ABSTRACT
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.
Subject(s)
Adenocarcinoma/pathology , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Esophagogastric Junction , Esophageal Squamous Cell Carcinoma , Humans , Neoplasm Staging , Prognosis , Survival AnalysisABSTRACT
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.
Subject(s)
Adenocarcinoma/secondary , Adenocarcinoma/therapy , Chemoradiotherapy, Adjuvant/adverse effects , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Neoplasm Recurrence, Local , Radiotherapy, Intensity-Modulated , Adult , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Chemoradiotherapy, Adjuvant/methods , Esophagectomy/adverse effects , Female , Fluorouracil/administration & dosage , Humans , Induction Chemotherapy/adverse effects , Irinotecan , Lymphatic Metastasis , Male , Middle Aged , Neoadjuvant Therapy , Paclitaxel/administration & dosage , Platinum Compounds/administration & dosage , Radiotherapy, Intensity-Modulated/adverse effects , Survival Rate , Tumor BurdenABSTRACT
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.
Subject(s)
Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Neoplasm Metastasis , Stomach Neoplasms/pathology , Esophageal Neoplasms/metabolism , Europe , Humans , Immunohistochemistry , In Situ Hybridization , Prognosis , Stomach Neoplasms/metabolism , United StatesABSTRACT
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.
Subject(s)
Adenocarcinoma/mortality , Esophageal Neoplasms/mortality , Esophagogastric Junction , Neoplasm Recurrence, Local/epidemiology , Stomach Neoplasms/mortality , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Aged , Brain Neoplasms/secondary , Combined Modality Therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Female , Humans , Male , Middle Aged , Retrospective Studies , Stomach Neoplasms/pathology , Stomach Neoplasms/therapyABSTRACT
BACKGROUND: Venous thromboembolism(VTE) is a significant, common comorbidity of cancer patients associated with increased mortality. We evaluated the incidence and risk factors for developing a new VTE in ambulatory cancer patients while they were receiving therapy for advanced cancer. We also examined the affect of developing a new VTE on survival for patients with gastroesophageal malignancies. METHODS: All patients with non-hematologic malignancies who were treated using investigator-initiated therapeutic protocols at Memorial Sloan Kettering Cancer Center (MSKCC) from 2003 through to 2005 were identified for this cohort study. The occurrence of VTE was prospectively recorded in an actively managed clinical research database. Baseline laboratory parameters, treatment details and tumor type were correlated with VTE risk and patient survival. RESULTS: 115 out of 2120 patients being treated for advanced malignancy developed a new VTE (12.8 VTEs/100 person-years). In multivariate analysis, a diagnosis of gastroesophageal cancer (hazard ratio (HR), 2.76 (1.41-5.38); P=0.003), pancreatic cancer (HR, 2.26 (1.06-4.80); P=0.05), use of white cell growth factors (HR 1.69(1.09-2.64); P=0.02) and irinotecan therapy (HR, 1.89 (1.29-3.59); P=0.05) were independently associated with VTE development. Hemoglobin >10 g dL(-1) (HR, 0.52 (0.3-0.91); P=0.02) and albumin ≥ 4 g dL(-1) (HR, 0.61 (0.39-0.94); P=0.024) were associated with reduced VTE risk. The unadjusted HR for death among ambulatory gastroesophageal cancer patients with VTE is 0.89 (0.61-1.3), P=0.53. After adjusting for confounding risk factors associated with survival, the HR for death associated with VTE is 0.78 (0.5-1.2), P=0.25. CONCLUSION: Upper gastrointestinal malignancies are independently associated with the development of a new VTE, implicating tumor biology in VTE development. Even after adjusting for prognostic factors, we were unable to demonstrate an adverse impact on survival due to the new development of VTE amongst patients with active gastroesophageal malignancy receiving therapy.
Subject(s)
Gastrointestinal Neoplasms/etiology , Venous Thromboembolism/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/mortality , Humans , Male , Medical Oncology/methods , Middle Aged , Multivariate Analysis , Prognosis , Prospective Studies , Risk Factors , Treatment Outcome , Venous Thromboembolism/complications , Venous Thromboembolism/mortalityABSTRACT
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.
Subject(s)
Carcinoma, Small Cell/mortality , Carcinoma, Small Cell/therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Esophagogastric Junction , Aged , Carcinoma, Small Cell/pathology , Carcinoma, Small Cell/secondary , Combined Modality Therapy , Esophageal Neoplasms/pathology , Female , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Retrospective Studies , Survival Rate , Treatment OutcomeABSTRACT
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.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , Radiotherapy, Adjuvant , Adenocarcinoma/mortality , Adenocarcinoma/radiotherapy , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease Progression , Erlotinib Hydrochloride , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neutropenia/chemically induced , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/radiotherapy , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects , Survival Analysis , Thrombocytopenia/chemically induced , Treatment Outcome , GemcitabineABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Intestinal Perforation/chemically induced , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Female , Humans , Male , Middle Aged , Risk FactorsABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Flavonoids/administration & dosage , Neoplasms/drug therapy , Neoplasms/immunology , Piperidines/administration & dosage , Taxoids/administration & dosage , Adult , Aged , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Docetaxel , Drug Administration Schedule , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Male , Middle Aged , Treatment Outcome , GemcitabineABSTRACT
BACKGROUND: The purpose of the study was to evaluate the efficacy of weekly paclitaxel (Taxol) in advanced esophageal cancer. PATIENTS AND METHODS: One hundred and two patients with advanced esophageal cancer were treated with paclitaxel 80 mg/m2 weekly over a 1-h infusion. One cycle was defined as 4 weeks of therapy. Ninety-five patients were assessable for toxicity and 86 patients who completed at least two cycles of treatment were assessable for response. Sixty-six patients had adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy. RESULTS: A median of three cycles was delivered (range 1-11). Partial responses (PRs) were seen in 11 patients [13%, 95% confidence interval (CI) 6% to 20%]. In patients without prior chemotherapy, PRs were seen in 10 patients (15%, 95% CI 6% to 24%), with comparable response in adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was seen in patients with prior chemotherapy (1/21, 5%). The median duration of response was 172 days. The median survival was 274 days. Therapy was well tolerated with minimal hematologic or grade 3 or 4 toxicity. CONCLUSION: Weekly paclitaxel has limited activity in esophageal cancer. The median survival, modest activity, and tolerance of therapy indicate that weekly paclitaxel may be an option in patients unable to tolerate combination chemotherapy.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Esophageal Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/adverse effects , Arthralgia/chemically induced , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Drug Administration Schedule , Esophageal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Infusions, Intravenous , Male , Middle Aged , Neutropenia/chemically induced , Paclitaxel/adverse effects , Survival Analysis , Thrombocytopenia/chemically induced , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The aim of the study was to evaluate the efficacy and toxicity of neoadjuvant chemotherapy with intravenous (i.v.) cisplatin and fluorouracil (5-FU), surgery and postoperative intraperitoneal (i.p.) floxuridine (FUdR) and leucovorin (LV) in patients with locally advanced gastric cancer. PATIENTS AND METHODS: Preoperative staging was confirmed by laparoscopy (LAP). Two cycles of i.v. cisplatin (20 mg/m(2)/day, rapid infusion) and 5-FU (1000 mg/m(2), continuous 24-h infusion), given on days 1-5 and 29-34, were followed by a radical gastrectomy and a D2 lymphadenectomy. Patients having R0 resections were to receive three cycles of i.p. FUdR (1000 mg/m(2)) and LV (240 mg/m(2)), given on days 1-3, 15-17 and 29-31. Intraperitoneal chemotherapy was begun 5-10 days from surgery. RESULTS: Thirty-eight patients were treated. Both preoperative and postoperative chemotherapy were well tolerated. T stage downstaging (pretreatment LAP versus surgical pathological stage) was seen in 23% of patients. The R0 resection rate was 84%. Neither an increase in postoperative morbidity nor operative mortality was noted. With a median follow-up of 43.0 months, 15 patients (39.5%) are still alive (median survival 30.3 months). Good pathologic response, seen in five patients (15%), was associated with better survival (P = 0.053). Peritoneal and hepatic failures were found in 22% and 9% of patients, respectively. Quality of life seemed to be preserved. CONCLUSIONS: Neoadjuvant cisplatin/5-FU followed by postoperative i.p. FUdR/LV can be safely delivered to patients undergoing radical gastrectomy and D2 lymphadenectomy. The R0 resection and the survival rates are encouraging. An association between pathologic response and patient outcome was suggested.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Floxuridine/administration & dosage , Leucovorin/administration & dosage , Neoadjuvant Therapy/methods , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant/adverse effects , Chemotherapy, Adjuvant/methods , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy/methods , Disease-Free Survival , Endoscopy, Digestive System/adverse effects , Feasibility Studies , Female , Floxuridine/adverse effects , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Injections, Intraperitoneal , Leucovorin/adverse effects , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Staging , Postoperative Period , Quality of Life , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis , Treatment FailureABSTRACT
Small-cell carcinoma (SmCC) of the gastrointestinal tract is a very rare and aggressive malignancy. To better define its clinicopathological features, the records of all patients with this disease seen at Memorial Sloan Kettering Cancer Center between 1980 and 2002 (n=64) were reviewed. The most common primary tumour locations were in the large bowel and oesophagus. Predisposing medical conditions for non-small-cell cancers, positive family cancer history, and metachronous tumours were common. In all, 37% had mixed tumour histology and 48% presented with extensive disease, according to the Veterans' Administration Lung Study group (VALSG) staging system used for small-cell lung cancer. Treatment outcome in limited disease (LD) suggested a role for surgery and chemotherapy. Platinum-based regimens resulted in a 50% response rate. The 2-year survival was 23% and two prognostic factors were identified, the extent of disease according to the VALSG system (P<0.01) and TNM stage (P=0.03). Anatomic location had no clinical impact. In conclusion, SmCC from various gastrointestinal sites can be viewed as one clinical entity. Mixed tumour histology is common and may affect therapy. Surgery, combined with chemotherapy, should be considered for LD. The value of the VALSG system was implied and possible differences from small-cell lung cancer were noted.
Subject(s)
Carcinoma, Small Cell/mortality , Carcinoma, Small Cell/pathology , Gastrointestinal Neoplasms/mortality , Gastrointestinal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Small Cell/therapy , Disease Progression , Female , Gastrointestinal Neoplasms/therapy , Humans , Male , Middle Aged , Neoplasm Metastasis , Prognosis , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: ras genes encode Ras proteins that are important for signal transduction in cancer cells. Farnesyl protein transferase (FPTase) is an enzyme that is responsible for a critical post-translational modification of Ras. PATIENTS AND METHODS: We report the results of a phase II trial of SCH 66336, an FPTase inhibitor, in patients with metastatic colorectal cancer. This is the first reported experience of an FPTase inhibitor in this disease. All patients were considered refractory to first- and second-line therapy. A total of 21 evaluable patients were treated with a starting dose of 200 mg b.i.d. given continuously. RESULTS: The major side-effects were fatigue (grade 1 in 42%, grade 2 in 42% and grade 3 in 14%), diarrhea (grade 1 in 23% and grade 3 in 42%) and nausea (grade 2 in 16%). Elevations in serum creatinine (grade 2 or 3) were observed in 19% of patients and appeared to be related to dehydration induced by diarrhea. Significant hematological toxicity was not observed (only grade 1 thrombocytopenia in 19% and grade 2 or 3 anemia in 28%). Pharmacological studies revealed adequate mean pre-dose plasma concentrations in this group of patients on day 15 of therapy. No objective responses were observed, although stable disease was seen in three patients for several months. Administration of SCH 66336 was accompanied by gastrointestinal toxicity. CONCLUSIONS: Future development of this compound cannot be recommended as monotherapy in this disease.
Subject(s)
Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm , Enzyme Inhibitors/administration & dosage , Fluorouracil/administration & dosage , Piperidines/administration & dosage , Pyridines/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Biopsy, Needle , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance , Female , Follow-Up Studies , Humans , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Male , Middle Aged , Neoplasm Staging , Survival Analysis , Treatment OutcomeABSTRACT
Gastric cancer is a common cancer worldwide with a high mortality rate. Despite curative intent resection, locoregional failure as a frequent site of recurrence is responsible in part for this high mortality. Many attempts have been made to decrease the risk of recurrence after resection. Studies involving postoperative chemotherapy as a single modality have not clearly demonstrated benefit. Similarly, most studies of postoperative radiation therapy have not clearly shown an improvement in overall survival. Recently, however, a USA Intergroup study indicated a survival advantage for chemoradiation therapy compared to surgery alone for patients with locally advanced gastric cancer. "Intergroup-116" is a large-scale randomized trial designed to evaluate the role of adjuvant chemotherapy plus radiotherapy following curative intent gastric resection. The data from this study demonstrate a survival benefit with adjuvant chemoradiation that may in large part be due to better locoregional control. While many patients had a less then adequate lymph node dissection, survival was not associated with the type of lymph node dissection performed. Toxicity was acceptable. "Intergroup-116" indicates that postoperative chemoradiation should be considered as a standard care option for patients with locally advanced gastric cancer. Future studies should evaluate potentially more effective systemic therapy, molecularly-directed treatment, and possibly, whether or not more formal lymph node dissections would obviate the need for radiation.
Subject(s)
Stomach Neoplasms/therapy , Chemotherapy, Adjuvant , Combined Modality Therapy , Gastrectomy , Humans , Lymph Node Excision , Neoplasm Staging , Radiotherapy, Adjuvant , Randomized Controlled Trials as Topic , Risk , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival RateABSTRACT
BACKGROUND: Advanced hepatocellular carcinoma has a poor prognosis. In a Phase II clinical trial, two academic centers assessed irinotecan, a topoisomerase-1 inhibitor with broad spectrum clinical activity, in patients who had advanced hepatocellular cancer. METHODS: Patients who had had up to one prior chemotherapy regimen were eligible. Bidimensionally measurable disease, a good performance status, and adequate major organ function were required. At a starting dose of 125 mg/m2, irinotecan was administered weekly for 4 weeks followed by a 2 week break, which constituted 1 treatment cycle. Patients were restaged radiologically after two cycles of therapy. Dose attenuations were made as indicated for toxicity. RESULTS: Fourteen patients were enrolled over a 10-week period in 1997. There were ten males and four females. The median age was 58 years (range, 38-74 yrs). The Eastern Cooperative Oncology Group median performance status was 1 (range, 0-1). Two patients had prior chemotherapy (14%), and 1 patient (7%) had had radiation. A total of 30 cycles of therapy were delivered (median, 1; range, 1-6). Considerable toxicity was observed, mostly neutropenia, diarrhea, nausea, vomiting, and fatigue. All patients required at least one dose attenuation for toxicity. One partial response (7%; confidence interval, 0-20%) was noted to last 7 months. One patient had transient stable disease, and all others (86%) had progression of disease as their best response. CONCLUSIONS: Irinotecan had modest activity in advanced hepatocellular cancer. Toxicity was substantial, presumably reflecting impaired underlying liver function or poor ability to metabolize and eliminate the drug. The current study indicated that continued new therapy assessment is warranted for this disease.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Carcinoma, Hepatocellular/pathology , Diarrhea/chemically induced , Fatigue/chemically induced , Female , Humans , Irinotecan , Liver Neoplasms/pathology , Male , Middle Aged , Nausea/chemically induced , Neutropenia/chemically induced , Prognosis , Treatment Outcome , Vomiting/chemically inducedABSTRACT
BACKGROUND: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome. METHODS: Patients having surgical debulking and IP 5-fluoro-2'-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively. RESULTS: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m2 daily for 3 days) and IP leucovorin (240 mg/m2) with a median cycle number of 4 (range, 1-28). The median number of complications was 1 (range, 0-5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0-132 months). The median survival was 34 months (range, 2-132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection. CONCLUSIONS: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Appendiceal Neoplasms , Colonic Neoplasms , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/surgery , Adenocarcinoma/secondary , Adolescent , Adult , Aged , Antimetabolites, Antineoplastic/therapeutic use , Combined Modality Therapy , Female , Floxuridine/therapeutic use , Formyltetrahydrofolates/therapeutic use , Humans , Infusions, Parenteral/methods , Leucovorin/therapeutic use , Male , Middle Aged , Peritoneal Neoplasms/secondary , Retrospective Studies , Survival AnalysisABSTRACT
PURPOSE: In a phase II trial of paclitaxel, cisplatin, and fluorouracil in metastatic esophageal cancer, we identified significant activity for the combination of agents, but there was severe associated toxicity. We therefore undertook a phase II trial of paclitaxel and cisplatin without fluorouracil. PATIENTS AND METHODS: Thirty-eight patients with carcinoma of the esophagus or gastroesophageal junction were treated. No patient who underwent prior chemotherapy was allowed to take part in the study. The majority (33 patients) had adenocarcinoma, and most (36 patients, 95%) had metastatic disease. Paclitaxel, 200 to 250 mg/m2, was given by 24-hour infusion on day 1, followed by cisplatin, 75 mg/m2, on day 2, with granulocyte colony stimulating factor support. Treatment was cycled every 21 days in the outpatient setting. The first 16 patients received paclitaxel at 250 mg/m2, but because of toxicity and treatment-related deaths, the dose was reduced to 200 mg/m2. RESULTS: Thirty-two patients were evaluable for response. Six patients were evaluated for toxicity after receiving only one cycle (due to toxicity or treatment-related death). Partial responses were seen in 14 patients (44%); responses occurred in 13/28 patients with adenocarcinoma (46%) and in one of four patients with squamous carcinoma (25%). Median duration of response was 3.9 months, and median survival was 6.9 months. Of twenty-five patients with dysphagia before therapy, eighteen patients (72%) had complete resolution of dysphagia, and two (8%) had partial resolution. Toxicity included grade 3/4 fatigue in 35% of patients and grade 4 neutropenia in 47% of patients. Nineteen patients (50%) required hospitalization for toxicity, and four patients (11%) died from therapy-related complications. CONCLUSION: The combination of paclitaxel and cisplatin has significant activity in esophageal adenocarcinoma. Because of hospitalization for toxicity and deaths resulting from treatment, the combination of paclitaxel and cisplatin used in this trial cannot be recommended. The optimal dose and schedule of paclitaxel/cisplatin combination therapy remain to be established.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma/drug therapy , Cisplatin/therapeutic use , Esophageal Neoplasms/drug therapy , Paclitaxel/therapeutic use , Adenocarcinoma/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/toxicity , Carcinoma, Squamous Cell/drug therapy , Cisplatin/administration & dosage , Cisplatin/toxicity , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/toxicity , Time FactorsABSTRACT
PURPOSE: High levels (> 200,000 molecules per carcinoma cell) of the LewisY antigen are expressed on the surface of most (> 75%) gastric carcinomas. The BMS-182248-01 is a chimeric variant of anti-LewisY monoclonal antibody that is conjugated with doxorubicin. In a phase I study, BMS-182248-01 resulted in a partial response in a patient with gastric carcinoma. We, therefore, conducted a multi-institutional phase II study of BMS-182248-01 in patients with advanced gastric carcinoma. METHODS AND PATIENTS: Only patients with evidence of LewisY antigen by immunohistochemical method on their gastric carcinoma were treated. Patients with unresectable gastric adenocarcinoma were eligible. Patients had to have adequate liver, renal, and marrow functions. Written consent was obtained from all patients. All patients were hospitalized. BMS-182248-01 was administered at the starting dose of 700 mg/m2 i.v. over 24 hours on day 1 every 3 weeks. RESULTS: Fifteen patients were enrolled. There were 10 men and 5 women. The median age at enrollment was 56 years, with ages ranging from 34 to 80 years. No objective responses were observed. Five patients had disease stabilization. The remaining 10 patients progressed on study. Rapidly reversible gastrointestinal toxicity, primarily nausea and emesis, was predominant. There was no neutropenia, thrombocytopenia, or cardiomyopathy. CONCLUSIONS: Although BMS-182248-01 represents a novel approach of monoclonal antibody conjugated with an active chemotherapy agent, delivered intracellularly, it was ineffective in patients with gastric carcinoma whose tumors carried LewisY antigen.