’s symptoms and side effects is an important part of cancer care. This is called palliative care or supportive care. Palliative care can continue even when active treatment to cure or slow down the cancer stops. Be sure to talk with your loved one’s health care team about new symptoms or changes to existing symptoms.

Options to relieve symptoms may include:

  • Medications, such as corticosteroids that lower swelling in the brain, anti-seizure drugs, and pain medicine

  • Assistive devices, such as wheelchairs, canes, and walkers

  • Emotional support, such as counseling

  • Rehabilitation, such as problem-solving therapy, speech and language therapy, and physical therapy

  • Eating healthy

  • Complementary therapies, such as breathing exercises, massage, meditation, and acupuncture

Managing caregiving responsibilities

Learn as much as you can about your loved one’s diagnosis, treatment options, and chance of recovery. It is also important to ask about the medical, financial, and coping resources available to you and your loved one. As the disease and its treatment changes, so will your role. It is critical to:

  • Get to know your loved one’s health care team. Request a meeting with the team to get clear, accurate information about your loved one’s illness and treatment. Also, learn what role each provider on the team plays.

  • Ask for help from family and friends. Identify tasks that need to be done. Then organize a network of people who can help you with the tasks. Some people create an email list or web page. You may also use one of many websites available to make this process easier. Learn more about sharing responsibilities.

  • Learn how to provide day-to-day and medical care. Ask your loved one’s health care team for information on the best ways to provide daily living care. This may include bathing, dressing, and giving meals. Also ask how to provide medical care, such as giving injections or wound care.

  • Consider professional caregivers. If possible, it may be helpful to hire medical professionals to handle medical responsibilities you are not comfortable doing. You can also hire non-medical home care aids to help with everyday caregiving tasks, such as grooming and cooking. Find out if your loved one’s health insurance pays for these services. Learn more about other caregiving options.

  • Explore community resources. Many communities have a wide range of resources for caregivers, including case management, legal aid, financial assistance, and counseling. Your loved one’s health care team can provide referrals.

  • Stay organized. Use resources to organize the person’s medical information, track medical bills and health insurance claims, track treatments, manage medications, monitor side effects, and plan doctor’s appointments. The free Cancer.Net mobile app can also help.

Learn more about how to manage common caregiving tasks and providing care at home.

Planning ahead

A brain tumor or brain metastases may affect a person’s ability to communicate or make decisions. Talk with your loved one now about his or her priorities for treatment. These could range from surviving as long as possible to maintaining a specific quality of life, even if that means stopping treatment. If this is difficult for your family to discuss, ask a member of his or her health care team, social worker, or counselor to help lead the conversation.

Topics to discuss include:

  • An advance directive. An advance directive is a legal document that states who a person wants to speak for them if they are too sick to make decisions. It also provides information about the types of care the patient does and does not want. Give a copy of the document to your loved one’s health care team and keep a copy at home.

  • Hospice care. People expected to live less than 6 months may want to consider a type of palliative care called hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. Your loved one should think ahead about where he or she would be most comfortable as the cancer progresses. This could be at home, in the hospital, or in a hospice environment. Nursing care and special equipment can make staying at home an option for many families.

Caring for yourself

It can be hard to balance all of your caregiving responsibilities along with the responsibilities of your own life. Caregivers of people with a brain tumor or brain metastases are likely to be affected emotionally. For example, you may experience anxiety or depression. It is also likely for a caregiver to have physical symptoms such as feeling very tired. Events such as the disease worsening, an increase in symptoms, changes in treatment, or moving your loved one to hospice care can cause a lot of stress.

The personality changes common to brain tumors can also be very distressing. You may feel sad about watching the person you love act in a different way. You may also feel guilty about anger, frustration, or other emotions. It is important to remember that there is no right way to feel as a caregiver. And that it is okay to take care of yourself too. In fact, your mental and physical health is important to the well-being of your loved one.

Ask an oncology social worker or your loved one’s health care team about:

  • How to connect with other caregivers

  • Online or local support groups

  • Individual or family counseling from a professional mental health worker

  • Stress management techniques, such as meditation, deep breathing, and yoga

Learn more about how you can take care of yourself.

Caregiving during the final days

As a person nears the end of his or her life, it is difficult to know what to expect. Knowing how to provide care in the final days can help make the process more peaceful for your loved one and you. When you feel it is appropriate, talk with the person’s health care team about how to:

  • Recognize the signs of approaching death

  • Provide comfort

  • Ease pain your loved one feels

  • Get urgent help from medical staff, if you feel it is needed

  • Handle practical matters after death

Your loved one’s health care team can also provide information on coping with grief and loss. This can help you prepare for the loss of your loved one and the changes you may experience when your caregiving journey ends.

Related Resources

ASCO Answers Fact Sheet: When Cancer Spreads to the Brain (PDF)

ASCO Answers Fact Sheet: Effective Caregiving at Home (PDF)

Caregiving Basics

Long-Distance Caregiving

How I Went From Caregiver to Patient Advocate

More Information

American Brain Tumor Association

University of California, San Francisco: Orientation to Caregiving: A Handbook for Family Caregivers of Patients with Brain Tumors and Transitions in Care for Patients with Brain Tumors: Palliative and Hospice Care (PDFs)

Comparative survival in patients with brain metastases from non-small-cell lung cancer treated before and after implementation of radiosurgery

J.N. Greenspoon, MSc MD*, P.M. Ellis, MD PhD*, G. Pond, PhD*†, S. Caetano, MSc†, J. Broomfield, MD*, A. Swaminath, MD*

doi: https://doi.org/10.3747/co.24.3420

ABSTRACT

Introduction

Survival after a diagnosis of brain metastasis in non-small-cell lung cancer (nsclc) is generally poor. We previously reported a median survival of approximately 4 months in a cohort of patients treated with whole-brain radiotherapy (wbrt). Since that time, we implemented a program of stereotactic radiosurgery (srs). In the present study, we examined survival and prognostic factors in a consecutive cohort of patients after the introduction of the srs program.

Methods

Data from a retrospective review of 167 nsclc patients with brain metastasis referred to a tertiary cancer centre during 2010–2012 were compared with data from a prior cohort of 91 patients treated during 2005–2007 (“pre-srs cohort”).

Results

Median overall survival from the date of diagnosis of brain metastasis (4.3 months in the srs cohort vs. 3.9 months in the pre-srs cohort, p = 0.74) was not significantly different in the cohorts. The result was similar when the no-treatment group was excluded from the srs cohort. Within the srs cohort only, significant differences is overall survival were observed between treatment groups (srs, wbrt plus srs, wbrt, and no treatment), with improved survival being observed on univariate and multivariate analysis for patients receiving srs compared with patients receiving wbrt alone (p < 0.001).

Conclusions

No improvement in survival was observed for nsclc patients with brain metastases after the implementation of srs. Selected patients (younger age, female sex, good performance status, fewer brain metastases) treated with srs appeared to demonstrate improved survival. However, those observations might also reflect better patient selection for srs or a greater tendency to offer those patients systemic therapy in addition to srs.

KEYWORDS: Non-small-cell lung cancer, brain metastasis, radiosurgery, whole-brain radiotherapy, radiosurgery practice

Brain metastases (bMets) are a common occurrence in patients with advanced lung cancer. Approximately 10% of patients with non-small-cell lung cancer (nsclc) present with bMets1. Estimates suggest that up to 50% of patients will develop bMets during the course of their illness, and that figure appears to be rising1–4.

For nsclc patients with bMets, prognosis is generally poor5–9. The goals of treatment are to minimize toxicity and to maximize both length and quality of life10,11. Previous evaluation of a cohort of nsclc patients with bMets at our institution treated primarily with whole-brain radiation therapy (wbrt) with or without surgery demonstrated a median survival of approximately 4 months from diagnosis with bMets12.

Most patients with bMets present with a limited number of lesions (up to 4)2,3. The improved toxicity profile associated with newer radiation techniques such as stereotactic radiosurgery (srs)—in particular, the reduction in late toxicities—has led to a paradigm shift in treatment4. The sophisticated planning and imaging techniques in srs target cranial lesions with high levels of precision8, permitting an escalation of the radiation dose to the target lesion or lesions, while sparing the surrounding normal tissues5–11. Traditional wbrt has been supplemented with, and more recently replaced by, srs alone5–9. The goal of srs is tumour ablation, analogous to surgery. However, srs is minimally invasive and can routinely treat multiple lesions4, making srs an attractive treatment option in the setting of nsclc with bMets, for which both length and quality of life are the goals of treatment10.

The addition of srs to wbrt was shown, in a planned subgroup analysis in a randomized controlled trial, to improve survival in patients with a single brain metastasis8. A subgroup analysis of those data showed an increased survival benefit in patients with nsclc and bMets8. In patients with nsclc and limited bMets, srs has become the preferred treatment approach. Recently, a meta-analysis of individual patient data from three randomized controlled trials suggested that srs alone might confer a survival advantage over srs plus wbrt in younger patients with 1–4 bMets, despite increased risk after srs for the development of additional bMets9. There is a rationale to consider srs because of its better side-effect profile compared with that for wbrt7,10 and its ability to successfully salvage additional bMets5–7,9. The sustained control of new central nervous system metastases with the use of salvage srs might permit more aggressive management of extracranial disease and could potentially increase overall survival (os) for these patients11.

In July 2010, srs became widely available at our institution. Since that time, we have expanded our use of srs alone for patients with nsclc and bMets. Evaluation of that change in policy was an important component of the implementation strategy. We therefore undertook the present study to examine the effect on outcomes in nsclc patients with bMets after implementation of the srs program. We hypothesized that the availability of srs for the treatment of bMets would result in os improvements for nsclc patients with bMets in the more recent srs cohort.

METHODS

We previously reported management and outcomes for a cohort of nsclc patients undergoing treatment for bMets during 2005–2007 (“pre-srs cohort”)12. In the present study, we collected treatment and outcomes data for a second cohort of nsclc patients diagnosed with bMets from July 2010 to December 2012 after implementation of the srs program (“srs cohort”).

All patients were treated at the Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, and were followed from the diagnosis of bMets until death. The Juravinski Cancer Centre is a comprehensive cancer centre that provides service to a population of approximately 2 million. Study methods for the pre-srs cohort were previously described12. Patients eligible for the srs cohort included those with nsclc and a diagnosis of bMets, including those treated with supportive care. In contrast, the pre-srs cohort included only nsclc patients with bMets who were planned to be treated with brain radiotherapy; it also excluded patients who were referred to other centres for srs12,13. Patients referred from other institutions for srs were included in the srs cohort. Patients identified from the electronic medical record were cross-referenced against an internal srs database to ensure accuracy of the selection process.

All patients were seen in a specialized multidisciplinary bMets clinic. The clinic was attended by a neuro-radiation oncologist and a neurosurgeon. Data extracted from the medical record included demographics, disease information, treatments, and outcomes. Information about date of diagnosis of bMets, number of lesions, treatment of bMets, recurrence of bMets, and any subsequent treatment was also collected. The study was approved by the Hamilton Integrated Research Ethics Board.

The primary outcome was os in the srs and pre-srs cohorts. Secondary outcomes included survival according to the type of radiation used in the srs cohort and a subset analysis of os by age group. Summary statistics are used to describe patient characteristics at diagnosis and at presentation with bMets, as well as outcomes. The Fisher exact test, Wilcoxon rank-sum test, and Cochran–Armitage test for trend were used to identify statistically significant differences between the cohorts in patient and tumour characteristics. The Kaplan–Meier method was used to calculate time-to-event outcomes for os, from the time of bMets diagnosis. Cox proportional hazards regression was used to investigate factors prognostic for the outcomes of interest14,15. Forward stepwise selection was used to construct an optimal model of prognosticators. The effect of cohort was tested, adjusting for factors identified in the optimal model. The use of any systemic therapy was summarized. Statistical significance was defined as a p value less than 0.05, and all tests were two-sided.

RESULTS

Table i summarizes the characteristics of patients in the pre-srs (n = 91) and srs (n = 167) cohorts. The pre-srs cohort did not include patients for whom wbrt was not planned. Our primary analysis controlled for that difference by performing two survival analyses: one in which both cohorts were evaluated in total, and the other in which the srs cohort excluded the no-treatment group. Demographic and baseline disease characteristics were similar between the two cohorts, with the exception of initial nsclc stage (p = 0.004). The patients in the srs cohort were more likely to be stage iv at initial nsclc presentation (78.4% vs. 60.4%). In the srs cohort, 29 patients (17.4%) received no initial cranial radiotherapy for their bMets (therefore receiving supportive care), leaving 138 patients in the srs cohort in the “intended to have cranial radiotherapy” group.

TABLE I Demographic data and treatment summary

In comparing the two cohorts, no difference in os was observed (log-rank p = 0.74). The lack of a significant os difference remained after the no-treatment group was excluded from the srs cohort. There was similarly no difference in os between the two cohorts in a multivariate analysis adjusting for age, Eastern Cooperative Oncology Group performance status, sex, number of bMets, and histology (p = 0.88, and p = 0.39 after excluding the no-treatment group). For patients in the srs cohort, median os was 1.2 months for supportive care, 3.8 months for wbrt, 10.1 months for srs alone, and 7.0 months for srs plus wbrt (Figure 1).

FIGURE 1 Survival in the stereotactic radiotherapy cohort by treatment for brain metastases. WBRT = whole-brain radiotherapy; SRS = stereotactic radiosurgery.

Of the 167 patients in the srs cohort, 43 had srs alone as upfront treatment for their bMets, and 23 patients had srs plus wbrt. Regional brain recurrence was observed in 41.9% of patients receiving srs alone and in 13.0% of patients receiving srs and wbrt. “Local recurrence” was defined as a growth in the largest diameter of a treated lesion of more than 20%. Local recurrence was coded only if it was detected less than 12 months after srs in the setting of positive perfusion magnetic resonance imaging or surgical resection showing viable tumour; otherwise, growth in a treated lesion less than 12 months after srs was thought to be treatment-related change or radiation necrosis. No local recurrences were observed in the srs-only group, and local failure was only 8.7% in the srs plus wbrt group. Salvage wbrt was prescribed in 9 of 43 patients (20.9%) who received upfront srs alone. Salvage srs for regional brain progression was performed in 9 of 43 patients (20.9%) in the srs-only group and in 3 of 23 patients (13.0%) in the srs plus wbrt group. The median number of salvage srs treatments was 2 (range: 1–13).

In the srs cohort, univariable regression analysis showed that age, sex, histology, Eastern Cooperative Oncology Group performance status at diagnosis of bMets, score on the graded prognostic assessment, neurologic symptoms at diagnosis of bMets, pre-diagnosis extracranial radiation therapy, and receipt of initial radiation therapy for the treatment of the bMets were all statistically significant prognostic factors (all p ≤ 0.004, Table ii). Multivariable regression analysis on the srs cohort showed that score on the graded prognostic assessment, neurologic symptoms at diagnosis of bMets, adenocarcinoma histology, female sex, and upfront treatment of the primary disease were all prognostic. Overall survival, adjusted for factors in the optimal model, was significantly worse for patients who were treated with supportive care alone (p < 0.001) than for patients treated with wbrt alone (hazard ratio: 0.33; 95% confidence interval: 0.20 to 0.53), srs alone (hazard ratio: 0.18; 95% confidence interval: 0.10 to 0.31), or both (hazard ratio: 0.20; 95% confidence interval: 0.10 to 0.39). After excluding patients treated with supportive care only, the use of srs and srs plus wbrt, compared with wbrt alone, were prognostic for longer survival even adjusting for other factors in the optimal model (p = 0.001).

TABLE II Regression analysis for overall survival in the stereotactic radiosurgery (SRS) cohort

Table iii presents the uptake of chemotherapy within each cohort according to age group. A clear increase in the uptake of chemotherapy was evident in all age groups in the srs cohort. Although the interaction between age group and srs did not attain statistical significance (p = 0.094), definite trends were observed. Specifically, in patients less than 60 years of age, a strong trend toward improved survival was evident in the srs cohort compared with the pre-srs cohort. However, in patients more than 70 years of age, a trend toward worse survival was observed in the srs cohort compared with the pre-srs cohort.

TABLE III Chemotherapy use and overall survival in the study cohorts by age

DISCUSSION AND CONCLUSIONS

Our analysis of two unselected cohorts of patients, one from before and one from after implementation of srs, observed no change in os. Although we hypothesized several reasons why the implementation of srs might improve survival, our findings highlight the complexity in outcomes for patients with nsclc and bMets1,14,15. Given the numerous and complex factors that influence prognosis (for example, burden of systemic disease and performance status), our study highlights the importance of evaluating patient-reported outcomes, quality of life, and the resource implications of new treatment approaches and programs in this population1,10,14.

Our study shows that practice has changed significantly over time. In the pre-srs cohort, wbrt was the only definitive option available locally. In patients with limited prognosis, travel to other centres for srs would often not be practical, and therefore the best treatment that was locally available was routinely offered to patients. In the srs cohort, 39.6% of patients received srs as part of their initial treatment plan. However, many patients with bMets still required wbrt to treat their disease. It is apparent that more factors than just the presence of bMets are influential in the treatment decisions arrived at by patient and physician. In the srs cohort, survival outcomes were better for patients who received srs alone or srs plus wbrt than for patients treated with wbrt alone (Figure 1, Table ii). That finding highlights the potential capability for physicians acting in a specialized bMets clinic, at a tertiary referral cancer centre, to identify nsclc patients with a more favourable prognosis for the receipt of more individualized bMets treatment16.

The choice between srs alone and srs plus wbrt in the setting of limited bMets from nsclc is one with some controversy5–9. The addition of wbrt has been associated with lower rates of regional brain recurrence and local control, but also with increased cognitive toxicity7,10. In randomized trials, no difference in os was observed between the two treatment approaches5–9. In our srs cohort, only 20.9% of patients who received upfront srs alone went on to receive salvage wbrt. That finding supports the use of srs alone as the preferred upfront management for nsclc and bMets, given that the focus in this population is providing treatment to maximize disease control and to minimize upfront toxicity, thereby maximizing quality of life7,10. The fact that only 20.9% of patients in the srs cohort who received upfront srs alone went on to receive salvage wbrt highlights a potential impact of a specialized bMets clinic16. Such a clinic would follow a patient closely after initial treatment and would be able to salvage regional brain recurrences with further srs alone by treating new lesions early and thus preventing the need for wbrt.

At the same time that srs was introduced for this patient population, other significant changes in management occurred. In patients less than 60 years of age, the uptake of palliative chemotherapy increased, with uptake in the srs cohort being 75% compared with 34% in the pre-srs cohort. Those changes also coincided with a trend toward improved survival in patients less than 60 years of age in the srs cohort compared with their peers in the pre-srs cohort. That hypothesis-generating outcome is consistent with the recent meta-analysis by Sahgal et al.9, in which improved survival was observed for patients less than 50 years of age treated with srs alone compared with those treated with upfront wbrt. One hypothesis that those findings support is that, by limiting the acute toxicity of wbrt, patients and oncologists are more likely to pursue palliative chemotherapy, which could ultimately influence a patient’s os11,17.

Our evaluation identified certain subgroups in our srs cohort for whom survival was improved. Although no overall difference in survival was observed between the two cohorts, patients in the srs cohort who were treated with upfront srs or who were less than 60 years of age certainly appeared to have the best outcomes. That observation is consistent with a recent meta-analysis of randomized trials9, and we showed that it can be generalized to an unselected nsclc population with bMets.

One important limitation of our study in the absence of patient-reported quality-of-life data. Although bMets in nsclc are not routinely curable, the goal of care when managing these patients is to maximize both length and quality of life7,10. One of the main reasons that we use srs to manage bMets is to provide a noninvasive method to control bMets without causing general neurologic toxicity5–9.

That approach has opened up many more management options for our patients, as evidenced by an increase in the uptake of systemic therapy and salvage brain radiotherapy, while avoiding wbrt. Without a clear survival benefit across all patients, oncologists must continue to focus on patient selection, determining who is best suited to benefit from upfront srs alone and who is best suited for a more supportive treatment regimen9. Future prospective studies that evaluate patient-reported quality of life and resource utilization will help to guide oncologists and decision-makers as they continue to develop new methods for the management of the common diagnosis of nsclc with bMets.

Another limitation of this retrospective cohort study is that the populations being compared are likely fundamentally different. We did observe a difference between the populations in stage at presentation; however, other differences that we were not able to observe or measure also likely exist. Those hidden differences make it impossible to understand purely the causes of the results that we observed, thus making our conclusions hypothesis-generating.

Our study found, contrary to our hypothesis, no difference in the primary study outcome. We observed no difference in survival for nsclc patients with bMets between the pre-srs and the srs cohorts. We did observe that, within the srs cohort, survival was longer in patients who received upfront srs alone than in those who received upfront wbrt alone. Known patient factors, as shown in our multivariable regression (Table ii), remain important for selecting patients for srs; however, other unknown factors that are influencing outcome are clearly implicitly used by experienced physicians to select patients for srs. We encourage future research to investigate how best to select nsclc patients with bMets for the various treatment options. The lack of a major shift in prognosis in our study also highlights the need to focus future research on patient-reported outcomes and quality of life.

ACKNOWLEDGMENTS

This work was presented as a mini oral abstract at the International Association for the Study of Lung Cancer 2015 World Conference on Lung Cancer; Denver, CO, U.S.A.; 6–9 September 2015.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS

*Department of Oncology and,
†Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON..

1. Dawe DE, Greenspoon JN, Ellis PM. Brain metastases in non-small-cell lung cancer. Clin Lung Cancer 2014;15:249–57.

2. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep 2012;14:48–54.

3. Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neurooncool 2005;75:5–14.

4. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radio – surgery for patients with multiple brain metastases (jlgk0901): a multi-institutional prospective observational study. Lancet Oncol 2014;15:387–95.

5. Aoyama H, Shirato H, Tago M, et al. Stereotactic radio-surgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295:2483–91.

6. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the eortc 22952–26001 study. J Clin Oncol 2010;29:134–41.

7. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomized controlled trial. Lancet Oncol 2009;10:1037–44.

8. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase iii results of the rtog 9508 randomized trial. Lancet 2004;363:1665–72.

9. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015;91:710–17.

10. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organization for Research and Treatment of Cancer phase iii trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013;31:65–72.

11. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status and quality of life at the end of life. JAMA Oncol 2015;1:778–84.

12. Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol 2013;20:e300–6.

14. Barnholtz-Sloan JS, Yu C, Sloan AE, et al. A nomogram for individualized estimation of survival among patients with brain metastases. Neuro Oncol 2012;14:910–18.

15. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655–61.

16. Danielson B, Fairchild A. Beyond palliative radiotherapy: a pilot multidisciplinary brain metastases. Support Care Cancer 2012;20:773–81.

17. Pilkington G, Boland A, Brown T, Oyee J, Bagust A, Dick-son R. A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer. Thorax 2015;70:359–67.

Correspondence to: Jeffrey Noah Greenspoon, Department of Oncology, McMaster University, 699 Concession Street, Hamilton, Ontario L8V 5C2. E-mail: [email protected]

(Return to Top)

Current Oncology, VOLUME 24, NUMBER 2, April 2017

What is stage IV lung cancer?

Stage IV lung cancer is the most advanced stage of the disease. In this stage, the disease has spread, or metastasized, from the lung in which it originated to the other lung, the pericardium (membrane around the heart and lungs), chest and/or other areas of the body. Stage IV lung cancer, also called metastatic lung cancer, may be found in the lymph nodes and multiple organs, including the kidneys and the adrenal gland, but it most often spreads to the bones, liver and/or brain. Metastatic tumors, or metastases, are considered secondary tumors and are still considered lung cancer, even when found in other parts of the body. Stage IV lung cancer, which may also be referred to as extensive-stage cancer, spreads to other parts of the body through the lymph system or bloodstream.

Many patients are found to have stage IV lung cancer when they are first diagnosed with the disease. In fact, according to the National Cancer Institute, about 66 percent of patients diagnosed with small cell lung cancer and about 40 percent of patients diagnosed with non-small cell lung cancer have stage IV disease.

At Cancer Treatment Centers of America® (CTCA), we offer a variety of treatment options to patients with stage IV lung cancer, including immunotherapy, radiation therapy and chemotherapy. In some cases, treatments may be palliative, used to ease the symptoms associated with the disease and improve quality of life. Qualifying patients may also be candidates for clinical trials, which may offer treatments not otherwise available.

Learn more about lung cancer

Stage IV lung cancer symptoms

The symptoms of stage IV lung cancer may depend on where in the body the disease has spread. For instance:

  • If the cancer has spread to the bones, it may cause bone pain or fractures.
  • If the cancer has spread to the liver, it may cause nausea, fatigue, bloating, jaundice or swelling in the extremities.
  • If the cancer has spread to the brain, it may cause headaches, vision issues, difficulty speaking or seizures.

Other symptoms of stage IV lung cancer include:

  • Lumps in the neck or around the collarbone
  • Abdominal or back pain
  • Weakness
  • Fatigue
  • Loss of appetite
  • Numbness or tingling

Learn more about lung cancer symptoms

Types of stage IV lung cancer

There are two main types of lung cancer: small cell lung cancer and non-small cell lung cancer. In most cases, patients first diagnosed with either type are found to have stage IV disease.

As their names suggests, these types of lung cancer are diagnosed when a pathologist identifies a specific type of diseased cell. Designating the type of lung cancer is a critical first step in understanding treatment options.

Small cell lung cancer

About 10 percent of all lung cancers are small cell lung cancers. This disease is often very aggressive and may spread quickly. There are two main subtypes of small cell lung cancer:

  • Small cell carcinoma (oat-cell cancer)
  • Combined small cell carcinoma

Non-small cell lung cancer

This is the most common type of lung cancer, accounting for 90 percent of all lung cancer diagnoses. Non-small lung cancers may grow more slowly than small cell lung cancers. There are three main types of non-small cell lung cancer:

  • Adenocarcinoma of the lung
  • Squamous cell lung cancer
  • Large-cell undifferentiated carcinoma

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Substages of stage IV lung cancer

Stage IV lung cancer may be divided into stage IVA and stage IVB, depending on the where the disease has spread.

Stage IVA

In stage IVA lung cancer, the disease has spread to areas around the lung and/or one distant organ. Areas around the lung may include the lymph nodes and/or the previously healthy lung.

Stage IVB

In stage IVB lung cancer, the disease has spread to multiple places in one or more distant organs or bones.

Extensive stage

Advanced small cell lung cancer may also be referred to as extensive-stage small cell lung cancer. In this stage, the cancer has spread to other parts of the body such as the other lung, the bone and/or bone marrow, the brain or the fluid around the lungs. Most patients are found to have extensive-stage disease when first diagnosed with small cell lung cancer.

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Treatments of stage IV lung cancer

Treatment options for stage IV lung cancer may depend on where and how extensively the cancer has spread. In some cases, treatments may be considered palliative, offered to ease side effects and improve quality of life. Treatment options include:

Chemotherapy: Drugs may be given alone, in combination and/or with other treatments. Chemotherapy may not be an appropriate option to treat lung cancer metastases in the brain.

Radiation therapy: This treatment may be used to shrink tumors and ease disease-related side effects.

Immunotherapy: Drugs known as checkpoint inhibitors may be used to help the immune system better recognize and attack lung cancer cells.

Surgery: Surgery may be an option to remove tumors from the lungs and the chest cavity and to remove affected lymph nodes. This treatment may not an option if the cancer has spread to multiple organs, but it may be used to remove tumors that are causing pain or other side effects.

Targeted therapy:These drugs are designed to target specific receptors or proteins on cancer cells to slow tumor growth.

Photodynamic therapy: This palliative treatment uses light and light-sensitive agents to shrink tumors in the lung.

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Clinical trials for stage IV lung cancer

Clinical trials are a key testing ground for determining the effectiveness and safety of new treatments for many types and stages of cancer, including stage IV lung cancer. As part of our commitment to providing innovative treatment options to our patients, the doctors at CTCA® may recommend that stage IV lung cancer patients enroll in carefully selected clinical trials.

Clinical trials may offer treatment options before they are approved by the U.S. Food and Drug Administration and that may be otherwise unavailable. Talk to your doctor about whether a clinical trial is a good option for you and ask about the risks and various requirements involved.

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Integrative care for stage IV lung cancer

Stage IV lung cancer and treatments for the disease may also come with symptoms and side effects that may affect your quality of life. Depending on where the disease has spread, stage IV lung cancer may cause symptoms such as pain, fatigue or difficulty breathing. Likewise, treatments for stage IV lung cancer may cause loss of appetite, nausea, neuropathy and/or other side effects. At CTCA, our team of doctors and clinicians work closely with integrative care experts, including nutrition-therapy, naturopathic providers, physical therapists and mind-body therapists, to help you manage side effects and maintain your strength and stamina throughout treatment.

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