Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.

We report analytic and consensus processes that produced recommendations for pathologic stage groups (pTNM) of esophageal and esophagogastric junction cancer for the AJCC/UICC cancer staging manuals, 8th edition. The Worldwide Esophageal Cancer Collaboration provided data for 22,654 patients with epithelial esophageal cancers; 13,300 without preoperative therapy had pathologic assessment after esophagectomy or endoscopic treatment. Risk-adjusted survival for each patient was developed using random survival forest analysis to identify data-driven pathologic stage groups wherein survival decreased monotonically with increasing group, was distinctive between groups, and homogeneous within groups. The AJCC Upper GI Task Force, by smoothing, simplifying, expanding, and assessing clinical applicability, produced consensus pathologic stage groups. For pT1-3N0M0 squamous cell carcinoma (SCC) and pT1-2N0M0 adenocarcinoma, pT was inadequate for grouping; subcategorizing pT1 and adding histologic grade enhanced staging; cancer location improved SCC staging. Consensus eliminated location for pT2N0M0 and pT3N0M0G1 SCC groups, and despite similar survival, restricted stage 0 to pTis, excluding pT1aN0M0G1. Metastases markedly reduced survival; pT, pN, and pM sufficiently grouped advanced cancers. Stage IIA and IIB had different compositions for SCC and adenocarcinoma, but similar survival. Consensus stage IV subgrouping acknowledged pT4N+ and pN3 cancers had poor survival, similar to pM1. Anatomic pathologic stage grouping, based on pTNM only, produced identical consensus stage groups for SCC and adenocarcinoma at the cost of homogeneity in early groups. Pathologic staging can neither direct pre-treatment decisions nor aid in prognostication for treatment other than esophagectomy or endoscopic therapy. However, it provides a clean, single therapy reference point for esophageal cancer.

Outcomes of induction chemotherapy followed by chemoradiation using intensity-modulated radiation therapy for esophageal adenocarcinoma.

This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.

Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis.

BACKGROUND: To determine whether human epidermal growth factor receptor 2 (HER2) status is an independent prognostic factor in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor samples from 381 metastatic gastric/GEJ cancer patients enrolled at Krankenhaus Nordwest and Memorial Sloan-Kettering Cancer Centers on six first-line trials of chemotherapy without trastuzumab were examined for HER2 by immunohistochemistry (IHC) and in situ hybridization (ISH). IHC 3+ or ISH-positive tumors were considered HER2 positive. RESULTS: Seventy-eight of 381 patients (20%) had HER2-positive disease. In the multivariate logistic model, there were significantly higher rates of HER2 positivity in patients with liver metastasis (liver metastasis 31%; no liver metastasis 11%; P = 0.025) and intestinal histology (intestinal 33%; diffuse/mixed 8%; P = 0.001). No significant differences in HER2 positivity were found between resections and biopsies or primaries and metastases. Patients with HER2-positive gastric cancer had longer median overall survival compared with HER2-negative gastric cancer patients (13.9 versus 11.4 months, P = 0.047), but multivariate analysis indicated that HER2 status was not an independent prognostic factor (hazard ratio 0.79; 0.44-1.14; P = 0.194). CONCLUSIONS: Approximately 20% of Western patients with metastatic gastric cancer are HER2 positive. Unlike breast cancer, HER2 positivity is not independently prognostic of patient outcome in metastatic gastric or GEJ.

Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma.

BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.

Small-cell carcinoma of the esophagus and gastroesophageal junction: review of the Memorial Sloan-Kettering experience.

BACKGROUND: Esophageal small-cell carcinoma (SCC) is rare, highly malignant and the optimal treatment approach has not been defined. PATIENTS AND METHODS: We report the largest single-institution retrospective review of patients with esophageal and gastroesophageal (GE) junction SCC. RESULTS: Twenty-five patients were identified, with complete records available for 22. Eighty-two percent were male, 82% had pure SCC histology and 86% of tumors were in the lower esophagus or GE junction. On the basis of the Veterans' Administration Lung Study Group criteria, 14 patients (64%) presented with limited disease (LD). Median survival was 19.8 months (range, 1.5 months to 11.2+ years); for LD patients, 22.3 months (range, 6 months to 11.2+ years); for extensive disease (ED) patients, 8.5 months (range, 1.5 months to 2.2 years, P = 0.02). With a median follow-up of 38 months, six patients (27%) are alive, one with ED and five with LD. Two LD patients are alive and free of disease for >5 years. Four of the five LD patients who are long-term survivors received induction chemotherapy followed by chemoradiotherapy without surgery. CONCLUSIONS: Our data indicate that patients with LD esophageal SCC treated with induction chemotherapy followed by consolidative chemoradiation can achieve long-term survival. The contribution of surgery remains unclear.

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.

Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle. RESULTS: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 +/- 0.69 micromol/L (flavopiridol 20 mg/m2) to 4.54 +/- 0.08 micromol/L (flavopiridol 60 mg/m2) in cycle 1. CONCLUSIONS: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.

Systemic chemotherapy does not increase the risk of gastrointestinal perforation.

BACKGROUND: Gastrointestinal perforation is a rare complication of gastric cancer. Although there is the perception of chemotherapy aggravating the perforation risk, the rate of perforation in patients with gastric cancer receiving chemotherapy is unknown. This study describes the incidence and clinical course of patients with gastric or gastroesophageal junction (GEJ) carcinoma who experience a perforation while receiving chemotherapy. PATIENTS AND METHODS: The records of patients with gastric or GEJ adenocarcinoma over a 6-year period who received chemotherapy for locally advanced or metastatic disease were reviewed. Extracted information included demographics, treatment received, and overall survival was calculated. RESULTS: 1032 patients at MSKCC received systemic cytotoxic chemotherapy for locally advanced or metastatic gastric or GEJ carcinoma; 11 patients experienced a perforation (1.1%, 95% CI 0.5-1.9%); 5/11 (45%) patients received further chemotherapy and had a median survival of 5.6 months. CONCLUSIONS: The rate of perforation in patients with advanced GEJ/gastric adenocarcinoma receiving chemotherapy is 1.1%, which is the same rate as in surgical series of patients presenting with perforation. Chemotherapy does not significantly add to the risk of gastrointestinal perforation.

Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus.

BACKGROUND: Carcinomas of the esophagus and gastroesophageal junction are uncommon and account for approximately 1% of all malignancies in the United States. Advanced squamous cell carcinoma or adenocarcinoma of these sites remains incurable. The median survival of patients is between 4 and 8 months, and their prognosis has not changed in the past several decades. Undoubtedly, there is an urgent need to develop new effective drugs for patients with carcinoma of the esophagus or the gastroesophageal junction. PURPOSE: Our purpose was to evaluate the response rate, duration of response, and toxic effects in previously untreated patients with unresectable local-regional or metastatic carcinoma of the esophagus who were enrolled in a phase II study of paclitaxel (Taxol). METHODS: Fifty-two patients with either metastatic or local-regional unresectable carcinoma of the esophagus were eligible for this study. All patients were premedicated with dexamethasone, cimetidine, and diphenhydramine hydrochloride to prevent allergic reaction. The starting dose of paclitaxel was 250 mg/m2 repeated every 21 days. Patients received 5 micrograms/kg granulocyte-colony stimulating factor (G-CSF) subcutaneously daily 24 hours after the completion of paclitaxel to reduce the duration and severity of granulocytopenia. RESULTS: Of the 52 patients who were initially enrolled, 50 (44 men and six women) were evaluated for toxic effects and response. Thirty-two had adenocarcinoma, and 18 had squamous cell carcinoma. The median age was 58 years (range, 36-77 years). The median Zubrod performance status was 1 (range, 0-1). The median number of courses was four, and the total number of courses administered was 227. The median dose of paclitaxel was 250 mg/m2 (range, 150-280 mg/m2). Paclitaxel dosage was reduced in 52 (23%) of 227 courses and increased in 15 (7%) of 227 courses. Sixteen (32%) patients achieved either a complete or partial response, and 11 (22%) achieved a minor response. Among 32 patients with adenocarcinoma, 11 (34%; 95% confidence interval [CI] = 18%-50%) had either a complete or partial response and six had a minor response. Five (28%; 95% CI = 7%-49%) of 18 patients with squamous cell carcinoma had a partial response, and five (28%) had a minor response. The median duration of partial response was 17 weeks (range, 7 to > or = 58 weeks). At a median follow-up of 9 months, 32 patients remain alive, with an actuarial median survival duration of 13.2 months (range, 2 to > or = 17.5 months). Paclitaxel followed by G-CSF was very well tolerated. CONCLUSIONS: These data indicate that paclitaxel is an active agent against adenocarcinoma and squamous cell carcinoma of the esophagus.

Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric cancer cells.

BACKGROUND: Protein kinase C (PKC) is a family of enzymes that function in processes relevant to carcinogenesis, tumor cell metastasis, and apoptosis. Safingol, an optical isomer (the L-threo enantiomer) of dihydrosphingosine, is a specific inhibitor of PKC and might represent a novel agent for anticancer therapy. Preclinical animal studies show that safingol alone has a minimal effect on tumor cell growth, but combining this compound with conventional chemotherapy agents dramatically potentiates their antitumor effects. It has been suggested that many chemotherapeutic agents exert their antitumor effects by inducing apoptosis. PURPOSE: We wanted to determine the extent to which safingol, alone or in combination with a standard chemotherapeutic agent (mitomycin C [MMC]), would promote apoptosis in gastric cancer cells in vitro. Furthermore, we investigated whether the induction of apoptosis in the treated cells was affected by their p53 tumor suppressor status or their drug-resistance status. METHODS: SK-GT-5 (p53-deficient and MMC-resistant) and MKN-74 (p53 wild-type and MMC-sensitive) gastric cancer cells were exposed to either no drug, safingol (50 microM) alone, MMC (5 micrograms/mL) alone, or a combination of safingol (50 microM) and MMC (5 micrograms/mL). In some experiments, cells were exposed simultaneously to safingol and the PKC activator, 3-phorbol 12-myristate 13-acetate (PMA), prior to treatment with MMC. Apoptosis was measured by two methods: 1) quantitative fluorescence microscopy of nuclear chromatin condensation in cells stained with the dye, bisbenzamide trihydrochloride (Hoechst-33258), and 2) terminal deoxynucleotidyl transferase (TdT) labeling of the 3'-OH ends of DNA fragments produced in apoptotic cells. RESULTS: As determined by quantitative fluorescence microscopy, exposure of SK-GT-5 cells to safingol alone induced apoptosis in 2% +/- 1% (mean +/- SD) of the cells, and MMC alone increased that level to 18% +/- 1%. However, the combination of safingol and MMC induced apoptosis in 39% +/- 1% of the cells (P < .001, for the drug combination versus MMC alone). With MKN-74 cells, safingol alone induced apoptosis in 8% +/- 3% of the cells, whereas MMC alone induced apoptosis in 40% +/- 4% of treated cells and the combination of safingol and MMC induced apoptosis in 83% +/- 4% of the cells. Similar results were obtained with the TdT assay. Simultaneous exposure of cells to safingol and PMA abrogated the safingol-mediated enhancement of MMC-induced apoptosis. CONCLUSIONS: The PKC inhibitor safingol enhances the cytotoxic effect of the chemotherapeutic agent MMC in gastric cancer cells by promoting drug-induced apoptosis. The induction of apoptosis occurs regardless of the p53 status or the drug-resistance status of the cells.

Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma.

BACKGROUND: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker. METHODS: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. RESULTS: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016). CONCLUSION: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.

Gene amplification in gastric and esophageal adenocarcinomas.

In a United States series of 28 gastric/esophageal adenocarcinomas of poorly to moderately differentiated histopathology, we detected gene amplification in 21% of the tumors. Using the modified DNA in-gel renaturation assay to detect down to 7-8 copies of amplified DNA sequences, we identified 3 gastric tumors with amplified DNA sequences and confirmed by Southern hybridization analysis that HER-2/neu was amplified greater than 5-fold in these specimens. Immunohistochemical staining of tumor tissue sections with p185 HER-2/neu antibodies demonstrated that only the 3 gastric adenocarcinomas with corresponding HER-2/neu gene amplification displayed membrane immunoreactivity. Amplification of c-met was identified in 2 tumors, and this was the first study to assay for multiple copies of this protooncogene in fresh gastric tumor tissues. Amplification of c-erbB was observed in one tumor, and no evidence for amplification of int-2 was obtained in this series of adenocarcinomas.

Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion.

A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.

Phase I clinical trial and pharmacokinetics of 4'-carboxyphthalato(1,2-diaminocyclohexane)platinum(II).

4'-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) is a new, second generation platinum analog which had demonstrated in vitro activity in L1210 cell lines resistant to cisplatin and had less nephrotoxicity than did cisplatin in preclinical animal testing. A Phase I trial with this agent has been performed in 45 patients with advanced refractory cancers. Nine dosage levels, ranging from 40 to 800 mg/sq m, were studied. Major toxicities seen were myelosuppression, nephrotoxicity (which was generally mild), nausea and vomiting (which was quantitatively less than that seen with cis-platin), allergic reactions, and a peripheral neuropathy. The dose-limiting toxicity was thrombocytopenia. Pharmacokinetics performed at three dosage levels indicates that 4'-carboxyphthalato-(1,2-diaminocyclohexane)platinum(II) has a long t1/2 of 20 to 30 hr (total platinum) and is only partially excreted in the urine and that a high proportion of the drug is nonfilterable within 30 to 60 min of administration. Therapeutic responses were seen in nasopharyngeal carcinoma, adenocarcinoma of the cervix, and lung and gastric cancer. As a starting dose for Phase II studies, which are planned for patients with ovarian, testicular, lung, gastric, and esophageal cancers, 640 mg/sq m given every 3 to 4 weeks is recommended.

11p13-15 is a specific region of chromosomal rearrangement in gastric and esophageal adenocarcinomas.

In a cytogenetic analysis of 9 gastric and lower esophageal adenocarcinomas, we detected nonrandom rearrangements involving the region 11p13-15 in 8, thus identifying for the first time a specific chromosomal lesion in these tumors. In addition, rearrangements involving 3p21, translocations among the D group chromosomes, and i(5p) were each observed in more than half of the cases. The overall pattern of aberrations encountered in adenocarcinomas of gastric and lower esophageal origin was similar, suggesting that the tumors arising at these anatomical sites are biologically related. We also encountered cytogenetic evidence for gene amplification in the form of homogeneously staining regions and double-minute chromosomes in primary as well as metastatic lesions, which is consistent with amplification of a number of cellular oncogenes in these tumors detected by others and us at the molecular level. These cytogenetic findings are discussed in relation to nonrandom chromosome abnormalities and gene amplification reported in other types of adenocarcinoma.

Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma.

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.

Flow cytometry as a predictive indicator in patients with operable gastric cancer.

Adenocarcinoma of the proximal portion of the stomach (gastroesophageal [GE] junction and cardia) is increasing in incidence. The inferior survival of patients with GE-cardia lesions as compared with patients with tumors located in the body and antrum has been attributed to anatomic features. To determine if a biological difference could explain the varying prognosis, flow cytometric studies were performed prospectively in 50 patients with operable gastric cancer and analyzed for association with site, histology, gender, age, stage, and disease-free survival. DNA aneuploidy significantly correlated with tumor location: 96% of GE-cardia carcinomas were aneuploid as compared with 48% of body-antrum tumors (P = .0008). Nodal involvement was more common in aneuploid tumors (P = .0548), and women were more likely to have diploid tumors than were men (P = .0233). The median disease-free survival for patients with diploid tumors was 18.5 months as compared with 5.4 months for patients with aneuploid carcinomas (P = .076). Furthermore, within the body-antrum of the stomach, patients with diploid tumors had a significantly better disease-free survival than did those with aneuploid tumors from the same site (18.4 v 4.7 months, P = .0185). These results indicate there is a difference in the DNA content of gastric tumors located in different sites within the stomach and that DNA content correlates with prognosis.

Neoadjuvant chemotherapy plus concurrent chemotherapy and high-dose radiation for squamous cell carcinoma of the esophagus: a preliminary analysis of the phase II intergroup trial 0122.

PURPOSE: To determine the preliminary acute toxicity and survival results of neoadjuvant chemotherapy followed by concurrent chemotherapy plus high-dose radiation therapy in patients with local/regional squamous cell carcinoma of the esophagus. MATERIALS AND METHODS: Forty-five patients with clinical stage T1-4N0-1M0 squamous cell carcinoma were entered onto the trial. Eight patients were declared ineligible after registration. Patients received three monthly cycles of fluorouracil (5-FU; 1,000 mg/m2/24hr for 5 days) and cisplatin (100 mg/m2 on day 1) (neoadjuvant segment) followed by two additional monthly cycles of 5-FU (1,000 mg/m2/24hr for 5 days) and cisplatin (75 mg/m2 on day 1) plus concurrent 64.8 Gy (combined modality segment). RESULTS: With a median follow-up of 15 months in surviving patients, the incidence of total grade 3+ toxicity during the neoadjuvant chemotherapy segment was 61%, and during the combined modality segment was 72%. Of the 33 patients who started radiation therapy, 91% were able to complete the full course. There were six deaths during treatment, five of which (11%), because of nadir sepsis and/or dehydration, were treatment-related. For the 37 eligible patients, the median disease-free survival duration was 9 months, and the overall median survival was 20 months. CONCLUSION: The preliminary analysis of this trial demonstrated that the incidence of grade 3+ toxicity was similar to that reported in the combined modality arm of the prior Radiation Therapy Oncology Group (RTOG) intergroup esophageal trial RTOG 85-01. However, because of the increased incidence of treatment-related mortality, this treatment program will not be used as an experimental arm of intergroup trial INT 0123 (RTOG 94-05).

Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer.

PURPOSE: We performed a phase I study to determine the appropriate dose of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluorouracil (FU) and than to determine the maximum-tolerated dose (MTD) of FU when given with PN401. PATIENTS AND METHODS: Patients with advanced cancer received oral PN401 as either a suspension or a tablet in escalating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD > or = 50 mumol/L. In the first phase of the study, all patients received a fixed dose of FU 600 mg/m2 as a rapid intravenous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN401 therapy commenced 24 hours after FU. After determination of the appropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. RESULTS: Thirty-eight patients with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g given in tablet form resulted in high bioavailability of URD, with sustained plasma concentrations greater than 50 mumol/L. In the second phase of the study, FU doses were escalated from 600 to 1,000 mg/m2. FU was given as a rapid intravenous bolus weekly for 6 weeks with a 2-week rest. The MTD of FU given in this fashion with PN401 rescue was 1,000 mg/m2, at which level two of six patients had neutropenic fever. FU at doses of 800 mg/m2 for 6 weeks was well tolerated without significant toxicity when given with PN401 rescue. CONCLUSION: Oral PN401 is well tolerated and total doses of 6 g every 6 hours yield sustained levels of URD in the target range of 50 mumol/L. The MTD of FU with PN401 rescue is 1,000 mg/m2 and the recommended dose for phase II trials is 800 mg/m2 given weekly for 6 weeks with dose escalation. Further studies to define better the appropriate interval for PN401 rescue and the appropriate dose of FU when given with biochemical modulation, such as with leucovorin, are indicated.

Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin.

Although many trials have evaluated the severity and treatment of nausea and vomiting immediately after cisplatin administration, no studies have focused on vomiting occurring more than 24 hours after chemotherapy--delayed emesis. Two consecutive trials were undertaken to evaluate the incidence, course (trial 1), and severity (trial 2) of delayed nausea and emesis and to develop methods to study these conditions. Eighty-six patients receiving cisplatin (120 mg/m2) for the first time were entered. On the day of cisplatin treatment, all received intravenous (IV) metoclopramide (3 mg/kg X 2 doses) plus dexamethasone (20 mg IV X 1 dose) with either diphenhydramine (50 mg IV) or lorazepam (1.0 to 1.5 mg/m2). Sixty-two percent of patients experienced no vomiting during the 24 hours immediately after administration of cisplatin. Overall, 93% of studied patients experienced some degree of delayed nausea or vomiting from 24 to 120 hours after cisplatin. In trial 1, the incidence of delayed vomiting ranged from 21% to 61% and delayed nausea from 24% to 78% in 58 patients. The highest incidence of both delayed nausea and emesis occurred during the period from 48 to 72 hours after administration of cisplatin. Patients who had no emesis during the initial 24 hours after cisplatin were less likely to experience delayed emesis. The severity of delayed nausea and vomiting was evaluated in 28 patients in trial 2. The amount of delayed nausea and vomiting was assessed daily by patients using a visual analogue scale and by an observer rating. The highest nausea and vomiting scores were seen during the period from 48 to 72 hours after administration of cisplatin, with acceptable correlation between patient scores and observer ratings. Although the nausea and vomiting occurring 24 or more hours after cisplatin administration is not as severe as that seen during the initial 24 hours after administration of cisplatin in patients not receiving antiemetics, it is a common condition that merits both further study and specific treatment.