Background The management of unresectable or metastatic gastrointestinal stromal tumors (GISTs) has previously been difficult as they are resistant to conventional chemotherapy and radiation. The development of imatinib mesylate has made a major impact on the management of advanced GISTs. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib.
Background
The management of unresectable or metastatic gastrointestinal stromal tumors (GISTs) has previously been difficult as they are resistant to conventional chemotherapy and radiation. The development of imatinib mesylate has made a major impact on the management of advanced GISTs. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib.Case presentation A 47-year-old man presented in July 1999 with a jejunal GIST with multiple hepatic metastases. The jejunal primary was resected and after unsuccessful cytoreductive chemotherapy, the liver metastases were also resected in December 1999. The patient subsequently relapsed in August 2001 with symptomatic hepatic, subcutaneous gluteal, left choroidal and right ocular metastases all confirmed on CT and PET scanning. Biopsy confirmed recurrent GIST. MRI and lumbar puncture excluded central nervous system involvement. The patient was commenced on imatinib 400 mg bd in September 2001 through a clinical trial. The symptoms improved with objective PET and CT scan response until December 2002 when the patient developed a right-sided foot drop. MRI scan showed a left parasagittal tumor which was resected and confirmed histologically to be metastatic GIST. Imatinib was ceased pre-operatively due to the trial protocol but recommenced in February 2003 on a compassionate use program. The left parasagittal metastasis recurred and required subsequent re-excision in September 2003 and January 2004. Control of the systemic GIST was temporarily lost on reduction of the dose of imatinib (due to limited drug supply) but on increasing the dose back to 800 mg per day, systemic disease was stabilized for a period of time before generalised progression occurred.
Case presentation
A 47-year-old man presented in July 1999 with a jejunal GIST with multiple hepatic metastases. The jejunal primary was resected and after unsuccessful cytoreductive chemotherapy, the liver metastases were also resected in December 1999. The patient subsequently relapsed in August 2001 with symptomatic hepatic, subcutaneous gluteal, left choroidal and right ocular metastases all confirmed on CT and PET scanning. Biopsy confirmed recurrent GIST. MRI and lumbar puncture excluded central nervous system involvement. The patient was commenced on imatinib 400 mg bd in September 2001 through a clinical trial.The symptoms improved with objective PET and CT scan response until December 2002 when the patient developed a right-sided foot drop. MRI scan showed a left parasagittal tumor which was resected and confirmed histologically to be metastatic GIST. Imatinib was ceased pre-operatively due to the trial protocol but recommenced in February 2003 on a compassionate use program. The left parasagittal metastasis recurred and required subsequent re-excision in September 2003 and January 2004. Control of the systemic GIST was temporarily lost on reduction of the dose of imatinib (due to limited drug supply) but on increasing the dose back to 800 mg per day, systemic disease was stabilized for a period of time before generalised progression occurred.Conclusion This case illustrates that the brain can be a sanctuary site to treatment of GISTs with imatinib. Maintaining dosing of imatinib in the face of isolated sites of disease progression is also important, as other metastatic sites may still be sensitive.
Conclusion
This case illustrates that the brain can be a sanctuary site to treatment of GISTs with imatinib. Maintaining dosing of imatinib in the face of isolated sites of disease progression is also important, as other metastatic sites may still be sensitive.

Background Gastrointestinal stromal tumors (GISTs) are rare mesenchymal gastrointestinal tumors which can have an aggressive course. Management of these tumors apart from surgical resection has been difficult in the past because they are resistant to conventional chemotherapy [ 1 ] and radiation. The development of imatinib mesylate [ 2 ] a receptor tyrosine kinase inhibitor has made a major impact on the management of advanced GISTs. It specifically targets the c- kit  (CD117) proto-oncogene gain of function mutation characterising GISTs, blocking the c- kit  kinase, leading to growth cessation and significant durable clinical remissions. This oral drug is also active in all phases of chronic myeloid leukemia (CML) as it also targets the  bcr-abl  tyrosine kinase. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib.
Background
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal gastrointestinal tumors which can have an aggressive course. Management of these tumors apart from surgical resection has been difficult in the past because they are resistant to conventional chemotherapy [ 1 ] and radiation. The development of imatinib mesylate [ 2 ] a receptor tyrosine kinase inhibitor has made a major impact on the management of advanced GISTs. It specifically targets the c- kit  (CD117) proto-oncogene gain of function mutation characterising GISTs, blocking the c- kit  kinase, leading to growth cessation and significant durable clinical remissions. This oral drug is also active in all phases of chronic myeloid leukemia (CML) as it also targets the  bcr-abl  tyrosine kinase. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib.kitkitbcr-ablCase presentation A 47-year-old man presented in July 1999 with melena. A small bowel series and CT abdomen showed a jejunal mass and a 5 × 5 cm complex hepatic mass. A biopsy of the liver lesion revealed a spindle cell tumor. Laparotomy was performed, and the 7.5 cm jejunal mass was resected. A total of 4 liver lesions were noted, but not resected. The histopathology confirmed a gastrointestinal stromal tumor with clear resection margins. He subsequently had 4 cycles of attempted cytoreductive chemotherapy using doxorubicin and dacarbazine. A repeat CT scan showed progression of the liver metastases. An extended right hemihepatectomy was performed in December 1999 with successful excision of all 4 liver metastases. The patient remained well until review in August 2001 when he complained of lethargy, right upper quadrant abdominal pain, diplopia and blurred vision in the left eye. Examination revealed weakness of the right lateral rectus ocular muscle, an amelanotic left choroidal lesion, hepatomegaly and a subcutaneous nodule in the gluteal region. An enhancing lesion in the infero-lateral region of the right globe was confirmed on CT which was thought to be the cause of the ocular muscle weakness. The CT scan also demonstrated a recurrence of multiple hepatic metastases. There were no intracerebral lesions. The gluteal lesion was biopsied and confirmed recurrence of GIST (CD117 positive). A positron emission tomogram (PET) scan also confirmed disease recurrence in the same distribution. Lumbar puncture and MRI scan of the brain excluded the presence of leptomeningeal or cerebral metastases. The patient was commenced on imatinib mesylate (STI-571, Gleevec, Novartis) 400 mg bd in September 2001 as part of a clinical trial. He felt much improved by November 2001 when a repeat CT abdomen showed stable disease but PET scan now showed no FDG uptake. By January 2002 his diplopia had completely resolved but the left-sided choroidal lesion remained unchanged on fundoscopy. The buttock lesion had also resolved. A progress CT in December 2002 showed minor enlargement of one of the liver lesions. A PET scan however continued to show no areas of abnormal FDG uptake. The patient at that time had developed a right-sided foot drop. MRI of the brain and spine demonstrated a left parasagittal tumor with radiographic features consistent with a meningioma (see Figure  1 ). Imatinib was ceased preoperatively as per the trial protocol. A craniotomy was performed on the 28 th  January 2003 with complete resection of the lesion. Histopathology demonstrated metastatic GIST (CD117 positive) (see Figures  2  and  3 ). Post operatively the patient developed recurrent diplopia (due to recurrent right lateral rectus weakness) with blurred vision off imatinib. This was recommenced at a dose of 400 mg bd on the 14 th  February 2003 after being ceased 6 weeks earlier because of the documented disease progression in the brain as required by the trial protocol. Drug supply was obtained through a compassionate use program. Repeat fundoscopy in February 2003 showed the choroidal lesion had enlarged. His foot drop persisted, however his diplopia again had completely resolved by March 2003. Mutational analysis on the tumor blocks was carried out. An in-frame GCCTAT insertion/duplication in exon 9 of c- kit  in the original jejunal tumor, the liver and the cerebral metastases were detected (See Figure  4 ). No mutations were found in exons 11, 13 or 17 in any of the samples. Due to limited drug supply available on compassionate use (pending local approval for reimbursement), the patient's dose of imatinib mesylate was reduced to 400 mg per day in March 2003. Six weeks later, his diplopia had returned and a progress CT abdomen demonstrated a minor progression of the liver lesions. His liver function tests remained normal. A subsequent PET scan again showed no abnormal uptake despite disease progression on the CT scan. His dose of imatinib mesylate was increased initially to 600 mg per day with resolution of the diplopia. By May 2003 his foot drop had worsened and his dose of imatinib mesylate was increased back to 800 mg per day. Despite the increase in dose, his foot drop worsened. A repeat CT brain demonstrated a recurrence of the cerebral metastasis with surrounding vasogenic oedema in the previous site of resection. A repeat abdominal CT showed no significant change in the size of the liver metastasis and mild shrinking of the nodule in the buttock. Due to limited treatment options available for the cerebral metastasis, a re-resection of the cranial metastasis was offered. A repeat MRI of the brain in late July 2003 confirmed the presence of the left parasagittal lesion with surrounding edema but no mass effect. Repeat craniotomy and incomplete debulking of the parasagittal metastasis was performed on the 9 th  September 2003. A small residual area of tumor was seen on the postoperative scan. Abdominal imaging two months later showed that two of the liver lesions had increased in size with the other areas stable. He was not a candidate for further hepatic resection as there was insufficient liver reserve due to the past surgery. Radiofrequency ablation was declined as the patient did not have symptoms referable to the area. The patient remained well until December 2003 when he experienced symptoms of headaches, worsening diplopia, right foot drop and left arm weakness. MRI scan confirmed recurrence of the cerebral metastasis with extension across the falx cerebri. He declined cranial radiotherapy treatment at the time and instead underwent a third resection of the lesion in January 2004 where incomplete debulking was achieved with early improvement of his limb weakness. In April 2004 the patient enrolled into a randomised placebo controlled clinical trial of a novel multi-kinase inhibitor SU-11248 (Pfizer) for the treatment of imatinib refractory GIST. However his condition slowly deteriorated and he died in July 2004.
Case presentation
A 47-year-old man presented in July 1999 with melena. A small bowel series and CT abdomen showed a jejunal mass and a 5 × 5 cm complex hepatic mass. A biopsy of the liver lesion revealed a spindle cell tumor. Laparotomy was performed, and the 7.5 cm jejunal mass was resected. A total of 4 liver lesions were noted, but not resected. The histopathology confirmed a gastrointestinal stromal tumor with clear resection margins. He subsequently had 4 cycles of attempted cytoreductive chemotherapy using doxorubicin and dacarbazine. A repeat CT scan showed progression of the liver metastases. An extended right hemihepatectomy was performed in December 1999 with successful excision of all 4 liver metastases.The patient remained well until review in August 2001 when he complained of lethargy, right upper quadrant abdominal pain, diplopia and blurred vision in the left eye. Examination revealed weakness of the right lateral rectus ocular muscle, an amelanotic left choroidal lesion, hepatomegaly and a subcutaneous nodule in the gluteal region. An enhancing lesion in the infero-lateral region of the right globe was confirmed on CT which was thought to be the cause of the ocular muscle weakness. The CT scan also demonstrated a recurrence of multiple hepatic metastases. There were no intracerebral lesions. The gluteal lesion was biopsied and confirmed recurrence of GIST (CD117 positive). A positron emission tomogram (PET) scan also confirmed disease recurrence in the same distribution. Lumbar puncture and MRI scan of the brain excluded the presence of leptomeningeal or cerebral metastases. The patient was commenced on imatinib mesylate (STI-571, Gleevec, Novartis) 400 mg bd in September 2001 as part of a clinical trial. He felt much improved by November 2001 when a repeat CT abdomen showed stable disease but PET scan now showed no FDG uptake. By January 2002 his diplopia had completely resolved but the left-sided choroidal lesion remained unchanged on fundoscopy. The buttock lesion had also resolved.A progress CT in December 2002 showed minor enlargement of one of the liver lesions. A PET scan however continued to show no areas of abnormal FDG uptake. The patient at that time had developed a right-sided foot drop. MRI of the brain and spine demonstrated a left parasagittal tumor with radiographic features consistent with a meningioma (see Figure  1 ). Imatinib was ceased preoperatively as per the trial protocol. A craniotomy was performed on the 28 th  January 2003 with complete resection of the lesion. Histopathology demonstrated metastatic GIST (CD117 positive) (see Figures  2  and  3 ). Post operatively the patient developed recurrent diplopia (due to recurrent right lateral rectus weakness) with blurred vision off imatinib. This was recommenced at a dose of 400 mg bd on the 14 th  February 2003 after being ceased 6 weeks earlier because of the documented disease progression in the brain as required by the trial protocol. Drug supply was obtained through a compassionate use program. Repeat fundoscopy in February 2003 showed the choroidal lesion had enlarged. His foot drop persisted, however his diplopia again had completely resolved by March 2003.Mutational analysis on the tumor blocks was carried out. An in-frame GCCTAT insertion/duplication in exon 9 of c- kit  in the original jejunal tumor, the liver and the cerebral metastases were detected (See Figure  4 ). No mutations were found in exons 11, 13 or 17 in any of the samples.kitDue to limited drug supply available on compassionate use (pending local approval for reimbursement), the patient's dose of imatinib mesylate was reduced to 400 mg per day in March 2003. Six weeks later, his diplopia had returned and a progress CT abdomen demonstrated a minor progression of the liver lesions. His liver function tests remained normal. A subsequent PET scan again showed no abnormal uptake despite disease progression on the CT scan. His dose of imatinib mesylate was increased initially to 600 mg per day with resolution of the diplopia.By May 2003 his foot drop had worsened and his dose of imatinib mesylate was increased back to 800 mg per day. Despite the increase in dose, his foot drop worsened. A repeat CT brain demonstrated a recurrence of the cerebral metastasis with surrounding vasogenic oedema in the previous site of resection. A repeat abdominal CT showed no significant change in the size of the liver metastasis and mild shrinking of the nodule in the buttock.Due to limited treatment options available for the cerebral metastasis, a re-resection of the cranial metastasis was offered. A repeat MRI of the brain in late July 2003 confirmed the presence of the left parasagittal lesion with surrounding edema but no mass effect. Repeat craniotomy and incomplete debulking of the parasagittal metastasis was performed on the 9 th  September 2003. A small residual area of tumor was seen on the postoperative scan. Abdominal imaging two months later showed that two of the liver lesions had increased in size with the other areas stable. He was not a candidate for further hepatic resection as there was insufficient liver reserve due to the past surgery. Radiofrequency ablation was declined as the patient did not have symptoms referable to the area.The patient remained well until December 2003 when he experienced symptoms of headaches, worsening diplopia, right foot drop and left arm weakness. MRI scan confirmed recurrence of the cerebral metastasis with extension across the falx cerebri. He declined cranial radiotherapy treatment at the time and instead underwent a third resection of the lesion in January 2004 where incomplete debulking was achieved with early improvement of his limb weakness. In April 2004 the patient enrolled into a randomised placebo controlled clinical trial of a novel multi-kinase inhibitor SU-11248 (Pfizer) for the treatment of imatinib refractory GIST. However his condition slowly deteriorated and he died in July 2004.Discussion This case illustrates a man who has had evidence of presumed ocular involvement by the GIST that initially responded to imatinib who had a cranial relapse while the systemic disease initially remained controlled. This would imply that the central nervous system could be a sanctuary site where the imatinib mesylate does not achieve adequate levels. Preclinical mice models of CML have shown development of central nervous involvement on imatinib despite systemic disease control with cerebral spinal fluid levels being 155 times lower than plasma [ 3 ]. This is supported by clinical data from treatment of CML, where isolated cerebral relapses [ 4 , 5 ] have been described and low cerebrospinal fluid (CSF) levels of imatinib mesylate documented during therapy with the drug [ 6 ]. One case of cerebral metastases from advanced GIST responding to imatinib mesylate has been published [ 7 ]. We would postulate that the blood brain barrier might be disrupted in some individuals thereby allowing better penetration of the drug to the brain. However in those individuals with good systemic disease control, the central nervous system may represent a sanctuary site for imatinib sensitive disease to progress. There appears to be a relationship between the presence of different activating kinase mutations of  kit  and clinical outcomes of GISTs on imatinib [ 8 ]. The exon 9 mutation encoding the extracellular domain occurs in approximately 15% of GISTs resulting in duplication of Ala 502  and Tyr 503  This may be marker for malignant course of the disease as 71% have a highly malignant course and 59% arise exclusively in the small intestine [ 9 ]. Patients with exon 9 mutations also have a much worse prognosis than those with the more commonly found exon 11 mutations [ 8 ]. The difference is likely to be due to differences in downstream signalling in these mutations affecting the susceptibility of the GIST to imatinib and in our case may have compounded the problem with reduced CSF levels of the drug. Exon 17 mutations have been found in some GISTs that have relapsed on imatinib and are thought to be a mechanism of acquired resistance [ 10 ]. The absence of this superadded mutation would lend support to the central nervous system in being a sanctuary site in this patient.
Discussion
This case illustrates a man who has had evidence of presumed ocular involvement by the GIST that initially responded to imatinib who had a cranial relapse while the systemic disease initially remained controlled. This would imply that the central nervous system could be a sanctuary site where the imatinib mesylate does not achieve adequate levels. Preclinical mice models of CML have shown development of central nervous involvement on imatinib despite systemic disease control with cerebral spinal fluid levels being 155 times lower than plasma [ 3 ]. This is supported by clinical data from treatment of CML, where isolated cerebral relapses [ 4 , 5 ] have been described and low cerebrospinal fluid (CSF) levels of imatinib mesylate documented during therapy with the drug [ 6 ]. One case of cerebral metastases from advanced GIST responding to imatinib mesylate has been published [ 7 ]. We would postulate that the blood brain barrier might be disrupted in some individuals thereby allowing better penetration of the drug to the brain. However in those individuals with good systemic disease control, the central nervous system may represent a sanctuary site for imatinib sensitive disease to progress.There appears to be a relationship between the presence of different activating kinase mutations of  kit  and clinical outcomes of GISTs on imatinib [ 8 ]. The exon 9 mutation encoding the extracellular domain occurs in approximately 15% of GISTs resulting in duplication of Ala 502  and Tyr 503  This may be marker for malignant course of the disease as 71% have a highly malignant course and 59% arise exclusively in the small intestine [ 9 ]. Patients with exon 9 mutations also have a much worse prognosis than those with the more commonly found exon 11 mutations [ 8 ]. The difference is likely to be due to differences in downstream signalling in these mutations affecting the susceptibility of the GIST to imatinib and in our case may have compounded the problem with reduced CSF levels of the drug. Exon 17 mutations have been found in some GISTs that have relapsed on imatinib and are thought to be a mechanism of acquired resistance [ 10 ]. The absence of this superadded mutation would lend support to the central nervous system in being a sanctuary site in this patient.kitConclusions The central nervous system can be a sanctuary site to treatment of GIST with imatinib mesylate. Prolonged control of the recurrences in this location was achieved by repeated resections. This patient also highlights the importance of maintaining dosing of imatinib mesylate in the face of isolated sites of disease progression, as other metastatic sites may still be sensitive. Cessation and lowering of the dose of the drug led to temporary loss of systemic control in this case.
Conclusions
The central nervous system can be a sanctuary site to treatment of GIST with imatinib mesylate. Prolonged control of the recurrences in this location was achieved by repeated resections. This patient also highlights the importance of maintaining dosing of imatinib mesylate in the face of isolated sites of disease progression, as other metastatic sites may still be sensitive. Cessation and lowering of the dose of the drug led to temporary loss of systemic control in this case.Competing interests David Goldstein and Paul Waring have both consulted and spoken on behalf of Novartis Pharma on imatinib and GIST.
Competing interests
David Goldstein and Paul Waring have both consulted and spoken on behalf of Novartis Pharma on imatinib and GIST.Authors' contributions BH, DY, DG and GC participated in the clinical care of the case. PW and VB performed the mutation analysis and prepared the histopathology images. BH and DY drafted the manuscript. All authors read and approved the final manuscript.
Authors' contributions
BH, DY, DG and GC participated in the clinical care of the case. PW and VB performed the mutation analysis and prepared the histopathology images. BH and DY drafted the manuscript. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Prostate cancer continues to occur in over 230,000 men each year. Although the majority of these will be diagnosed in the early stages, there remains a proportion who will either be diagnosed in late stage disease or develop progressive disease. In patients with advanced disease, research has recently focused on using chemotherapy for symptom management and palliation. Given that the focus is not on cure, the effect of chemotherapy on quality of life is of utmost importance. The present article will 1) summarize the current chemotherapeutic studies that have included a quality of life component, with a particular focus on pain and fatigue, 2) discuss the issue of distress in advanced prostate cancer patients treated with chemotherapy, and 3) suggest future research directions.From the studies that have investigated quality of life, it appears that several chemotherapeutic agents reduce pain and fatigue, although the development of fatigue is often the dose-limiting factor of some agents. The assessment of overall quality of life has occurred in several studies, however, an examination into the impact of chemotherapy on functional status and interpersonal relationships has not been studied. Finally, in contrast to the numerous studies in early stage prostate cancer patients, the presence and effect of distress in chemotherapy-treated prostate patients has not been examined. As such, increased attention is needed to quality of life during phase I-III chemotherapy trials.

Background and significance Prostate cancer will be diagnosed in an estimated 230,110 men during 2004 [ 1 ]. There will also be approximately 29,900 men who will die from prostate cancer this year, making it the second leading cause of cancer death among men. While early detection and improved treatments have resulted in improved 5-year survival rates for individuals with early stage prostate cancer (recent data have put the 5-year survival rates at 100% for men diagnosed with local and regional prostate cancer), there remains a proportion of men (roughly 14%) who will be diagnosed with advanced prostate cancer. For these individuals, the 5-year survival rate is much lower. Indeed only 34% of men diagnosed with distant disease will survive for 5 years [ 1 ]. For men with late stage disease, chemotherapy is increasingly being examined as a treatment option, although the goal is usually palliative in nature and may not extend length of survival [ 2 , 3 ]. Chemotherapy is also being explored as adjuvant therapy in men with early stage disease where length of survival may be lengthened by its administration. In both cases, but particularly among men receiving chemotherapy as treatment for advanced cancer, the effect that chemotherapy may have on quality of life (QOL) is extremely important. This QOL includes not only the individual's physical well-being, but their mental well-being, role functioning and levels of emotional distress as well. At present, few studies have examined the impact of chemotherapy on the physical and emotional QOL of prostate cancer patients. The goals of the current article are to: 1) summarize the current chemotherapeutic studies that have included a quality of life component, with a particular focus on pain and fatigue, 2) discuss the issue of distress in advanced prostate cancer patients treated with chemotherapy, and 3) suggest future research directions. Impact of chemotherapy on quality of life The inclusion of QOL endpoints in chemotherapy trials with cancer patients started in earnest during the last decade, with the majority of studies assessing the impact of chemotherapeutic agents on symptoms such as pain and fatigue. Since then, the inclusion of QOL endpoints has become a more common outcome in chemotherapy studies, although many continue to neglect the psychological component, focusing instead on the occurrence of symptoms and their impact on physical QOL.
Background and significance
Prostate cancer will be diagnosed in an estimated 230,110 men during 2004 [ 1 ]. There will also be approximately 29,900 men who will die from prostate cancer this year, making it the second leading cause of cancer death among men. While early detection and improved treatments have resulted in improved 5-year survival rates for individuals with early stage prostate cancer (recent data have put the 5-year survival rates at 100% for men diagnosed with local and regional prostate cancer), there remains a proportion of men (roughly 14%) who will be diagnosed with advanced prostate cancer. For these individuals, the 5-year survival rate is much lower. Indeed only 34% of men diagnosed with distant disease will survive for 5 years [ 1 ].For men with late stage disease, chemotherapy is increasingly being examined as a treatment option, although the goal is usually palliative in nature and may not extend length of survival [ 2 , 3 ]. Chemotherapy is also being explored as adjuvant therapy in men with early stage disease where length of survival may be lengthened by its administration. In both cases, but particularly among men receiving chemotherapy as treatment for advanced cancer, the effect that chemotherapy may have on quality of life (QOL) is extremely important. This QOL includes not only the individual's physical well-being, but their mental well-being, role functioning and levels of emotional distress as well. At present, few studies have examined the impact of chemotherapy on the physical and emotional QOL of prostate cancer patients. The goals of the current article are to: 1) summarize the current chemotherapeutic studies that have included a quality of life component, with a particular focus on pain and fatigue, 2) discuss the issue of distress in advanced prostate cancer patients treated with chemotherapy, and 3) suggest future research directions.Impact of chemotherapy on quality of life The inclusion of QOL endpoints in chemotherapy trials with cancer patients started in earnest during the last decade, with the majority of studies assessing the impact of chemotherapeutic agents on symptoms such as pain and fatigue. Since then, the inclusion of QOL endpoints has become a more common outcome in chemotherapy studies, although many continue to neglect the psychological component, focusing instead on the occurrence of symptoms and their impact on physical QOL.
Impact of chemotherapy on quality of life
The inclusion of QOL endpoints in chemotherapy trials with cancer patients started in earnest during the last decade, with the majority of studies assessing the impact of chemotherapeutic agents on symptoms such as pain and fatigue. Since then, the inclusion of QOL endpoints has become a more common outcome in chemotherapy studies, although many continue to neglect the psychological component, focusing instead on the occurrence of symptoms and their impact on physical QOL.Methods A comprehensive search of English-language articles in PubMed was conducted to identify studies that had assessed quality of life and/or emotional distress as part of chemotherapeutic trials in advanced cancer patients (Table  1 ). The keywords "advanced cancer", "chemotherapy", and "quality of life" were included in each search. In subsequent searches "distress", "anxiety", and "depression" were added. Table 1 Summary of reviewed articles Authors Chemotherapeutic agent QOL measure Direction of effect Tannock et al. (1996) Mitoxantrone EORTC QLQ-30; Pain rating Improved pain, mood & physical activity Beer et al., (2001) Docetaxel Present Pain Intensity scale Improved pain Sinibaldi et al. (1999) Docetaxel Brief Pain Inventory Improved pain Copur et al. (2001) Docetaxel Numeric rating scale Improved pain Gravis et al. (2003) Docetaxel EORTC QLQ-30; Pain VAS Improved role, social functioning, overall QOL, pain, fatigue, constipation Small et al. (2000) Suramin Brief Pain Inventory Improved pain Fuse et al. (1996) Cisplatin/carboplatin Rating scale Improved pain Kreis et al. (1999). Docetaxel Physician-graded events Presence of fatigue dose-limiting factor Hamilton et al. (2003) Vinblastine Physician-graded events Presence of fatigue dose-limiting factor van Andel et al. (2003) Epirubicin QLQ-30 Reduced fatigue, transient improvement in emotional, social and cognitive functioning Kornblith et al. (2001) Docetaxel FACT-P, Mental Health Inventory-17 Transient improvements in emotional well-being, improved overall QOL Pain In one of the first studies to examine the impact of chemotherapy on pain, Tannock, Osoba, Stockler et al. [ 4 ] randomized 161 hormone-resistant prostate cancer patients either to prednisolone or prednisolone plus mitoxantrone. The goal was to determine the impact on pain reduction as a palliative endpoint. Also included was the overall assessment of QOL using the EORTC QLQ-30 and a specific prostate cancer QOL measure composed of nine analog scales. The results demonstrated that the addition of mitoxantrone to prednisolone reduced pain in 29% of patients compared to 10% for those who only received prednisolone. Improvements in pain, mood, and physical activity were also observed on the QOL measures for the individuals who received mitoxantrone. Additional analyses from this study revealed that after six weeks of treatment, pain and physical functioning remained improved in the mitoxantrone plus prednisone group. Moreover, after 12 weeks of treatment, overall quality of life in this group was improved, as was quality of life in four functional domains and nine specific symptoms [ 5 ]. Additional studies with mitoxantrone have demonstrated that up to 40% of patients will report reductions in pain and improvements in QOL [ 6 ]. As a result, in hormone-resistant prostate cancer patients, mitoxantrone is believed to be of some benefit [ 4 ]. Pain was also assessed in several studies utilizing docetaxel either alone or in combination with estramustine in androgen-independent prostate cancer [ 7 - 9 ]. In one study, the administration of docetaxel as a single agent resulted in pain relief, defined as two-point reduction in the Present Pain Intensity scale on two consecutive evaluations, in 30% of patients [ 10 ]. Moreover, an additional 18% reduced their consumption of analgesics by at least 50%. Mean pain scores on quality of life scales were also reduced over the course of treatment [ 7 ]. In two studies using the combination of docetaxel and estramustine, pain reductions were observed in 70% and 82% of patients [ 8 , 9 ]. Unfortunately, the methods used to assess pain are not thoroughly reported in either study. In a recent study, docetaxel was administered intravenously on a daily basis for 6 consecutive weeks followed by a 2-week break between each of up to 4 cycles [ 11 ]. The authors assessed QOL prior to the start of chemotherapy, the first day of each treatment cycle, and then 15 and 30 days after the last treatment. At baseline, metastatic, hormone-refractory prostate cancer patients reported decreased QOL in role, social functioning, and overall QOL, as well as pain, fatigue, and constipation. Of note, following the first cycle, all patients reported improved QOL and pain relative to baseline levels. At the end of treatment, pain levels had increased somewhat, but were still lower than baseline levels. Combined, these studies suggest that docetaxel is effective in reducing pain in androgen-independent patients. Reductions in pain have also been observed in studies using suramin and epirubicin. In a study by Small et al. [ 12 ], comparing suramin plus hydrocortisone to a placebo plus hydrocortisone, reduction in pain for longer durations were observed in the suramin treated group. Interestingly, however, more global measures of QOL were not impacted by that treatment. Despite the reduction in pain, because overall QOL and survival rates are similar to hydrocortisone treated patients, whether suramin should be regularly used in the treatment of hormone-refractory prostate cancer patients is unclear. This is also true for suramin with anthracycline regimens, where the combination, because it does not offer significant improvements in disease management, is not recommended to hormone-resistant prostate cancer patients [ 13 - 18 ]. Pain reduction has also been observed in prostate cancer patients treated with epirubicin [ 19 ]. Interestingly, the reductions in pain did not correspond to patient-reported improvements in QOL. As a result, like suramin, the authors concluded that epirubicin should not be used as a monotherapy. The use of the more commonly known platinum compounds (e.g., cisplatin, carboplatin) have also demonstrated beneficial efforts on pain reduction. In advanced prostate cancer patients treated with a carboplatin/epirubicin/etoposide regimen, pain relief was observed in 44% of the patients [ 20 ]. The overall point of these studies is that for prostate cancer patients with advanced disease, there are a variety of chemotherapeutic agents that have beneficial palliative effects, specifically pain reduction. Despite this, there is no definitive palliative pain regimen in this population and no defined algorithm for pain management using chemotherapy. Fatigue Several studies have investigated the relationship between chemotherapeutic agents and fatigue in prostate cancer patients. Among the agents studied are the taxanes, specifically docetaxel and paclitaxel. In phase I studies of docetaxel and estramustine, the presence of fatigue has been used to identify the dose-limiting factor [ 21 , 22 ]. Currently, a phase III trial is underway to determine the impact on QOL of docetaxel/estramustine compared with mitoxantrone/prednisolone [ 23 ]. In a similar phase I/II study examining the effect of vinblastine for androgen-independent prostate cancer, fatigue was also reported as the dose-limiting factor. More importantly, however, the agent was found to be inactive resulting in the conclusion that vinblastine is not an appropriate treatment [ 24 ]. Fatigue was also an endpoint in a well-designed study that assessed the effect of 25 mg/m2 epirubicin administered intravenously on a weekly basis compared to 100 mg/m2 administered every 4-weeks [ 19 ]. After four weeks of treatment, individuals who were in the Epi100 group reported less fatigue. They also reported better emotional, social, and cognitive functioning as measured by QLQ-30, although these differences disappeared at repeated assessments. The effect of subsequent administration of either dosage of epirubicin on fatigue was not reported, although the authors note that there were no differences at subsequent assessments between groups. As such, it is unknown whether epirubicin decreases or increases fatigue in prostate cancer patients over time. Quality of Life (QOL) In contrast to the numerous QOL studies of early-stage prostate cancer patients, beyond pain and fatigue, the assessment of QOL in advanced stage prostate cancer patients is relatively lacking. By and large there are no studies assessing the common areas of physical well-being (e.g., urinary and sexual functioning) or psychological well-being (e.g., distress related to treatment or sequelae), and social or family well-being in chemotherapy treated patients. The notable exception is a study of the QOL of 44 hormone refractory prostate cancer patients and their partners by Kornblith et al. [ 25 ]. In a phase II study of docetaxel, estramustine, and low dose hydrocortisone, prostate cancer patients were assessed with the Functional Assessment of Cancer Therapy-Prostate, as well as the Mental Health Inventory-17. Over a period of 6-months, men reported significant improvements on the Emotional Well-being subscale. Further examination, however, revealed that when compared to the baseline assessment, emotional well-being was only better at the two and four month assessments. Total FACT-P scores improved over the course of treatment as well, as did prostate cancer-specific concerns, although the former was not significant [ 25 ]. The authors concluded that the benefits of the chemotherapeutic regimen were limited to the first four-months of treatment. Impact of chemotherapy on emotional distress In contrast to the various studies that have investigated the presence of emotional distress, depression, and anxiety in early stage prostate cancer patients, there is remarkably little concerning these issues in those with advanced cancer. Indeed, a Pubmed search using the terms "distress AND advanced prostate cancer" resulted in only 12 studies. Of these, only 3 studies specifically focused on advanced prostate cancer [ 25 - 27 ], with 1 of these focusing on physical symptom distress [ 26 ] and another focused on a group of asymptomatic men with nonmetastatic prostate cancer receiving androgen deprivation therapy [ 27 ]. Only one of the studies, the previously cited Kornblith et al. [ 25 ] study assessed distress in chemotherapy treated men. The result, therefore, is an overwhelming lack of information concerning the emotional functioning of chemotherapy-treated prostate cancer patients. It is hard to believe that these individuals who are frequently androgen-deprived, have a short life expectancy, and are being treated with chemotherapy for palliative purposes are not experiencing some emotional distress. Even as part of phase II studies, where the sample sizes are small, emotional distress should be examined if for no other reason than to provide initial information as to what changes may be seen in a larger sample, and what issues need to be assessed.
Methods
A comprehensive search of English-language articles in PubMed was conducted to identify studies that had assessed quality of life and/or emotional distress as part of chemotherapeutic trials in advanced cancer patients (Table  1 ). The keywords "advanced cancer", "chemotherapy", and "quality of life" were included in each search. In subsequent searches "distress", "anxiety", and "depression" were added.Summary of reviewed articlesAuthorsChemotherapeutic agentQOL measureDirection of effectPain In one of the first studies to examine the impact of chemotherapy on pain, Tannock, Osoba, Stockler et al. [ 4 ] randomized 161 hormone-resistant prostate cancer patients either to prednisolone or prednisolone plus mitoxantrone. The goal was to determine the impact on pain reduction as a palliative endpoint. Also included was the overall assessment of QOL using the EORTC QLQ-30 and a specific prostate cancer QOL measure composed of nine analog scales. The results demonstrated that the addition of mitoxantrone to prednisolone reduced pain in 29% of patients compared to 10% for those who only received prednisolone. Improvements in pain, mood, and physical activity were also observed on the QOL measures for the individuals who received mitoxantrone. Additional analyses from this study revealed that after six weeks of treatment, pain and physical functioning remained improved in the mitoxantrone plus prednisone group. Moreover, after 12 weeks of treatment, overall quality of life in this group was improved, as was quality of life in four functional domains and nine specific symptoms [ 5 ]. Additional studies with mitoxantrone have demonstrated that up to 40% of patients will report reductions in pain and improvements in QOL [ 6 ]. As a result, in hormone-resistant prostate cancer patients, mitoxantrone is believed to be of some benefit [ 4 ]. Pain was also assessed in several studies utilizing docetaxel either alone or in combination with estramustine in androgen-independent prostate cancer [ 7 - 9 ]. In one study, the administration of docetaxel as a single agent resulted in pain relief, defined as two-point reduction in the Present Pain Intensity scale on two consecutive evaluations, in 30% of patients [ 10 ]. Moreover, an additional 18% reduced their consumption of analgesics by at least 50%. Mean pain scores on quality of life scales were also reduced over the course of treatment [ 7 ]. In two studies using the combination of docetaxel and estramustine, pain reductions were observed in 70% and 82% of patients [ 8 , 9 ]. Unfortunately, the methods used to assess pain are not thoroughly reported in either study. In a recent study, docetaxel was administered intravenously on a daily basis for 6 consecutive weeks followed by a 2-week break between each of up to 4 cycles [ 11 ]. The authors assessed QOL prior to the start of chemotherapy, the first day of each treatment cycle, and then 15 and 30 days after the last treatment. At baseline, metastatic, hormone-refractory prostate cancer patients reported decreased QOL in role, social functioning, and overall QOL, as well as pain, fatigue, and constipation. Of note, following the first cycle, all patients reported improved QOL and pain relative to baseline levels. At the end of treatment, pain levels had increased somewhat, but were still lower than baseline levels. Combined, these studies suggest that docetaxel is effective in reducing pain in androgen-independent patients. Reductions in pain have also been observed in studies using suramin and epirubicin. In a study by Small et al. [ 12 ], comparing suramin plus hydrocortisone to a placebo plus hydrocortisone, reduction in pain for longer durations were observed in the suramin treated group. Interestingly, however, more global measures of QOL were not impacted by that treatment. Despite the reduction in pain, because overall QOL and survival rates are similar to hydrocortisone treated patients, whether suramin should be regularly used in the treatment of hormone-refractory prostate cancer patients is unclear. This is also true for suramin with anthracycline regimens, where the combination, because it does not offer significant improvements in disease management, is not recommended to hormone-resistant prostate cancer patients [ 13 - 18 ]. Pain reduction has also been observed in prostate cancer patients treated with epirubicin [ 19 ]. Interestingly, the reductions in pain did not correspond to patient-reported improvements in QOL. As a result, like suramin, the authors concluded that epirubicin should not be used as a monotherapy. The use of the more commonly known platinum compounds (e.g., cisplatin, carboplatin) have also demonstrated beneficial efforts on pain reduction. In advanced prostate cancer patients treated with a carboplatin/epirubicin/etoposide regimen, pain relief was observed in 44% of the patients [ 20 ]. The overall point of these studies is that for prostate cancer patients with advanced disease, there are a variety of chemotherapeutic agents that have beneficial palliative effects, specifically pain reduction. Despite this, there is no definitive palliative pain regimen in this population and no defined algorithm for pain management using chemotherapy.
Pain
In one of the first studies to examine the impact of chemotherapy on pain, Tannock, Osoba, Stockler et al. [ 4 ] randomized 161 hormone-resistant prostate cancer patients either to prednisolone or prednisolone plus mitoxantrone. The goal was to determine the impact on pain reduction as a palliative endpoint. Also included was the overall assessment of QOL using the EORTC QLQ-30 and a specific prostate cancer QOL measure composed of nine analog scales. The results demonstrated that the addition of mitoxantrone to prednisolone reduced pain in 29% of patients compared to 10% for those who only received prednisolone. Improvements in pain, mood, and physical activity were also observed on the QOL measures for the individuals who received mitoxantrone. Additional analyses from this study revealed that after six weeks of treatment, pain and physical functioning remained improved in the mitoxantrone plus prednisone group. Moreover, after 12 weeks of treatment, overall quality of life in this group was improved, as was quality of life in four functional domains and nine specific symptoms [ 5 ]. Additional studies with mitoxantrone have demonstrated that up to 40% of patients will report reductions in pain and improvements in QOL [ 6 ]. As a result, in hormone-resistant prostate cancer patients, mitoxantrone is believed to be of some benefit [ 4 ].Pain was also assessed in several studies utilizing docetaxel either alone or in combination with estramustine in androgen-independent prostate cancer [ 7 - 9 ]. In one study, the administration of docetaxel as a single agent resulted in pain relief, defined as two-point reduction in the Present Pain Intensity scale on two consecutive evaluations, in 30% of patients [ 10 ]. Moreover, an additional 18% reduced their consumption of analgesics by at least 50%. Mean pain scores on quality of life scales were also reduced over the course of treatment [ 7 ]. In two studies using the combination of docetaxel and estramustine, pain reductions were observed in 70% and 82% of patients [ 8 , 9 ]. Unfortunately, the methods used to assess pain are not thoroughly reported in either study.In a recent study, docetaxel was administered intravenously on a daily basis for 6 consecutive weeks followed by a 2-week break between each of up to 4 cycles [ 11 ]. The authors assessed QOL prior to the start of chemotherapy, the first day of each treatment cycle, and then 15 and 30 days after the last treatment. At baseline, metastatic, hormone-refractory prostate cancer patients reported decreased QOL in role, social functioning, and overall QOL, as well as pain, fatigue, and constipation. Of note, following the first cycle, all patients reported improved QOL and pain relative to baseline levels. At the end of treatment, pain levels had increased somewhat, but were still lower than baseline levels. Combined, these studies suggest that docetaxel is effective in reducing pain in androgen-independent patients.Reductions in pain have also been observed in studies using suramin and epirubicin. In a study by Small et al. [ 12 ], comparing suramin plus hydrocortisone to a placebo plus hydrocortisone, reduction in pain for longer durations were observed in the suramin treated group. Interestingly, however, more global measures of QOL were not impacted by that treatment. Despite the reduction in pain, because overall QOL and survival rates are similar to hydrocortisone treated patients, whether suramin should be regularly used in the treatment of hormone-refractory prostate cancer patients is unclear. This is also true for suramin with anthracycline regimens, where the combination, because it does not offer significant improvements in disease management, is not recommended to hormone-resistant prostate cancer patients [ 13 - 18 ]. Pain reduction has also been observed in prostate cancer patients treated with epirubicin [ 19 ]. Interestingly, the reductions in pain did not correspond to patient-reported improvements in QOL. As a result, like suramin, the authors concluded that epirubicin should not be used as a monotherapy.The use of the more commonly known platinum compounds (e.g., cisplatin, carboplatin) have also demonstrated beneficial efforts on pain reduction. In advanced prostate cancer patients treated with a carboplatin/epirubicin/etoposide regimen, pain relief was observed in 44% of the patients [ 20 ].The overall point of these studies is that for prostate cancer patients with advanced disease, there are a variety of chemotherapeutic agents that have beneficial palliative effects, specifically pain reduction. Despite this, there is no definitive palliative pain regimen in this population and no defined algorithm for pain management using chemotherapy.Fatigue Several studies have investigated the relationship between chemotherapeutic agents and fatigue in prostate cancer patients. Among the agents studied are the taxanes, specifically docetaxel and paclitaxel. In phase I studies of docetaxel and estramustine, the presence of fatigue has been used to identify the dose-limiting factor [ 21 , 22 ]. Currently, a phase III trial is underway to determine the impact on QOL of docetaxel/estramustine compared with mitoxantrone/prednisolone [ 23 ]. In a similar phase I/II study examining the effect of vinblastine for androgen-independent prostate cancer, fatigue was also reported as the dose-limiting factor. More importantly, however, the agent was found to be inactive resulting in the conclusion that vinblastine is not an appropriate treatment [ 24 ]. Fatigue was also an endpoint in a well-designed study that assessed the effect of 25 mg/m2 epirubicin administered intravenously on a weekly basis compared to 100 mg/m2 administered every 4-weeks [ 19 ]. After four weeks of treatment, individuals who were in the Epi100 group reported less fatigue. They also reported better emotional, social, and cognitive functioning as measured by QLQ-30, although these differences disappeared at repeated assessments. The effect of subsequent administration of either dosage of epirubicin on fatigue was not reported, although the authors note that there were no differences at subsequent assessments between groups. As such, it is unknown whether epirubicin decreases or increases fatigue in prostate cancer patients over time.
Fatigue
Several studies have investigated the relationship between chemotherapeutic agents and fatigue in prostate cancer patients. Among the agents studied are the taxanes, specifically docetaxel and paclitaxel. In phase I studies of docetaxel and estramustine, the presence of fatigue has been used to identify the dose-limiting factor [ 21 , 22 ]. Currently, a phase III trial is underway to determine the impact on QOL of docetaxel/estramustine compared with mitoxantrone/prednisolone [ 23 ]. In a similar phase I/II study examining the effect of vinblastine for androgen-independent prostate cancer, fatigue was also reported as the dose-limiting factor. More importantly, however, the agent was found to be inactive resulting in the conclusion that vinblastine is not an appropriate treatment [ 24 ].Fatigue was also an endpoint in a well-designed study that assessed the effect of 25 mg/m2 epirubicin administered intravenously on a weekly basis compared to 100 mg/m2 administered every 4-weeks [ 19 ]. After four weeks of treatment, individuals who were in the Epi100 group reported less fatigue. They also reported better emotional, social, and cognitive functioning as measured by QLQ-30, although these differences disappeared at repeated assessments. The effect of subsequent administration of either dosage of epirubicin on fatigue was not reported, although the authors note that there were no differences at subsequent assessments between groups. As such, it is unknown whether epirubicin decreases or increases fatigue in prostate cancer patients over time.Quality of Life (QOL) In contrast to the numerous QOL studies of early-stage prostate cancer patients, beyond pain and fatigue, the assessment of QOL in advanced stage prostate cancer patients is relatively lacking. By and large there are no studies assessing the common areas of physical well-being (e.g., urinary and sexual functioning) or psychological well-being (e.g., distress related to treatment or sequelae), and social or family well-being in chemotherapy treated patients. The notable exception is a study of the QOL of 44 hormone refractory prostate cancer patients and their partners by Kornblith et al. [ 25 ]. In a phase II study of docetaxel, estramustine, and low dose hydrocortisone, prostate cancer patients were assessed with the Functional Assessment of Cancer Therapy-Prostate, as well as the Mental Health Inventory-17. Over a period of 6-months, men reported significant improvements on the Emotional Well-being subscale. Further examination, however, revealed that when compared to the baseline assessment, emotional well-being was only better at the two and four month assessments. Total FACT-P scores improved over the course of treatment as well, as did prostate cancer-specific concerns, although the former was not significant [ 25 ]. The authors concluded that the benefits of the chemotherapeutic regimen were limited to the first four-months of treatment.
Quality of Life (QOL)
In contrast to the numerous QOL studies of early-stage prostate cancer patients, beyond pain and fatigue, the assessment of QOL in advanced stage prostate cancer patients is relatively lacking. By and large there are no studies assessing the common areas of physical well-being (e.g., urinary and sexual functioning) or psychological well-being (e.g., distress related to treatment or sequelae), and social or family well-being in chemotherapy treated patients. The notable exception is a study of the QOL of 44 hormone refractory prostate cancer patients and their partners by Kornblith et al. [ 25 ]. In a phase II study of docetaxel, estramustine, and low dose hydrocortisone, prostate cancer patients were assessed with the Functional Assessment of Cancer Therapy-Prostate, as well as the Mental Health Inventory-17. Over a period of 6-months, men reported significant improvements on the Emotional Well-being subscale. Further examination, however, revealed that when compared to the baseline assessment, emotional well-being was only better at the two and four month assessments. Total FACT-P scores improved over the course of treatment as well, as did prostate cancer-specific concerns, although the former was not significant [ 25 ]. The authors concluded that the benefits of the chemotherapeutic regimen were limited to the first four-months of treatment.Impact of chemotherapy on emotional distress In contrast to the various studies that have investigated the presence of emotional distress, depression, and anxiety in early stage prostate cancer patients, there is remarkably little concerning these issues in those with advanced cancer. Indeed, a Pubmed search using the terms "distress AND advanced prostate cancer" resulted in only 12 studies. Of these, only 3 studies specifically focused on advanced prostate cancer [ 25 - 27 ], with 1 of these focusing on physical symptom distress [ 26 ] and another focused on a group of asymptomatic men with nonmetastatic prostate cancer receiving androgen deprivation therapy [ 27 ]. Only one of the studies, the previously cited Kornblith et al. [ 25 ] study assessed distress in chemotherapy treated men. The result, therefore, is an overwhelming lack of information concerning the emotional functioning of chemotherapy-treated prostate cancer patients. It is hard to believe that these individuals who are frequently androgen-deprived, have a short life expectancy, and are being treated with chemotherapy for palliative purposes are not experiencing some emotional distress. Even as part of phase II studies, where the sample sizes are small, emotional distress should be examined if for no other reason than to provide initial information as to what changes may be seen in a larger sample, and what issues need to be assessed.
Impact of chemotherapy on emotional distress
In contrast to the various studies that have investigated the presence of emotional distress, depression, and anxiety in early stage prostate cancer patients, there is remarkably little concerning these issues in those with advanced cancer. Indeed, a Pubmed search using the terms "distress AND advanced prostate cancer" resulted in only 12 studies. Of these, only 3 studies specifically focused on advanced prostate cancer [ 25 - 27 ], with 1 of these focusing on physical symptom distress [ 26 ] and another focused on a group of asymptomatic men with nonmetastatic prostate cancer receiving androgen deprivation therapy [ 27 ]. Only one of the studies, the previously cited Kornblith et al. [ 25 ] study assessed distress in chemotherapy treated men. The result, therefore, is an overwhelming lack of information concerning the emotional functioning of chemotherapy-treated prostate cancer patients. It is hard to believe that these individuals who are frequently androgen-deprived, have a short life expectancy, and are being treated with chemotherapy for palliative purposes are not experiencing some emotional distress. Even as part of phase II studies, where the sample sizes are small, emotional distress should be examined if for no other reason than to provide initial information as to what changes may be seen in a larger sample, and what issues need to be assessed.Conclusions and implications Chemotherapy is being examined with greater frequency in the treatment of advanced prostate cancer. Since the goal of treatment for these individuals is more likely to be palliation than cure, understanding the impact on QOL is that much more important. For example, understanding the impact on QOL can assist clinicians and patients in decision-making by providing data on whether symptom benefit obtained outweighs the toxicities from treatment. Thus far, several studies have identified improvements in pain and fatigue as a result of chemotherapeutic protocols, although in some studies, the presence of fatigue is a dose-limiting factor. Disappointing is the lack of focus on the more global aspects of quality of life, the impact on physical, psychological, social, and family well-being. How the treatment of the individual affects their relationships with others (e.g., marital relationship, sexual functioning) has yet to be studied in this population. Also yet to be studied is the impact on emotional well-being. The presence of distress in cancer patients is well-documented (e.g., [ 28 ]), and it is known that early-stage prostate cancer patients exhibit distress (bother) over physical side effects (i.e., urinary and sexual functioning). In addition, distress related to PSA tests has been documented. What then is the emotional well-being of advanced prostate cancers like? Does the administration of chemotherapy play a role in either the development of distress or its reduction? As the continued development and testing of chemotherapeutic medications for advanced prostate cancer moves from phase I through phase II and III trials, it is of ever-increasing importance to assess the impact on QOL and distress. Only through its inclusion will a clearer picture of the efficacy of chemotherapy be observed. Future research can do this by developing protocols that include HRQOL parameters as a standard part of the design process. Both the industry that develops and tests the compound and the academics who deliver it to the patient should be involved in identifying which aspects of QOL are essential to target.
Conclusions and implications
Chemotherapy is being examined with greater frequency in the treatment of advanced prostate cancer. Since the goal of treatment for these individuals is more likely to be palliation than cure, understanding the impact on QOL is that much more important. For example, understanding the impact on QOL can assist clinicians and patients in decision-making by providing data on whether symptom benefit obtained outweighs the toxicities from treatment.Thus far, several studies have identified improvements in pain and fatigue as a result of chemotherapeutic protocols, although in some studies, the presence of fatigue is a dose-limiting factor. Disappointing is the lack of focus on the more global aspects of quality of life, the impact on physical, psychological, social, and family well-being. How the treatment of the individual affects their relationships with others (e.g., marital relationship, sexual functioning) has yet to be studied in this population. Also yet to be studied is the impact on emotional well-being. The presence of distress in cancer patients is well-documented (e.g., [ 28 ]), and it is known that early-stage prostate cancer patients exhibit distress (bother) over physical side effects (i.e., urinary and sexual functioning). In addition, distress related to PSA tests has been documented. What then is the emotional well-being of advanced prostate cancers like? Does the administration of chemotherapy play a role in either the development of distress or its reduction? As the continued development and testing of chemotherapeutic medications for advanced prostate cancer moves from phase I through phase II and III trials, it is of ever-increasing importance to assess the impact on QOL and distress. Only through its inclusion will a clearer picture of the efficacy of chemotherapy be observed. Future research can do this by developing protocols that include HRQOL parameters as a standard part of the design process. Both the industry that develops and tests the compound and the academics who deliver it to the patient should be involved in identifying which aspects of QOL are essential to target.