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Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer
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The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer Dimitri A. Raptis*, Chris Fessas, Peter Belasyse-Smith, Tom R. Kurzawinski Department of Hepatopancreaticobiliary & Endocrine Surgery, University College London Hospitals, NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK
article info
abstract
Article history:
Introduction: The prognosis of patients with pancreatic cancer remains poor despite recent
Received 8 February 2010
advances in treatment. It is not known whether delays in referring, diagnosing and treating
Received in revised form
these patients and the way they present can affect their survival.
1 March 2010
Aims: In our study we investigated the impact of clinical presentation (jaundice, abdominal
Accepted 4 March 2010
pain, weight loss) and delays in management of these patients on their treatment and survival. Methods: Data on all patients with pancreatic cancer referred to the Pancreatic Unit
Keywords:
(1997e2002) were collected prospectively and analysed using SPSS 16. The delay in diag-
Pancreatic cancer
nosis and treatment for each patient was measured by estimating the time from the
Surgery
beginning of symptoms to the date of the referral letter (T1), the time from the referral date
Prognostic factors
to the date of first review at the Unit (T2) and the time from date of review to the date of
Delay in diagnosis
diagnosis/treatment (T3). Treatments were defined as 1) pancreatic resections, 2) gastric
Two-week-wait
and biliary bypass and 3) biliary stents. The term ‘operability’ was used to describe patients
Target referral
thought to have a potentially removable tumour and had an operation and ‘resectability’
Survival
applied to the patients whose tumour was actually removed at the operation. Follow-up time and survival were recorded by reviewing the patient’s notes, hospital electronic databases and by contacting patients General Practitioners. Results: There were a total of 355 patients with pancreatic cancer. Median age at diagnosis was 64 (i.q.r. 56e71) years and median follow-up was 8 (i.q.r. 4e14) months. The overall 1, 3 and 5 years patient’s survival was 26%, 5% and 4% respectively. 1, 3 and 5 years survival of inoperable patients was 24%, 2% and 0% and for operable patients was 35%, 13% and 9% respectively. The median survival time for those patients that underwent operation was significantly higher than those that did not (12 vs 6 months, p < 0.001). The overall median time from initial symptoms to diagnosis/treatment (T1 þ T2 þ T3) was 102 (i.q.r. 56e182) days, T1 was 65 (i.q.r. 31e143), T2 17 (i.q.r. 8e28) and T3 11 (i.q.r. 6e21) days. The time delay from symptoms to referral (T1) had minimal clinical relevance to survival, with a hazard ratio of only 1.001 (95% CI 0.001e0.002, p ¼ 0.043) per day. Of all 355 patients, 305 (86%) were reviewed and treated within 62 days from the GP referral (T2 þ T3). There was no significant difference in operability, resectability and survival of patients that
Abbreviations: i.q.r., interquartile range; PDAC, pancreatic ductal adenocarcinoma; HR, hazard ratio; T1, time from the beginning of symptom to the date of the letter referring patient to Pancreatic Unit; T2, time from referral date to the date of review at the Unit; T3, time from the date of review to the date of diagnosis/treatment. * Corresponding author. Tel.: þ44 41798820542. E-mail address: [email protected] (D.A. Raptis). 1479-666X/$ e see front matter ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2010.03.001
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were diagnosed/treated before or after 62 days from referral (T2 þ T3) (median months 6.5 and 7.9 respectively, p ¼ 0.134). Patients presenting with jaundice were referred (T1, median 56 vs 103) and diagnosed/ treated (T2 þ T3, median 96 vs 130) days ( p < 0.001) sooner, had a higher operability rate (33% vs 21%, p ¼ 0.035) but not a significantly higher resectability rate of (37% vs 29%) ( p ¼ 0.608). Isolated or combined mode of clinical presentation had no significant effect on survival ( p ¼ 0.965). On multivariate regression analysis, prognostic factors of survival were a resectable tumour and the time from the beginning of symptoms to referral. Conclusion: This study showed that pre-hospital delays in referring patients to a specialist unit, but not hospital related 62 days target, had an no impact on operability, resectability and survival. Clinical presentation also had no impact on the survival. We confirmed that pancreatic resection is the most important factor in determining the length of survival in patients with pancreatic cancer. Our study implies that the successful implementation of the 62 days National Cancer Waits Target across the UK is unlikely to have an impact on prognosis in patients with pancreatic cancer. Focusing on early referral to specialist Pancreatic Units might be more effective. ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignant diseases1,2 ranking fourth as a leading cause of cancer-related deaths in the Western world.3 The prognosis of this cancer is poor, with an overall 5-year survival rate of only 1e4%.3 Prognosis of any malignant tumour depends on its biological behaviour, reflected by its ability to invade locally or metastasize, along with the efficacy of the available treatments. Sadly, in the case of pancreatic cancer, we are faced by a tumour with aggressive biological behaviour, which invades locally and metastasizes early. Disease specific factors reflecting poor prognosis described in the literature are, distant metastasis, TNM staging, lymph node involvement, neural, vascular and peri-pancreatic invasion, tumour differentiation and size (>3 cm) and involvement of resection margins.4,5 Currently available treatments have only small impact on the natural history of the disease. Surgery is potentially the only chance for cure,6 but only 10% of patients have resectable tumours and 5-year survival rate after successful resection is in the range of 15e25%.5,7e10 Advances in operative techniques and in perioperative care have increased the resectability of pancreatic cancer and have decreased the operative morbidity and mortality, but have not affected prognosis.11e15 Palliative and adjuvant chemotherapies have so far had minimal impact on survival.16,17 Apart from biological behaviour of the tumour and the efficacy of treatment, the third important factor, which is thought to affect prognosis, is the speediness of diagnosis and treatment. Cancers progress over time and it is a justifiable assumption that early detection of disease and implementation of treatment can improve prognosis. Clinical features of pancreatic cancer such as weight loss, abdominal pain and jaundice, especially in the early stages of the disease, can be vague and non-specific, causing delays in patients seeking help and late referral.18 These pre-hospital, but also hospital related delays in diagnosing and treating patients with
pancreatic cancer can be one of the reasons why the majority of patients present with locally advanced and/or metastatic disease. The mortality rates for several cancers in the UK are higher than other European countries19,20 and this has been partially attributed to long waiting times for treatment.2 As part of the ‘NHS Cancer Plan’, the UK government introduced the ‘Cancer waiting times targets’ in the year 2000, stipulating that patients with suspected cancer should be seen by a specialist within 14 days and treated within 48 days. The overall time from referral of the patient with suspected cancer to diagnosis and starting treatment should not exceed 62 days.21 Furthermore, Trusts that do not comply with these targets would incur financial penalties.
Objective The aim of this study was to evaluate whether the nature of clinical presentation (jaundice, abdominal pain, weight loss) and time delay in referring, diagnosing and treating patients with pancreatic cancer had any effect on operability, resectability and survival.
Methods In the period between January of 1997 and December of 2002, 335 patients with pancreatic cancer were admitted to the Pancreatic Unit at the Middlesex Hospital, London, UK. Information on all the patients diagnosed with pancreatic cancer was collected prospectively in a Pancreatic Database. Patients with ampullary, peri-ampullary and duodenal cancer, neuroendocrine and cystic pancreatic neoplasms were not included in this study. Patient’s data included sex, age and clinical presentation (jaundice, abdominal pain, weight loss) as described by patients and documented in their notes. The delay in diagnosis and treatment for each patient was measured by estimating the time from the beginning of
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symptoms to the date of the letter referring the patient to the Pancreatic Unit at The Middlesex Hospital (T1), the time from the referral date to the date of review at the Unit (either clinic appointment or admission for investigations, whichever came first) (T2) and time from date of review to the date of diagnosis/treatment (T3). The date of diagnosis/treatment was defined in descending order of preference either as the date of operation, the date of histology report in inoperable cases or if the biopsy was not available, the date of the CT scan reporting a diagnosis of pancreatic cancer. The basis on which diagnosis of pancreatic cancer was made (histology, cytology, radiology, clinical features) was recorded. Treatments were defined as 1) pancreatic resections, 2) gastric and biliary bypass and 3) biliary stents. The term operability was used to describe patients thought to have potentially removable tumour and had an operation (resection or bypass) and the term resectability applied to the patients whose tumour was actually removed at operation (resections only). Follow-up time and survival were recorded by reviewing patients’ notes, hospital electronic databases and by contacting patient’s General Practitioners.
Statistical analysis Continuous variables were compared using either the Student’s t, the ManneWhitney U or one-way ANOVA tests when appropriate. Difference among proportion was compared with Fisher’s exact test. All calculated p values were two-sided and p value of 0.05 was considered statistically significant. Cumulative survival was calculated using the KaplaneMeier Log Rank test. Both variables with and without significance in univariate analysis were included in the Cox regression model to calculate multivariate analysis and hazard ratios. Statistical analysis was performed on SPSS 16 for Mac.
Results There were a total of 355 patients with PDAC, 213 (60%) of them male. Median age at diagnosis was 64 (i.q.r. 56e71) years and median follow-up was 8 (i.q.r. 4e14) months. The basis of the diagnosis was histology of the primary tumour in 298 (84%) patients and of metastasis in 25 (7%). Seven patients (2%) had positive cytology and the remaining 25 patients (7%) had diagnosis established by a combination of radiological imaging, laparotomy findings, elevated CA19-9 and a clinical course highly suggestive of pancreatic cancer. Out of the 355 patients, 101 (29%) underwent operation and only 33 (overall 9%) of those had a resectable tumour. Table 1 shows patient’s management. The overall 1, 3 and 5 years patient’s survival was 26%, 5% and 4% respectively. 1, 3 and 5 years survival of inoperable patients was 24%, 2% and 0% and for operable patients was 35%, 13% and 9% respectively (Table 1). The median survival time for those patients that underwent operation was significantly higher than those that did not (12 vs 6 months, p < 0.001). For operable patients 1, 3, and 5 years survival for bypasses was 21%, 5% and 0% and for resectable patients was 66%, 31% and 25% respectively. Patients with a resectable
cancer had a significantly higher median survival time when compared to those that received a bypass and endoscopic stents (16 vs 8 months, p < 0.001) (Fig. 1). There was no significant statistical difference in median survival between the inoperable and bypassed patients (Table 1, Fig. 1) The overall median time from initial symptoms to diagnosis/treatment (T1 þ T2 þ T3) was 102 (i.q.r. 56e182) days. The median time from initial symptoms to referral to Pancreatic Unit (T1) was 65 (i.q.r. 31e143) days. The time delay from symptoms to referral alone (T1) had minimal clinical relevance with hazard rate ratio of only 1.001 (95% CI 0.001e0.002, p ¼ 0.043) per day. By using the 75% quartile (143 days) as a cut-off point, patients who presented to their GP within less than 143 days from the beginning of symptoms had a higher operability (32% vs 19%, p ¼ 0.039) but not significantly higher resectability (34% vs 21%, p ¼ 0.379) rates when compared to those who presented within more than 143 days. Patients that presented within 143 days from their initiation of symptoms to their GP visit had a favourable survival when compared to those that presented after 143 days (Table 1, Fig. 2)
Table 1 e Clinical features, management and survival of patients with PDAC.
Symptomatic Jaundicea Abdominal paina Weight lossa Othera,b Combined Symptoms not recorded Time from symptom <31 days >31 days <65 days >65 days <143 days >143 days
No. of patients (%)
1, 3, 5 years survival in %
329 83 63 3 16 164 26
27, 4, 3 35, 3, 0 18, 1, 0 0, 0, 0 26, 1, 1 27, 5, 3 26, 6, 6
(93) (25) (19) (1) (5) (50) (7)
to GP referrald 177 (50) 30, 178 (50) 26, 177 (50) 32, 178 (50) 23, 177 (50) 31, 178 (50) 17,
Inoperable Operable Bypass Resectable Whipple PPPD Distal pancreatectomy
254 101 68 33 14 16 3
(71) (29) (19) (10) (4) (5) (1)
Overall survival
355 (100)
24, 35, 21, 66, e e e
Median survival month 7 9 7 3 8 6 7
7, 7 4, 3 6, 5 4, 3 6, 5 1, 1 2, 0 13, 9 5, 0 31, 25
26, 5, 4
p Value
0.098 0.715 0.068 0.456 0.074 0.956c
8 8 8 6 8 6
0.014
6 12 8 16
<0.001e 0.258f <0.001g,h
e e e 7
a Isolated. b Other ¼ malaise, nausea or anorexia. c Symptomatic vs asymptomatic. d Based on the interquartile range, 143 ¼ 75th quartile. e Inoperable vs operable. f Inoperable vs bypass. g Inoperable vs resectable and bypass. h Resectable vs bypass.
0.492 0.180
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The median time from referral to review at the Pancreatic Unit (T2) was 17 (i.q.r. 8e28) days. 153 patients (43%) were reviewed at the Unit within 14 days from referral, while for the remaining 202 (57%) it took longer than 14 days. The median time from review to diagnosis/treatment (T3) was 11 (i.q.r. 6e21) days. 337 patients (95%) had the diagnosis made and started treatment within 48 days, while in 18 cases (5%) it took longer than 48 days.
Of all 355 patients with PDAC attending our unit, 305 (86%) were reviewed and treated within 62 days, while in only 50 (14%) it took longer than 62 days from the GP referral (T2 þ T3). There were no significant differences in operability, resectability and survival (Fig. 3) of patients that were diagnosed/ treated before or after 62 days from referral (T2 þ T3) (median month 7 and 8 respectively, p ¼ 0.134). Tables 1 and 2 show the clinical features at presentation as described by the patients. A total of 329 (93%) patients had either isolated or combined symptoms and for 26 (7%) no specific symptoms were recorded. Patients presenting with jaundice (228/355, 64%) (either isolated or combined with other symptoms) were referred (T1, median 56 vs 103) and diagnosed/treated (T2 þ T3, median 96 vs 130) days ( p < 0.001) sooner, had a higher operability rate (33% vs 21%, p ¼ 0.035) but not significantly higher resectability rates (37% vs 29%) ( p ¼ 0.608). Patients presenting with abdominal pain or weight loss had a longer time from becoming symptomatic to referral (T1 median 98 vs 41 p < 0.001 and 76 vs 60 days p ¼ 0.026 respectively) and to diagnosis/treatment (T2 þ T3, median 131 vs 82 p < 0.001 and 120 vs 101 days p < 0.001 days respectively). Abdominal pain or weight loss had no significant effect on operability or resectability. Table 2 shows the 1-, 3-, and 5-year survival of patients with isolated or combined clinical features of jaundice, abdominal pain or weight loss. Isolated or combined mode of clinical presentation had no significant effect on survival ( p ¼ 0.074). Survival of patients with no recorded symptoms had survival similar to the symptomatic patients ( p ¼ 0.956). On multivariate regression analysis, prognostic factors of survival were a resectable PDAC (HR 4.41, 95% CI 2.4e8.1, p < 0.001) and the time from the beginning of symptoms to referral (HR 1.000e1.001, 95% CI 1.001e1.002, p ¼ 0.018). Multivariate analysis excluded that the time from referral to
Fig. 2 e Survival of patients being seen by the GP within less or more than 143 days from their symptoms.
Fig. 3 e Survival of patients being treated within or after 62 days from the GP referral.
Fig. 1 e Treatment groups and patients survival.
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Table 2 e Time from symptoms to diagnosis, operability, resectability and survival of patients with or without clinical features of jaundice, abdominal pain or weight loss. Jaundice
Number of patients (%) Time from symptoms to GP referrala Time from GP referral to treatmenta Time from Symptoms to treatmenta Operability % Resectability % Survival (1, 3 and 5 years %)
Abdominal pain
Weight loss
Yes
No
Yes
No
Yes
No
228 (64) 56 (159) 28 (27) 96 (107) 32 37 20, 7, 1
127 (36) 103 (83) 28 (132) 130 (163) 21 29 31, 4, 3
185 (52) 98 (146) 29 (28) 131 (149) 25 34 25, 7, 5
170 (48) 41 (49) 28 (25) 82 (74) 33 35 31, 3, 3
121 (34) 76 (141) 28 (29) 120 (139) 26 48 28, 6, 3
234 (66) 60 (90) 29 (25) 101 (112) 31 28 27, 5, 5
a Median time in months (i.q.r.).
treatment was an independent predicting factor of survival ( p ¼ 0.108) (Table 3).
Discussion In the fight against cancer, ingenuity and resources of modern medicine are pitched against the biological diversity of tumour. The common sense view, that early detection of cancer improves prognosis, and that delay in diagnosis and treatment has an adverse effect on survival, have been both intuitively accepted as true by many doctors, politicians and general public. Cancer screening programmes in high risks groups provided evidence that time matters, not only detecting and treating early cancers and improving prognosis, but also identifying patients who benefit from prophylactic surgery, which prevents the development of cancer altogether.22e25 Screening of the general population for common cancers also saves lives but is less effective and sometimes controversial.23,24, 26e28 Screening strategies, however, are very different from attempts to minimize diagnostic and treatment time delays in patients who develop symptoms. Biological behaviour of any individual tumour, from the moment of its inception until the beginning of symptoms, is determined by the subtle interplay of environmental and genetic factors, which remain largely undetectable and beyond our control. The fact of life is that in a great majority of cases, diagnosis and treatment of cancer start with the beginning of symptoms. The symptomatic stage is however the shortest in the many phases in the life of a neoplasm.
Table 3 e Variables used in Cox regression analysis and Hazard risk ratios of the independent predictors of survival.
Time from symptoms to referral Male sex Age Jaundice Abdominal pain Weight loss Resectable cancer Inoperable/bypass Time from referral to treatment
p Value
Hazard risk ratio
0.010 0.777 0.839 0.727 0.811 0.726 <0.001 0.697 0.108
1.001 (1.000e1.002)
3.214 (2.033e5.082)
The cancer waiting list target initiative, championed by the UK Department of Health, 21was based on the assumption that there are real large delays in the referring, diagnosing and treatment of patients with cancer and anticipation that diagnosing and treating symptomatic patients with cancer as quickly as possible, without any delay can improve outcomes and prognosis. There is, however, very little convincing evidence in the medical literature, that such strategy is effective in increasing survival for patients with cancer. In a study published almost 30 years ago, McDermott et al.29 showed that in patients with rectal cancer operability was unaffected by the duration of symptoms and indicated that earlier diagnosis during the symptomatic period cannot be expected to improve cancer specific survival rates. Two other studies of patients with colorectal cancer published more recently, showed that length of the patients history (duration of symptoms) at the time of surgery was not associated with survival time, tumour extent and completeness of resection.30,31 Longer delays in diagnosing and treating patients with breast cancer have been associated with significantly worse survival, locally advanced disease and metastases in one study32 but a much larger study published in The Lancet the same year33 found that delays in diagnosis of 3 months or more were not associated with decreased survival and paradoxically, patients who presented early and were treated in less than 30 days, had significantly worse outcomes. Similarly, two studies of non-small cell lung cancer were unable to demonstrate a significant effect of delayed diagnosis on prognosis and again, paradoxically, shorter delay was associated with poorer prognosis.34,35 No evidence was also found that delays in referral or diagnosis of patients with ovarian cancer affected survival at 18 months.36 Paradoxical observation that patients with shortest delay in diagnosis present with more advanced disease and have worst survival was made in women with endometrial cancer. Interestingly, this trend was most obvious in the delay from GP referral to first hospital visit.37 Similar observations of lack of any correlation between delays in diagnosis and treatment and survival were made in patients with wide variety of malignancies such as stomach, prostate, neuroendocrine, bone cancer, medulloblastoma and melanoma.38e46 Our study looked at the 355 patients with pancreatic cancer who received their treatment in an established Pancreatic Unit at the Middlesex Hospital during the 5-year period before the 62 days cancer waiting target was formally introduced and
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monitored by the management of our hospital. We are confident, that patients included in our study had a correct diagnosis of pancreatic cancer, as this diagnosis was made by an experienced team of surgeons, radiologists, gastroenterologists and histopathologists and was confirmed by biopsy in 93% of the patients. In our series, less than a third of patients referred to the Pancreatic Unit had surgery, only 10% had resectable tumours and 5-year survival was 4% overall and 25% in patients with resectable disease. Similar outcomes for patients with pancreatic cancer have been reported from other specialist centres, and we believe that our study reflects not only local but also the wider experience of treating patients with pancreatic cancer.47 Unsurprisingly, patients who had resectable tumour, had the best survival, an observation that confirms surgery as the most important modality in treating pancreatic cancer. Patients who had surgery (either resection or bypass) also had a significantly better survival than patients not operated upon, however, survival of patients who had a bypass was not different from patients who had biliary stents. The longest delays were experienced in the pre-hospital phase, which depends entirely on the patient’s awareness of being ill and their willingness to seek medical help as well as the rapidity with which GPs realise the gravity of the situation and refer patients to specialist units. Patients referred to our Pancreatic Unit within 143 days from the beginning of symptoms were more likely to have surgery and survived longer, despite not having significantly higher resectability rates. This observation might suggests that patients referred earlier had less advanced stage of the disease. Pre-hospital delay was twice as long as time taken to review, diagnose and treat patients with pancreatic cancer in the hospital. From the point of referral, almost half of our patients were seen within 14 days, 95% of them were diagnosed and treated within 48 days and the overall target of 62 days for reviewing, diagnosing and treating patients with cancer was met in 86% of our patients. This suggests that hospital delays were small even before the 62 days target was introduced and that whether patients were treated within or outside 62 days had no effect on their length of survival. This study had some potential limitations. The main limitations would be information bias given the source of information to compute delays (from clinical notes) and recall bias in obtaining symptoms’ onset. Patients with pancreatic cancer are generally elderly and have major co-morbidities. The unspecific (vague) clinical picture of abdominal pain and weight loss could be confusing and delay the referral to the specialist. As a result, the time taken to diagnose pancreatic carcinoma may also depend upon the patient’s willingness to seek medical advice and the grade of suspicion of the General Practitioner to refer the patient to the specialist. In our study we have failed to show an impact of clinical presentation upon prognosis. Evidence in the literature is conflicting, with some studies showing that patients presenting with jaundice have a favourable survival48 and others showing no survival benefit49 when compared to patients presenting without jaundice. Most of our patients presented with jaundice (64%) and although they were referred, diagnosed and treated faster and offered surgery more often, the resectability rate and survival were similar to patients who presented without jaundice. It took longer to refer and
diagnose patients with abdominal pain and weight loss but this delay had no effect on operability, resectability or survival.
Conclusion This study showed that pre-hospital delays in referring patients to a specialist unit, but not the hospital related 62 days target had an impact on operability, resectability and survival. The type of clinical presentation also had no impact on survival. We confirmed, that pancreatic resection is the most important factor in determining the length of survival in patients with pancreatic cancer. Our study implies that even the successful implementation of 62 days National Cancer Waits Target across the UK is unlikely to have an impact upon the prognosis of patients with pancreatic cancer. Focusing on early referral to specialist Pancreatic Units might be more effective.
Acknowledgements The authors would like to acknowledge that patients recruited into this study were referred to Mr CRG Russell and thank him for reviewing the manuscript.
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10. Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg 2004;91(5):586e94. 11. Siriwardana HP, Siriwardena AK. Systematic review of outcome of synchronous portal-superior mesenteric vein resection during pancreatectomy for cancer. Br J Surg 2006;93 (6):662e73. 12. Baumel H, Huguier M, Manderscheid JC, Fabre JM, Houry S, Fagot H. Results of resection for cancer of the exocrine pancreas: a study from the French association of surgery. Br J Surg 1994;81(1):102e7. 13. Janes Jr RH, Niederhuber JE, Chmiel JS, Winchester DP, Ocwieja KC, Karnell JH, et al. National patterns of care for pancreatic cancer. Results of a survey by the commission on cancer. Ann Surg 1996;223(3):261e72. 14. Yeo CJ, Cameron JL. Pancreatic cancer. Curr Probl Surg 1999;36 (2):59e152. 15. Buchler MW, Wagner M, Schmied BM, Uhl W, Friess H, Z’Graggen K. Changes in morbidity after pancreatic resection: toward the end of completion pancreatectomy. Arch Surg 2003;138(12):1310e4. discussion 1315. 16. Burris 3rd HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15(6):2403e13. 17. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350(12):1200e10. 18. Murr MM, Sarr MG, Oishi AJ, van Heerden JA. Pancreatic cancer. CA Cancer J Clin 1994;44(5):304e18. 19. Berrino FCR, Este`ve J, Gatta G, Hakulinen T, Micheli A, Saint M, et al., editors. Survival of cancer patients in Europe: the EUROCARE-2 study. 2000/01/05; 1999. 20. Fernandez E, La Vecchia C, Porta M, Negri E, Lucchini F, Levi F. Trends in pancreatic cancer mortality in Europe, 1955e1989. Int J Cancer 1994;57(6):786e92. 21. Department of Health. Referral guidelines for suspected cancer. Available at: www.doh.gov.uk/pub/docs/doh/guidelines.pdf; 2000. 22. Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells Jr SA. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353(11): 1105e13. 23. Fatouros M, Baltoyiannis G, Roukos DH. The predominant role of surgery in the prevention and new trends in the surgical treatment of women with BRCA1/2 mutations. Ann Surg Oncol 2008;15(1):21e33. 24. Schussele Filliettaz S, Juillerat P, Burnand B, Arditi C, Windsor A, Beglinger C, et al. Appropriateness of colonoscopy in Europe (EPAGE II). Chronic diarrhea and known inflammatory bowel disease. Endoscopy 2009;41(3): 218e26. 25. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360(13): 1320e8. 26. Andriole GL, Crawford ED, Grubb 3rd RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360(13): 1310e9. 27. Auvinen A, Rietbergen JB, Denis LJ, Schroder FH, Prorok PC. Prospective evaluation plan for randomised trials of prostate cancer screening. The international prostate cancer screening trial evaluation group. J Med Screen 1996;3(2): 97e104.
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28. Gotzsche PC, Hartling OJ, Nielsen M, Brodersen J, Jorgensen KJ. Breast screening: the facts e or maybe not. BMJ 2009;338:b86. 29. McDermott F, Hughes E, Pihl E, Milne BJ, Price A. Symptom duration and survival prospects in carcinoma of the rectum. Surg Gynecol Obstet 1981;153(3):321e6. 30. Bharucha S, Hughes S, Kenyon V, Anderson ID, Carlson GL, Scott NA. Targets and elective colorectal cancer: outcome and symptom delay at surgical resection. Colorectal Dis 2005;7(2): 169e71. 31. Gonzalez-Hermoso F, Perez-Palma J, Marchena-Gomez J, Lorenzo-Rocha N, Medina-Arana V. Can early diagnosis of symptomatic colorectal cancer improve the prognosis? World J Surg 2004;28(7):716e20. 32. Richards MA, Smith P, Ramirez AJ, Fentiman IS, Rubens RD. The influence on survival of delay in the presentation and treatment of symptomatic breast cancer. Br J Cancer 1999;79 (5e6):858e64. 33. Sainsbury R, Johnston C, Haward B. Effect on survival of delays in referral of patients with breast-cancer symptoms: a retrospective analysis. Lancet 1999;353(9159):1132e5. 34. Quarterman RL, McMillan A, Ratcliffe MB, Block MI. Effect of preoperative delay on prognosis for patients with early stage non-small cell lung cancer. J Thorac Cardiovasc Surg 2003;125 (1):108e13. discussion 113e4. 35. Myrdal G, Lambe M, Hillerdal G, Lamberg K, Agustsson T, Stahle E. Effect of delays on prognosis in patients with nonsmall cell lung cancer. Thorax 2004;59(1):45e9. 36. Kirwan JM, Tincello DG, Herod JJ, Frost O, Kingston RE. Effect of delays in primary care referral on survival of women with epithelial ovarian cancer: retrospective audit. BMJ 2002;324 (7330):148e51. 37. Crawford SC, Davis JA, Siddiqui NA, de Caestecker L, Gillis CR, Hole D, et al. The waiting time paradox: population based retrospective study of treatment delay and survival of women with endometrial cancer in Scotland. BMJ 2002;325(7357):196. 38. Windham TC, Termuhlen PM, Ajani JA, Mansfield PF. Adenocarcinoma of the stomach in patients age 35 years and younger: no impact of early diagnosis on survival outcome. J Surg Oncol 2002;81(3):118e24. discussion 124e5. 39. Maconi G, Kurihara H, Panizzo V, Russo A, Cristaldi M, Marrelli D, et al. Gastric cancer in young patients with no alarm symptoms: focus on delay in diagnosis, stage of neoplasm and survival. Scand J Gastroenterol 2003;38(12): 1249e55. 40. Graefen M, Walz J, Chun KH, Schlomm T, Haese A, Huland H. Reasonable delay of surgical treatment in men with localized prostate cancer e impact on prognosis? Eur Urol 2005;47(6): 756e60. 41. Khan MA, Mangold LA, Epstein JI, Boitnott JK, Walsh PC, Partin AW. Impact of surgical delay on long-term cancer control for clinically localized prostate cancer. J Urol 2004;172 (5 Pt 1):1835e9. 42. Toth-Fejel S, Pommier RF. Relationships among delay of diagnosis, extent of disease, and survival in patients with abdominal carcinoid tumors. Am J Surg 2004;187(5):575e9. 43. Goyal S, Roscoe J, Ryder WD, Gattamaneni HR, Eden TO. Symptom interval in young people with bone cancer. Eur J Cancer 2004;40(15):2280e6. 44. Halperin EC, Watson DM, George SL. Duration of symptoms prior to diagnosis is related inversely to presenting disease stage in children with medulloblastoma. Cancer 2001;91(8): 1444e50. 45. Bacci G, Ferrari S, Longhi A, Mellano D, Giacomini S, Forni C. Delay in diagnosis of high-grade osteosarcoma of the extremities. Has it any effect on the stage of disease? Tumori 2000;86(3):204e6.
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46. Bennett DR, Wasson D, MacArthur JD, McMillen MA. The effect of misdiagnosis and delay in diagnosis on clinical outcome in melanomas of the foot. J Am Coll Surg 1994;179 (3):279e84. 47. Office for National Statistics. Cancer survival: cancer survival trends by period of diagnosis and sex age-standardised relative survival at one and five years, and average increase in relative survival between successive five-year periods of diagnosis, 1971e1990.
Available at: http://www.statistics.gov.uk/StatBase/xsdataset. asp?More¼Y&vlnk¼982&All¼Y&B2.x¼58&B2.y¼19.2009; 2009. 48. Yamaguchi K, Nishihara K, Tsuneyoshi M. Non-icteric pancreas head carcinoma fares worse than icteric pancreas head carcinoma. J Surg Oncol 1992;49(4):253e8. 49. Gilliam AD, Lobo DN, Rowlands BJ, Beckingham IJ. The ‘twoweek’ target for the diagnosis of pancreatic carcinoma: an achievable aim? Eur J Surg Oncol 2003;29(7):575e9.
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The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net
Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer Dimitri A. Raptis*, Chris Fessas, Peter Belasyse-Smith, Tom R. Kurzawinski Department of Hepatopancreaticobiliary & Endocrine Surgery, University College London Hospitals, NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK
article info
abstract
Article history:
Introduction: The prognosis of patients with pancreatic cancer remains poor despite recent
Received 8 February 2010
advances in treatment. It is not known whether delays in referring, diagnosing and treating
Received in revised form
these patients and the way they present can affect their survival.
1 March 2010
Aims: In our study we investigated the impact of clinical presentation (jaundice, abdominal
Accepted 4 March 2010
pain, weight loss) and delays in management of these patients on their treatment and survival. Methods: Data on all patients with pancreatic cancer referred to the Pancreatic Unit
Keywords:
(1997e2002) were collected prospectively and analysed using SPSS 16. The delay in diag-
Pancreatic cancer
nosis and treatment for each patient was measured by estimating the time from the
Surgery
beginning of symptoms to the date of the referral letter (T1), the time from the referral date
Prognostic factors
to the date of first review at the Unit (T2) and the time from date of review to the date of
Delay in diagnosis
diagnosis/treatment (T3). Treatments were defined as 1) pancreatic resections, 2) gastric
Two-week-wait
and biliary bypass and 3) biliary stents. The term ‘operability’ was used to describe patients
Target referral
thought to have a potentially removable tumour and had an operation and ‘resectability’
Survival
applied to the patients whose tumour was actually removed at the operation. Follow-up time and survival were recorded by reviewing the patient’s notes, hospital electronic databases and by contacting patients General Practitioners. Results: There were a total of 355 patients with pancreatic cancer. Median age at diagnosis was 64 (i.q.r. 56e71) years and median follow-up was 8 (i.q.r. 4e14) months. The overall 1, 3 and 5 years patient’s survival was 26%, 5% and 4% respectively. 1, 3 and 5 years survival of inoperable patients was 24%, 2% and 0% and for operable patients was 35%, 13% and 9% respectively. The median survival time for those patients that underwent operation was significantly higher than those that did not (12 vs 6 months, p < 0.001). The overall median time from initial symptoms to diagnosis/treatment (T1 þ T2 þ T3) was 102 (i.q.r. 56e182) days, T1 was 65 (i.q.r. 31e143), T2 17 (i.q.r. 8e28) and T3 11 (i.q.r. 6e21) days. The time delay from symptoms to referral (T1) had minimal clinical relevance to survival, with a hazard ratio of only 1.001 (95% CI 0.001e0.002, p ¼ 0.043) per day. Of all 355 patients, 305 (86%) were reviewed and treated within 62 days from the GP referral (T2 þ T3). There was no significant difference in operability, resectability and survival of patients that
Abbreviations: i.q.r., interquartile range; PDAC, pancreatic ductal adenocarcinoma; HR, hazard ratio; T1, time from the beginning of symptom to the date of the letter referring patient to Pancreatic Unit; T2, time from referral date to the date of review at the Unit; T3, time from the date of review to the date of diagnosis/treatment. * Corresponding author. Tel.: þ44 41798820542. E-mail address: [email protected] (D.A. Raptis). 1479-666X/$ e see front matter ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.surge.2010.03.001
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were diagnosed/treated before or after 62 days from referral (T2 þ T3) (median months 6.5 and 7.9 respectively, p ¼ 0.134). Patients presenting with jaundice were referred (T1, median 56 vs 103) and diagnosed/ treated (T2 þ T3, median 96 vs 130) days ( p < 0.001) sooner, had a higher operability rate (33% vs 21%, p ¼ 0.035) but not a significantly higher resectability rate of (37% vs 29%) ( p ¼ 0.608). Isolated or combined mode of clinical presentation had no significant effect on survival ( p ¼ 0.965). On multivariate regression analysis, prognostic factors of survival were a resectable tumour and the time from the beginning of symptoms to referral. Conclusion: This study showed that pre-hospital delays in referring patients to a specialist unit, but not hospital related 62 days target, had an no impact on operability, resectability and survival. Clinical presentation also had no impact on the survival. We confirmed that pancreatic resection is the most important factor in determining the length of survival in patients with pancreatic cancer. Our study implies that the successful implementation of the 62 days National Cancer Waits Target across the UK is unlikely to have an impact on prognosis in patients with pancreatic cancer. Focusing on early referral to specialist Pancreatic Units might be more effective. ª 2010 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignant diseases1,2 ranking fourth as a leading cause of cancer-related deaths in the Western world.3 The prognosis of this cancer is poor, with an overall 5-year survival rate of only 1e4%.3 Prognosis of any malignant tumour depends on its biological behaviour, reflected by its ability to invade locally or metastasize, along with the efficacy of the available treatments. Sadly, in the case of pancreatic cancer, we are faced by a tumour with aggressive biological behaviour, which invades locally and metastasizes early. Disease specific factors reflecting poor prognosis described in the literature are, distant metastasis, TNM staging, lymph node involvement, neural, vascular and peri-pancreatic invasion, tumour differentiation and size (>3 cm) and involvement of resection margins.4,5 Currently available treatments have only small impact on the natural history of the disease. Surgery is potentially the only chance for cure,6 but only 10% of patients have resectable tumours and 5-year survival rate after successful resection is in the range of 15e25%.5,7e10 Advances in operative techniques and in perioperative care have increased the resectability of pancreatic cancer and have decreased the operative morbidity and mortality, but have not affected prognosis.11e15 Palliative and adjuvant chemotherapies have so far had minimal impact on survival.16,17 Apart from biological behaviour of the tumour and the efficacy of treatment, the third important factor, which is thought to affect prognosis, is the speediness of diagnosis and treatment. Cancers progress over time and it is a justifiable assumption that early detection of disease and implementation of treatment can improve prognosis. Clinical features of pancreatic cancer such as weight loss, abdominal pain and jaundice, especially in the early stages of the disease, can be vague and non-specific, causing delays in patients seeking help and late referral.18 These pre-hospital, but also hospital related delays in diagnosing and treating patients with
pancreatic cancer can be one of the reasons why the majority of patients present with locally advanced and/or metastatic disease. The mortality rates for several cancers in the UK are higher than other European countries19,20 and this has been partially attributed to long waiting times for treatment.2 As part of the ‘NHS Cancer Plan’, the UK government introduced the ‘Cancer waiting times targets’ in the year 2000, stipulating that patients with suspected cancer should be seen by a specialist within 14 days and treated within 48 days. The overall time from referral of the patient with suspected cancer to diagnosis and starting treatment should not exceed 62 days.21 Furthermore, Trusts that do not comply with these targets would incur financial penalties.
Objective The aim of this study was to evaluate whether the nature of clinical presentation (jaundice, abdominal pain, weight loss) and time delay in referring, diagnosing and treating patients with pancreatic cancer had any effect on operability, resectability and survival.
Methods In the period between January of 1997 and December of 2002, 335 patients with pancreatic cancer were admitted to the Pancreatic Unit at the Middlesex Hospital, London, UK. Information on all the patients diagnosed with pancreatic cancer was collected prospectively in a Pancreatic Database. Patients with ampullary, peri-ampullary and duodenal cancer, neuroendocrine and cystic pancreatic neoplasms were not included in this study. Patient’s data included sex, age and clinical presentation (jaundice, abdominal pain, weight loss) as described by patients and documented in their notes. The delay in diagnosis and treatment for each patient was measured by estimating the time from the beginning of
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symptoms to the date of the letter referring the patient to the Pancreatic Unit at The Middlesex Hospital (T1), the time from the referral date to the date of review at the Unit (either clinic appointment or admission for investigations, whichever came first) (T2) and time from date of review to the date of diagnosis/treatment (T3). The date of diagnosis/treatment was defined in descending order of preference either as the date of operation, the date of histology report in inoperable cases or if the biopsy was not available, the date of the CT scan reporting a diagnosis of pancreatic cancer. The basis on which diagnosis of pancreatic cancer was made (histology, cytology, radiology, clinical features) was recorded. Treatments were defined as 1) pancreatic resections, 2) gastric and biliary bypass and 3) biliary stents. The term operability was used to describe patients thought to have potentially removable tumour and had an operation (resection or bypass) and the term resectability applied to the patients whose tumour was actually removed at operation (resections only). Follow-up time and survival were recorded by reviewing patients’ notes, hospital electronic databases and by contacting patient’s General Practitioners.
Statistical analysis Continuous variables were compared using either the Student’s t, the ManneWhitney U or one-way ANOVA tests when appropriate. Difference among proportion was compared with Fisher’s exact test. All calculated p values were two-sided and p value of 0.05 was considered statistically significant. Cumulative survival was calculated using the KaplaneMeier Log Rank test. Both variables with and without significance in univariate analysis were included in the Cox regression model to calculate multivariate analysis and hazard ratios. Statistical analysis was performed on SPSS 16 for Mac.
Results There were a total of 355 patients with PDAC, 213 (60%) of them male. Median age at diagnosis was 64 (i.q.r. 56e71) years and median follow-up was 8 (i.q.r. 4e14) months. The basis of the diagnosis was histology of the primary tumour in 298 (84%) patients and of metastasis in 25 (7%). Seven patients (2%) had positive cytology and the remaining 25 patients (7%) had diagnosis established by a combination of radiological imaging, laparotomy findings, elevated CA19-9 and a clinical course highly suggestive of pancreatic cancer. Out of the 355 patients, 101 (29%) underwent operation and only 33 (overall 9%) of those had a resectable tumour. Table 1 shows patient’s management. The overall 1, 3 and 5 years patient’s survival was 26%, 5% and 4% respectively. 1, 3 and 5 years survival of inoperable patients was 24%, 2% and 0% and for operable patients was 35%, 13% and 9% respectively (Table 1). The median survival time for those patients that underwent operation was significantly higher than those that did not (12 vs 6 months, p < 0.001). For operable patients 1, 3, and 5 years survival for bypasses was 21%, 5% and 0% and for resectable patients was 66%, 31% and 25% respectively. Patients with a resectable
cancer had a significantly higher median survival time when compared to those that received a bypass and endoscopic stents (16 vs 8 months, p < 0.001) (Fig. 1). There was no significant statistical difference in median survival between the inoperable and bypassed patients (Table 1, Fig. 1) The overall median time from initial symptoms to diagnosis/treatment (T1 þ T2 þ T3) was 102 (i.q.r. 56e182) days. The median time from initial symptoms to referral to Pancreatic Unit (T1) was 65 (i.q.r. 31e143) days. The time delay from symptoms to referral alone (T1) had minimal clinical relevance with hazard rate ratio of only 1.001 (95% CI 0.001e0.002, p ¼ 0.043) per day. By using the 75% quartile (143 days) as a cut-off point, patients who presented to their GP within less than 143 days from the beginning of symptoms had a higher operability (32% vs 19%, p ¼ 0.039) but not significantly higher resectability (34% vs 21%, p ¼ 0.379) rates when compared to those who presented within more than 143 days. Patients that presented within 143 days from their initiation of symptoms to their GP visit had a favourable survival when compared to those that presented after 143 days (Table 1, Fig. 2)
Table 1 e Clinical features, management and survival of patients with PDAC.
Symptomatic Jaundicea Abdominal paina Weight lossa Othera,b Combined Symptoms not recorded Time from symptom <31 days >31 days <65 days >65 days <143 days >143 days
No. of patients (%)
1, 3, 5 years survival in %
329 83 63 3 16 164 26
27, 4, 3 35, 3, 0 18, 1, 0 0, 0, 0 26, 1, 1 27, 5, 3 26, 6, 6
(93) (25) (19) (1) (5) (50) (7)
to GP referrald 177 (50) 30, 178 (50) 26, 177 (50) 32, 178 (50) 23, 177 (50) 31, 178 (50) 17,
Inoperable Operable Bypass Resectable Whipple PPPD Distal pancreatectomy
254 101 68 33 14 16 3
(71) (29) (19) (10) (4) (5) (1)
Overall survival
355 (100)
24, 35, 21, 66, e e e
Median survival month 7 9 7 3 8 6 7
7, 7 4, 3 6, 5 4, 3 6, 5 1, 1 2, 0 13, 9 5, 0 31, 25
26, 5, 4
p Value
0.098 0.715 0.068 0.456 0.074 0.956c
8 8 8 6 8 6
0.014
6 12 8 16
<0.001e 0.258f <0.001g,h
e e e 7
a Isolated. b Other ¼ malaise, nausea or anorexia. c Symptomatic vs asymptomatic. d Based on the interquartile range, 143 ¼ 75th quartile. e Inoperable vs operable. f Inoperable vs bypass. g Inoperable vs resectable and bypass. h Resectable vs bypass.
0.492 0.180
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The median time from referral to review at the Pancreatic Unit (T2) was 17 (i.q.r. 8e28) days. 153 patients (43%) were reviewed at the Unit within 14 days from referral, while for the remaining 202 (57%) it took longer than 14 days. The median time from review to diagnosis/treatment (T3) was 11 (i.q.r. 6e21) days. 337 patients (95%) had the diagnosis made and started treatment within 48 days, while in 18 cases (5%) it took longer than 48 days.
Of all 355 patients with PDAC attending our unit, 305 (86%) were reviewed and treated within 62 days, while in only 50 (14%) it took longer than 62 days from the GP referral (T2 þ T3). There were no significant differences in operability, resectability and survival (Fig. 3) of patients that were diagnosed/ treated before or after 62 days from referral (T2 þ T3) (median month 7 and 8 respectively, p ¼ 0.134). Tables 1 and 2 show the clinical features at presentation as described by the patients. A total of 329 (93%) patients had either isolated or combined symptoms and for 26 (7%) no specific symptoms were recorded. Patients presenting with jaundice (228/355, 64%) (either isolated or combined with other symptoms) were referred (T1, median 56 vs 103) and diagnosed/treated (T2 þ T3, median 96 vs 130) days ( p < 0.001) sooner, had a higher operability rate (33% vs 21%, p ¼ 0.035) but not significantly higher resectability rates (37% vs 29%) ( p ¼ 0.608). Patients presenting with abdominal pain or weight loss had a longer time from becoming symptomatic to referral (T1 median 98 vs 41 p < 0.001 and 76 vs 60 days p ¼ 0.026 respectively) and to diagnosis/treatment (T2 þ T3, median 131 vs 82 p < 0.001 and 120 vs 101 days p < 0.001 days respectively). Abdominal pain or weight loss had no significant effect on operability or resectability. Table 2 shows the 1-, 3-, and 5-year survival of patients with isolated or combined clinical features of jaundice, abdominal pain or weight loss. Isolated or combined mode of clinical presentation had no significant effect on survival ( p ¼ 0.074). Survival of patients with no recorded symptoms had survival similar to the symptomatic patients ( p ¼ 0.956). On multivariate regression analysis, prognostic factors of survival were a resectable PDAC (HR 4.41, 95% CI 2.4e8.1, p < 0.001) and the time from the beginning of symptoms to referral (HR 1.000e1.001, 95% CI 1.001e1.002, p ¼ 0.018). Multivariate analysis excluded that the time from referral to
Fig. 2 e Survival of patients being seen by the GP within less or more than 143 days from their symptoms.
Fig. 3 e Survival of patients being treated within or after 62 days from the GP referral.
Fig. 1 e Treatment groups and patients survival.
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Table 2 e Time from symptoms to diagnosis, operability, resectability and survival of patients with or without clinical features of jaundice, abdominal pain or weight loss. Jaundice
Number of patients (%) Time from symptoms to GP referrala Time from GP referral to treatmenta Time from Symptoms to treatmenta Operability % Resectability % Survival (1, 3 and 5 years %)
Abdominal pain
Weight loss
Yes
No
Yes
No
Yes
No
228 (64) 56 (159) 28 (27) 96 (107) 32 37 20, 7, 1
127 (36) 103 (83) 28 (132) 130 (163) 21 29 31, 4, 3
185 (52) 98 (146) 29 (28) 131 (149) 25 34 25, 7, 5
170 (48) 41 (49) 28 (25) 82 (74) 33 35 31, 3, 3
121 (34) 76 (141) 28 (29) 120 (139) 26 48 28, 6, 3
234 (66) 60 (90) 29 (25) 101 (112) 31 28 27, 5, 5
a Median time in months (i.q.r.).
treatment was an independent predicting factor of survival ( p ¼ 0.108) (Table 3).
Discussion In the fight against cancer, ingenuity and resources of modern medicine are pitched against the biological diversity of tumour. The common sense view, that early detection of cancer improves prognosis, and that delay in diagnosis and treatment has an adverse effect on survival, have been both intuitively accepted as true by many doctors, politicians and general public. Cancer screening programmes in high risks groups provided evidence that time matters, not only detecting and treating early cancers and improving prognosis, but also identifying patients who benefit from prophylactic surgery, which prevents the development of cancer altogether.22e25 Screening of the general population for common cancers also saves lives but is less effective and sometimes controversial.23,24, 26e28 Screening strategies, however, are very different from attempts to minimize diagnostic and treatment time delays in patients who develop symptoms. Biological behaviour of any individual tumour, from the moment of its inception until the beginning of symptoms, is determined by the subtle interplay of environmental and genetic factors, which remain largely undetectable and beyond our control. The fact of life is that in a great majority of cases, diagnosis and treatment of cancer start with the beginning of symptoms. The symptomatic stage is however the shortest in the many phases in the life of a neoplasm.
Table 3 e Variables used in Cox regression analysis and Hazard risk ratios of the independent predictors of survival.
Time from symptoms to referral Male sex Age Jaundice Abdominal pain Weight loss Resectable cancer Inoperable/bypass Time from referral to treatment
p Value
Hazard risk ratio
0.010 0.777 0.839 0.727 0.811 0.726 <0.001 0.697 0.108
1.001 (1.000e1.002)
3.214 (2.033e5.082)
The cancer waiting list target initiative, championed by the UK Department of Health, 21was based on the assumption that there are real large delays in the referring, diagnosing and treatment of patients with cancer and anticipation that diagnosing and treating symptomatic patients with cancer as quickly as possible, without any delay can improve outcomes and prognosis. There is, however, very little convincing evidence in the medical literature, that such strategy is effective in increasing survival for patients with cancer. In a study published almost 30 years ago, McDermott et al.29 showed that in patients with rectal cancer operability was unaffected by the duration of symptoms and indicated that earlier diagnosis during the symptomatic period cannot be expected to improve cancer specific survival rates. Two other studies of patients with colorectal cancer published more recently, showed that length of the patients history (duration of symptoms) at the time of surgery was not associated with survival time, tumour extent and completeness of resection.30,31 Longer delays in diagnosing and treating patients with breast cancer have been associated with significantly worse survival, locally advanced disease and metastases in one study32 but a much larger study published in The Lancet the same year33 found that delays in diagnosis of 3 months or more were not associated with decreased survival and paradoxically, patients who presented early and were treated in less than 30 days, had significantly worse outcomes. Similarly, two studies of non-small cell lung cancer were unable to demonstrate a significant effect of delayed diagnosis on prognosis and again, paradoxically, shorter delay was associated with poorer prognosis.34,35 No evidence was also found that delays in referral or diagnosis of patients with ovarian cancer affected survival at 18 months.36 Paradoxical observation that patients with shortest delay in diagnosis present with more advanced disease and have worst survival was made in women with endometrial cancer. Interestingly, this trend was most obvious in the delay from GP referral to first hospital visit.37 Similar observations of lack of any correlation between delays in diagnosis and treatment and survival were made in patients with wide variety of malignancies such as stomach, prostate, neuroendocrine, bone cancer, medulloblastoma and melanoma.38e46 Our study looked at the 355 patients with pancreatic cancer who received their treatment in an established Pancreatic Unit at the Middlesex Hospital during the 5-year period before the 62 days cancer waiting target was formally introduced and
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monitored by the management of our hospital. We are confident, that patients included in our study had a correct diagnosis of pancreatic cancer, as this diagnosis was made by an experienced team of surgeons, radiologists, gastroenterologists and histopathologists and was confirmed by biopsy in 93% of the patients. In our series, less than a third of patients referred to the Pancreatic Unit had surgery, only 10% had resectable tumours and 5-year survival was 4% overall and 25% in patients with resectable disease. Similar outcomes for patients with pancreatic cancer have been reported from other specialist centres, and we believe that our study reflects not only local but also the wider experience of treating patients with pancreatic cancer.47 Unsurprisingly, patients who had resectable tumour, had the best survival, an observation that confirms surgery as the most important modality in treating pancreatic cancer. Patients who had surgery (either resection or bypass) also had a significantly better survival than patients not operated upon, however, survival of patients who had a bypass was not different from patients who had biliary stents. The longest delays were experienced in the pre-hospital phase, which depends entirely on the patient’s awareness of being ill and their willingness to seek medical help as well as the rapidity with which GPs realise the gravity of the situation and refer patients to specialist units. Patients referred to our Pancreatic Unit within 143 days from the beginning of symptoms were more likely to have surgery and survived longer, despite not having significantly higher resectability rates. This observation might suggests that patients referred earlier had less advanced stage of the disease. Pre-hospital delay was twice as long as time taken to review, diagnose and treat patients with pancreatic cancer in the hospital. From the point of referral, almost half of our patients were seen within 14 days, 95% of them were diagnosed and treated within 48 days and the overall target of 62 days for reviewing, diagnosing and treating patients with cancer was met in 86% of our patients. This suggests that hospital delays were small even before the 62 days target was introduced and that whether patients were treated within or outside 62 days had no effect on their length of survival. This study had some potential limitations. The main limitations would be information bias given the source of information to compute delays (from clinical notes) and recall bias in obtaining symptoms’ onset. Patients with pancreatic cancer are generally elderly and have major co-morbidities. The unspecific (vague) clinical picture of abdominal pain and weight loss could be confusing and delay the referral to the specialist. As a result, the time taken to diagnose pancreatic carcinoma may also depend upon the patient’s willingness to seek medical advice and the grade of suspicion of the General Practitioner to refer the patient to the specialist. In our study we have failed to show an impact of clinical presentation upon prognosis. Evidence in the literature is conflicting, with some studies showing that patients presenting with jaundice have a favourable survival48 and others showing no survival benefit49 when compared to patients presenting without jaundice. Most of our patients presented with jaundice (64%) and although they were referred, diagnosed and treated faster and offered surgery more often, the resectability rate and survival were similar to patients who presented without jaundice. It took longer to refer and
diagnose patients with abdominal pain and weight loss but this delay had no effect on operability, resectability or survival.
Conclusion This study showed that pre-hospital delays in referring patients to a specialist unit, but not the hospital related 62 days target had an impact on operability, resectability and survival. The type of clinical presentation also had no impact on survival. We confirmed, that pancreatic resection is the most important factor in determining the length of survival in patients with pancreatic cancer. Our study implies that even the successful implementation of 62 days National Cancer Waits Target across the UK is unlikely to have an impact upon the prognosis of patients with pancreatic cancer. Focusing on early referral to specialist Pancreatic Units might be more effective.
Acknowledgements The authors would like to acknowledge that patients recruited into this study were referred to Mr CRG Russell and thank him for reviewing the manuscript.
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