Peritoneal metastases in elderly patients with colorectal cancer.

BACKGROUND: With the introduction of cytoreductive surgery with intraperitoneal chemotherapy and the development of new systemic anti-cancer agents, the treatment of colorectal cancer (CRC) patients with peritoneal metastases has changed. Real-world data on the treatment of elderly patients and their clinical outcomes is lacking. METHODS: All CRC patients diagnosed with synchronous peritoneal metastases (SPM) during 2008-2019 (n = 7,748) were identified from the Netherlands Cancer Registry. Trends in treatment and postoperative mortality were described by age category (<70, 70-74, 75-79, ≥80 years) and period of diagnosis (2008-2013, 2014-2019). Kaplan-Meier curves were constructed, and log-rank tests were performed to evaluate differences in overall survival (OS). RESULTS: With increasing age, less patients received multimodality treatment and systemic treatment. Of the patients aged <70 years, 38% underwent multimodality treatment and 35% palliative systemic therapy, declining to 4% and 12% in patients ≥80 years. A large and increasing proportion of elderly patients did not receive cancer-directed treatment, this increased from 32% in 2008-2013 to 41% in 2014-2019 in 75-79 years old patients and from 52% to 65% in ≥80 years old. Postoperative mortality decreased in all age categories over time, OS remained stable. The median OS of elderly patients ranged from 8 months in 70-74 years old to 3 months in patients aged ≥80 years. DISCUSSION: Age strongly affects treatment of patients with SPM, with a large and increasing proportion of elderly patients not receiving cancer-directed treatment. Their prognosis remains very poor. There is a need for therapeutic options that are well tolerable for elderly patients.

Treatment Strategies and Prognosis of Patients With Synchronous or Metachronous Colorectal Peritoneal Metastases: A Population-Based Study.

BACKGROUND: This study aimed to compare treatment strategies and survival of patients with synchronous colorectal peritoneal metastases (CPM) and patients with metachronous CPM in a nationwide cohort. METHODS: All patients from the Netherlands Cancer Registry with synchronous or metachronous CPM whose primary colorectal cancer (CRC) was diagnosed between 1 January and 30 June 2015 were included in the study. Treatments were categorized as (A) cytoreductive surgery and hyperthermic intraperitoneal chemotherapy [CRS-HIPEC]; (B) palliative treatment; or (C) best supportive care. Overall survival (OS) for all the patients and disease-free survival (DFS) for those who underwent CRS-HIPEC were compared between the two groups. RESULTS: Of 7233 patients, 743 had a diagnosis of CPM, including 409 patients with synchronous CPM and 334 patients with metachronous CPM. The median OS was 8.1 months for the patients with synchronous CPM versus 12 months for the patients with metachronous CPM (p = 0.003). After multivariable correction, OS no longer differed between the patients with synchronous CPM and those with metachronous CPM (HR 1.03 [0.83-1.27]). The patients with metachronous CPM more often underwent CRS-HIPEC than the patients with synchronous CPM (16 % vs 8 %; p = 0.001). The two groups did not differ statistically in terms of DFS and OS (median DFS, 21.5 vs 14.1 months, respectively; p = 0.094; median OS, 37.8 vs. 35.8 months, respectively; p = 0.553). CONCLUSION: This population-based study showed that survival for the patients with synchronous CPM and patients with metachronous CPM did not significantly differ. This suggests that a similar prognosis may be expected for patients selected for treatment regardless of the onset of CPM.

The difference in association between aspirin use and other thrombocyte aggregation inhibitors and survival in patients with colorectal cancer.

BACKGROUND: Several studies have suggested that the association between aspirin and improved cancer survival is mediated through the mechanism of aspirin as thrombocyte aggregation inhibitors (TAI). The aim of this study was to provide epidemiological evidence for this mechanism assessing the association between overall survival and the use of aspirin and non-aspirin TAI in patients with colorectal cancer. METHODS: In this observational study, data from the Netherlands Comprehensive Cancer Organisation were linked to PHARMO Database Network. Patients using aspirin or aspirin in combination with non-aspirin TAI (dual users) were selected and compared with non-users. The association between overall survival and the use of (non-)aspirin TAI was analysed using Cox regression models with the use of (non-)aspirin TAI as a time-varying covariate. RESULTS: In total, 9196 patients were identified with colorectal cancer and 1766 patients used TAI after diagnosis. Non-aspirin TAI were mostly clopidogrel and dipyridamole. Aspirin use was associated with a significant increased overall survival and hazard ratio (HR) 0.41 (95% confidence interval [CI] 0.37-0.47), and the use of non-aspirin TAI was not associated with survival of HR 0.92 (95% CI 0.70-1.22). Dual users did not have an improved overall survival when compared with patients using solely aspirin. CONCLUSIONS: Aspirin use after diagnosis of colorectal cancer was associated with significantly lower mortality rates and this effect remained significant after adjusting for potential confounders. No additional survival benefit was observed in patients using both aspirin and another TAI.

Intensity of adjuvant chemotherapy regimens and grade III-V toxicities among elderly stage III colon cancer patients.

PURPOSE: The aim of this study was to provide insight in the use, intensity and toxicity of therapy with capecitabine and oxaliplatin (CAPOX) and capecitabine monotherapy (CapMono) among elderly stage III colon cancer patients treated in everyday clinical practice. METHODS: Data from the Netherlands Cancer Registry were used. All stage III colon cancer patients aged ≥70 years diagnosed in the southeastern part between 2005 and 2012 and treated with CAPOX or CapMono were included. Differences in completion of all planned cycles, cumulative dosages and toxicity between both regimens were evaluated. RESULTS: One hundred ninety-three patients received CAPOX and 164 patients received CapMono; 33% (n = 63) of the patients receiving CAPOX completed all planned cycles of both agents, whereas 55% (n = 90) of the patients receiving CapMono completed all planned cycles (P < 0.0001). The median cumulative dosage capecitabine was lower for patients treated with CAPOX (163,744 mg/m(2), interquartile range [IQR] 83,397-202,858 mg/m(2)) than for patients treated with CapMono (189,195 mg/m(2), IQR 111,667-228,125 mg/m(2), P = 0.0003); 54% (n = 105) of the patients treated with CAPOX developed grade III-V toxicity, whereas 38% (n = 63) of the patients treated with CapMono developed grade III-V toxicity (P = 0.0026). After adjustment for patient and tumour characteristics, CapMono was associated with a lower odds of developing grade III-V toxicity than CAPOX (odds ratio 0.54, 95% confidence interval 0.33-0.89). For patients treated with CAPOX, the most common toxicities were gastrointestinal (29%), haematological (14%), neurological (11%) and other toxicity (13%). For patients treated with CapMono, dermatological (17%), gastrointestinal (13%) and other toxicity (11%) were the most common. CONCLUSION: CAPOX is associated with significantly more grade III-V toxicities than CapMono, which had a pronounced impact on the cumulative dosage received and completion of all planned cycles. In this light, CapMono seems preferable over CAPOX.

Histological subtype and systemic metastases strongly influence treatment and survival in patients with synchronous colorectal peritoneal metastases.

BACKGROUND: Treatment possibilities for colorectal peritoneal metastases (PM) are increasing. It is however unclear how treatment choice and outcome are influenced by histological subtype and the presence of systemic metastases. Therefore, this study assessed the impact of histological subtype and systemic metastases on treatment choice and survival in patients with colorectal PM. METHODS: This population-based study included patients with synchronous PM originating from colorectal adenocarcinoma (AC), mucinous adenocarcinoma (MC), or signet ring cell carcinoma (SRCC). Data of patients diagnosed between 2005 and 2014 were extracted from the National Cancer Registry (IKNL) of the Netherlands. Treatment strategy and survival were analyzed with logistic regression and cox proportional hazard analyses. RESULTS: In total, 5516 patients were included, of whom 71.8% had an AC, 21.2% an MC, and 7.0% had an SRCC. The use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) was dependent on histological subtype and the presence of systemic metastases, and increased over time, especially in AC and MC patients. The relative survival gain of CRS + HIPEC, corrected for systemic metastases, was comparable in AC, MC, and SRCC patients (hazard ratio: 0.17, 0.21, and 0.13, respectively). Compared to supportive care only, the absolute survival gain was 30, 35, and 18 months, respectively. Systemic therapy improved survival in all histological subtypes. CONCLUSIONS: Histological subtype and the presence of systemic metastases strongly influenced treatment choice and survival in patients with synchronous colorectal PM. These results can be used to optimize treatment strategy for patients with synchronous colorectal PM.

Incidence and treatment of recurrent disease after cytoreductive surgery and intraperitoneal chemotherapy for peritoneally metastasized colorectal cancer: A systematic review.

INTRODUCTION: The optimal treatment for peritoneal carcinomatosis (PC) of colorectal origin is a combination of cytoreductive surgery and intraperitoneal chemotherapy (CRS + IPC). Although 5-year survival rates of up to 40% have been reported, recurrent disease remains common and is estimated to be a strong negative prognostic factor for survival. This systematic review elaborates on the incidence of recurrent disease and the possibilities to prevent and treat recurrence. METHODS: Two searches were performed. To identify the magnitude of recurrent the disease, a search was performed in Pubmed and EMBASE until September 2014. A second search was performed in Pubmed to identify treatment of recurrent disease with secondary CRS + IPC. RESULTS: The first search resulted in 139 and 94 articles in Pubmed and EMBASE respectively. Among those, 28 were included. Overall recurrence rates ranged from 22.5 to 82%. Local, systemic and combined local-systemic recurrence ranged from 6 to 42.5%, 10.4-43% and 5.8-21.5%. Median time to recurrence varied from 9 to 23 months, three-year disease free survival ranged from 14 to 41.5%. The second search resulted in 140 articles among which 17 met the inclusion criteria. A total of 190 patients underwent secondary CRS. Median survival after the second procedure ranged from 18 to 55.7 months. One, two and three-year survival ranged between 66 and 94, 44-50 and 0-66%. CONCLUSION: Recurrence is very common after cytoreductive surgery and intraperitoneal chemotherapy for PC of colorectal origin. Repeat cytoreductive surgery suggests a potential survival benefit for a highly selected group. Therefore, strategies to prevent recurrence are of the utmost importance.

Trends in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of synchronous peritoneal carcinomatosis of colorectal origin in the Netherlands.

BACKGROUND: Population-based data on the percentage of colorectal cancer (CRC) patients with synchronous peritoneal carcinomatosis (PC) being treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently lacking. The current population-based study describes trends in the use of CRS-HIPEC in the Netherlands, one of the first countries where CRS and HIPEC was introduced. METHODS: All patients diagnosed with synchronous PC of CRC between 2005 and 2012 were extracted from the Netherlands Cancer Registry (n = 4623). Patients with primary appendiceal cancer were excluded resulting in a study population of 4430 patients. Trends in the use of CRS-HIPEC over time were analyzed by means of a Cochrane-Armitage trend test. Survival proportions were calculated as the time between diagnosis and date of death or last follow-up (January 2014). RESULTS: Of the total 4430 patients with synchronous PC, 297 (6.4%) underwent treatment with CRS-HIPEC. The proportion of colorectal PC patients receiving CRS-HIPEC increased significantly over time from 3.6% in 2005-2006 to 9.7% in 2011-2012 (p < 0.0001). Overall median survival (MS) for patients treated with CRS-HIPEC was 32.3 months, whereas MS rates were respectively 12.6, 6.1 and 1.5 for months palliative chemotherapy with/without surgery, palliative surgery and best supportive care. CONCLUSION: The proportion of patients diagnosed with synchronous PC from CRC treated with CRS-HIPEC has increased significantly over time and currently almost 10% of PC patients are treated with CRS-HIPEC. Median survival in this population based group is 32.3 months.

Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma.

BACKGROUND: Colorectal mucinous adenocarcinoma (MC) has been associated with impaired prognosis compared with nonmucinous adenocarcinoma (NMC). Response to palliative chemotherapy is poor in metastatic disease, but the benefit of adjuvant chemotherapeutic treatment has never been assessed in large patient groups. This study analyses overall survival and efficacy of adjuvant chemotherapy in terms of survival in patients following radical resection for MC. PATIENTS AND METHODS: This population-based study involved 27 251 unselected patients diagnosed with colorectal carcinoma between 1990 and 2010 and recorded in a prospective pathology-based registry. Kaplan-Meier analysis and log-rank testing were used to estimate survival. Cox proportional hazard model was used to calculate multivariate hazard ratios for death. RESULTS: MC was found in 12.3% (N = 3052) of colorectal tumors with a different distribution compared with NMC, with 24.4% located in the rectum and 54.3% in the proximal colon (versus 38.0% and 30.6%), P < 0.0001. NMC was more often classified as stage I disease than MC (20.5% versus 10.9%), P < 0.0001. After adjustments for covariates, MC was associated with a higher risk of death only when located in the rectum [hazard ratio 1.22; 95% confidence interval (CI) 1.11-1.34]. Multivariate regression analysis showed a similar survival after adjuvant chemotherapy for stage III MC and NMC patients. CONCLUSIONS: The poor prognosis for MC is only present in rectal cancer. In the adjuvant setting, there is no difference in the efficacy of chemotherapy between MC and NMC; therefore, current adjuvant treatment recommendations should not take histology into account.

Intraoperative radiotherapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Five consecutive case reports of locally advanced rectal cancer with synchronous peritoneal carcinomatosis.

PURPOSE: Treatment of rectal cancer has markedly improved since the introduction of neoadjuvant strategies and better surgical techniques. However, treatment remains troublesome for patients with locally advanced rectal cancer (LARC) or with peritoneal carcinomatosis (PC). Patients presenting with LARC may now benefit from the integration of intra-operative radiotherapy (IORT) into multimodality treatment. Selected patients with PC now undergo cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) resulting in improved survival. Some patients present with locally advanced disease and synchronous peritoneal carcinomatosis and fulfill the eligibility criteria for both HIPEC and IORT, raising the question whether the combined application of both modalities within one operative procedure is feasible. CASE SERIES: This report includes five consecutive cases of rectal cancer patients presenting with LARC and synchronous PC who were treated with a multimodality treatment including IORT and HIPEC after cytoreductive surgery. Postoperative complications and survival are described. RESULTS: The combination of cytoreductive surgery with HIPEC and IORT appeared to be feasible and well tolerated. The observed complications did not differ from the morbidity associated with extensive pelvic surgery without HIPEC or IORT. No inhospital mortality occurred. One patient died after 11 months of recurrent disease. All other patients are currently alive with one patient already surviving 38 months. CONCLUSION: The current case series shows that a multimodality treatment containing IORT and HIPEC is feasible and safe with promising survival rates. This strategy may, therefore, be considered in selected rectal cancer patients presenting with both LARC and synchronous PC.

Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy.

BACKGROUND: Although systemic therapies have shown to result in survival benefit in patients with metastatic colorectal cancer (mCRC), outcomes in patients with peritoneal carcinomatosis (PC) are poor. No data are available on outcomes of current chemotherapy schedules plus targeted agents in mCRC patients with PC. METHODS: Previously untreated mCRC patients treated with chemotherapy in the CAIRO study and with chemotherapy and targeted therapy in the CAIRO2 study were included and retrospectively analysed according to presence or absence of PC at randomisation. Patient demographics, primary tumour characteristics, progression-free survival (PFS), overall survival (OS), and occurrence of toxicity were evaluated. RESULTS: Thirty-four patients with PC were identified in the CAIRO study and 47 patients in the CAIRO2 study. Median OS was decreased for patients with PC compared with patients without PC (CAIRO: 10.4 versus 17.3 months, respectively (p ≤ 0.001); CAIRO2: 15.2 versus 20.7 months, respectively (p < 0.001)). Median number of treatment cycles did not differ between patients with or without PC in both studies. Occurrence of major toxicity was more frequent in patients with PC treated with sequential chemotherapy in the CAIRO study as compared to patients without PC. This was not reflected in reasons to discontinue treatment. In the CAIRO2 study, no differences in major toxicity were observed. CONCLUSION: Our data demonstrate decreased efficacy of current standard chemotherapy with and without targeted agents in mCRC patients with PC. This suggests that the poor outcome cannot be explained by undertreatment or increased susceptibility to toxicity, but rather by relative resistance to treatment.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

AIM: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. PATIENTS AND METHODS: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'untranslated region of the TS gene were genotyped. RESULTS: There was a positive association between tumor T stage and the VNTR genotypes (p = 0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. CONCLUSION: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

AIM: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. PATIENTS AND METHODS: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'-untranslated region of the TS gene were genotyped. RESULTS: There was a positive association between tumor T stage and the VNTR genotypes (p=0.05).In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. CONCLUSION: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

Variation in treatment and outcome of patients with rectal cancer by region, hospital type and volume in the Netherlands.

BACKGROUND: Aim of this study was to describe treatment patterns and outcome according to region and hospital type and volume among patients with rectal cancer in the Netherlands. METHODS: All patients with rectal carcinoma diagnosed in the period 2001-2006 were selected from the Netherlands Cancer Registry. Logistic regression analyses were performed to examine the influence of relevant factors on the odds of receiving preoperative radiotherapy and on the odds of postoperative mortality. Relative survival analysis was used to estimate relative excess risk of dying according to hospital type and volume. RESULTS: In total, 16 039 patients were selected. Patients diagnosed in a teaching or university hospital had a lower odds (OR 0.85; 95% CI 0.73-0.99 and OR 0.70; 95% CI 0.52-0.92) and patients diagnosed in a hospital performing >50 resections per year had a higher odds (OR 1.95; 95% CI 1.09-1.76) of receiving preoperative radiotherapy. A large variation between individual hospitals in rates of preoperative radiotherapy and between Comprehensive Cancer Centre-regions in the administration of preoperative chemoradiation was revealed. Postoperative mortality was not correlated to hospital type or volume. Patients with T1-M0 tumours diagnosed in a hospital with >50 resections per year had a better survival compared to patients diagnosed in a hospital with <25 resections per year (RER 0.11; 95% CI 0.02-0.78). CONCLUSION: This study demonstrated variation in treatment and outcome of patients with rectal cancer in the Netherlands, with differences related to hospital volume and hospitals teaching or academic status. However, variation in treatment patterns between individual hospitals proved to be much larger than could be explained by the investigated characteristics. Future studies should focus on the reasons behind these differences, which could lead to a higher proportion of patients receiving optimal treatment for their stage of the disease.

Reduction of in-hospital mortality following regionalisation of pancreatic surgery in the south-east of the Netherlands.

BACKGROUND: In the late nineties of the former century, surgery for pancreatic and peri-ampullary cancer in the southern part of The Netherlands was performed mainly in low-volume hospitals (<5 resections/year). Results reported by the Comprehensive Cancer Center South (CCCS) in 2005 revealed the clearly disappointing results of this practice. The former stimulated the regionalisation of pancreatic surgery by 3 collaborating surgical units into one non-academic teaching hospital in the eastern part of the CCCS-region starting from July 2005. METHODS: All of the 76 patients in this regional cohort group in whom a resection of a (peri-)pancreatic tumour was performed with curative intent have been followed up prospectively. The results of surgical morbidity and in-hospital mortality were compared with the results of the CCCS cohort group which were reported previously. RESULTS: Ever since the regionalisation the annual number of patients undergoing resection of a pancreatic tumour increased from 10 to 33, resulting in a total number of 76 patients. Post-operative complications, reoperation rate and in-hospital mortality decreased significantly to 34.2%, 18.4% and 2.6% respectively, as compared to 71.9%, 37.8 and 24.4% in the time period before regionalisation (p < 0.01). CONCLUSION: These unique comparative prospective data derived from daily practice in a collaborative surgical region in The Netherlands (CCCS) support the need for centralisation of pancreatic surgery in order to improve standard of care in pancreatic surgery. This can be achieved by collaboration in a large regional hospital.

Quality assurance in rectal cancer treatment in the Netherlands: a catch up compared to colon cancer treatment.

BACKGROUND: In the Netherlands, the Total Mesorectal Excision (TME) surgical technique for rectal cancer was introduced together with pre-operative radiotherapy in a quality controlled manner within the framework of the TME trial (1996-1999). The aim of this study is to examine the effects of the structural changes in rectal cancer care on survival compared to colon cancer for patients treated before, during and after the TME trial. METHOD: We compared overall survival of all patients with curatively resected colon (n = 15,266) and rectal cancer (n = 5839) in the regions of Comprehensive Cancer Centres South and West between 1990 and 2005, adjusting for prognostic variables. RESULTS: In the pre-trial period, rectal cancer had a significant lower survival compared to colon cancer (HR 1.248, P < 0.01). However, in the post-trial period, survival after rectal cancer was similar to colon cancer (HR 0.987, n.s.). CONCLUSION: Although survival improved significantly for both colon and rectal cancer in the last 15 years, the substantially worse results after rectal cancer have been eliminated. This study shows the lasting effects that structural surgical training and quality assurance can have on survival outcome.

Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity.

BACKGROUND: Adjuvant 5-fluorouracil-based chemotherapy significantly decreases mortality among patients with stage III colon cancer, but is less prescribed with rising age. We were interested in the pattern of adjuvant treatment and possible effects on survival among elderly patients. PATIENTS AND METHODS: All resected patients aged 65-79 with stage III colon carcinoma, diagnosed between 1995 and 2001 in the Comprehensive Cancer Centre South registry area in the Netherlands were included (n=577). We examined determinants of receipt of adjuvant chemotherapy and their relation to survival. RESULTS: The proportion of elderly patients receiving adjuvant chemotherapy increased from 19% in 1995 to 50% in 2001, but a large inter-hospital variation remained. In a multivariable analysis, females [odds ratio (OR) 0.5, P=0.006], patients with comorbidity [OR 0.5, P=0.005], and patients with a low socioeconomic status [OR 0.5, P=0.02] received less adjuvant therapy. Between 1995 and 2001 survival of elderly patients improved (hazard ratio 0.8, P=0.04). CONCLUSION: Although an increasing proportion of elderly patients with colon cancer are treated with adjuvant chemotherapy, many elderly patients still do not receive this treatment. As expected, receipt of adjuvant treatment decreased in the presence of comorbidity, but the clinical rationale for undertreatment of women and patients with low socioeconomic status is not clear.