Gary Y. Yang

Phase II Study of Weekly Intravenous Oxaliplatin Combined With Oral Daily Capecitabine and Radiotherapy With Biologic Correlates in Neoadjuvant Treatment of Rectal Adenocarcinoma

PURPOSE To evaluate the efficacy of a combination of capecitabine, oxaliplatin, and radiotherapy (RT) in the neoadjuvant treatment of Stage II and III rectal cancers. METHODS Capecitabine was given at 725 mg/m(2) orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given intravenously at 50 mg/m(2) once weekly five times starting the first day of RT. The radiation dose was 50.4 Gy in 28 fractions (1.8 Gy/fraction), five fractions weekly. Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and apoptosis. RESULTS A total of 25 patients were enrolled in this study; 6 patients (24%) had a complete pathologic response. T-downstaging occurred in 52% of patients, and N-downstaging occurred in 53%. Grade 3 diarrhea was the most common Grade 3-4 toxicity, occurring in 20% of patients. Only 2 patients experienced disease recurrence, with a median of 20 months of follow-up. Thymidylate synthase, thymidine phosphorylase, ERCC1, and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies, nor did they predict for T-downstaging or a complete pathologic response. CONCLUSION Capecitabine at 725 mg/m(2) orally twice daily, oxaliplatin 50 mg/m(2)/wk, and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls.

Pilot study of gefitinib, oxaliplatin, and radiotherapy for esophageal adenocarcinoma: tissue effect predicts clinical response.

Purpose:Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer is associated with poor prognosis. Preclinical studies indicate synergism between the EGFR inhibitor gefitinib and oxaliplatin or radiotherapy (RT). We report here early results of a planned phase I/II study of gefitinib, oxaliplatin, and RT for locally advanced, unresectable esophageal cancer. Methods and Materials:The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m2 on days 1, 15, and 29, and RT (50.4 Gy in 28 1.8-Gy fractions). Four-quadrant biopsies were obtained at 1-cm intervals along the length of the tumor before and after treatment and the specimens were immunostained for EGFR, Erk, Akt, and their phosphorylated (activated) forms. Results:Enrollment was halted at 6 evaluable cases [all male; median age, 72.5 years (range, 51–75); and all with Eastern Cooperative Oncology Group performance status of 1]. All 6 tumors were adenocarcinomas; 5 were stage III and 1 stage IVA. Oxaliplatin was given at 85 mg/m2 in 3 cases and at 100 mg/m2 in 3 cases. Gefitinib therapy lasted a median 24 weeks; the median number of oxaliplatin doses was 6.5. Best responses were mucosal complete response (n = 1), partial response (n = 1), stable disease (n = 1), and progressive disease (n = 3). EGFR was expressed by tumor in 5 cases and Erk and Akt in 6 cases before treatment; no changes were noted after treatment. EGFR expression did not correlate with survival or response. No grade 4 toxicities were noted; grade 3 toxicities were diarrhea (n = 1), vomiting (n = 1), fatigue (n = 1), and constipation (n = 2). Median overall and disease-free survival times were 10.8 months and 8.4 months. Conclusions:Gefitinib in combination with oxaliplatin and RT was tolerable, but had limited clinical activity and did not down-regulate total or activated EGFR, Akt, or Erk in esophageal tumor samples.

Treatment of locally advanced unresectable pancreatic cancer: a 10-year experience

PURPOSE We retrospectively analyzed the results of patients with locally advanced unresectable pancreatic cancer (LAPC) treated with either chemoradiation (CRT) or chemotherapy alone over the past decade. METHODS AND MATERIALS Between December 1998 and October 2009, 116 patients with LAPC were treated at our institution. Eighty-four patients received concurrent chemoradiation [RT (+) group], primarily 5-flourouracil based (70%). Thirty-two patients received chemotherapy alone [RT (-) group], the majority gemcitabine based (78%). Progression-free survival (PFS) and overall survival (OS) were calculated from date of diagnosis to date of first recurrence and to date of death or last follow-up, respectively. Univariate statistical analysis was used to determine significant prognostic factors for overall survival. RESULTS Median patient age was 67 years. Sixty patients were female (52%). Median follow-up was 11 months (range, 1.6-59.4 months). The RT (+) group received a median radiation dose of 50.4 Gy, was more likely to present with ECOG 0-1 performance status, and experienced less grade 3-4 toxicity. PFS was 10.9 versus 9.1 months (P=0.748) and median survival was 12.5 versus 9.1 months (P=0.998) for the RT (+) and RT (-) groups respectively (P=0.748). On univariate analysis, patients who experienced grade 3-4 toxicity had worse overall survival than those who did not (P=0.02). CONCLUSIONS Optimal management for LAPC continues to evolve. Patients who developed treatment-related grade 3-4 toxicity have a poorer prognosis. Survival rates were not statistically significant between chemotherapy and chemoradiotherapy groups.

Epidermal Growth Factor Receptor-Directed Therapy in Esophageal Cancer

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US. The long-term survival of patients with this cancer remains poor; only 25% of patients undergoing surgical excision are alive after 5 years. Multimodal programs that incorporate radiotherapy, chemotherapy and surgery for localized tumors may result in a modest survival advantage. However, significant strides in this disease can result from the inclusion of targeted therapies. The epidermal growth factor receptor (EGFR) family represents one such target and is receiving increasing attention due to the advent of specific inhibitors. Studies conducted by us and others have shown that the overexpression of EGFR family signaling intermediates is common in Barrett’s esophagus and EAC. In the latter case, EGFR expression may have prognostic significance. EGFR inhibitors, including oral tyrosine kinase inhibitors and monoclonal antibodies, result in a synergistic antitumor effect with chemotherapeutic agents or with radiotherapy. Therefore, several ongoing studies include EGFR-directed therapy either alone or in combination with chemoradiotherapy for this disease. Our study of gefitinib, oxaliplatin and radiotherapy suggested that gefitinib can be safely incorporated into an oxaliplatin-based chemoradiation program for esophageal cancer, although the clinical activity of this combination is modest. Herein, we review the current literature on this subject.

FDG PET imaging in the staging and management of gastric cancer

Gastric cancer is a leading cause of cancer death worldwide. Complete resection offers the only chance for permanent control, and accurate staging and evaluation of treatment response are crucial for appropriate management. Positron Emission Tomography (PET) is increasingly used to complement anatomic imaging in cancer management. PET use in gastric cancer has been limited by 1) some gastric histologies are not PET avid, 2) spatial resolution limits the ability to distinguish between primary tumor and compartment I or II lymph nodes, and 3) the lack of a unified criteria in how to interpret PET for management decisions. New criteria have been proposed establishing response metrics in the utilization of PET. More study is needed to support these criteria in routine practice and establish the place of PET in the staging and management of gastric cancer.

The Role of Chemotherapy and Radiation in the Treatment of Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

Approximately one out of every three patients with non-small cell lung cancer (NSCLC) has locally advanced disease that is surgically unresectable. If their performance status allows, it is current practice to treat these patients with a combination of chemotherapy and external beam irradiation. There have been several studies supporting the addition of chemotherapy to radiation, particularly when delivered concurrently. There is debate over which treatment agents and schedules are most optimal, even with the most proven treatments delivering only modest results, with high rates of local and distant disease failure. Advances in imaging and radiation planning and delivery technology have allowed for the potential for improvement of the therapeutic ratio by reducing normal tissue exposure and ensuring for more precise delivery, while new systemic agents show promising activity in NSCLC. Pemetrexed is a pyrrolopyrimidine-based folate anti-metabolite that works by inhibiting a variety of enzymes of thymidylate and purine synthesis, thus leading to cell stasis and death. Similar to other cytotoxic antifolates, pemetrexed has been shown in pre-clinical study to act as an effective radiosensitizer. At present, it is being studied in phase I and II studies when combined with other systemic agents and radiation therapy in the treatment of locally advanced NSCLC, and the results have been promising. It has the advantage of allowing for relatively safe delivery of full systemic doses when combined other agents and radiation therapy, a distinction over combined modality treatments. Its efficacy, particularly in non-squamous NSCLC, in phase I and II studies has lead to investigations in the phase III setting where a more defined role for pemetrexed in locally advanced non-squamous NSCLC will potentially be defined. This review summarizes the use of combined modality treatment in locally advanced NSCLC, outlines recent advances in radiation planning and treatment, and reviews the current data on the use concurrent chemoradiation regimens featuring pemetrexed.

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma

Purpose:The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was demonstrated to be a safe regimen for locally advanced esophageal carcinoma in a prior phase I study. We now report the efficacy data for 42 patients treated with this regimen. Methods:Each chemotherapy cycle lasted 29 days and consisted of 5-fluorouracil, 180 mg/m2 protracted-infusion from days 1 to 29, and oxaliplatin, 85 mg/m2 on days 1, 15, and 29. The first cycle was administered concurrently with radiation. The radiation field included regional lymph nodes as well as the primary tumor or tumor bed to a dose of 50.4 Gy in 28 fractions. After concurrent chemoradiotherapy, 1 to 2 additional cycles of chemotherapy were administered. If esophagectomy was indicated, it occurred 4 weeks after completion of concurrent chemoradiotherapy. In the adjuvant group, concurrent chemoradiotherapy was initiated 4 weeks after surgery. Results:Median age was 61 years (range 38–78 years); 30 (71%) of the patients were male. Thirty-three patients had adenocarcinoma, and 9 had squamous cell carcinoma. Concurrent chemoradiotherapy was administered preoperatively (group 1) in 24 patients, definitively (group 2) in 13 patients, and as adjuvant treatment (group 3) in 5 patients. In group 1, 16 patients were down-staged including 1 patient with minimal residual disease and 5 with a complete pathologic response; 4 patients were not down-staged, and 4 did not undergo esophagectomy (2 progressed, 1 died of unrelated causes, and 1 refused). In group 2, 1 patient had a complete clinical response, 4 others were down-staged, 2 had stable disease, and 6 progressed. Four patients in group 3 progressed. Median survival was 28 months for group 1, 12 months for group 2, and not reached at 14 months for group 3. There was one grade 4 toxicity (anaphylaxis) in group 2. Grade 3 toxicities were reported for 5 patients in group 1 and 1 patient in group 2. They consisted of hypotension (n = 1), fatigue (n = 2), diarrhea (n = 2), neuropathy (n = 1), mucositis (n = 1), pneumonitis (n = 1), dehydration (n = 1), emesis (n = 1), and weight loss (n = 1). Conclusions:Our study supports the incorporation of oxaliplatin into a multimodal concurrent chemoradiotherapy protocol for locally advanced esophageal cancer.

Chemotherapy-Induced Carcinoembryonic Antigen Surge in Patients with Metastatic Colorectal Cancer

Objectives: To investigate the incidence of carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer (MCRC) and its implications on clinical outcome. Methods: A retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CEA levels compared to baseline. The incidence of CEA surge and its association with clinical outcome was investigated. Results: Eighty-nine patients were evaluable for CEA surge. A CEA surge was documented in 10 patients. The CEA surge lasted <4 months in all 10 patients and was associated with a clinical benefit. No significant correlation was noted between CEA surge and site of primary tumor, site of metastatic disease, or tumor differentiation. Conclusions: CEA surges can be observed in patients receiving chemotherapy for MCRC and are often associated with a clinical benefit. None of the CEA surges satisfied the American Society of Clinical Oncology definition of CEA progression. A rise in CEA after initiation of chemotherapy, unless lasting >4 months, cannot be used as an indicator of progressive disease.

Cancer immunotherapy and heat-shock proteins: promises and challenges

Recent mechanistic studies on the role of heat-shock proteins (HSPs) to induce innate and adaptive immune responses have resulted in conflicting reports. Whereas some groups reported that HSPs have direct immunological function, others emphasised the endotoxin contamination of HSP preparations and questioned the antigen-specificity of HSP vaccines. The present review will discuss these issues and suggest that HSPs have diverse and distinct immunological functions that could be superimposed on effects resulting from endotoxin contamination or misunderstood by using experimental procedures with inadequate controls. To understand the actual function of HSPs in their interaction with the immune system, methods and procedures need to be optimised and appropriate controls need to be used. These points should also clarify the conflicting findings about HSPs and promote our knowledge about other immuologically important components that may be present in HSP preparations.

Induction Chemotherapy with Nedaplatin with 5-FU Followed by Intensity-modulated Radiotherapy Concurrent with Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma

OBJECTIVE This Phase II study was conducted to evaluate the activity and feasibility of a regimen of nedaplatin and 5-fluorouracil as induction chemotherapy, followed by intensity-modulated radiotherapy concurrent with chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. METHODS Patients received neoadjuvant chemotherapy comprised two cycles of 5-fluorouracil at 700 mg/m(2)/day administered on days 1-4 as continuous intravenous infusion and nedaplatin (100 mg/m(2) administered i.v. over 2 h) given after the administration of 5-fluorouracil on day 1, repeated every 3 weeks, followed by intensity-modulated radiotherapy concurrent with nedaplatin. During intensity-modulated radiotherapy, nedaplatin was administered at a dose of 100 mg/m(2) intravenous infusion on days 1, 22 and 43, given approximately 60 min before radiation. RESULTS Fifty-nine (95.8%) of the 60 patients were assessable for response. Thirty-eight cases of complete response and 14 cases of partial response were confirmed after completion of chemoradiation, with the objective response rate of 86.7% (95% CI, 78.1-95.3%). The median follow-up period was 48 months (range, 30-62 months). The 3-year progression-free survival and overall survival were 75.0% (95% CI, 63.0-87.0%) and 85.5% (95% CI, 75.9-95.1%). No patient showed Grade 3 or higher renal dysfunction. The most commonly observed late effect was xerostomia, but the severity diminished over time, and the detectable xerostomia at 24 months was 10.2%. There were no treatment-related deaths during this study. CONCLUSIONS Neoadjuvant chemotherapy with nedaplatin and 5-fluorouracil followed by concomitant nedaplatin and intensity-modulated radiotherapy is an effective and safe treatment for Southern China patients affected by locoregionally advanced nasopharyngeal carcinoma.