New Prognostic Index to Predict Survival in Patients with Cancer of Unknown Primary Site with Unfavourable Prognosis
Article Outline
Abstract
Aims
To identify independent prognostic factors in patients with cancer of unknown primary site (CUP) who do not belong to prognostically favourable subsets, and to develop a prognostic index for predicting survival in these patients.
Materials and methods
In this prospective study, univariate and multivariate analyses of prognostic factors were conducted in a population of 145 patients with CUP in two clinical institutions. Subsets of patients with favourable prognostic features and those requiring well-defined treatment were excluded.
Results
The 1-year overall survival rate for all patients was 42% and the median overall survival was 330 days. Overall survival was significantly related to the following pre-treatment prognostic factors: poor Eastern Cooperative Oncology Group performance status (ECOG PS)
≥2, presence of liver metastasis, elevated serum lactate dehydrogenase (LDH), high white blood cell count, anaemia, age≥63 years, and prolonged QTc interval in electrocardiography (ECG). In multivariate analysis, four independent adverse prognostic parameters were retained: elevated LDH (hazard ratio 2.21; 95% confidence interval 1.41–3.47; P=0.001), prolonged QTc interval (hazard ratio 2.10; 95% confidence interval 1.28–3.44; P=0.003), liver metastasis (hazard ratio 1.77; 95% confidence interval 1.11–2.81; P=0.016) and ECOG PS≥2 (hazard ratio 1.69; 95% confidence interval 1.05–2.73; P=0.03). We developed a prognostic index for overall survival based on the following subgroups: good prognosis (no or one adverse factor), intermediate prognosis (two adverse factors) and poor prognosis (three or four adverse factors). The median overall survival for the three subgroups was 420, 152 and 60 days, respectively, P<0.0001.
Conclusions
This study validated previously identified important prognostic factors for survival in patients with CUP. Prolonged QTc was additionally identified as a strong adverse prognostic factor. We developed a simple prognostic index using performance status, LDH, presence of liver metastasis and QTc interval in ECG, which allowed assignment of patients into three subgroups with divergent outcome.
Key words: Neoplasms of unknown origin, prognostic factors, prolonged QTc interval, survival analysis
Introduction
Cancer of unknown primary site (CUP) represents a group of heterogeneous tumours that share the unique clinical characteristics of metastatic epithelial disease, with no identifiable site of origin during pre-treatment evaluation 1, 2. Several groups have proposed different diagnostic and therapeutic protocols for this complex disease 2, 3, 4.
CUP accounts for 5% of all cancer and is considered to have an incidence equal to or higher than that of non-Hodgkin's lymphoma, ovarian cancer or rectal carcinoma 1, 2, 3, 5. The exact incidence is unknown because many of these patients are assigned other diagnoses and are therefore not accurately represented in tumour registries. Even after post-mortem examination, the primary site is not identified in almost half the cases. The most common primary sites identified at autopsy are the lung and pancreas [6].
The definition of this disease has varied over time according to the inclusion criteria and evolution of diagnostic tools used. CUP demonstrates common characteristics, such as aggressiveness, early dissemination and silent primary tumour. The clinical course is often dominated by symptoms and signs related to metastasis. The primary tumour may either have a slow growth, or become involuted and undetectable. It has been hypothesised that cancer may remain dormant until subclones with angiogenic phenotypes arise and lead to metastases [7]. The common sites of involvement are the liver, lymph nodes, lungs and bones 1, 2, 5.
The overall prognosis is very poor, with a median survival of 4–12 months despite treatment, with <50% of patients alive at 1 year and <10% at 5 years after diagnosis 1, 2, 4. A number of prognostic factors have been identified in patients with CUP, but only a few, such as poor performance status, presence of liver metastasis and high serum lactate dehydrogenase (LDH) have been widely accepted as useful prognostic markers. Specific treatment options are available for patients with favourable features and they will have better survival if treated appropriately 1, 5, 8, 9, 10. Unfortunately, only a minority of CUP patients (∼15%) fall into one of the favourable subsets and there is no agreement regarding the best approach for most patients. More studies and inclusion of novel prognostic factors are needed to determine a role for pre-treatment prognosis in CUP. QTc interval evaluation is one of the suggested safety biomarkers that may have an important place in the clinical prediction of cancer patient survival [11]. QT interval reflects the traditional electrocardiographic (ECG) parameter of duration of ventricular repolarisation, and has been linked to the occurrence of ventricular arrhythmia and sudden cardiac death 12, 13.
We conducted an analysis to identify independent prognostic factors with a significant effect on survival in patients with CUP who did not belonging to prognostically favourable subsets. We developed a simple prognostic index for the selection of patients before undergoing chemotherapy or other treatment.
Materials and Methods
We prospectively followed 145 consecutive chemotherapy-naive patients with CUP between March 2002 and March 2007 in Clinical Hospital Rijeka and General Hospital Pula, Croatia. Patients were required to be aged between 18 and 85 years and to undergo the following procedures: complete medical history and physical examination, including breast palpation and testicular and prostate examinations in men, a complete blood biochemistry profile, chest X-ray, faecal occult blood testing, gynaecological examination with ultrasonography and mammography in women, abdominopelvic and chest computerised tomography (all patients), bone scintigraphy and endoscopic work-up directed by patient symptoms, signs or laboratory abnormalities. Tumour serum marker analysis included: carcinoembryonic antigen, carbohydrate antigen 19-9, alpha-fetoprotein and, additionally, prostate-specific antigen and human chorionic gonadotrophin in men, and cancer antigens 125 and 15-3 in women. Specific pathological evaluation was required at diagnosis to establish the histological diagnosis of carcinoma and rule out other types of tumour, such as lymphoma, melanoma or sarcoma. Patients were excluded from the present study if they had any of the following favourable, already defined features, which require well-defined treatments: women with lone axillary lymph nodes containing adenocarcinoma; undifferentiated carcinoma with neuroendocrine features; poorly differentiated or undifferentiated carcinoma with characteristics of extragonadal germ cell syndrome; women with diffuse peritoneal carcinomatosis (papillary adenocarcinoma); and squamous carcinoma involving upper cervical lymph nodes. We also excluded from the study patients with carcinoma that involved a single potentially resectable tumour and those with prior cancer of any site. All patients provided written informed consent in accordance with institutional guidelines.
To identify potential prognostic factors, we analysed 16 pre-treatment clinical variables, including age, gender, performance status, smoking pattern, tumour histology, metastatic features (number of metastatic organs, presence of liver and lymph node metastasis), diabetes mellitus co-morbidity, biochemical–clinical variables [white blood cell count (WBC), anaemia, LDH, alkaline phosphatase (ALP) and QTc interval in ECG] and treatment with chemotherapy (Table 1). Age was categorised by using a cut-off of 63 years, which was the median age of patients included in this analysis. Performance status was determined according to the Eastern Cooperative Oncology Group (ECOG PS) standard and divided in two main groups ECOG 0 – 1 or ≥2. Biopsies were carried out on metastatic sites, but we did not attempt to confirm histology at all sites. Multiple metastases within a site were considered as a single metastatic site. Patients with numerous liver metastases without additional organ involvement were coded with involvement of a single organ site. Standard criteria were used to diagnose diabetes mellitus.
Table 1. Basic characteristics of 145 patients with cancer of unknown primary and univariate analysis of 1-year survival
| Clinical variable | No. of patients (%) | No. of deaths (%) | Median survival (days) | HR (95% CI) | P |
|---|---|---|---|---|---|
| Age | |||||
| Median (range) | 63 (34–85) | ||||
| <63 | 77 (53.1) | 42 (54.5) | 331 | ||
| ≥63 | 68 (46.9) | 42 (61.8) | 273 | 1.44 (1.01–2.06) | 0.045 |
| Gender | |||||
| Female | 60 (41.4) | 32 (53.3) | 280 | ||
| Male | 85 (58.6) | 52 (61.2) | 245 | 1.02 (0.70–1.48) | 0.92 |
| ECOG PS | |||||
| 0 and 1 | 70 (48.3) | 31 (44.3) | 390 | ||
| 2 or more | 75 (51.7) | 53 (70.7) | 125 | 2.43 (1.56–3.80) | <0.001 |
| Smoking | |||||
| No | 63 (43.4) | 35 (55.6) | 361 | ||
| Yes | 82 (56.6) | 49 (59.8) | 297 | 1.18 (0.82–1.69) | 0.38 |
| Tumour histology | |||||
| Not adenocarcinoma | 53 (36.6) | 31 (58.5) | 280 | ||
| Adenocarcinoma | 92 (63.4) | 53 (57.6) | 334 | 0.87 (0.60–1.26) | 0.46 |
| Number of organs involved | |||||
| One | 72 (49.7) | 38 (52.8) | 298 | ||
| Two or more | 73 (50.3) | 46 (63.0) | 368 | 1.19 (0.83–1.70) | 0.35 |
| Liver metastasis | |||||
| No | 99 (68.3) | 48 (48.5) | 386 | ||
| Yes | 46 (31.8) | 36 (78.3) | 100 | 2.07 (1.67–3.99) | <0.001 |
| Lymph node metastasis | |||||
| Yes | 40 (42.8) | 20 (50.0) | 298 | ||
| No | 105 (57.2) | 64 (61.0) | 370 | 1.45 (0.88–2.40) | 0.15 |
| Diabetes mellitus | |||||
| No | 111 (76.6) | 64 (57.7) | 386 | ||
| Yes | 34 (23.4) | 20 (58.9) | 298 | 0.82 (0.54–1.22) | 0.33 |
| White blood cells | |||||
| Normal | 114 (78.6) | 61 (53.5) | 360 | ||
| High | 31 (21.4) | 23 (74.2) | 158 | 1.89 (1.17–3.06) | 0.009 |
| Anaemia | |||||
| Non-anaemic | 72 (49.7) | 35 (48.6) | 386 | ||
| Anaemic | 73 (50.3) | 49 (67.1) | 211 | 1.75 (1.13–2.70) | 0.011 |
| LDH | |||||
| ≤1.25×ULN | 90 (62.1) | 41 (45.5) | 395 | ||
| >1.25×ULN | 55 (37.9) | 43 (78.2) | 96 | 2.75 (1.79–4.24) | <0.001 |
| ALP | |||||
| ≤1.25×ULN | 99 (68.3) | 54 (54.5) | 334 | ||
| >1.25×ULN | 46 (31.7) | 30 (65.2) | 210 | 1.29 (0.88–1.89) | 0.19 |
| Any positive tumour markers | |||||
| No | 68 (46.9) | 40 (58.8) | 305 | ||
| Any marker positive | 77 (53.1) | 44 (57.1) | 333 | 1.02 (0.71–1.46) | 0.91 |
| QTc interval in ECG, ms | |||||
| ≤440 | 113 (77.9) | 59 (52.2) | 361 | ||
| >440 | 32 (22.1) | 25 (78.1) | 86 | 2.23 (1.68–4.31) | <0.001 |
| Chemotherapy | |||||
| Yes | 87 (60,0) | 42 (48,3) | 298 | ||
| No | 58 (40,0) | 30 (51,7) | 334 | 1.34 (0.98–1.95) | 0.10 |
A high WBC was defined as a count >10×109/l. Similarly, variable anaemia was defined as a haemoglobin level <13.2g/dl. Elevated LDH and ALP were defined as 1.25 times the upper limit of normal of the hospital laboratory's standards. Any positive tumour marker was defined as a value above the upper limit of the reference range. ECGs were recorded at rest on a Schiller Cardiovit AT-2 plus cardiograph at a paper speed of 25mm/s. The QT interval was manually measured by two independent cardiologists for three consecutive beats in all 12 leads. QT interval is corrected for heart rate by dividing it by the square root of the R-R interval in ECG (Bazett formula) and QTc interval duration was defined as the mean duration of all QTc intervals measured. Prolonged QTc was defined as a QTc interval>440ms. We excluded patients with a history of long QT syndrome, sustained ventricular arrhythmia, complete bundle branch block, obligate pacemaker or important bradycardia defined as a heart rate <50bpm at rest, and treatment with drugs known to be associated with significant QT interval prolongation. Overall survival was the interval between diagnosis and death.
There were no sudden cardiac deaths.
Eighty-seven patients had received chemotherapy, 46 platinum based and 41 non-platinum based chemotherapy. The influence of chemotherapy in survival and improving the quality of life was not part of this study.
Stepwise Cox regression models were applied to study predictive factors using the initial characteristics of the patients and biological data. Factors that were identified as significant predictors of overall survival in the univariate setting were categorised for ease of interpretation in the multivariate setting, according to a backward stepwise selection procedure on all variables by removing non-significant variables in order of decreasing importance. Hazard ratios and 95% confidence intervals were calculated for all covariates. Overall survival curves between the prognostic subgroups according to the newly formed prognostic index were calculated according to the Kaplan – Meier method and compared by means of the Log-rank test. Two-way statistical tests were carried out and P<0.05 was considered significant. Factors that were identified as significant predictors of overall survival were used in the development of a prognostic index for stratification of patients into three risk subgroups. The analyses were carried out with the statistical software package SPSS version 13.0 for Windows.
Results
One hundred and forty-five patients, 85 men and 60 women, who presented with pathohistologically proven metastases from CUP and fulfilled diagnostic work-up criteria were included in this study. The median follow-up was 24 months.
The median survival was 330 days, range 23–1760, and 1-, 2- and 3-year survival rates were 42, 17 and 7%, respectively. There were no sudden cardiac deaths. The median age was 63 years, range 34–85 years. Most patients were men (58.6%). Half the patients (51.7%) had a poor performance status (ECOG PS≥2) and more than half were smokers. Adenocarcinoma histology predominated (63.4%) and about half the patients had more than one site of metastatic disease. Liver and lymph nodes were the dominant sites of disease at 31.8 and 42.8%, respectively. One quarter of the patients had diabetes. As expected, half had anaemia and there was a significant number of patients with elevated markers of disease progression (LDH and ALP). Half the patients (53.1%) were positive for a tumour marker. Thirty-two patients had a prolonged QTc interval in ECG.
Of 16 pre-treatment clinical factors, seven were associated with poor prognosis in univariate Cox analysis, including age≥63 years, ECOG PS≥2, liver metastasis, anaemia, elevated LDH, elevated WBC and prolonged QTc interval. Other pre-treatment factors were found not to be significant (Table 1). Multivariate Cox regression analysis revealed an independent prognostic effect for four factors. Patients with elevated LDH had a very poor median survival of 96 days, whereas those with normal LDH had a median survival of 395 days (hazard ratio 2.21; 95% confidence interval 1.41–3.47). Also, a prolonged QTc interval in ECG was a strong prognostic factor. Thirty-two patients with a prolonged QTc interval lived a significantly shorter time than those with a normal QTc interval, 86 vs 361 days, respectively (hazard ratio 2.10; 95% confidence interval 1.28–3.44). Patients with liver metastases had a median survival shorter than those with no liver involvement, 100 vs 386 days, respectively (hazard ratio 1.77; 95% confidence interval 1.11–2.81). Patients who had ECOG PS≥2 had a median survival of 125 days compared with those who had a better performance status with a median survival of 390 days (hazard ratio 1.69; 95% confidence interval 1.05–2.73). The results are given in Table 2.
Table 2. Factors associated to cancer-specific 1-year mortality on multivariate analysis in patients with cancer of unknown primary
| Poor prognostic factors | Multivariate analysis | |
|---|---|---|
| Hazard ratio (95% confidence interval) | P | |
| Elevated LDH (>1.25×ULN) | 2.21 (1.41–3.47) | 0.001 |
| QTc interval prolongation (>440ms) | 2.10 (1.28–3.44) | 0.003 |
| Liver metastasis | 1.77 (1.11–2.81) | 0.016 |
| ECOG PS≥2 | 1.69 (1.05–2.73) | 0.030 |
| Elevated WBC | 0.79 (0.47–1.34) | 0.39 |
| Anaemia | 1.12 (0.70–1.81) | 0.63 |
| Age≥63 years | 1.01 (0.63–1.61) | 0.95 |
A simple prognostic index using one point for each statistically significant poor prognostic factor (elevated serum LDH, prolonged QTc, liver involvement and poor ECOG PS) was developed. It allowed assignment of patients into three subgroups with divergent outcome. Twenty-nine patients without or with only one adverse factor were assigned to the ‘good prognosis’ group with a median survival of 420 days.
Thirty-four patients with two adverse factors were assigned to the ‘intermediate prognosis’ group with a median survival of 152 days. Eighty-two patients with three or four adverse factors were assigned to the ‘poor prognosis’ group with a median survival of 60 days, P≤0.001 (Fig. 1).
Fig. 1
Kaplan–Meier survival curves in three distinct patient subgroups: none or one adverse factor (n
=29, median survival 420 days), two adverse factors (n=34, median survival 152 days), three or four adverse factors (n=82, median survival 60 days). The four adverse prognostic factors were elevated lactate dehydrogenase, prolonged QTc interval, Eastern Cooperative Oncology Group performance status≥2 and liver metastasis.
Discussion
We identified four clinical baseline independent predictors of overall survival: elevated LDH, prolonged QTc interval, poor performance status and liver metastasis. Previous studies dealing with prognostic factors in patients with CUP have identified a number of negative predictors of survival, such as visceral metastases below the diaphragm, tumour location outside the retroperitoneum and peripheral lymph nodes, male gender, poor performance status, high number of metastatic sites, presence of liver metastases, elevated ALP and LDH, low serum albumin, lymphopenia, adenocarcinoma histology and no chemotherapy 1, 5, 8, 9, 10, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24.
To the best of our knowledge, this study is the first to evaluate prolonged QTc interval as an adverse factor in patients with CUP. QT interval is affected by various non-cardiac stimuli, and especially by inflammation and changes in the autonomic nervous system, both of which are present in advanced cancer. The mechanism underlying QTc prolongation is not yet fully understood, but it seems that QTc prolongation may be a new adjunct in risk stratification of patients with advanced cancer 25, 26. A prolonged QTc interval is an independent predictor for cardiac and all-cause mortality in older men and women. In the Zutphen study [27], elderly men with QTc intervals >420ms had a three-fold risk for coronary heart disease mortality, which is higher than the risk for cardiac mortality associated with prolonged QTc>460ms in men in the Rotterdam study [28]. In the Dutch Civil Servants Study [29], QTc interval>440ms was associated with a two-fold risk for both all-cause and cardiac mortality. Varterasian et al. [30] undertook a retrospective survey of baseline QTc in 128 adult patients with heterogeneous primary locations of advanced cancer and confirmed some earlier anecdotal reports that indicate that cancer patients have a longer QTc than other segments of the population. We identified that prolonged QTc is a powerful adverse independent prognostic factor in patients with CUP (hazard ratio 2.10). In our study, using 440ms as a cut-off value, 32 patients had a prolonged QTc interval and 25 of these (78.1%) did not survive for 1 year. Although the significance of anaemia, elevated WBC, and older age was shown in univariate analysis, neither remained an independent negative marker in multivariate analysis.
Van der Gaast et al. [10] built a prognostic model in a population of 79 patients using performance status and serum ALP as independent prognostic factors. Three subgroups were identified with median survival of >4 years, 10 months and 4 months, according to the presence of zero, one, or two adverse prognostic factors, respectively. However, this model was limited to CUP patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma. Lenzi et al. [8] identified very poor prognosis in male patients with metastatic involvement of non-lymph node sites and female patients older than 64 years with metastatic involvement of non-lymph node sites. Hess et al. [31] published a classification and regression tree analysis in 1000 consecutive patients. The worst prognosis was in patients with liver involvement, non-endocrine histology and older than 61 years. However, the applicability of this classification and regression tree analysis in daily practice was not feasible. Recent studies have confirmed the independent prognostic power of performance status, LDH and the presence of liver metastasis 15, 19, 20, 22, 23, 24, 32, 33.
With the inclusion of the novel adverse factor QTc interval, a simple prognostic index using performance status, liver metastasis and serum LDH levels was developed. Three prognostic subgroups were identified: good risk group with zero or one adverse factor, intermediate risk group with two adverse factors and poor risk group with three or four adverse factors, with almost a three-fold difference in median survival between the groups.
Ten patients survived more than 3 years, although they were not free of disease. None of these patients was found to have more than two adverse factors and none had a prolonged QTc interval.
Like some other recent studies in CUP patients, we had a small number of patients available for evaluation. Also, a complete immunohistochemical analysis was carried out in <40% of patients, due to a lack of equipment in the departments at the start of the study. However, the confounding effects of age, drugs and co-morbidity have still to be defined in CUP patients.
In conclusion, we prospectively followed 145 patients with CUP, evaluated prognostic factors and identified an important role for the novel prognostic factor QTc interval that can predict prognosis and response to treatment. A simple prognostic index using performance status, liver metastasis, serum LDH and prolonged QTc interval was developed, which allowed the assignment of patients into three subgroups with divergent outcome. Our proposed prognostic index should be validated in further studies and considered in the design of future randomised trials and may help clinicians and patients in clinical decision making and treatment based on the estimated prognosis. Further prospective trials will be designed in our institutions using this prognostic index.
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PII: S0936-6555(08)00404-4
doi:10.1016/j.clon.2008.09.007
© 2008 The Royal College of Radiologists. Published by Elsevier Inc. All rights reserved.
