A 'SMART' way to determine treatment goals in pharmacotherapy education.

AIM: Determining treatment goals is an important part of the treatment decision-making process, but medical students are not trained in a structural way on how to define these goals. 'SMART' criteria are widely used in non-medical professions for determining goals and may improve treatment goal setting. The aim of this study was to assess the effect of implementation of SMART criteria on medical students' ability to set treatment goals and to analyze the effects on treatment choice and monitoring. METHODS: We performed a prospective, randomized controlled minimal intervention study with one control and two intervention groups (WHO group and SMART group). Second year medical students had to complete a WHO six step treatment plan for four written case reports of patients with asthma. The treatment plans were assessed using a standard scoring sheet developed by a Delphi procedure among respiratory physicians from all eight university medical centres in the Netherlands. RESULTS: A total of 251 second year medical students participated. The SMART group had significantly higher scores for setting treatment goals than the WHO and control groups (68.5 % vs. 29.6 % and 30.8 %, respectively, both P < 0.001). The SMART group also had significantly better scores for treatment monitoring than the WHO and control groups (34.2 % vs. 19.3 % and 24.6 %, respectively, both P < 0.001). There were no between group differences in treatment choice. Regardless of the study group, better setting of treatment goals was associated with better treatment monitoring, an association not reported earlier. CONCLUSION: SMART criteria improve the setting of treatment goals and treatment monitoring.

Excision Repair Cross-Complementation group 1 (ERCC1) C118T SNP does not affect cellular response to oxaliplatin.

AIMS: ERCC1 is involved in the repair of oxaliplatin-induced DNA damage. Studies for the association of the C118T SNP with clinical response to treatment with platinum drugs have rendered inconsistent results. We investigated the ERCC1 C118T SNP with respect to overall and progression-free survival in patients with advanced colorectal cancer (ACC) treated with oxaliplatin and in vitro DNA repair capacity after oxaliplatin exposure. In addition we discuss discrepancies from other studies concerning ERCC1 C118T. MATERIALS AND METHODS: Progression-free survival was determined in 145 ACC patients treated with oxaliplatin-based chemotherapy in a phase 3 trial. For the in vitro studies regarding ERCC1 functionality, we transfected an ERCC1 negative cell line with 118C or 118T ERCC1. Cellular sensitivity and DNA repair capacity after exposure to oxaliplatin was examined by Sulphorodamine B growth inhibition assay, COMET assay and Rad51 foci staining. RESULTS: We found no association between ERCC1 C118T and progression-free or overall survival. In addition, transfection of either 118C or 118T restores DNA-repair capacity of UV20 cells to the same level and chemosensitivity to oxaliplatin was similar in ERCC1 118C and 118T transfected cells. CONCLUSION: This study shows that the ERCC1 C118T variants are not associated with survival in ACC patients treated with oxaliplatin or the in vitro sensitivity and DNA-repair capacity in 118C and 118T transfected cell lines. Therefore, ERCC1 C118T genotyping seems of no value in individualizing oxaliplatin based chemotherapy in ACC.

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Next to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients. METHODS: Germline DNA was isolated from 246 KRAS wild-type mCRC patients who were treated in the phase III CAIRO2 study with chemotherapy and bevacizumab alone or with the addition of cetuximab. Associations of epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) CA(14-22), cyclin D1 (CCND1) 932G>A, fragment-C gamma receptor (FCGR) 2A 535A>G and FCGR3A 818A>C polymorphisms with progression-free survival (PFS) and cetuximab-related skin toxicity were studied. RESULTS: In cetuximab-treated patients, the FCGR3A 818C-allele was associated with decreased PFS compared with the FCGR3A 818AA genotype (median PFS, 8.2 [95%CI, 6.7-10.3] versus 12.8 [95%CI, 10.3-14.7] months, respectively; HR, 1.57 [95%CI, 1.06-2.34]; P=.025). The EGFR20 genotype was associated with decreased PFS compared with the EGFR<20 genotype (median PFS, 7.6 [95%CI, 6.7-10.0] versus 12.4 [95%CI, 10.3-13.4] months, respectively; HR, 1.58 [95%CI, 1.06-2.35]; P=.024). The FCGR3A and EGFR polymorphisms were not associated with PFS in patients treated without cetuximab. None of the polymorphisms were associated with the incidence of grades 2-3 skin toxicity. CONCLUSION: EGFR and FCGR3A germline polymorphisms are associated with PFS in KRAS wild-type mCRC patients treated with cetuximab, bevacizumab and chemotherapy.

Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial.

PURPOSE: To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT). PATIENTS AND METHODS: In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed. RESULTS: The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively. CONCLUSION: Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

Comparison of three micromorphometric pathology classifications of melanoma metastases in the sentinel node.

OBJECTIVE: The purposes of this study were to determine which classification best predicts additional lymph node disease and survival, and to suggest a threshold below which a completion dissection may be omitted. SUMMARY BACKGROUND DATA: Three micromorphometric parameters of melanoma sentinel node metastases were compared: invasion depth from the capsule (Starz-classification), maximum diameter (Rotterdam-criteria), and location within the node (Dewar-classification). METHODS: The pathology slides of 116 patients with tumor-positive sentinel nodes were reviewed. The follow-up data were obtained from the prospectively kept database. The median follow-up duration was 53 months. RESULTS: Metastases with an invasion depth under 0.3 mm or diameter less than 0.1 mm were not associated with additional involved nodes. Four percent of the patients with metastases with an invasion depth of 0.3 to 1.0 mm had other involved nodes and 3% of the patients with metastases with a diameter of 0.1 to 1.0 mm. Other nodes were involved in 3% of subcapsular metastases, 9% of both subcapsular and parenchymal metastases, and 33% in case of multifocal or extensive disease. The smallest tumor invasion depth and diameter associated with additional involved nodes was 0.4 mm. Only 5-year overall survival in the 3 successive invasion depth categories were statistically significant: 92%, 83%, and 68%. Five-year overall survival was 81% in patients with one involved sentinel node and 60% if there were more. CONCLUSIONS: Invasion depth and diameter of the metastasis correlate best with the presence of additional nodal disease. Invasion depth best predicts overall survival. It seems justified to refrain from completion dissection in patients with a sentinel node tumor invasion depth up to 0.4 mm.

The influence of the use of CT-planning on the irradiated boost volume in breast conserving treatment.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the effect of CT-based delineation and planning on the irradiated boost volume. For this specific purpose we used the data as derived from 2 prospective phase III randomised trials. PATIENTS AND METHODS: Data from 1331 patients (

Is completion lymph node dissection needed in case of minimal melanoma metastasis in the sentinel node?

OBJECTIVE: The purpose of this study was to evaluate the micromorphometric Starz-classification in melanoma patients. SUMMARY BACKGROUND DATA: The micromorphometric Starz-classification suggests that melanoma patients with a sentinel node metastasis invading no more than 0.3 mm (S-I) or 0.31 to 1.0 mm (S-II) below the capsular level can be spared further surgery, while invasion of the metastasis of more than 1.0 mm (S-III) implies a need for completion dissection. METHODS: Seventy patients with sentinel node metastases were studied. Twenty patients with an S-I or S-II classification were spared further surgery and 50 S-III patients underwent completion dissection. The median follow-up time was 33 months. RESULTS: No lymph node recurrences were detected in the 20 S-I, II patients. Six of the 50 S-III patients (12%) had additional involved nodes in the dissection specimen. In these patients no recurrences developed in the cleared regional basins. Overall 3-year survival was 100% in the S-I, II patients and 80% in the S-III patients (P = 0.04). Three-year disease-free survival rates were 83% and 60%, respectively (P = 0.40). CONCLUSIONS: : This study suggests that further surgery is unnecessary in S-I and S-II patients, while it does seem prudent to carry out completion dissection in S-III patients. The distinct survival difference between the 2 groups of patients suggests that the S-classification also has prognostic implications.

Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer.

BACKGROUND: Fluoropyrimidine-based chemotherapy plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti-epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer. METHODS: We randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was progression-free survival. The mutation status of the KRAS gene was evaluated as a predictor of outcome. RESULTS: The median progression-free survival was 10.7 months in the CB group and 9.4 in the CBC group (P=0.01). Quality-of-life scores were lower in the CBC group. The overall survival and response rates did not differ significantly in the two groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased progression-free survival as compared with cetuximab-treated patients with wild-type-KRAS tumors or patients with mutated-KRAS tumors in the CB group. CONCLUSIONS: The addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group. (ClinicalTrials.gov number, NCT00208546.)

Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients.

PURPOSE: Oxaliplatin is detoxified by conjugation to glutathione via the enzyme Glutathione-S-transferase pi (GSTP1). The aim of this study is to investigate the association of GSTP1 Ile105Val genetic polymorphism with oxaliplatin efficacy and toxicity in advanced colorectal cancer (ACC) patients. EXPERIMENTAL DESIGN: A total of 91 ACC patients received capecitabine and oxaliplatin (CAPOX) as a part of a multicentre phase-III study of the Dutch Colorectal Cancer Group. Tumour response was evaluated according to RECIST, toxicity was graded using CTC, and GSTP1 Ile105Val was determined by pyrosequencing. RESULTS: Overall survival after CAPOX was similar for patients with the Ile/Ile (11.5 mo), Ile/Val (11.6 mo) and Val/Val (12.6 mo) genotypes (p=0.602). Likewise, there were no statistically significant differences in progression-free survival (p=0.252). Overall grades 3-4 toxicity was not related to genotype (p=0.313). There were no differences in any grade or grades 3-4 neurotoxicity amongst the patients who received > or =500 mg/m(2) of oxaliplatin (p-values of 0.376 and 0.772, respectively). CONCLUSIONS: The results of this study indicate that the GSTP1 genotype is not predictive for progression-free survival or overall survival in ACC patients treated with CAPOX. Moreover, overall neurotoxicity and neurotoxicity in patients receiving 500 mg/m(2) of oxaliplatin was not associated with GSTP1 genotype.

Evaluation of current TNM classification of penile carcinoma.

PURPOSE: The TNM classification is the most common tool for staging malignancies. The current classification for penile carcinoma has been unchanged since 1987. There are several shortcomings to this classification. Accurate clinical staging can be troublesome because several categories are defined by anatomical structures that cannot readily be identified by physical examination or imaging. A second drawback is substantial variability with respect to survival in certain T and N categories. We analyzed the prognostic value of the TNM classification in patients with penile carcinoma treated at our institute. We propose modifications to improve prognostic stratification and facilitate clinical staging. MATERIALS AND METHODS: The records of 513 patients treated between 1956 and 2006 were analyzed. All tumors were staged according to the most recent classification. We calculated disease specific survival in the different T and N categories. Survival in the different categories was compared using Kaplan-Meier analysis and the log rank test. RESULTS: Five-year disease specific survival in the entire group was 80.5% at a median followup of 58.7 months. There was no significant difference in survival between T2 and T3 tumors (p = 0.57). Furthermore, no significant survival difference was found between N1 and N2 categories (p = 0.18). Using a modified classification a significant difference in survival was found among all T and N categories. CONCLUSIONS: The current TNM classification for penile carcinoma does not adequately differentiate in terms of survival among several T and N categories. With some modifications prognostic stratification improves and clinical staging is facilitated.

Current questions in the treatment of advanced colorectal cancer: the CAIRO studies of the Dutch Colorectal Cancer Group.

The outcome of patients with advanced colorectal cancer has significantly improved in the past decade because of the development of new treatment strategies. The Dutch Colorectal Cancer Group (DCCG) is a national multidisciplinary clinical research group in The Netherlands. The 3 CAIRO studies of the DCCG address clinically relevant questions in patients with advanced colorectal cancer: the benefit of combination versus sequential therapy, targeting vascular endothelial growth factor and epidermal growth factor receptor, and the role of maintenance therapy. This article presents the outline of these studies and summarizes the current results.

Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients.

BACKGROUND: Current follow-up recommendations for patients with penile carcinoma are based on small numbers of patients. OBJECTIVES: To give further insight into the recurrence patterns of penile carcinoma in different treatment settings and provide recommendations for follow up. DESIGNS, SETTING, AND PARTICIPANTS: In this retrospective study, we analysed 700 patients from two referral centres for penile carcinoma for recurrences. MEASUREMENTS: Recurrences were categorized as local, regional, or distant. The rate of local recurrences was compared between patients undergoing penile-preserving treatments and partial/total amputation. Regional recurrences were compared between patients surgically staged as pN0 or pN+ and clinically node-negative (cN0) patients subjected to a wait-and-see policy. The total recurrence rate, type of recurrence, time to recurrence, and survival were calculated. RESULTS AND LIMITATIONS: 205 out of 700 patients (29.3%) had a recurrence, consisting of 18.6% local, 9.3% regional, and 1.4% distant recurrences. Of the recurrences, 92.2% occurred within 5 yr after primary treatment. All regional and distant recurrences occurred within 50 and 16 mo, respectively. The local recurrence rate was 27.7% after penile-preserving therapy and 5.3% after amputation. The regional recurrence rate was 2.3% in patients staged as pN0, 19.1% in patients staged as pN+, and 9.1% in patients undergoing a wait-and-see policy. The 5-yr disease-specific survival was 92% after a local recurrence and 32.7% after a regional recurrence. All patients with a distant recurrence died within 22 mo. Although the number of analysed patients is substantial, the results do not necessarily reflect those of other centres using different techniques for the management of penile carcinoma. CONCLUSIONS: Patients undergoing penile-preserving therapy, patients surgically staged as pN+, and those undergoing a wait-and-see policy for the nodal status are at high risk of developing a recurrence. Follow-up recommendations are provided based on the risk and impact on survival of a recurrence.

Axillary and extra-axillary lymph node recurrences after a tumor-negative sentinel node biopsy for breast cancer using intralesional tracer administration.

BACKGROUND: At our institution, tracer fluids are administered in the primary breast cancer and, in addition to the ones in the axilla, sentinel nodes outside the axilla are rigorously pursued. The objective of the present study of sentinel node-negative breast cancer patients was to determine the lymph node recurrence rates in the axilla and elsewhere, the false-negative rates, and the survival. METHODS: Between January 1999 and November 2005, 1,019 breast cancer patients underwent a sentinel node biopsy. In 748 of them, 755 sentinel node biopsies did not reveal a tumor-positive sentinel node and they did not undergo axillary node dissection. Metastases were revealed in 284 sentinel node biopsies performed in the remaining 271 patients: 247 in the axilla, 20 outside the axilla, and 17 both in the axilla and elsewhere. The median follow-up duration was 46 months. RESULTS: Two of the 748 sentinel node-negative patients developed an axillary lymph node recurrence (0.25%) and two others developed a supraclavicular lymph node recurrence (0.25%). The overall lymph node recurrence rate was 0.5%. The false-negative rates were 1.4% overall, 0.8% for the axilla, and 5.1% for the extra-axillary nodes. After five years, 95.9% of all sentinel node-negative patients were alive and 89.7% were alive without evidence of disease. CONCLUSION: The low recurrence and false-negative rates and promising survival figures show that our lymphatic mapping method with intralesional tracer administration is accurate for the axilla. Outside the axilla, 5.1% of involved sentinel nodes were missed.

Dissemination patterns in non-gastric MALT lymphoma.

BACKGROUND: In contrast to gastric extranodal marginal zone mucosa associated lymphoid tissue (MALT) lymphomas, there is little consensus on the value and clinical consequences of extensive staging at diagnosis and during follow-up in non-gastric MALT lymphomas. DESIGN AND METHODS: Complete clinical information at presentation and during follow-up was collected for 72 patients with non-gastric MALT lymphoma treated at the Netherlands Cancer Institute between 1977 and 2005. Dissemination patterns at presentation were studied for nine primary dominant organ groups in our series of 72 patients and in a similar cohort treated at Vienna University (for a total of 106 patients). RESULTS: Twenty-three of our patients (32%) had more than one site of extranodal MALT lymphomatous disease, 13 patients (18%) had regional nodal involvement and 7 (10%) had bone marrow involvement. Site-specific dissemination was seen in paired organs (orbit, lung) and in the gastrointestinal tract (stomach, colon) and primary pulmonary MALT lymphoma was specifically related to gastric involvement (p<0.0001). These patterns of dissemination were retained during relapsed disease. CONCLUSIONS: Primary extranodal non-gastric marginal zone MALT lymphoma frequently presents as stage IV disease (26%) and multifocal disease (32%) and with a site-specific dissemination pattern. After an extensive staging procedure at presentation, we recommend primary site-directed protocols during follow-up focused on the primary involved tract/organ system, regional lymph nodes and pulmonary and gastric relapses.

Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions.

PURPOSE: We present a single institute experience of the four most widely used diversions after cystectomy in 281 patients, with an evaluation of the association between clinical factors, complication rates, functional results, and metabolic complications. MATERIALS AND METHODS: Between 1990 and 2005, 281 consecutive cystectomies were performed at our institute. Four different diversions were offered: an ileal conduit according to Bricker (IC; 118 patients), an Indiana pouch (IP; 51 patients), and orthotopic diversions after cystectomy/neobladder (N; 62 patients), or sexuality-preserving cystectomy and neobladder (SPCN; 50 patients). RESULTS: Forty-four percent developed early complications: IC 48%, IP 43%, N 42%, and SPCN 38%. High ASA score was the only variable significantly associated with early major complications (ASA 1 vs. 3: HR, 0.32; 95%CI, 0.14-0.72). Late complication rate was 51% with fewer complications in the IC group, IC 39%, IP 63%, N 59%, and SPCN 60% (HR, 0.32; 95%CI, 0.14-0.72), which was explained by fewer uncomplicated urinary tract infections (one third of all late complications) in the IC group. There were no differences in experienced late major complications. We found no significant association between tumour stage, ASA, age, preoperative radiotherapy, gender, and diversion-related complication rates. Complete daytime and nighttime continence, respectively, was achieved in 96% and 73% after IP, 90% and 67% after neobladder, and 96% and 67% after SPCN. Metabolic changes were found in 24% of the patients: 21% after IC, 26% after IP, and 28% after orthotopic diversion (neobladder and SPCN combined); low vitamin B12 was measured in 23%, 15%, and 15% respectively. CONCLUSIONS: Cystectomy with any subsequent diversion remains a procedure with considerable morbidity. High ASA score was associated with more early complications. Orthotopic diversions provide good functional results, but at the cost of more late complications compared with ileal conduits. We found no evidence that age, ASA score, positive lymph nodes, extravesical tumour growth, or previous radiotherapy were contraindications per se for any diversion.

Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. FINDINGS: 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004). INTERPRETATION: Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.

Neoadjuvant chemotherapy in advanced penile carcinoma.

OBJECTIVE: Little data on the role of neoadjuvant chemotherapy for advanced penile carcinoma are available. We describe the experiences at our institute. METHODS: A total of 20 patients received neoadjuvant chemotherapy for downstaging of irresectable disease in the period from 1972 until August 2005. During this 34-yr period, five different chemotherapeutic regimens were used. We evaluated clinical tumour response, chemotherapeutic toxicity, rate and type of subsequent surgery, histopathologic features, and long-term clinical outcome. RESULTS: An objective tumour response was achieved in 12 of 19 evaluable patients. Overall 5-yr survival was 32%. A significant difference (p=0.012) in survival was found between responders (5-yr survival 56%) and nonresponders (all patients died within 9 mo). Nine responders underwent subsequent surgery with curative intent. Eight of them were long-term survivors without evidence of recurrent disease. Three nonresponders were operated on to improve local control. All died within 8 mo after surgery. Toxicity of chemotherapy was high with three toxic deaths and discontinuation of treatment in one patient. CONCLUSIONS: Of 20 patients with advanced penile carcinoma, 12 were responsive to neoadjuvant chemotherapy and 8 were long-term survivors after subsequent surgery. These results suggest that neoadjuvant chemotherapy is a valuable treatment option for patients with irresectable penile carcinoma, which is otherwise considered incurable. Surgery should be performed only in patients showing clinical response to chemotherapy because prognosis for nonresponding patients who underwent surgery was dismal and local control was not improved.

Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

OBJECTIVE: To evaluate the survival of patients with pseudomyxoma peritonei (PMP) treated by cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC), and to identify factors with prognostic value. SUMMARY BACKGROUND DATA: PMP is a clinical syndrome characterized by progressive intraperitoneal accumulation of mucous and mucinous implants, usually derived from a ruptured mucinous neoplasm of the appendix. Survival is dominated by pathology. METHODS: A total of 103 patients (34 men and 69 women) treated at The Netherlands Cancer Institute between 1996 and 2004 were identified. Survival was calculated from date of initial treatment and corrected for a second procedure. PMP was pathologically categorized into disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate subtype (PMCA-I). Clinical and pathologic factors were analyzed to identify their prognostic value for survival. RESULTS: Median follow-up was 51.5 months (range, 0.1-99.5 months). Recurrence developed in 44%. A second procedure for recurrence was performed in 11 patients. The median disease-free interval was 25.6 months (95% confidence interval [CI], 14.8-43.6 months). The 3-year and 5-year disease-free survival probability was 43.6% (95% CI, 34.4%-55.2%) and 37.4% (95% CI, 28.2%-49.5%), respectively. The disease-specific 3-year and 5-year survival probability was 70.9% (95% CI, 62.0%-81.2%) and 59.5% (95% CI 48.7%-72.5%), respectively. Factors associated with survival were pathological subtype, completeness of cytoreduction, and degree and location of tumor load (P < 0.05). The main prognostic factor, independently associated with survival, was the pathologic subtype (P < 0.01). CONCLUSION: Cytoreductive surgery in combination with intraoperative HIPEC is a feasible treatment strategy for PMP in terms of survival. The pathologic subtype remains the dominant factor in survival. Patients should be centralized to improve survival by a combination of surgical experience and adequate patient selection.

Progression of pseudomyxoma peritonei after combined modality treatment: management and outcome.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment strategy for pseudomyxoma peritonei (PMP) with curative intent. The aim of this study was to determine the patterns of failure in patients who underwent such a procedure and to evaluate management and outcome of progressive disease. METHODS: After exclusion of patients with overt malignancy, progression was studied in 96 PMP patients treated primarily by CRS with HIPEC. Location, pathology, management and outcome were recorded. RESULTS: Median follow-up was 51.5 months (0.1-99.5). Median progression free survival (PFS) was 28.2 months (95% CI 18.3->). Progressive disease was mainly located sub hepatic (38%) or in multiple regions (36%). Pathological dedifferentiation was observed in 8 patients (20%). The choice of treatment depended on pathology, extent of disease and PFS. Seventeen patients were treated for progression by second CRS with (n=8) or without HIPEC (n=10). The 3-years overall survival (OS) probability after this treatment was 100% and 53.3% (95% CI 28.2-100%), respectively. Fifteen patients with (slow) progression were observed. Three-years OS probability of these patients was 66.0% (95% CI 43.4-100%). All patients treated for progression by systemic chemotherapy only (n=6) had died of disease after a median follow up of 14.8 (9.8-33.6) months. A longer PFS after primary treatment was associated with longer OS after progression (P = 0.04). CONCLUSIONS: Progressive PMP after primary CRS with HIPEC is probably the result of technical failure and/or tumor biology. Management of progressive PMP can be valuable for selected patients and should depend primarily on the PFS.

Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882.

PURPOSE: To determine whether the effect of an additional "boost" radiation after breast conservative therapy (BCT) on local control depends on age and evaluate the impact of a treatment policy with a threshold for age. PATIENTS AND METHODS: We used data from EORTC 22881-10882 trial, with median follow-up of 77.4 months. Patients receiving BCT and 50Gy whole breast irradiation were randomized to no boost and 16Gy boost (N=5318). RESULTS: In univariate analysis, a boost reduced local failure by a factor of 2 (P<0.0001). Multivariate analysis showed local control increased with age (P=0.0003). There was no evidence that the relative effect of a boost on local control depends on age (P=0.97) However in younger patients the 5-year local failure was higher, therefore the absolute reduction was greater. If the threshold-age for boost treatment were set at 40 years, 8.4% of the study population would receive a boost, resulting in a 5-year local failure of 6.1% in the study population. Changing the threshold-age to 60 years, 67% of the study population would receive a boost and the 5-year local failure would be reduced to 4.4%. CONCLUSIONS: In younger patients a boost dose resulted in a greater absolute reduction of local failure. The relative risk reduction was however similar for all ages. Applying a treatment policy with a threshold-age of 60 would result in 0.6% increase in local failure in the total study population, while sparing the boost to 1/3 of the patients.