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Abstract

Objective:

To report cancer presentations with a median survival of 6 months or less and the effect of treatment on survival.

Methods:

We searched the MEDLINE database to find studies on solid and hematologic cancers that reported presentations consistently shown to have a median survival of 6 months or less. Independent prognostic factors were combined if their combination resulted in greater than 50% 6-month-mortality. For each terminal presentation, we evaluated whether treatment improved survival.

Results:

The search identified 1500 potentially relevant articles, of which 650 were evaluated and 383 were included. Despite different cancer characteristics, a fairly universal picture of terminal disease included decreasing performance status, advancing age, weight loss, metastatic disease, disease recurrence, and laboratory abnormalities indicating extensive disease. Most of the prognostic indicators found were continuous, independent risk factors for mortality. We found little evidence that treatment improved survival at these terminal stages, with increased risk for toxicity.

Conclusion:

This systematic review summarizes prognostic factors in advanced cancer that are consistently associated with a median survival of 6 months or less. There is little evidence that treatment prolongs survival at this stage.

Introduction

Evidence indicates that more treatment does not necessarily constitute better care.¹ There is no consensus on the point in advanced illness when further treatment provides little benefit.² Because of prognostic uncertainty, it would be useful to identify factors that indicate the terminal phase in the illness trajectory.³

This systematic review summarizes the data on common cancer presentations associated with a median survival of 6 months or less and the effect of treatment on survival. A similar study on terminal noncancer presentations has been published separately.⁴

Methods

The MEDLINE database was searched comprehensively to identify studies in any language published between 1980 and November 2010 that evaluated cancer survival, using the terms neoplasm and prognosis, survival, survival analysis, or median survival. Prognostic factors were searched for using terms such as performance status, weight loss, or neoplasm metastasis. The search was augmented by scanning the Surveillance Epidemiology and End Results survival monograph⁵ and references of identified reviews and articles.^6,7

Potentially relevant studies were retrieved and evaluated if they included a cancer presentation with a median survival of 1 year or less. We report only those presentations that had a median survival of 6 months or less in all studies reviewed. We chose easily identifiable clinical presentations and readily available laboratory tests. We extracted data on trials published between 1980 and 2010 but only include those between 1999 and 2010, allowing us to perform an extensive literature review while providing the most recent data.

If specific cancer presentations had median survivals that were above and below 6 months, further subgroup analyses explored potential heterogeneity in the results. For multivariate analysis, independent risk factors were combined and included if their combination was associated with a 50% or greater 6-month mortality risk.

Survival estimates were reported for the best available care. Once the results for each cancer were obtained, cancers with similar terminal presentations were reported together. For each of the presentations, we performed an additional search of randomized trials to evaluate whether treatment improved survival. We report “no survival benefit” when there is trial evidence of no significant survival benefit, and “no evidence of survival benefit” when these presentations were excluded from the trials. Further information on the trial evidence can be found in the Supplementary Tables available online at www.liebertonline.com/jpm.

Results

The search identified 1500 potentially relevant articles, and 650 were retrieved and evaluated. We included 289 studies in the prognosis analysis, with 94 additional studies on treatment (Fig. 1). The results for cancers in general are shown in Table 1, and for specific cancers, organized by cancer site, in Tables 2 and 3 (Supplementary References are available online at www.liebertonline.com/jpm). We define advanced as locally advanced or metastatic disease, and terminal as a presentation with a median survival of 6 months or less. Other terms used, such as refractory disease or anemia, are clarified in the tables.

FIG. 1.

Flow chart of studies search.

Table 1.

General Cancer Presentations

General cancer presentations		Survival benefit of treatment
Solid cancers in general
Any locally advanced or metastatic solid cancer with 1 or more of the following presentations:	Karnofsky Performance Status (KPS) < 60 or Eastern Cooperative Cancer Group (ECOG) performance status > 2	No evidence of survival advantage with treatment of underlying cancer
	Serum calcium > 11.2 mg/dL (>2.8 mmol/L)	No survival benefit with treatment of hypercalcemia or underlying cancer
	Episode of extremity venous thromboembolism or pulmonary embolism	No evidence of survival benefit with treatment of thromboembolic disease in terminal cancer
	Any brain metastasis with KPS < 70	Radiosurgical resection: no survival benefit for patients with KPS < 70, multiple lesions or extracranial metastasesRadiation therapy: no survival benefit
	≥2 brain metastases plus extracranial metastases
	Spinal cord compression with decreased ability to walk	Decompressive surgical resection: no evidence of survival benefit for those with comorbid illness, neurologic conditions, organ dysfunction or brain metastasesRadiotherapy or surgical laminectomy: no survival benefit
	Malignant pericardial effusion	No survival benefit with any treatment of pericardial effusion or underlying cancer
Carcinoma of unknown primary
Any metastatic adenocarcinoma or undifferentiated carcinoma of unknown primary with 1 or more of the following presentations:	KPS < 80 (ECOG performance status > 1)Hepatic, bone or adrenal metastasesRecurrence of disease after chemotherapySerum albumin < 3.5 g/dL or weight loss of ≥ 10% in 6 months	No survival benefit with any treatment

Presentations with a median survival of 6 months or less, and survival benefit of treatment. Supplementary References are available online at www.liebertonline.com/jpm

Table 2.

Solid Cancers by Site

Solid cancer by site		Survival benefit of treatment
	Breast neoplasms
Breast cancer
Any metastatic breast carcinoma with 1 or more of the following presentations:	KPS < 60 (ECOG performance status > 2)Moderate to severe hypercalcemia (serum calcium > 11.2 mg/dL)Spinal cord compression with decreased ability to walkSerum C-reactive protein > 10 mg/L and serum albumin < 3.5 g/dLPeritoneal or leptomeningeal metastases	Aromatase inhibitors, chemotherapy, biological agents (targeted immunotherapy such as lapatinib): no survival benefit seen for those with ECOG performance status > 2, comorbid conditions, ascites, brain or liver metastases, or organ dysfunctionPoor prognostic factors predict decreased treatment response and increased toxicity
Any metastatic breast carcinoma with 3 or more of the following presentations:	KPS < 80 (ECOG performance status ≥ 2)Serum lactate dehydrogenase > 500 IU/LAny liver metastasisAt least 2 sites of metastasesDisease-free interval from initial presentation to metastatic disease of < 24 monthsRecurrent or refractory disease after initial chemotherapy (unresponsive to treatment)Tumor with estrogen receptor-negative plus progesterone receptor- negative status
Metastatic breast carcinoma with brain metastases and 1 or more of the following presentations:	KPS < 80 (ECOG performance status ≥ 2)≥2 brain metastases plus extracranial metastasesTumor with estrogen receptor-negative and progesterone receptor-negative status
Central nervous system neoplasms
Primary brain cancer
Glioblastoma with 1 or more of the following presentations:	KPS < 70 (ECOG performance status ≥ 2)Suboptimal surgical resection or unresectable disease	Postoperative radiation therapy: no survival benefit for recurrent disease.
	Progressive or refractory disease despite initial treatment (unresponsive to treatment)	No evidence of survival benefit of treatment for those with ECOG performance status > 2, comorbid illness, or organ dysfunction
Glioblastoma with 2 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Age > 55 yearsRecurrent disease after initial treatmentLesion in critical hemispheric brain regionTumor volume > 50 cm³ prior to resectionHemoglobin < 12 g/dLPlatelet count > upper limit normal
Digestive system neoplasms
Colorectal cancer
Metastatic colorectal cancer with 1 or more of the following presentations:	KPS < 70 (ECOG performance status ≥ 2)Age > 75 yearsBrain metastases with KPS < 80, age > 70 years, extracranial metastases, or ≥ 2 brain lesions	Chemotherapy or targeted biological agents (such as cetuximab, bevacizumab): no evidence of survival benefit in those with unfavorable genetic profiles or the terminal presentations listed herePoor prognostic factors for survival also predict reduced response rates to treatment and increased toxicity
Metastatic colorectal carcinoma with 2 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Peritoneal carcinomatosis> 2 metastatic sitesMalignant ascitesRefractory disease after chemotherapy
Esophageal and gastric cancers
Locally advanced or metastatic esophageal or gastric cancer with 1 or more of the following presentations:	KPS < 80 (ECOG performance status > 1)Recurrent or refractory disease, with disease-free interval < 6 months	Chemotherapy or targeted biological agents (immunotherapy): no survival benefit for those with ECOG performance status ≥ 2, extensive disease, elevations of serum lactate dehydrogenase, or organ dysfunction
Locally advanced or metastatic esophageal or gastric cancer with 2 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Liver metastasesPeritoneal metastasesSerum alkaline phosphatase > 100 U/LSerum lactate dehydrogenase > 200 IU/LSerum hemoglobin < 1l g/dL
Hepatobiliary and pancreatic cancers
Locally advanced or metastatic biliary tract cancer (cholangiocarcinoma or gallbladder carcinoma) or pancreatic cancer with 1 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Biliary obstruction with jaundice, or total bilirubin level > 10 mg/dLRecurrent or refractory disease after initial chemotherapyLiver, peritoneal, or distant metastasesPortal vein thrombosis or other vascular invasionGross residual disease (visible cancer) after resectionPoorly differentiated or infiltrating diseaseSerum albumin < 3.5 g/dL or > 10% weight lossSerum lactate dehydrogenase > 500 IU/LEpisode of extremity venous thromboembolism or pulmonary embolisMalignant ascites	Chemotherapy for biliary tract cancers: no evidence of survival benefit in the terminal presentations listed hereChemotherapy for pancreatic cancer: no survival benefit (trend to worse survival) for those with KPS 70–80 or ECOG performance status 2
Any hepatocellular carcinoma with 1 or more of the following presentations:	KPS < 60 (ECOG performance status > 2)Severe end-stage cirrhosisLarge tumor size (maximum tumor diameter > 10 cm or tumor volume > 70% liver volume)Any brain metastasis	Transarterial chemoembolization, with or without percutaneous ablation therapy: no survival benefit for those with more advanced stages of disease, including large tumor size, elevations of serum bilirubin, or symptomatic cirrhosis
Unresectable locally advanced or metastatic hepatocellular carcinoma with 2 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Extrahepatic metastasesModerate to severe symptomatic cirrhosis (such as jaundice, ascites, fatigue or bleeding)Alpha-fetoprotein level ≥ 400 ng/mLPortal vein thrombosis
Head and neck neoplasms
Head and neck squamous cell carcinoma
Recurrent, refractory, or metastatic head and neck squamous cell carcinoma with 1 or more of the following presentations:	KPS < 90 (ECOG performance status ≥ 1)Recurrence of disease with any metastases> 10% weight lossMuscle invasion or residual tumor at primary sitePretreatment anemia (hemoglobin < 11 g/dL)Moderate to severe hypercalcemia (serum calcium > 11.2 mg/dL)	Chemotherapy with radiation therapy: no survival benefit for recurrent or metastatic disease No evidence of survival benefit for those with poor prognostic factors listed here, who have lower treatment response and increased toxicity
Thyroid cancer
Anaplastic thyroid carcinoma with 1 or more of the following presentations:	Extracapsular extension or metastasesUnresectable disease or incomplete resection	No survival benefit with any treatment
Skin and melanin neoplasms
Melanoma
Advanced or metastatic melanoma with 1 or more of the following presentations:	KPS < 80 (ECOG performance status ≥ 2)Serum lactate dehydrogenase > 2×the upper limit of normalModerate to severe hypercalcemia (serum calcium > 11.2 mg/dL)Metastasis to the brain or spineMetastases to liver and one other site	No survival benefit with any treatment
Thoracic neoplasms
Non–small cell lung cancer
Any locally advanced or metastatic non-small cell lung cancer with 1 or more of the following presentations:	KPS < 70 (ECOG performance status > 2)Weight loss of > 5% or serum albumin < 3 g/dLLiver metastasesBone or bone marrow metastasesBrain metastases with neurological symptoms, KPS < 70, age > 65 years, or extracranial metastasesPericardial effusionPleural effusion with evidence of distant metastasesSerum hemoglobin < 12 g/dLSerum calcium > 11 mg/dLAge > 70 years with pleural effusion, hypoalbuminemia, elevated serum lactate dehydrogenase, or hyponatremia (levels outside the normal range)	Platinum-based chemotherapy: no survival benefit for those with ECOG performance status ≥ 2Early palliative care added to standard oncology care for metastatic lung cancer: reduced amount of treatment given while increasing survival
Urogenital neoplasms
Female genital neoplasms
Locally advanced or metastatic ovarian, uterine endometrial or uterine cervical cancer with regional or distant spread, and 1 or more of the following presentations:	KPS < 60 (ECOG performance status > 2)Serum calcium > 11.2 mg/dLBrain metastases plus extracranial lesion or KPS < 70 or ≥ 2 brain metastasesIntestinal obstruction without successful repair, or urinary tract obstruction with stent placementUnresectable disease due to location of disease or comorbid illness	Chemotherapy: no evidence of survival benefit in ovarian cancer for those with the terminal presentations listed hereThose with poor prognostic factors have decreased treatment response and increased treatment-related mortalityChemotherapy in endometrial cancer: no survival benefit
Locally advanced or metastatic ovarian, uterine endometrial or uterine cervical cancer with regional or distant spread, and 2 or more of the following presentations:	KPS < 80 (ECOG performance status > 1)Recurrent or refractory disease (unresponsive to treatment)Disease-free interval from diagnosis to disease recurrence or persistence of < 6 monthsSuboptimal resection with bulky residual diseaseSignificant weight loss (>5%)Extra-abdominal metastases	Chemotherapy and radiation therapy for cervical cancer: no evidence of survival benefit for those with the prognostic factors listed hereThose with poor prognostic factors have decreased response to treatment
Male genital neoplasms
Hormone-refractory metastatic prostate cancer with 1 or more of the following presentations:	KPS < 60 (ECOG performance status > 2)KPS < 80 (ECOG performance status > 1) or significant fatigue, plus hemoglobin < 12 g/dLHemoglobin < 10 g/dLSpinal cord compression with decreased ability to walk	Hormonal therapy: no evidence of survival benefit in hormone-refractory diseaseEstramustine-taxane chemotherapy: no evidence of survival benefit in the terminal presentations listed here
Urologic neoplasms
Bladder and Renal cell carcinoma
Locally advanced or metastatic bladder or renal cell carcinoma with 1 or more of the following presentations:	KPS < 70 (ECOG performance status > 2)Brain metastases with ≥ 2 metastases, or extracranial metastasesSerum calcium > 11.2 mg/dL	Chemotherapy or biological agents (such as sunitinib, temsirolimus, interferon alfa): no evidence of survival benefit in those with KPS < 60, comorbid illness, organ dysfunction, or recurrent disease
Locally advanced or metastatic bladder or renal cell carcinoma with 3 or more of the following presentations:	KPS < 80 (ECOG performance status ≥ 2)Hemoglobin < 11.5 g/dLSerum lactate dehydrogenase > 300 IU/L or alkaline phosphatase > 220 U/LDisease-free interval from initial presentation to metastatic disease or disease progression ≤ 1 yearVisceral metastases

Presentations associated with a median survival of 6 months or less, and survival benefit of treatment. Supplementary References are available online at www.liebertonline.com/jpm

KPS, Karnofsky Performance Status; ECOG, Eastern Cooperative Oncology Group.

Table 3.

Hematologic Neoplasms

Hematologic neoplasm		Survival benefit of treatment
Acute leukemia
Acute lymphoblastic or myeloid leukemia with 1 or more of the following presentations:	Age > 70 yearsExtramedullary disease involving the central nervous systemDisease refractory to ≥ 2 courses chemotherapy (unresponsive to treatment)Recurrence with disease-free interval of < 14 months	Chemotherapy, with or without autologous stem cell transplantation: no survival benefit for those > 70 years or with the poor prognostic factors listed here, who have treatment resistance and increased treatment mortalityAllogeneic stem cell transplantation: no evidence of survival benefit for those with age > 50 years or the poor prognostic factors listed hereElderly patients (age > 60 years) with ECOG performance status > 2 have an 80% chance of dying during induction therapy
Acute lymphoblastic or myeloid leukemia with 2 or more of the following presentations:	Age > 60 yearsKPS < 80 (ECOG performance status ≥ 2)Central nervous system involvementEvidence of hemorrhage or infectionWhite blood cell count > 25×10⁹/LSerum lactate dehydrogenase levels > 500 IU/L
Chronic leukemia
Chronic myeloid leukemia in blast transformation with 1 or more of the following presentations:	Age > 50 years with blast transformation of predominantly myeloid originMyeloid blast transformation with white blood cell count > 50×10⁹/L, or platelet count < 100×10⁹/L, or hemoglobin < 10 g/dL> 50% blast cells in the peripheral bloodRecurrent or refractory disease after initial chemotherapy (unresponsive to treatment)	Chemotherapy, autologous stem cell transplantation, biological agents (targeted immunotherapy such as imatinib): no survival benefit, with allogeneic bone marrow transplantation associated with worse survival
Chronic lymphocytic leukemia with 1 or more of the following presentations:	Refractory disease to initial chemotherapyRecurrent disease after ≥ 2 courses of chemotherapy	Chemotherapy: no survival benefit in chronic lymphocytic leukemia, with trend to worse survival for early treatment
Lymphoma and multiple myeloma
Non-Hodgkin's lymphoma or multiple myeloma with 1 or more of the following presentations:	Secondary extranodal or extramedullary involvement of the central nervous systemPrimary central nervous system lymphoma related to human immunodeficiency virus	Chemotherapy for non-Hodgkin's lymphoma, with or without biological agents (targeted immunotherapy such as rituximab): no evidence for survival benefit with the terminal presentations listed hereThose with poor prognostic factors have limited treatment response and high toxicity (those > 60 years with bulky disease and ECOG performance status > 1 had 50% chance of treatment-related death)
Aggressive non-Hodgkin's lymphoma or multiple myeloma that is refractory or recurrent after initial treatment, with 2 or more of the following presentations:	KPS < 70 (ECOG performance status ≥ 2)Age > 65 yearsRefractory or progressive disease after chemotherapyElevated serum lactate dehydrogenase levels above normalSerum albumin < 3 g /dLMultiple myeloma with platelet count < 80×10⁹/LMultiple myeloma with serum creatinine ≥ 2 mg/dL	Melphalan-based chemotherapy for multiple myeloma: no evidence for survival benefit in the terminal presentations listed hereThose with poor prognostic factors had decreased treatment response and increased toxicityOther chemotherapy regimens, with or without stem cell transplantation: no survival benefit

Presentations associated with a median survival of 6 months or less, and survival benefit of treatment. Supplementary References are available online at www.liebertonline.com/jpm.

KPS, Karnofsky Performance Status; ECOG, Eastern Cooperative Oncology Group.

General solid cancer presentations

General terminal presentations of solid cancers

Survival in advanced cancers is strongly dependent on tumor-related factors, while in terminal disease patients generally enter a common final pathway, characterized by anorexia, weight loss, failing performance status, and systemic inflammation.^6,8,9

Performance status is one of the most significant survival predictors in advanced cancer.^10,11 The Karnofsky Performance Status (KPS)^10,12,13 and the Eastern Cooperative Oncology Group (ECOG) scales,¹⁴ described in Table 4, both have good reliability and validity. For any advanced solid cancer, a KPS less than 60 (ECOG status greater than 2) is associated with a median survival of 6 months or less (Supplementary Table 1 available online at www.liebertonline.com/jpm). There has been little change in survival over the past 30 years for those with poor functional status.^10,15 Of note, most oncology trials require an ECOG performance status of 0 or 1 for inclusion, and trials enrolling patients with ECOG status greater than 2 are extremely rare.¹⁶

Table 4.

Performance Status Score ^a

ECOG	Level of functional capacity	Karnofsky	Level of functional capacity
0	Fully active, able to carry on all predisease performance without restriction	100	Normal, no complaints, no evidence of disease
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.	90	Able to carry on normal activity, minor signs or symptoms of disease
		80	Normal activity with effort, some signs or symptoms of disease
2	Ambulatory and capable of all self-care but unable to carry out any work activity. Up and about more than 50% of waking hours	70	Cares for self, unable to carry on normal activity or to do active work
		60	Requires occasional assistance, but is able to care for most needs
3	Capable of only limited self-care, confined to bed or chair more than 50% of waking hours	50	Requires considerable assistance and frequent medical care
		40	Disabled, requires special care and assistance
4	Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair	30	Severely disables, hospitalization is indicated although death is not imminent
		20	Hospitalization is necessary, very sick, active supportive treatment necessary
		10	Moribund, fatal processes progressing rapidly
5	Dead	0	Dead

Karnofsky Performance Status^10,12,13 and Eastern Cooperative Oncology Group (ECOG) performance status scale.¹⁴

Other terminal presentations associated with any advanced solid cancer include serum calcium greater than 11.2 mg/dL, acute venous thromboembolism, brain metastasis with KPS less than 70 or 2 or more brain metastases with extracranial metastases, spinal cord compression with decreased ability to walk, and malignant pericardial effusion (Supplementary Table 1 available online at www.liebertonline.com/jpm). There is no evidence that treatment of the cancer or the specific complication improves survival in these terminal presentations (Supplementary Table 1 available online at www.liebertonline.com/jpm).

Carcinoma of unknown primary

Metastatic adenocarcinomas and poorly differentiated carcinomas of unknown primary site have a median survival of 6 months or less when associated with KPS less than 80, malnutrition, disease recurrence, or metastatic disease in the liver, bone or adrenal glands (Supplementary Table 1 available online at www.liebertonline.com/jpm). No improvement in survival has been seen with any treatment.

Solid neoplasms by site

Breast cancer

The clinical presentations for metastatic breast cancer associated with a median survival of ≤6 months can be found in Table 2 (Supplementary References are available online at www.liebertonline.com/jpm). There is no evidence from randomized trials that treatment improves survival for the terminal presentations listed here. These prognostic factors also predict poorer response to treatment and greater risk for serious toxicity (Supplementary Table 2 available online at www.liebertonline.com/jpm).

Central nervous system cancers

Primary brain cancer

Median survival for glioblastomas is 6 months or less when associated with a KPS of less than 70, suboptimal surgical resection, refractory disease, or two or more of the following: KPS less than 90, age greater than 55 years, recurrent disease, a lesion in a critical brain region, large tumor volume, anemia, or thrombocytosis (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival benefit of treatment has been seen for the terminal presentations listed here.

Digestive system cancers

Colorectal cancer

Median survival for metastatic colorectal cancer is 6 months or less when associated with KPS less than 70, age greater than 75 years, or two or more of the following: KPS less than 90, age greater than 70 years, peritoneal carcinomatosis, brain metastases, more than 2 metastatic sites, malignant ascites, or refractory disease (Supplementary Table 2 available online at www.liebertonline.com/jpm). There is no evidence of a treatment survival benefit for those with the presentations listed here, who have reduced treatment response rates and increased toxicity.

Esophageal and gastric cancers

Median survival for advanced esophageal and gastric cancers is 6 months or less when associated with a KPS less than 80, a disease-free interval less than 6 months, or two or more of the following: KPS less than 90, liver or peritoneal metastases, serum alkaline phosphatase greater than 100 U/L, lactate dehydrogenase greater than 200 IU/L, or serum hemoglobin less than 1l g/L (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival benefit has been seen with treatment for these terminal presentations.

Hepatobiliary and pancreatic cancers

Median survival for locally advanced or metastatic pancreatic and biliary tract cancers is 6 months or less when associated with KPS less than 90, visceral or distant metastases, malignant ascites, biliary obstruction, recurrent or refractory disease, poorly differentiated or infiltrating disease, gross residual disease, malnutrition, serum lactate dehydrogenase greater than 500 IU/L, venous thromboembolism, or portal vein thrombosis (Supplementary Table 2 available online at www.liebertonline.com/jpm). There is no treatment survival benefit for patients with advanced pancreatic or biliary tract cancer and an ECOG performance status greater than 1, and no evidence of a survival benefit for the other terminal presentations listed here.

Locally advanced or metastatic hepatocellular carcinoma has a median survival of 6 months or less when associated with KPS less than 60, severe symptomatic cirrhosis, large tumor volume, any brain metastasis, or two or more of the following: KPS less than 90, extrahepatic metastases, moderate cirrhosis, alfa-fetoprotein level 400 ng/mL or greater, or portal vein thrombosis (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival benefit has been seen with treatment for those with large tumor size, jaundice or symptomatic cirrhosis.

Head and neck cancers

Squamous cell carcinomas of head and neck

Median survival for recurrent, refractory or metastatic squamous cell carcinoma of the head and neck is 6 months or less when associated with a KPS less than 90, significant weight loss, unresectable disease, cancer recurrence with any metastasis, pretreatment anemia, or hypercalcemia (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival advantage has been seen for any treatment of recurrent or metastatic head and neck cancer.

Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma is the most lethal of all cancers.⁵ Most patients have evidence of extracapsular extension with incomplete resection at surgery or distant metastatic spread, and a median survival of 3–5 months (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival benefit has been seen with any treatment.

Skin and melanin neoplasms

Melanoma

Locally advanced or metastatic melanoma has a median survival of 6 months or less when associated with a KPS less than 80, serum calcium greater than 11.2 mg/dL, serum lactate dehydrogenase greater than 400 IU/L, metastases to the brain or spine, or metastases to the liver plus one other site (Supplementary Table 2 available online at www.liebertonline.com/jpm). Chemotherapy does not significantly improve survival while increasing treatment-related toxicity.

Thoracic cancers

Non-small–cell lung carcinoma

The clinical presentations of locally advanced or metastatic non-small cell lung cancer that are associated with a median survival of 6 months or less are shown in Table 2, with Supplementary References available online at www.liebertonline.com/jpm. No survival benefit has been seen with treatment for patients with KPS less than 70, who have been shown to have decreased treatment response and increased toxicity (Supplementary Table 2 available online at www.liebertonline.com/jpm).

Urogenital cancers

Female genital cancers

Median survival for locally advanced or metastatic ovarian, endometrial and cervical cancers is 6 months or less when associated with KPS less than 60, hypercalcemia, brain metastases, intestinal or urinary tract obstruction, unresectable disease, or two or more of the following: KPS less than 80, recurrent or refractory disease, disease-free interval of less than 6 months, suboptimal resection, significant weight loss, or extra-abdominal metastases (Supplementary Table 2 available online at www.liebertonline.com/jpm). No survival benefit has been seen for treatment in these terminal presentations.

Male genital cancers

Once metastatic prostate cancer becomes refractory to hormonal androgen blockade, median survival is 6 months or less for those with KPS less than 60, hemoglobin less than 10 g/dL, serum hemoglobin less than 12 g/dL with KPS less than 80, or spinal cord compression with decreased ability to walk (Supplementary Table 2 available online at www.liebertonline.com/jpm). There is no evidence of a survival advantage of treatment in patients with the terminal presentations listed here.

Urologic neoplasms

Median survival for locally advanced or metastatic bladder and renal cell carcinomas is 6 months or less when associated with KPS less than 70, hypercalcemia, brain metastases, or three or more of the following: KPS less than 80, serum lactate dehydrogenase greater than 300 IU/L or alkaline phosphatase greater than 220 U/L, disease-free interval of less than 1 year, visceral metastases, or hemoglobin less than 11.5 g/dL (Supplementary Table 2 available online at www.liebertonline.com/jpm). There is no evidence of a survival benefit with treatment in patients with KPS less than 60, comorbid illness, organ dysfunction, or recurrent disease.

Hematologic neoplasms

Acute leukemias

Acute lymphoblastic and myeloid leukemias have a median survival of 6 months or less when associated with age greater than 70 years, disease refractory to two or more courses of chemotherapy, recurrence with extramedullary disease involving the central nervous system, recurrence after a disease-free interval of less than 14 months, or 2 or more of the following: age greater than 60 years, KPS less than 80, central nervous system involvement, evidence of hemorrhage or infection, white blood cell count greater than 25×10⁹/L, or serum lactate dehydrogenase less than 500 IU/L. No treatment for acute leukemia has been shown to improve survival for elderly patients or those with these poor prognostic factors (Supplementary Table 3 available online at www.liebertonline.com/jpm).

Chronic leukemias

Median survival for chronic myeloid leukemia with progression to blast phase is 6 months or less when associated with greater than 50% blast cells in the peripheral blood, recurrent or refractory disease, or myeloid blast transformation associated with age greater than 50 years, white blood cell count greater than 50×10⁹/L, platelet count less than 100×10⁹/L, or hemoglobin less than 10 g/dL (Supplementary Table 3 available online at www.liebertonline.com/jpm). No survival advantage has been seen with any treatment for chronic leukemia.

Chronic lymphocytic leukemia has a median survival 6 months or less when disease is recurrent after twol or more courses of chemotherapy or refractory to treatment (Supplementary Table 3 available online at www.liebertonline.com/jpm). No treatment for has been shown to improve survival.

Non-Hodgkin's lymphoma and multiple myeloma

Median survival for aggressive non-Hodgkin's lymphoma and multiple myeloma is 6 months or less when associated with secondary extranodal or extramedullary involvement of the central nervous system, primary central nervous system lymphoma related to human immunodeficiency virus, or two or more of the following: KPS less than 70, age greater than 65 years, refractory disease, elevated serum lactate dehydrogenase, hypoalbuminemia, myeloma with platelet count less than 80×10⁹/L, or myeloma with serum creatinine 2 mg/dL or greater (Supplementary Table 3 available online at www.liebertonline.com/jpm). There is no evidence of a survival benefit with treatment for these terminal presentations.

Discussion

This systematic review reports on presentations that have been consistently shown to have a median survival of 6 months or less. The course of most cancers eventuates in a fairly universal clinical picture, with certain indicators of terminal disease, including decreasing performance status, advancing age, weight loss, metastases to the brain, spine, or liver, disease, recurrence and laboratory abnormalities indicative of inflammation or extensive disease. Most of these prognostic indicators are continuous, independent risk factors for mortality. Cancers with relatively good prognosis and treatment options, such as breast cancer, become terminal when the patient manifests KPS less than 60 or at least three prognostic factors, while cancers with poor prognosis, such as biliary cancers, become terminal with KPS less than 90 or 1 prognostic factor. Our review of studies from 1980 to 1998 showed that survival for these presentations has not changed significantly over the past 30 years, despite many treatment advances.

We found little evidence that treatment prolongs survival in terminal disease. Patients with poor performance status, bulky disease, advanced age, or organ dysfunction generally fail to respond to treatment while experiencing increased toxicity.^17–25 Aggressive treatment for patients with poor prognostic factors may even worsen survival compared with no treatment, as is seen with pancreatic cancer, acute leukemia, and non-Hodgkin's lymphoma.^19,21,22,26 However, for many terminal cancers little evidence is available, because randomized treatment data from this population is lacking. Over 90% of trial participants have ECOG performance status 0 or 1, no comorbid illness, and no evidence of organ dysfunction.¹⁶ Where they have been included, subgroup analysis has shown that treatment does not reduce mortality.^{19,23,26–28} Future randomized trials in patients with terminal disease would be necessary to clarify the efficacy of treatment.

This review has several limitations. This is a qualitative study that provides an overview of common terminal cancer presentations found in published studies; quantitative validation studies are still needed. Although we have included data on terminal presentations of the most common cancers and the effect of numerous treatments, this is not an exhaustive list. We can still search for prognostic factors that could identify those individuals with these presentations who may have an extended prognosis. By definition, half of the patients with a median survival of 6 months will live longer than this, so clinicians must be careful in communicating this uncertainty in honest prognostic discussions with patients, while continuing to search for potentially effective treatments that may provide a survival benefit.

Another limitation of this review is that different types of studies and different populations of cancer patients were combined in the analysis. In this case, it is possible that publication bias or selection bias could have altered the results. However, indicators of mortality were remarkably similar across studies, and we only included those clinical presentations that were consistently shown to have a median survival of 6 months or less in all studies. Finally, we only report on survival in this analysis, and do not provide information on intermediate treatment outcomes such as progression-free survival or quality-of-life measures. Palliative treatments without a known survival benefit could still be offered if they are thought to improve other clinically relevant outcomes.

The “terminal illness” criterion for Medicare hospice eligibility requires enrollees to have a “life expectancy of 6 months or less, assuming the disease runs its normal course.”²⁹ Because prediction of individual prognosis is inexact, with a tendency to overestimate survival, hospice referrals are often delayed until death is imminent.^6,30 Median survival in hospice across the United States is less than 3 weeks; over one third of hospice patients die within 7 days after enrollment, many receiving chemotherapy shortly before death.^2,31

Prognostic discussions are hampered, in part, by physicians' reluctance to broach the subject.^32,33 However, surveys indicate that the majority of patients want prognostic information, which allows them to make informed treatment decisions and prepare for the future.^34,35 In one study, patients with metastatic cancer who had an accurate understanding of their prognosis were less likely to choose aggressive treatments, but had similar survival, compared with patients who overestimated their chances of survival.³⁶

Evidence is accumulating that earlier transition to palliative care may actually prolong survival in some cases.³⁷ One trial randomized patients with metastatic lung cancer to standard oncologic care with or without early palliative care and found that those randomized to palliative care received less chemotherapy and had a median survival that was 2.7 months longer than those receiving standard care.³⁸

In conclusion, this systematic review summarizes prognostic factors common to terminal cancer presentations, and reveals a lack of evidence that treatment prolongs survival at these stages. This could serve as a resource to help physicians provide guidance to cancer patients. Future prognostic studies and randomized trials aimed at this population are needed to validate these findings.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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Supplementary Material

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Systematic Review of Cancer Presentations with a Median Survival of Six Months or Less

Abstract

Abstract

Objective:

Methods:

Results:

Conclusion:

Introduction

Methods

Results

General solid cancer presentations

General terminal presentations of solid cancers

Carcinoma of unknown primary

Solid neoplasms by site

Breast cancer

Central nervous system cancers

Primary brain cancer

Digestive system cancers

Colorectal cancer

Esophageal and gastric cancers

Hepatobiliary and pancreatic cancers

Head and neck cancers

Squamous cell carcinomas of head and neck

Anaplastic thyroid carcinoma

Skin and melanin neoplasms

Melanoma

Thoracic cancers

Non-small–cell lung carcinoma

Urogenital cancers

Female genital cancers

Male genital cancers

Urologic neoplasms

Hematologic neoplasms

Acute leukemias

Chronic leukemias

Non-Hodgkin's lymphoma and multiple myeloma

Discussion

Footnotes

Author Disclosure Statement

References

Supplementary Material