Steven Sorscher

Multi-Institutional Experience with FOLFIRINOX in Pancreatic Adenocarcinoma

CONTEXT Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. OBJECTIVE The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. METHODS Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. RESULTS Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. CONCLUSION Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.

Five Fractions of Radiation Therapy Followed by 4 Cycles of FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer

BACKGROUND Preoperative radiation therapy with 5-fluorouracil chemotherapy is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents demonstrate increased morbidity with little benefit. We evaluate a template that: (1) includes the benefits of preoperative radiation therapy on local response/control; (2) provides preoperative multidrug chemotherapy; and (3) avoids the morbidity of concurrent radiation therapy and multidrug chemotherapy. METHODS AND MATERIALS Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for pelvic surgery, provided response was sufficient. Preoperative treatment was 5 fractions radiation therapy (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of FOLFOX [5-fluorouracil, oxaliplatin, leucovorin]. Extirpative surgery was performed 4 to 9 weeks after preoperative chemotherapy. Postoperative chemotherapy was at the discretion of the medical oncologist. The principal objectives were to achieve T stage downstaging (ypT < cT) and preoperative grade 3+ gastrointestinal morbidity equal to or better than that of historical controls. RESULTS 76 evaluable cases included 7 cT4 and 69 cT3; 59 (78%) cN+, and 7 cM1. Grade 3 preoperative GI morbidity occurred in 7 cases (9%) (no grade 4 or 5). Sphincter-preserving surgery was performed on 57 (75%) patients. At surgery, 53 patients (70%) had ypT0-2 residual disease, including 21 (28%) ypT0 and 19 (25%) ypT0N0 (complete response); 24 (32%) were ypN+. At 30 months, local control for all evaluable cases and freedom from disease for M0 evaluable cases were, respectively, 95% (95% confidence interval [CI]: 89%-100%) and 87% (95% CI: 76%-98%). Cases were subanalyzed by whether disease met requirements for the recently activated PROSPECT trial for intermediate-risk rectal cancer. Thirty-eight patients met PROSPECT eligibility and achieved 16 ypT0 (42%), 15 ypT0N0 (39%), and 33 ypT0-2 (87%). CONCLUSION This regimen achieved response and morbidity rates that compare favorably with those of conventionally fractionated radiation therapy and concurrent chemotherapy.

Marked Response to Single Agent Trastuzumab in a Patient with Metastatic HER-2 Gene Amplified Rectal Cancer

Overexpression or HER-2 gene amplification occurs in approximately 25% of invasive breast cancers and predicts response to the targeting therapeutic antibody trastuzumab (1). In this report, trastuzumab was used in the treatment of a patient with metastatic colorectal cancer harboring HER-2 gene amplification and overexpression. There was a marked radiographic response to the trastuzumab. If a larger series confirms the efficacy of trastuzumab use in patients with colorectal cancers with HER-2 gene amplification, trastuzumab could help improve the outlook for patients with this unusual colorectal cancer variant.

Biological therapy update in colorectal cancer

Colon and rectal cancer remain the second most common cause of cancer death in the US. Advances in the past 10 years have resulted in improved outcomes for patients. In addition to newer chemotherapeutics agents, the so-called ‘targeted’ or ‘biological’ therapies have improved survival in patients with metastatic disease. This review aims to summarize the mechanistic basis for the usefulness of these agents, the key clinical trials demonstrating their efficacy, and the studies now initiated with the hope of further incorporating their use in treating colon and rectal cancer.

A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma

OBJECTIVES Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. METHODS After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). RESULTS Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. CONCLUSIONS This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.

Immunogenicity of Influenza Vaccination in Patients With Cancer.

Background: Influenza leads to significant morbidity and mortality in patients with cancer. Patients with cancer receiving chemotherapy may not mount an adequate immune response to the vaccine. We performed this pilot study to evaluate the immunogenicity of influenza vaccination in patients with cancer receiving chemotherapy. Materials and Methods: During the 2011 to 2012 influenza season, patients undergoing chemotherapy for solid tumors were given trivalent inactivated influenza vaccine either on the day of chemotherapy (schedule A) or a week before chemotherapy (schedule B) by a single 0.5 mL injection in the deltoid muscle region. This was not a randomized trial. Hemagglutination inhibition assays were performed on blood samples from these patients taken at baseline, and 4 weeks postvaccination. Seroconversion rate (>4-fold increase in titers) and seroprotection rates (postvaccination titers of >1:40) were calculated for each vaccine component: influenza A (H1N1), A (H3N2) and B. Results: A total of 18 patients received influenza vaccination as part of this pilot study. Of these, 8 patients received the vaccine on schedule A and 10 patients received the vaccine on schedule B. Geometric mean titers against each strain significantly improved after vaccination for both groups, as measured by signed rank test. Seroconversion to at least 1 strain was observed in 75% of patients on schedule A, and 70% of patients vaccinated on schedule B. Seroprotection to at least 1 strain was observed in 100% of patients in the schedule A group, and 60% of patients vaccinated on schedule B. Seroconversion and seroprotection rates against the 3 influenza strains were not significantly different between the 2 groups. Conclusions: Patients with nonhematological malignancies who are receiving chemotherapy mount an immune response to influenza vaccination. Timing of influenza vaccination in relation to chemotherapy does not seem to matter.

Hepatocellular carcinoma developing years after extended field radiation for Hodgkin's lymphoma

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Temozolomide-associated myelodysplasia 6 years after treatment of a patient with pancreatic neuroendocrine tumor.

Temozolomide (TMZ) is a commonly used alkylating agent for the treatment of high-grade gliomas. Here we report the first case of a patient treated with TMZ for a well-differentiated neuroendocrine ...

A case of squamous cell carcinoma of the skin due to the molecularly confirmed Lynch Syndrome

Patients with Lynch Syndrome are at high risk for developing a variety of cancers including cancers of the colon or rectum, small bowel, stomach, uterus, renal pelvis, ureter, biliary tract, ovaries, brain and pancreas (N Engl J Med 348: 919-32, 2003; Gut 57:1097-101, 2008; NCCN, Inc Guideline. Ft. Washington, PA. Online Version 2.2014). Lack of MLH-1 and MSH-2 expression commonly result from germline mutations in this inherited cancer syndrome. Here, we report the case of a patient with a molecularly confirmed germline mutation in MLH-1 along with a colon cancer showing lack of expression of MLH-1 as well as a squamous cell cancer of the skin from the abdominal wall also demonstrating lack of expression of MLH-1. This case appears to represent the second case report of a squamous cell skin cancer apparently due to the Lynch Syndrome and further supports a proposed relationship between Lynch Syndrome and these tumors.

HER-2 overexpression in breast tumors lacking gene amplification.

thoughtful cost-effective analysis of trastuzumab therapy by examining the costs and benefits of alternative HER-2 testing strategies, including the use of immunohistochemical analysis (IHC) and fluorescence in situ hybridization (FISH). The authors define a false-positive IHC test as “the probability of a 3 HercepTest (DAKO, Carpinteria, CA) result conditional on a negative FISH result.” Several questions arise when using a test that detects “false-positive” protein overexpression (IHC) based on a test that detects gene amplification (FISH). The authors themselves cite several studies that suggest single-genecopy HER-2 overexpressors in 3% to 8% of breast tumors. 2-4 Their own data suggest that the false-positive rate is 1.7% (95% CI, 0.4% to 2.9%; Table 2 of their article). 1 In practical terms, therefore, if FISH is negative in a 3 HercepTest tumor, it is still about three times more likely that overexpression is occurring due to single-gene overexpression. The authors also point out that “the likelihood that single-gene overexpression will respond to trastuzumab is unknown.” With these results, why administer FISH testing in the 3 HercepTest group? The study of Elkin et al provides important new information regarding IHC and FISH. However, only a more definitive test for protein expression should be used to define false-positives, not an assay for gene amplification. Also, until the response of single-gene overexpressing tumors to trastuzumab is known, it would seem that a positive result from FISH testing in the 3 HercepTest group can only confirm a more likely response, but a negative result may lack therapeutic usefulness.