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The Oncologist, Vol. 13, No. suppl_1, 21-27, January 2008; doi:10.1634/theoncologist.13-S1-21
© 2008 AlphaMed Press

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Local Control of Regional and Metastatic Lesions and Indication for Systemic Chemotherapy in Patients with Non-Small Cell Lung Cancer

Ikuo Sekinea, Minako Sumib, Nagahiro Saijoc

aDivision of Internal Medicine and Thoracic Oncology, and bDivision of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan; cDivision of Internal Medicine, National Cancer Center Hospital East, Kashiwa, Japan

Key Words. Non-small cell lung cancer • Chemotherapy • Pleural effusion • Bone metastasis • Brain metastasis

Correspondence: Ikuo Sekine, M.D., Ph.D., Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. Telephone: 81-3-3542-2511; Fax: 81-3-3542-3815; e-mail: isekine{at}ncc.go.jp

Received August 28, 2007; accepted for publication November 5, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Pleural Effusions
 Brain Metastases
 Bone Metastases
 Treatment Algorithm
 Acknowledgments
 References
 
Systemic chemotherapy is the mainstay of treatment in patients with advanced non-small cell lung cancer. Local control of regional and metastatic lesions may be needed before systemic therapy can be started in patients with pleural effusions or bone or brain metastases. The indication for systemic chemotherapy depends on the symptoms and performance status of the patient. In addition, a risk assessment considering complications such as hemodynamic and respiratory compromise by effusions, pathological bone fractures, and neurologic deterioration caused by brain metastases is critical in selecting which patients should receive first-line systemic chemotherapy before local therapy, although predictive factors for these complications have not yet been established. Chemotherapy has been considered to have only a limited role in the treatment of patients with pleural effusions and brain and bone metastases, but recently developed anticancer agents have shown substantial antitumor effects in these types of patients with a good general condition.


   INTRODUCTION
Top
 Abstract
 Introduction
Pleural Effusions
 Brain Metastases
 Bone Metastases
 Treatment Algorithm
 Acknowledgments
 References
 
The majority of patients with non-small cell lung cancer (NSCLC) develop distant metastases either by the time of the initial diagnosis or during recurrence following surgery for the primary lesion. While systemic chemotherapy is the mainstay of treatment in patients with advanced NSCLC, local control of regional and metastatic lesions may be needed before systemic therapy can be used in patients with pleural effusions, bone metastases, or brain metastases. The general rule about whether local control should precede systemic chemotherapy varies according to the performance status (PS) of a patient and the responsiveness of the tumor to chemotherapy. If possible, systemic chemotherapy should be employed early in patients with malignant lymphoma and germ-cell tumors, as they are highly responsive and can be cured even at an advanced stage. It is unlikely that small-cell lung cancer can be cured, but because it responds well to chemotherapy, chemotherapeutic agents are frequently given prior to local therapy. In patients with advanced NSCLC, however, local therapy is often required before chemotherapy is administered because of the limited efficacy of chemotherapy in these patients.


   PLEURAL EFFUSIONS
Top
 Abstract
 Introduction
 Pleural Effusions
Brain Metastases
 Bone Metastases
 Treatment Algorithm
 Acknowledgments
 References
 
Malignant pleural effusions are a common clinical problem in patients with neoplastic disease, and may be the first presenting sign in as many as 10% of patients. Indeed, approximately 15% of lung cancer patients present with malignant pleural effusions at diagnosis [1]. In fact, lung cancer is the most common cause of malignant pleural effusions, accounting for 17%–56% of cases [2]. Dyspnea is the most common symptom in patients with malignant effusions, occurring in more than half of cases, followed by cough and chest pain, although 5%–25% of patients have no respiratory complaints [3].

PS is significantly associated with survival in patients with pleural effusions [4]. Pleural effusions have been treated with the aim of palliation because NSCLC patients with pleural effusions are advanced stage by definition; massive effusions can cause hemodynamic and respiratory compromise, and the development of a symptomatic pleural effusion can drastically alter the quality of life and survival of patients [2]. Recently, however, as a result of the availability of ultrasound, computed tomography (CT), and positron emission tomography scans, NSCLC patients with small, asymptomatic pleural effusions can now be identified, and the treatment approach can be reconsidered in the setting of systemic disease control because relatively effective chemotherapy regimens have been developed.

It should be noted that pleural effusions can affect drug pharmacokinetics: methotrexate administered i.v. to patients with massive effusions is slowly released from third-space fluid, resulting in prolongation of the terminal half-life of the drug in the plasma, and potentially also increasing its toxicity [5, 6]. Similarly, levels of 5-fluorouracil decline rapidly in the plasma, but persist for longer in the effusion [7]. The pharmacokinetics of other drugs in patients with effusions are poorly studied, but drugs may accumulate in effusions and only slowly be redistributed throughout the body [8].

Patients with a small pleural effusion causing no symptoms can be treated with primary systemic chemotherapy, although there is a risk that the effusion will become symptomatic and require therapy. Patients with effusion-related dyspnea and those with a massive pleural effusion should be treated with a therapeutic thoracentesis; a large-volume thoracentesis allows rapid relief of symptoms in many patients. If systemic disease progression is a significant concern, an initial thoracentesis may create a window of opportunity in which to gain control over symptoms before starting chemotherapy. For patients whose effusions recur rapidly, more aggressive interventions may be required to achieve durable palliation, including chest tube drainage followed by chemical pleurodesis, and thoracoscopy with talc poudrage [8]. If patients gain durable palliation and are restored to a good PS by these treatments, then systemic chemotherapy is indicated. If not, their condition is suggestive of terminal-stage disease with a very short life expectancy.

Patients with NSCLC and pleural effusions are commonly included in chemotherapy clinical trials while they retain a good PS. Although the control of effusions by systemic chemotherapy has rarely been described, the efficacy of chemotherapy in treating effusions is considered to be comparable to the systemic response to chemotherapy. A retrospective study of 34 NSCLC patients with malignant pleural effusions treated with cisplatin, ifosfamide, and irinotecan showed that effusions disappeared for >4 weeks in 13 (38%) patients, while a partial response in measurable primary or metastatic lesions was obtained in 25 (66%) patients [9]. Active mutations of epidermal growth factor receptor (EGFR) have been detected in samples of pleural effusion fluid, and in patients with NSCLC they were associated with a clinical response to gefitinib, an EGFR tyrosine kinase inhibitor [10]. These results suggest that, in the near future, investigation of pleural effusion fluid could be important in selecting a chemotherapy regimen in patients with advanced NSCLC.


   BRAIN METASTASES
Top
 Abstract
 Introduction
 Pleural Effusions
 Brain Metastases
Bone Metastases
 Treatment Algorithm
 Acknowledgments
 References
 
Lung cancer is the most common primary source of brain metastases, which develop in 10%–64% of lung cancer patients during the clinical course of the disease [11]. Even among newly diagnosed, asymptomatic patients with potentially operable NSCLC, routine brain scans identify brain metastases in 3%–10% of patients [12]. It is believed that the incidence of brain metastases is increasing as a result of an aging population, better control of extracerebral disease by more active systemic therapy, and better detection of small metastases following the development of imaging modalities such as magnetic resonance imaging (MRI).

Two thirds of cancer patients found to have brain metastases at autopsy had experienced neurologic symptoms resulting from the metastases, with only 10% of patients diagnosed by CT or MRI between 1973 and 1993 being asymptomatic [13]. Symptoms include headache, focal weakness, nausea, vomiting, and altered mental status. Seizures occur in about 20% of patients with brain metastases. When lung cancer patients are routinely screened, only 10% present to the physician with symptoms of brain metastases [12]. Thus, although the exact percentage is unknown, there are many patients with NSCLC who have brain metastases but no neurologic symptoms. The prognosis for patients with brain metastases is influenced largely by PS, age, and control of the primary and extracranial tumors. Whole brain radiotherapy (WBRT), with or without stereotactic irradiation, has been the treatment of choice for most patients with brain metastases, with a median survival time of 3–6 months after radiotherapy. This relatively short survival is related to progressive systemic disease rather than the brain metastases [11]. Therefore, systemic chemotherapy can be administered in many patients with brain metastases and is in fact important for their survival.

Chemotherapy has not been thought to have a major role in the treatment of patients with brain metastases because of a poor PS in many cases and the prevailing belief that the blood–brain barrier (BBB) may play a role in limiting delivery of chemotherapeutic agents to the central nervous system. However, the accumulation of contrast medium during CT or MRI assessments and the development of edema surrounding metastatic lesions suggest that tumor-induced vessels do not possess normal anatomical and physiological properties, and the BBB at the site of established brain metastases may be partly disrupted [14]. While one study demonstrated that the concentration of cisplatin in the brain metastases of patients who received the agent before surgery did not differ from that found in extracranial metastases [15], another study found that paclitaxel concentration in brain metastases was in the therapeutic range, while in brain tissue the concentration was below the limit of detection [16]. This observation is supported by objective response rates of brain metastases to systemic chemotherapy of 27%–50% in previously untreated patients with NSCLC, which are comparable to systemic response rates (Table 1) [17–23]. Gefitinib has also been shown to be effective against brain metastases arising from NSCLC; objective responses were obtained in 13 of 25 case reports of gefitinib use in such patients [24]. Thus, systemic chemotherapy is an important treatment option for NSCLC patients with brain metastases, as long as a good PS is maintained without neurologic symptoms.


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  		Table 1. Chemotherapy in previously untreated non-small cell lung cancer patients with brain metastases

 
The advantages of administering chemotherapy before radiotherapy can be summarized as follows: (a) it is useful to judge the tumor's response to chemotherapy; (b) radiotherapy decreases blood supply to the tumor and thus may hamper the ability of chemotherapeutic agents to reach the metastases; and (c) chemotherapy delivered before radiotherapy may be less toxic to the brain than chemotherapy after radiotherapy, because radiotherapy may open the BBB and allow the entry of potentially neurotoxic agents. Evidence for this is available for methotrexate treatment, and may also apply to other agents [25]. A randomized phase III trial of cisplatin plus vinorelbine followed by WBRT (arm A; n = 86) versus the same chemotherapy with early concurrent WBRT (arm B; n = 85) in NSCLC patients with brain metastases showed that the respective intracranial response rates evaluated after two cycles of chemotherapy were 27% and 33%, and that the overall response rates were 21% and 20%. The median survival time was 5.5 months in arm A and 4.8 months in arm B (p = .83). There was no difference between the arms in terms of hematologic and neurologic toxicities. These results suggest that chemotherapy is effective against brain metastases arising from NSCLC, and that the timing (early or delayed) of WBRT does not influence the survival of these patients [21].


   BONE METASTASES
Top
 Abstract
 Introduction
 Pleural Effusions
 Brain Metastases
 Bone Metastases
Treatment Algorithm
 Acknowledgments
 References
 
Bone metastases are common in patients with lung cancer, with an incidence of 30%–55% at autopsy. These metastases are usually osteolytic, and are distributed mainly in the spine, pelvis, ribs, and extremities. The most common symptom of bone metastases is pain, which is either diffuse or localized. It is characteristically described as dull and constant in presentation, worsening at night. The pain gradually increases in intensity, and can be exacerbated by certain movements or positions, such as standing, walking, or sitting [26]. However, up to 25% of patients with bone metastases are free of pain, and patients with multiple bone metastases typically report pain in only a few sites. The factors that convert a painless lesion to a painful one are unknown [27]. As bone destruction progresses, mechanical weakness and loss of structural integrity lead to pathological fracture; spinal instability, defined as mechanical instability in the spine related to extensive bone destruction [28]; cord compression, and hypercalcemia [26, 29]. The prognosis for patients with bone metastases varies among the different tumor types. The median survival time from diagnosis of bone metastases in patients with prostate cancer or breast cancer is measurable in years, whereas for lung cancer it is only 6–7 months [29]. The second most important prognostic factor in patients with bone metastases is PS; the median survival time for patients with a Karnofsky PS score of <50, 50–70, or 80–100 who received radiotherapy to the metastatic site was 2–3 months, 5 months, and 12 months, respectively [30, 31].

Bone destruction and its complications severely limit the activity and mobility of patients. For patients with a high risk for these complications, radiotherapy is the treatment of choice and orthopedic interventions may be necessary in some cases [26, 29].

Pathologic fractures occur in 8%–30% of all cancer patients, with the ribs, vertebrae, and long bones being the most frequent fracture sites [26, 29]. A long-bone fracture, especially when located at the proximal part of the femur, has a detrimental effect on the quality of life of patients with advanced cancer. Important factors in predicting an impending fracture of the long bones are pain that is exacerbated by movement and radiographic findings such as a predominantly osteolytic appearance, a large lesion, and axial cortical involvement [32, 33].

Spinal instability is the cause of back pain in 10% of patients with advanced cancer [26]. It can cause unbearable pain that is mechanical in origin, and frequently the patient is only comfortable when lying still [26]. Neither radiation therapy nor chemotherapy, even if successful in controlling the tumor, will alleviate the pain. As in the treatment of pathological fractures of the long bones, stabilization of the vertebral segments is required for pain relief [28]. However, major surgery is associated with significant morbidity and mortality, and good results can be obtained only in carefully selected patients. Percutaneous vertebroplasty provides rapid and effective relief from the pain associated with spinal instability.

Spinal cord compression occurs in 2%–5% of cancer patients [34]. The incidence varies with the type of cancer, and is 2.6% for NSCLC [35]. The cumulative incidence for all cancers decreases with age: it is 4.4% for patients aged 40–50 years, 3.9% for patients aged 50–60 years, 2.9% for patients aged 60–70 years, 1.7% for patients aged 70– 80 years, and 0.5% for those aged >80 years [34]. About 60%–80% of spinal cord compressions occur in the thoracic region, 15%–30% in the lumbar region, and 10% in the cervical region. Multiple compression sites occur in approximately 7%–14% of cases [26, 34]. Early diagnosis and treatment are important for successful rehabilitation, but 48%–96% of patients present with motor weakness, bladder dysfunction, and inability to walk. In 83%–96% of patients, the first symptom is pain at the affected site, which may have been present from as little as 1 day to as long as 2 years, with a median duration of 8 weeks. It is generally exacerbated by coughing, sneezing, and straining, and typically increases in intensity over several weeks. Thus, the development of back pain in a cancer patient is a warning sign for possible spinal cord compression [26, 34].

Asymptomatic patients with bone metastases are potentially candidates for initial systemic chemotherapy, unless they show no risk factors for structural complications in radiographic assessments. These patients have been included in clinical trials of systemic chemotherapy; however, only limited information is available on the efficacy of chemotherapy for bone metastases, mainly because it is difficult to assess response to treatment in the bone, and bone metastases are defined as nontarget lesions in the Response Evaluation Criteria in Solid Tumors [36]. In patients with breast cancer, objective response rates of osteolytic lesions to standard chemotherapy regimens vary in the range of 20%–60% [37]. There are currently no reports on the objective response of bone metastases to chemotherapy in patients with NSCLC, but pain relief has been observed in 30%–61% of NSCLC patients receiving cisplatin-based chemotherapy, gemcitabine, or gefitinib [38–40].

Bisphosphonates, pyrophosphate analogues with a phosphorus–carbon–phosphorus (P–C–P)-containing central structure that promotes binding to the mineralized bone matrix, provide an additional treatment strategy for metastatic bone disease. Approximately 25%–40% of i.v. administered bisphosphonates are excreted by the kidney, and the remainder binds avidly to exposed bone mineral around resorbing osteoclasts, leading to inhibition of bone resorption and apoptosis of osteoclasts [26]. In addition to clinical use for hypercalcemia of malignancy, bisphosphonates are a routine treatment to prevent skeletal-related events (SREs) in patients with metastatic breast cancer and multiple myeloma. A recent meta-analysis evaluating randomized trials in these patients that lasted for 6 months or longer showed that bisphosphonates led to a significantly lower risk, versus placebo, for vertebral fractures (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.57–0.84), nonvertebral fractures (OR, 0.65; CI, 0.64–0.99), radiotherapy (OR, 0.67; CI, 0.57–0.79), and hypercalcemia (OR, 0.54; CI, 0.36–0.81). In contrast, trials of <6 months' duration did not show any significant results for any skeletal morbidity outcome [41]. In patients with NSCLC, however, the role of bisphosphonates in the treatment of bone metastases has been less investigated. A recent phase III trial of zoledronic acid, a new generation bisphosphonate that has 100-1,000 times the potency of pamidronate in vitro, showed that 4 mg zoledronic acid led to a significantly lower annual incidence of SREs (1.74 per year versus 2.71 per year; p = .012) and longer median time to first SRE (7.8 months versus 5.1 months; p = .009) compared with placebo in 773 patients with lung cancer and other solid tumors [42, 43]. There are no criteria regarding the indication and duration of bisphosphonate therapy in patients with NSCLC. Evidence of bone destruction on plain radiographs, which is suggestive of receiving a benefit of bisphosphonates in patients with breast cancer [44], also may be an important factor in patients with NSCLC.

The presence or absence of bone pain should not be a factor in initiating bisphosphonates in patients with breast cancer [44], but no reports are available on this issue in patients with NSCLC. Because a relatively long duration of treatment (>6 months) is required for patients to get a benefit from bisphosphonates, patient prognosis is considered another factor to determine the indication of this type of agent [26].


   TREATMENT ALGORITHM
Top
 Abstract
 Introduction
 Pleural Effusions
 Brain Metastases
 Bone Metastases
 Treatment Algorithm
Acknowledgments
 References
 
Pleural effusions, brain metastases, bone metastases, and their associated morbidities give rise to a vexing clinical problem in patients with advanced NSCLC. Approaches to treating these patients are illustrated in Figure 1. The use of systemic chemotherapy depends on the symptoms and PS of the patients. In addition, a risk assessment looking at complications is critical in selecting which patients should receive first-line systemic chemotherapy, although factors predictive of these complications have not yet been established. Chemotherapy has previously been considered to have only a limited role in the treatment of patients with pleural effusions and brain and bone metastases, but recently developed anticancer agents have been shown to have substantial antitumor effects in patients with a good general condition.


Figure 1
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  		Figure 1. Treatment approaches for patients who have advanced non-small cell lung cancer with local problems.

 

   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Pleural Effusions
 Brain Metastases
 Bone Metastases
 Treatment Algorithm
 Acknowledgments
References
 
We thank Mika Nagai for invaluable assistance in the collection and arrangement of the large number of papers.


   REFERENCES
Top
 Abstract
 Introduction
 Pleural Effusions
 Brain Metastases
 Bone Metastases
 Treatment Algorithm
 Acknowledgments
 References
 

  1. Wozniak A, Gadgeel S. In: Pass H, Carbone D, Minna J et al, eds. Lung Cancer: Principles and Practice. Clinical presentation of non-small cell carcinoma of the lung. Third Edition. Philadelphia: Lippincott Williams & Wilkins, 2005:291-303.
  2. Fenton KN, Richardson JD. Diagnosis and management of malignant pleural effusions. Am J Surg 1995;170:69–74.[CrossRef][Medline]
  3. DeCamp MM Jr, Mentzer SJ, Swanson SJ et al. Malignant effusive disease of the pleura and pericardium. Chest 1997;112(4 suppl):291S–295S.[CrossRef][Medline]
  4. Burrows CM, Mathews WC, Colt HG. Predicting survival in patients with recurrent symptomatic malignant pleural effusions: An assessment of the prognostic values of physiologic, morphologic, and quality of life measures of extent of disease. Chest 2000;117:73–78.[CrossRef][Medline]
  5. Evans WE, Pratt CB. Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther 1978;23:68–72.[Medline]
  6. Li J, Gwilt P. The effect of malignant effusions on methotrexate disposition. Cancer Chemother Pharmacol 2002;50:373–382.[CrossRef][Medline]
  7. Wagner T. [Pharmacokinetics of 5-fluorouracil and its permeation in pleural effusions in the therapy of metastatic breast cancer.]. Onkologie 1984;7:22–26; German.[Medline]
  8. Spira A, Brahmer J. In: Abeloff M, Armitage J, Niederhuber J et al, eds. Clinical Oncology. Effusions. Third Edition. Philadelphia: Elsevier Churchill Livingstone, 2004:1179-1212.
  9. Fujita A, Takabatake H, Tagaki S et al. Combination chemotherapy in patients with malignant pleural effusions from non-small cell lung cancer: Cisplatin, ifosfamide, and irinotecan with recombinant human granulocyte colony-stimulating factor support. Chest 2001;119:340–343.[CrossRef][Medline]
  10. Kimura H, Fujiwara Y, Sone T et al. EGFR mutation status in tumour-derived DNA from pleural effusion fluid is a practical basis for predicting the response to gefitinib. Br J Cancer 2006;95:1390–1395.[CrossRef][Medline]
  11. Tosoni A, Ermani M, Brandes AA. The pathogenesis and treatment of brain metastases: A comprehensive review. Crit Rev Oncol Hematol 2004;52:199–215.[Medline]
  12. Gavrilovic IT, Posner JB. Brain metastases: Epidemiology and pathophysiology. J Neurooncol 2005;75:5–14.[CrossRef][Medline]
  13. Nussbaum ES, Djalilian HR, Cho KH et al. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer 1996;78:1781–1788.[CrossRef][Medline]
  14. van den Bent MJ. The role of chemotherapy in brain metastases. Eur J Cancer 2003;39:2114–2120.[CrossRef][Medline]
  15. Stewart DJ, Molepo JM, Green RM et al. Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin. Br J Cancer 1995;71:598–604.[Medline]
  16. Heimans JJ, Vermorken JB, Wolbers JG et al. Paclitaxel (Taxol) concentrations in brain tumor tissue. Ann Oncol 1994;5:951–953.[Abstract/Free Full Text]
  17. Minotti V, Crino L, Meacci ML et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 1998;20:93–98.[CrossRef][Medline]
  18. Crino L, Scagliotti GV, Ricci S et al. Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 1999;17:3522–3530.[Abstract/Free Full Text]
  19. Franciosi V, Cocconi G, Michiara M et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, non-small cell lung carcinoma, or malignant melanoma: A prospective study. Cancer 1999;85:1599–1605.[CrossRef][Medline]
  20. Fujita A, Fukuoka S, Takabatake H et al. Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer. Oncology 2000;59:291–295.[CrossRef][Medline]
  21. Robinet G, Thomas P, Breton JL et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol 2001;12:59–67.[Abstract/Free Full Text]
  22. Bernardo G, Cuzzoni Q, Strada MR et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: A phase II study. Cancer Invest 2002;20:293–302.[CrossRef][Medline]
  23. Cortes J, Rodriguez J, Aramendia JM et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology 2003;64:28–35.[CrossRef][Medline]
  24. Katz A, Zalewski P. Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib. Br J Cancer 2003;89(suppl 2):S15–S18.
  25. Grimm S, DeAngelis L. In: Kufw D, Bast R, Hait W et al, eds. Cancer Medicine. Brain metastases. Seventh Edition. Hamilton, Canada: BC Decker Inc. 2006:1065-1070.
  26. Coleman R, Rubens R. In: Abeloff M, Armitage J, Niederhuber J et al, eds. Clinical Oncology. Bone metastases. Third Edition. Philadelphia: Elsevier Churchill Livingstone, 2004:1091-1128.
  27. Cherny N, Portenoy R. In: Wall P, Melzack R, eds. Textbook of Pain. Cancer pain: Principles of assessment and syndromes. Fourth Edition. Edinburgh, UK: Churchill Livingstone, 2002:1017-1064.
  28. Galasko CS, Norris HE, Crank S. Spinal instability secondary to metastatic cancer. J Bone Joint Surg Am 2000;82:570–594.[Free Full Text]
  29. Selvaggi G, Scagliotti GV. Management of bone metastases in cancer: A review. Crit Rev Oncol Hematol 2005;56:365–378.[Medline]
  30. van der Linden YM, Steenland E, van Houwelingen HC et al. Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: Results on survival in the Dutch Bone Metastasis Study. Radiother Oncol 2006;78:245–253.[CrossRef][Medline]
  31. Chow E, Fung K, Panzarella T et al. A predictive model for survival in metastatic cancer patients attending an outpatient palliative radiotherapy clinic. Int J Radiat Oncol Biol Phys 2002;53:1291–1302.[CrossRef][Medline]
  32. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 1989;256–264.
  33. Van der Linden YM, Dijkstra PD, Kroon HM et al. Comparative analysis of risk factors for pathological fracture with femoral metastases. J Bone Joint Surg Br 2004;86:566–573.[Medline]
  34. Prasad D, Schiff D. Malignant spinal-cord compression. Lancet Oncol 2005;6:15–24.[Medline]
  35. Loblaw DA, Laperriere NJ, Mackillop WJ. A population-based study of malignant spinal cord compression in Ontario. Clin Oncol (R Coll Radiol) 2003;15:211–217.[Medline]
  36. Kimura M, Tominaga T. Outstanding problems with response evaluation criteria in solid tumors (RECIST) in breast cancer. Breast Cancer 2002;9:153–159.[Medline]
  37. Harvey HA. Issues concerning the role of chemotherapy and hormonal therapy of bone metastases from breast carcinoma. Cancer 1997;80(8 suppl):1646–1651.[Medline]
  38. Vansteenkiste J, Vandebroek J, Nackaerts K et al. Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: Detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine. Lung Cancer 2003;40:191–199.[CrossRef][Medline]
  39. Ellis PA, Smith IE, Hardy JR et al. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 1995;71:366–370.[Medline]
  40. Zhang XT, Li LY, Wang SL et al. Improvements in quality of life and disease-related symptoms in patients with advanced non-small cell lung cancer treated with gefitinib. Chin Med J (Engl) 2005;118:1661–1664.[Medline]
  41. Ross JR, Saunders Y, Edmonds PM et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003;327:469.[Abstract/Free Full Text]
  42. Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–3157.[Abstract/Free Full Text]
  43. Rosen LS, Gordon D, Tchekmedyian NS et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: A randomized, phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613–2621.[CrossRef][Medline]
  44. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042–4057.[Abstract/Free Full Text]




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