Recurrence Patterns and Long-term Results After Induction Chemotherapy, Chemoradiotherapy, and Curative Surgery in Patients With Locally Advanced Esophageal Cancer.

OBJECTIVE: The long-term follow up data of 2 prospective phase II trials is reported (NCT00072033, NCT00445861), which investigated neoadjuvant chemoradiation followed by surgery in patients with esophageal carcinoma. Postoperative complications as well as prognostic factors and patterns of relapse during long-term observation are shown. SUMMARY OF BACKGROUND DATA: Long-term follow-up is often missing in the complex setting of multimodal treatments of esophageal carcinoma; this leads to rather undifferentiated follow-up guidelines for this tumor entity. METHODS: In the first trial, patients received induction chemotherapy followed by chemoradiation and surgery. In the second trial, cetuximab was added to the same neoadjuvant treatment concomitant with induction chemotherapy and chemoradiation. RESULTS: Eighty-two patients underwent surgery; the median follow-up time was 6.8 and 6.4 years, respectively. Fifty-five percent were diagnosed with adenocarcinoma, 80% clinically node-positive, 68% received transthoracic esophagectomy, and 32% transhiatal or transmediastinal resection. Five patients died postoperatively in-hospital due to complications (6%). The median overall survival was 4.3 years, and the median event-free survival was 2.7 years. Patients with adenocarcinoma rarely relapsed after a 3-year event-free survival. Whereas patients with residual tumor cells after neoadjuvant therapy primarily experienced relapse within the first 2 postoperative years, this in contrast to several patients with complete remission who also experienced late relapses 4 years after surgery. CONCLUSION: After curative surgery in a multimodal setting, the histological type and the response to neoadjuvant therapy predicted the time frame of relapse; this knowledge may influence further follow-up guidelines for esophageal carcinoma.

Prospective multicenter registration study of colorectal cancer: significant variations in radicality and oncosurgical quality-Swiss Group for Clinical Cancer Research Protocol SAKK 40/00.

PURPOSE: This study aimed to investigate in a multicenter cohort study the radicality of colorectal cancer resections, to assess the oncosurgical quality of colorectal specimens, and to compare the performance between centers. METHODS: One German and nine Swiss hospitals agreed to prospectively register all patients with primary colorectal cancer resected between September 2001 and June 2005. The median number of eligible patients with one primary tumor included per center was 95 (range 12-204). RESULTS: The following variations of median values or percentages between centers were found: length of bowel specimen 20-39 cm (25.8 cm), maximum height of mesocolon 6.5-12.5 cm (9.0 cm), number of examined lymph nodes 9-24 (16), distance to nearer bowel resection margin in colon cancer 4.8-12 cm (7 cm), and in rectal cancer 2-3 cm (2.5 cm), central ligation of major artery 40-97 % (71 %), blood loss 200-500 ml (300 ml), need for perioperative blood transfusion 5-40 % (19 %), tumor opened during mobilization 0-11 % (5 %), T4-tumors not en-bloc resected 0-33 % (4 %), inadvertent perforation of mesocolon/mesorectum 0-8 % (4 %), no-touch isolation technique 36-86 % (67 %), abdominoperineal resection for rectal cancer 0-30 % (17 %), rectal cancer specimen with circumferential margin ≤1 mm 0-19 % (10 %), in-hospital mortality 0-6 % (2 %), anastomotic leak or intra-abdominal abscess 0-17 % (7 %), re-operation 0-17 % (8 %). CONCLUSION: In colorectal cancer, surgery considerable variations between different centers were found with regard to radicality and oncosurgical quality, suggesting a potential for targeted improvement of surgical technique.

Is surgical quality more important than radicality? Long-term outcomes of stage I-III colon cancer (SAKK 40/00).

BACKGROUND: To prospectively determine the influence of variations of surgical radicality and surgical quality on long-term outcome in patients with stage I-III colon cancer. METHODS: From a prospective multicenter cohort study including 1040 patients undergoing surgery for colorectal cancer from 09/2001 to 06/2005 in nine Swiss and one German hospital, 423 patients with stage I-III colon cancer were selected and analyzed. Surgeons and pathologists filled in standardized forms prospectively assessing items of oncosurgical radicality and quality. Patients had standardized follow-up according to national guidelines. RESULTS: Follow-up was median 6.2 years (range 0.3-10.4) showing a 5-year disease-free survival/overall survival of 83 %/87 % in stage I (n = 85), 69 %/77 % in stage II (n = 187), and 53 %/61 % in stage III (n = 151) colon cancer. Despite remarkable variations of oncosurgical radicality and quality, the multivariate model revealed that mainly quality items correlated significantly with disease-free survival (surgical tumor lesion HR 2.12, p = 0.036, perioperative blood transfusion HR 1.67, p = 0.018, emergency resection HR 1.74, p = 0.035) and overall survival (early venous ligation HR 0.66, p = 0.023, surgical tumor lesion HR 2.28, p = 0.027, perioperative blood transfusion HR1.79, p = 0.010, emergency resection HR 1.88, p = 0.026), while radicality parameters (length of specimen, distance of the tumor to nearest bowel resection site, number of lymph nodes, height of resected mesocolon and of central vascular dissection) did not. CONCLUSION: Surgical quality seems to have a stronger impact on oncologic long-term outcome in stage I - III colon cancer than surgical radicality.

The SAKK cancer-specific geriatric assessment (C-SGA): a pilot study of a brief tool for clinical decision-making in older cancer patients.

BACKGROUND: Recommendations from international task forces on geriatric assessment emphasize the need for research including validation of cancer-specific geriatric assessment (C-SGA) tools in oncological settings. This study was to evaluate the feasibility of the SAKK Cancer-Specific Geriatric Assessment (C-SGA) in clinical practice. METHODS: A cross sectional study of cancer patients ≥65 years old (N = 51) with pathologically confirmed cancer presenting for initiation of chemotherapy treatment (07/01/2009-03/31/2011) at two oncology departments in Swiss canton hospitals: Kantonsspital Graubünden (KSGR N = 25), Kantonsspital St. Gallen (KSSG N = 26). Data was collected using three instruments, the SAKK C-SGA plus physician and patient evaluation forms. The SAKK C-SGA includes six measures covering five geriatric assessment domains (comorbidity, function, psychosocial, nutrition, cognition) using a mix of medical record abstraction (MRA) and patient interview. Five individual domains and one overall SAKK C-SGA score were calculated and dichotomized as below/above literature-based cut-offs. The SAKK C-SGA was evaluated by: patient and physician estimated time to complete, ease of completing, and difficult or unanswered questions. RESULTS: Time to complete the patient questionnaire was considered acceptable by almost all (≥96%) patients and physicians. Patients reported slightly shorter times to complete the questionnaire than physicians (17.33 ± 7.34 vs. 20.59 ± 6.53 minutes, p = 0.02). Both groups rated the patient questionnaire as easy/fairly easy to complete (91% vs. 84% respectively, p = 0.14) with few difficult or unanswered questions. The MRA took on average 8.32 ± 4.72 minutes to complete. Physicians (100%) considered time to complete MRA acceptable, 96% rated it as easy/fairly easy to complete. Individual study site populations differed on health-related characteristics (excellent/good physician-rated general health KSGR 71% vs. KSSG 32%, p = 0.007). The overall mean C-SGA score was 2.4 ± 1.12. Patients at KSGR had lower C-SGA scores (2.00 ± 1.19 vs. 2.81 ± 0.90, p = 0.009) and a smaller proportion (28% vs.65%, p = 0.008) was above the C-SGA cut-off score compared to KSSG. CONCLUSIONS: These results suggest the SAKK C-SGA is a feasible practical tool for use in clinical practice. It demonstrated discriminative ability based on objective geriatric assessment measures, but additional investigations on use for clinical decision-making are warranted. The SAKK C-SGA also provides important usable domain information for intervention to optimize outcomes in older cancer patients.

A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). DESIGN AND METHODS: Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. RESULTS: Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥ 3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. CONCLUSIONS: Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted.

Endosonographic radial tumor thickness after neoadjuvant chemoradiation therapy to predict response and survival in patients with locally advanced esophageal cancer: a prospective multicenter phase ll study by the Swiss Group for Clinical Cancer Research (SAKK 75/02).

BACKGROUND: EUS response assessment in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation therapy (CRT) is limited by disintegration of the involved anatomic structures. OBJECTIVE: Predictive and prognostic values of a prospectively defined maximum tumor thickness (MTT). DESIGN: Prospective open-label phase ll study (SAKK 75/02). SETTING: Multicenter, nationwide. PATIENTS: Of 66 patients with primary CRT, 56 underwent en bloc esophagectomy. INTERVENTIONS: EUS-measured MTT before and 2-5 weeks after CRT (yMTT). MAIN OUTCOME MEASUREMENTS: Cutoffs: (1) absolute thickness (yMTT) after CRT < or = 6 mm; (2) relative reduction compared with baseline (ratio yMTT/MTT) < or = 50%. Correlation between EUS measurements and histopathologic tumor regression grade (TRG) and overall survival (OS). RESULTS: Sixteen of 56 patients were not included for EUS evaluation (10 severe stenosis, 5 MTT not measured, 1 intolerance to second EUS). Characteristics (n = 40) were as follow: median age, 60 years; squamous cell carcinoma, 42%; and adenocarcinoma (AC), 58%. Initial stage was: 10 T2N1, 3 T3N0, 26 T3N1, 1 T3Nx; 14 of 23 AC Siewert type 1. Wilcoxon rank sum test showed significant correlation of TRG1 with yMTT < or = 6 mm (P = .008) and yMTT/MTT < or = 50% (P = .003). The effect of yMTT on TRG1 was significant (P = .0193; odds ratio, 0.687 [95% CI, 0.502-0.941]). The predefined cutoff of < or = 6 mm for yMTT was predictive for TRG1 (P = .0037; Fisher exact test). After a median follow-up of 28.6 months, there was a clear trend for benefit in OS with yMTT < or = 6 mm and yMTT/MTT < or = 50%. LIMITATIONS: Small sample size. CONCLUSION: In a multicenter setting, MTT measured by EUS after CRT was highly predictive for response and showed a clear trend for predicting survival.

Limited predictive value of FDG-PET for response assessment in the preoperative treatment of esophageal cancer: results of a prospective multi-center trial (SAKK 75/02).

BACKGROUND: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery. PATIENTS AND METHODS: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT. RESULTS: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%). CONCLUSIONS: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery.

Predicting mortality and adverse events in patients with advanced pancreatic cancer treated with palliative gemcitabine-based chemotherapy in a multicentre phase III randomized clinical trial: the APC-SAKK risk scores.

BACKGROUND: The prognosis of advanced pancreatic cancer (APC) is poor and differs considerably among patients. Therefore, it is clinically relevant to identify patients with APC who are more likely to benefit from palliative chemotherapy with reduced risk of toxicity. To date, there is no prognostic score universally recommended to help clinicians in planning the therapeutic management. METHODS: Using individual patient data from 319 cases of APC treated with gemcitabine-based chemotherapy and enrolled in the SAKK 44/00-CECOG/PAN.1.3.001 randomized trial, several baseline variables, including inflammatory markers, were analysed post hoc as predictors of mortality and/or grade 3 or 4 chemotherapy-related toxicity and separate risk scores were developed. RESULTS: Median survival of the study patients was 7.9 months (interquartile range 3.7-13.3 months). Independent predictors of mortality included increased Aspartate transaminase (ASAT), low performance status, increased derived neutrophil to lymphocyte ratio, increased Carbohydrate Antigen 19-9 (CA 19-9), low haemoglobin, presence of pain, presence of metastasis and increased alkaline phosphatase (ALP). During the study, 117 patients experienced at least one grade 3 or 4 adverse event. Independent predictors of toxicity included white blood cells, ALP, renal function and bilirubin levels at baseline. Both models displayed moderate levels of discrimination (C-statistic 0.68 and 0.64 for mortality and toxicity, respectively) and adequate calibration. CONCLUSIONS: We developed simple-to-use prognostic scores for mortality and severe toxicity for patients with APC. These scores can be useful in daily practice to identify patients with increased risk of death or toxicity and to plan the most appropriate therapeutic strategy to improve survival and quality of life. Further prospective studies to validate such scores are needed.

Clinical and pharmacogenetic determinants of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial.

PURPOSE: Irinotecan (CPT-11) in combination with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. We assessed potential clinical variables that may predict toxicity and more specifically the role of UGT1A1 polymorphisms associated with irinotecan toxicity. We used data from the PETACC3 trial, which randomised patients in adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan. PATIENTS AND METHODS: Clinical and toxicity data were available for 2982 patients, DNA was available for 1200 (40%) of these patients. We genotyped the polymorphisms UGT1A1*28 and UGT1A1-3156G > A. Risk factors for neutropenia and diarrhoea were assessed by univariable and multivariable analyses. RESULTS: In univariable analysis, UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia (incidence: 44% versus 26%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.4-3.7). In multivariable analysis, the most important predictors (ordered in terms of contribution to R2) were baseline neutrophil count (OR for 1-unit (109/l) decrease: 1.8, 95% CI: 1.3-1.7), female sex (OR: 1.8, 95% CI: 1.1-3.0), body surface area (OR for 0.1-unit increase: 0.8, 95% CI: 0.7-1.0), UGT1A1 (OR: 2.8, 95% CI: 1.6-5.0), age (OR per 10 years: 1.3, 95% CI: 1.1-1.6) and poor performance status (OR: 1.6, 95% CI: 1.0-2.6). The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhoea were sex and age. CONCLUSIONS: We found that a complex of risk factors is involved in the development of toxicity, including UGT1A1. Parameters that are readily available in clinical practice, notably sex, age and performance status, are stronger predictors than the UGT1A1*28 genotype. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the determinants of toxicity risk, notably in females.

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients.

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.

External beam radiotherapy for unresectable hepatocellular carcinoma, an international multicenter phase I trial, SAKK 77/07 and SASL 26.

PURPOSE: To assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC). METHODS: Patients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if ≥90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54-70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1-3, and ≤10% in dose levels 4-5. Best objective response of target liver lesions and adverse events (AE's) were assessed as secondary endpoints. RESULTS: The trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/µL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients. Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact. CONCLUSION: Conventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00777894 , registered October 21st, 2008.

Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

Endometrial Cancer (EC) is still a challenge for gynecological oncologists because the treatment of the advanced disease remains an unmet need for patients. The Cancer Genome Atlas Research Network (TCGA) recently provided a comprehensive genomic and transcriptomic analysis of EC, offering a new classification of the disease, based on genetic features, which defines four subgroups of cancer rather than the two traditionally recognized. In the molecular classification two types of EC, the polymerase epsilon (POLE)-ultramutated and the microsatellite instability (MSI)-hypermutated, seem to present an enhanced immune microenvironment and a high mutation burden. The blockade of the immune checkpoints is an innovative approach that has largely demonstrated to be effective in solid malignancies, such as lung, renal and melanoma; it acts by reducing the cancer-induced immune-suppression through inhibition of the PD-1/PD-L1 (Programmed Death and PD-Ligand) axis. All available evidence supporting an over-expression of the PD-1/PD-L1 pathway in EC has been reviewed. In particular in the POLE and MSI ECs an up-regulation of this pathway was found, aiming to suggest a rationale for testing the PD-1/PD-L1 immunotherapy in these cancer subgroups.

Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer.

PURPOSE: To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS: The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.

Azacytidine for acute myeloid leukemia in elderly or frail patients: a phase II trial (SAKK 30/07).

This phase II trial treated elderly or frail patients with acute myeloid leukemia (AML) with single-agent subcutaneous azacytidine at 100 mg/m(2), on 5 of 28 days for up to six cycles. Treatment was stopped for lack of response, or continued to progression in responders. The primary endpoint was response within 6 months. A response rate ≥ 34% was considered a positive trial outcome. From September 2008 to April 2010, 45 patients from 10 centers (median age 74 [55-86] years) were accrued. Patients received four (1-21) cycles. Best response was complete response/complete response with incomplete recovery of neutrophils and/or platelets (CR/CRi) in eight (18%; 95% confidence interval [CI]: 8-32%.), 0 (0%) partial response (PR), seven (16%) hematologic improvement, 17 (38%) stable disease. Three non-responding patients stopped treatment after six cycles, 31 patients stopped early and 11 patients continued treatment for 8-21 cycles. Adverse events (grade ≥ III) were infections (n = 13), febrile neutropenia (n = 8), thrombocytopenia (n = 7), dyspnea (p = 6), bleeding (n = 5) and anemia (n = 4). Median overall survival was 6 months. Peripheral blood blast counts, grouped at 30%, had a borderline significant association with response (p = 0.07). This modified azacytidine schedule is feasible for elderly or frail patients with AML in an outpatient setting with moderate, mainly hematologic, toxicity and response in a proportion of patients, although the primary objective was not reached.

Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: a multicenter phase II trial (SAKK 19/05).

PURPOSE: This phase II trial aimed to evaluate feasibility and efficacy of a first-line combination of targeted therapies for advanced non-squamous NSCLC: bevacizumab (B) and erlotinib (E), followed by platinum-based CT at disease progression (PD). METHODS: 103 patients with advanced non-squamous NSCLC were treated with B (15 mg/kg day 1 of each 21-day cycle) and E (150 mg daily) until PD or unacceptable toxicity. Upon PD patients received 6 cycles of CT (cisplatin/carboplatin and gemcitabine). The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE treatment. RESULTS: 101 patients were evaluable. Under BE, DSR at week 12 was 54.5%. 73 patients had at least stable disease (SD), including 1 complete remission and 17 partial responses (PR). No unexpected toxicities were observed. Median time to progression (TTP) under BE was 4.1 months. 62 patients started CT; 35 received at least 4 cycles (6 PR, 32 SD). At a median follow-up of 36 months, median overall survival (OS) was 14.1 months. CONCLUSIONS: First-line BE treatment followed by a fixed CT regimen at PD is feasible with acceptable toxicity and activity. In a non-squamous NSCLC population unselected for EGFR status, we found OS rates similar to standard CT.

Efficacy of cetuximab in metastatic castration-resistant prostate cancer might depend on EGFR and PTEN expression: results from a phase II trial (SAKK 08/07).

PURPOSE: The EGF receptor (EGFR) is overexpressed in the majority of metastatic castration-resistant prostate cancers (mCRPC) and might represent a valid therapeutic target. The combination of docetaxel and cetuximab, the monoclonal antibody against EGFR, has not been tested in patients with prostate cancer. EXPERIMENTAL DESIGN: Patients with mCRPC progressing during or within 90 days after at least 12 weeks of docetaxel were included in this phase II trial. Treatment consisted of docetaxel (75 mg/m(2) every 3 weeks or 35 mg/m(2) on days 1, 8, 15 every 4 weeks) in combination with cetuximab (400 mg/m(2) on day 1 and then 250 mg/m(2) weekly). The primary endpoint was progression-free survival (PFS) at 12 weeks defined as the absence of prostate-specific antigen (PSA), radiographic, or clinical progression. Evaluation of known biomarkers of response and resistance to cetuximab (EGFR, PTEN, amphiregulin, epiregulin) was conducted. RESULTS: Thirty-eight patients were enrolled at 15 Swiss centers. Median age was 68 years and median PSA was 212 ng/mL. PFS at 12 weeks was 34% [95% confidence interval (CI), 19%-52%], PFS at 24 weeks was 20%, and median overall survival (OS) was 13.3 months (95% CI, 7.3-15.4). Seven patients (20%) had a confirmed ≥ 50% and 11 patients (31%) a confirmed ≥ 30% PSA decline. About 47% of enrolled patients experienced grade 3 and 8% grade 4 toxicities. A significantly improved PFS was found in patients with overexpression of EGFR and persistent activity of PTEN. CONCLUSIONS: EGFR inhibition with cetuximab might improve the outcome of patients with mCRPC. A potential correlation between EGFR overexpression, persistent expression of PTEN, and EGFR inhibition should be investigated further.

Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II Trial (SAKK 75/06).

PURPOSE: This multicenter phase IB/II trial investigated cetuximab added to preoperative chemoradiotherapy for esophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced esophageal cancer received two 3-week cycles of induction chemoimmunotherapy (cisplatin 75 mg/m(2) day 1, docetaxel 75 mg/m(2) day 1, cetuximab 250 mg/m(2) days 1, 8,15 [400 mg/m(2) loading dose]) followed by chemoimmunoradiation therapy (CIRT) and surgery. CIRT consisted of 45 Gy radiotherapy (RT) plus concurrent cisplatin 25 mg/m(2) and cetuximab 250 mg/m(2) weekly for 5 weeks in cohort 1. If fewer than three of seven patients experienced limiting toxicity (LT), the next seven patients also received docetaxel (20 mg/m(2) weekly × 5). If fewer than three patients experienced LTs, 13 additional patients were treated at this dose. RESULTS: In total, 28 patients (median age, 64 years) with predominantly node-positive (82%) esophageal adenocarcinoma (15 patients) or squamous cell carcinoma (13 patients) were enrolled and 24 (86%) completed the entire trimodal therapy. During CIRT, no LT occurred, rash was not exacerbated within the RT field, and the main grade 3 toxicities were esophagitis (seven patients), anorexia (three), fatigue (three), and thrombosis (two). Surgery (R0 resection) was performed in 25 patients. Anastomotic leakage occurred in three patients: two recovered spontaneously and one successfully underwent re-operation. There were no deaths at 30 days and no treatment-related mortality after 12 months. Nineteen patients (68%) showed complete or near complete pathologic regression. CONCLUSION: Adding cetuximab to preoperative chemoradiotherapy is feasible without increasing postoperative mortality. Phase III investigation has begun based on the high histopathologic response and R0 resection rate.

Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization: a prospective multicenter phase II trial (protocol SAKK 34/02).

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (> or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients.