Local recurrence following adjuvant chemotherapy without radiotherapy in completely resected stomach and gastroesophageal junction adenocarcinoma.

BACKGROUND: The gold standard of adjuvant treatment after surgical resection of adenocarcinoma of the stomach or gastroesophageal junction (GEJ) is chemoradiotherapy. We retrospectively evaluated chemotherapy without radiotherapy in stomach and GEJ adenocarcinoma, using a combination of etoposide, adriamycin and cisplatin (modified EAP). PATIENTS AND METHODS: Sixty-five patients with completely resected gastric or GEJ adenocarcinoma and positive regional lymph nodes were treated with modified EAP over an 8-year period. RESULTS: Recurrent disease was diagnosed in 38/58 (69%) patients evaluable for analysis. Only two (5%) had locoregional recurrence. The main toxicity was hematological, with 22 (34%) patients developing neutropenic fever and 12 (18%) anemia requiring blood transfusion. The median survival for the entire group was 20 months, with a median time to recurrence of 11 months. Seventeen (26%) patients are alive for a median of 7+ years, with no evidence of recurrent disease. CONCLUSION: Our data cast doubt on the benefit of radiotherapy adjuvant to chemotherapy.

Wheat grass juice may improve hematological toxicity related to chemotherapy in breast cancer patients: a pilot study.

Myelotoxicity induced by chemotherapy may become life-threatening. Neutropenia may be prevented by granulocyte colony-stimulating factors (GCSF), and epoetin may prevent anemia, but both cause substantial side effects and increased costs. According to non-established data, wheat grass juice (WGJ) may prevent myelotoxicity when applied with chemotherapy. In this prospective matched control study, 60 patients with breast carcinoma on chemotherapy were enrolled and assigned to an intervention or control arm. Those in the intervention arm (A) were given 60 cc of WGJ orally daily during the first three cycles of chemotherapy, while those in the control arm (B) received only regular supportive therapy. Premature termination of treatment, dose reduction, and starting GCSF or epoetin were considered as "censoring events." Response rate to chemotherapy was calculated in patients with evaluable disease. Analysis of the results showed that five censoring events occurred in Arm A and 15 in Arm B (P = 0.01). Of the 15 events in Arm B, 11 were related to hematological events. No reduction in response rate was observed in patients who could be assessed for response. Side effects related to WGJ were minimal, including worsening of nausea in six patients, causing cessation of WGJ intake. In conclusion, it was found that WGJ taken during FAC chemotherapy may reduce myelotoxicity, dose reductions, and need for GCSF support, without diminishing efficacy of chemotherapy. These preliminary results need confirmation in a phase III study.

Epiphora (excessive tearing) and other ocular manifestations related to weekly docetaxel: underestimated dose-limiting toxicity.

PURPOSE: Epiphora due to canalicular stenosis is a recently described side effect of weekly docetaxel. We prospectively evaluated the incidence of this complication and other ocular manifestations in patients treated at our medical center. PATIENTS AND METHODS: Twenty-one consecutive patients (breast cancer: 14; metastatic non-small cell lung cancer: 6; metastatic nasopharyngeal carcinoma: 1) (female/male: 14/7; age range: 34-78 yr) were treated with weekly docetaxel (35 mg/m2/wk iv for 6 wk, cycles repeated every 49 d). A standard questionnaire regarding epiphora was completed before each dose of docetaxel. Patients who complained of excessive tearing underwent a thorough ophthalmologic evaluation before receiving the next dose. RESULTS: Epiphora due to stenosis of the lacrimal puncti and canaliculi developed in seven (33%) patients following a cumulative dose of 208-645 mg/m2 (median: 400 mg/m2). Two patients developed complete canalicular stenosis requiring surgery. Epiphora was accompanied by madarosis and ectodermalization of the palpebral and bulbar conjunctiva, complete in five patients. Treatment was discontinued due to epiphora in two (10%) patients. After a median follow-up of 11 mo, four patients still had epiphora. CONCLUSION: Epiphora due to canalicular stenosis is a frequent complication of weekly docetaxel and might be dose limiting. Irreversible damage requiring surgical intervention may develop despite close monitoring.

The expression of the ubiquitin ligase subunit Cks1 in human breast cancer.

INTRODUCTION: Loss of the cell-cycle inhibitory protein p27Kip1 is associated with a poor prognosis in breast cancer. The decrease in the levels of this protein is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1). Skp2 was recently found to be overexpressed in breast cancers, but the role of Cks1 in these cancers is unknown. The present study was undertaken to examine the role of Cks1 expression in breast cancer and its relation to p27Kip1 and Skp2 expression and to tumor aggressiveness. METHODS: The expressions of Cks1, Skp2, and p27Kip1 were examined immunohistochemically on formalin-fixed, paraffin-wax-embedded tissue sections from 50 patients with breast cancer and by immunoblot analysis on breast cancer cell lines. The relation between Cks1 levels and patients' clinical and histological parameters were examined by Cox regression and the Kaplan-Meier method. RESULTS: The expression of Cks1 was strongly associated with Skp2 expression (r = 0.477; P = 0.001) and inversely with p27Kip1 (r = -0.726; P < 0.0001). Overexpression of Cks1 was associated with loss of tumor differentiation, young age, lack of expression of estrogen receptors and of progesterone receptors, and decreased disease-free (P = 0.0007) and overall (P = 0.041) survival. In addition, Cks1 and Skp2 expression were increased by estradiol in estrogen-dependent cell lines but were down-regulated by tamoxifen. CONCLUSION: These results suggest that Cks1 is involved in p27Kip1 down-regulation and may have an important role in the development of aggressive tumor behavior in breast cancer.

The safety of full-dose chemotherapy with secondary prophylactic granulocyte colony stimulating factor (G-CSF) following a prior cycle with febrile neutropenia.

Secondary prophylactic administration of recombinant human granulocyte colony stimulating factor (G-CSF) following an episode of febrile neutropenia is recommended if maintenance of dose-intensity is desired. This policy was adopted in our center in patients treated with an intent for cure or durable complete response. The purpose of this study was to evaluate the safety and feasibility of this policy. Patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. Fifty-one patients who developed febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with the support of filgrastim (300 or 480 mg/d sc for at least 10 consecutive days). Diagnoses included lymphoma (n = 19), breast cancer (n = 15), germ cell tumor (n = 7), small-cell lung cancer (n = 5), and other solid tumors (n = 5). The incidence of febrile neutropenia during the first cycle given with filgrastim support (N1) was 8/51 (16%). Intravenous antibiotics were required for 3-7 d (median, 4.5 d). During the following cycle (N2), febrile neutropenia developed in 4/41 (10%) patients. Intravenous antibiotics were given for 2, 4, 5, and 7 d. Other dose-limiting toxicities developed in 1/51 patients who received N1 and in 1/41 patients who received N2. There was no drug-related death associated with either cycle. In conclusion, a policy of full-dose chemotherapy with secondary G-CSF support in patients who develop febrile neutropenia following moderately myelotoxic chemotherapy is relatively safe and feasible.

The additional value of PET/CT over PET in FDG imaging of oesophageal cancer.

PURPOSE: The aim of this study was to assess the value of combined PET/CT compared with PET reviewed side-by-side with CT, in patients with oesophageal cancer, before and after surgery. METHODS: Forty-one FDG PET/CT studies were performed in 32 patients with oesophageal cancer, before surgery (n = 18) or during follow-up after resection of the primary tumour (n = 23). One hundred and fifteen sites suspicious for malignancy were evaluated. PET/CT was prospectively compared with PET reviewed side-by-side with CT, for detection, accurate localisation and characterisation of malignant sites. PET/CT performance in different anatomical regions was compared before and after surgery. The impact of fused data on patient management was retrospectively assessed. RESULTS: PET/CT had an incremental value over PET for interpretation of 25 of 115 sites (22%), changing the initial characterisation of ten sites to either malignant (n = 1) or benign (n = 9), and defining the precise anatomical location of 15 sites. PET/CT provided better specificity and accuracy than PET for detecting sites of oesophageal cancer (81% and 90% vs 59% and 83% respectively, p < 0.01). Fusion was of special value for interpretation of cervical and abdomino-pelvic sites, for disease assessment in loco-regional lymph nodes before surgery and in regions of postoperative anatomical distortion. PET/CT had an impact on the further management of four patients (10%), by detecting nodal metastases that warranted disease upstaging (n = 2) and by excluding disease in sites of benign uptake after surgery (n = 2). CONCLUSION: PET/CT improves the accuracy of FDG imaging in oesophageal cancer and provides data of diagnostic and therapeutic significance for further patient management.

Paclitaxel, carboplatin, and oral etoposide in advanced gastric adenocarcinoma: association with severe myelotoxicity.

The prognosis of locally advanced or metastatic adenocarcinoma of the stomach is poor. In an attempt to improve therapeutic results, we undertook a phase II trial to investigate a combination of paclitaxel, carboplatin, and oral etoposide, all active drugs in this malignancy and with a synergistic effect in combination. Fourteen patients with advanced gastric adenocarcinoma were treated with paclitaxel 200 mg/m2 iv, carboplatin AUC-6 iv on d 1, and oral etoposide 50 mg/d alternating with 100 mg/d on d 1-10. Cycles were repeated every 3 wk. Of the 14 patients treated, partial response was observed in 3/12 (25%) evaluable patients. Median survival for the entire group was 7 mo. The treatment was associated with severe myelotoxicity. Neutropenic fever that required hospitalization developed in 7/14 (50%) of patients, and symptomatic anemia that required red blood cell transfusion was noted in 8/14 (57%). There was one drug-related death associated with neutropenic fever, Gram negative sepsis, grade 4 thrombocytopenia, and gastrointestinal bleeding. Nonhematological toxicity was moderate. We conclude that the current regimen of paclitaxel, carboplatin, and oral etoposide is not recommended in advanced gastric carcinoma owing to unacceptable myelotoxicity.

Severe toxicity related to the 5-fluorouracil/leucovorin combination (the Mayo Clinic regimen): a prospective study in colorectal cancer patients.

The Mayo Clinic regimen of leucovorin 20 mg/m followed immediately by 5-fluorouracil 425 mg/m administered for 5 consecutive days every 4 weeks is commonly used in the treatment of colorectal cancer. This study was aimed at prospectively determining the incidence and pattern of severe toxicity associated with this regimen. We evaluated prospectively 243 patients with colorectal cancer treated in our department with the Mayo Clinic regimen for the incidence of severe toxicity (defined as toxicity requiring hospitalization). Of the 243 patients, 32 (13%) were hospitalized for chemotherapy-related toxicity. Major toxicities included neutropenic fever in 21 (9%), grade III/IV mucositis in 25 (10%) and grade III/IV diarrhea in 20 (8%). There were five (2%) treatment-related deaths. Female patients exhibited a higher incidence of severe toxicity (18%) and toxic death (4/105) than did male patients (9% and 1/138, respectively). Elderly patients (> or =70 years) had a higher incidence of severe toxicity than younger patients did (24% versus 7%, < 0.001). Toxic death occurred in 4 of 89 patients aged 70 years or more compared to 1 of 154 in younger patients. Most episodes of severe toxicity (56%) and toxic deaths (4/5) were observed after the first cycle. We conclude that the Mayo Clinic regimen can be associated with severe toxicity, usually occurring after the first cycle. Female gender and advanced age predict severe toxicity; therefore, dose reduction in high-risk patients should be considered, especially during the first cycle.

Actual body weight for determining doses of chemotherapy in obese cancer patients: evaluation of treatment tolerability.

In our Department, doses of chemotherapy in obese cancer patients are routinely calculated according to actual body weight. As some physicians question this policy, we prospectively evaluated the safety of this approach. Of 606 consecutive patients, 178 (29%) were obese, defined as body mass index > or =27.3 kg/m2 for females and > or =27.8 kg/m2 for males; full-dose chemotherapy was initiated in 147 (24%). Severe chemotherapy- related toxicity (SCRT) (neutropenic fever, severe thrombocytopenia associated with significant bleeding and/or requiring platelet transfusion, or grade 3-4 nonhematologic toxicity other than alopecia, nausea, and vomiting) during the first three cycles was evaluated. SCRT was noted in 16/147 (11%) during the first cycle, 10/146 (7%) during the second cycle, and 6/142 (4%) during the third cycle. Drug doses were reduced due to toxicity in 15/146 (10%) during the second cycle and 11/142 (8%) during the third cycle. There were no treatment- related deaths. It was concluded that calculation of standard chemotherapy dose according to actual body weight in obese patients is relatively safe.