Gastric small cell carcinoma with marked response to neoadjuvant chemotherapy

We report a patient with gastric small cell carcinoma (SCC) who showed a marked response to neoadjuvant chemotherapy. The patient was a 72-year-old Japanese man who was admitted because of epigastralgia. Subsequent examination revealed the presence of advanced gastric carcinoma in the lesser curvature of the lower body of the stomach, with multiple abdominal lymph node metastases. Endoscopic biopsy specimens from the tumor revealed SCC with moderately differentiated adenocarcinoma. The patient received neoadjuvant chemotherapy consisting of carboplatin (400 mg/m², for 1 day), epirubicin (27 mg/m², for 1 day), etoposide (70 mg/m², for 3 days), and 5-fluorouracil (330 mg/m², for 11 days). Clinically, the primary tumor and lymph node metastases were markedly reduced. Subsequently the patient underwent curative surgery and was alive without recurrence for more than 3 years after the surgery.     

Intensive Chemotherapy for Anaplastic Thyroid Carcinoma: Combination of Cisplatin, Doxorubicin, Etoposide and Peplomycin with Granulocyte Colonystimulating Factor Support

The Japanese Society of Thyroid Surgery undertook a pilot studyof treatment for anaplastic thyroid carcinoma in a cooperativesetting. The treatment consisted of cisplatin 40 mg/m² dripintravenous infusion (div), day 1, adriamycin 60 mg/m² iv, day1, etoposide 100 mg/m²/day div, days 1–3, peplomycin 5mg/body/day sc, days 1–5 and granulocyte colony-stimulatingfactor (GCSF) 2 µg/kg/day sc, days 6–14. This wasscheduled to be repeated every 3 weeks. Local radiation therapywas added for patients in whom it was indicated. A total of17 patients (mean age, 66 yr) were enrolled. Ten patients hadadvanced disease with measurable lesions and 2 patients experiencedpartial remission lasting 2 and 3 months, respectively. Sixof 7 patients were treated with the same modality of treatmentas an adjuvant. Three died of progressive disease after 3–7months and three others have survived for 3–11 months.The toxicities of the chemotherapy were mainly bonemarrow suppression,despite G-CSF support. Transient liver dysfunction was alsonoticed. These results indicate that this combined a treatmentcan be given to patients with acceptable toxicity. The degreeof leukopenia was greater than expected, partly due to the advancedage of the patients and the low dose of G-CSF. In addition,8 available thyroid specimens were examined for the mdr 1 geneand P-glycoprotein, but all were negative. Further study ofanaplastic thyroid carcinoma by this cooperative group willbe carried out.     

A phase II trial of neoadjuvant cisplatin-fluorouracil followed by postoperative intraperitoneal floxuridine-leucovorin in patients with locally advanced gastric cancer

Background: The aim of the study was to evaluate the efficacyand toxicity of neoadjuvant chemotherapy with intravenous (i.v.)cisplatin and fluorouracil (5-FU), surgery and postoperativeintraperitoneal (i.p.) floxuridine (FUdR) and leucovorin (LV)in patients with locally advanced gastric cancer. Patients and methods: Preoperative staging was confirmed bylaparoscopy (LAP). Two cycles of i.v. cisplatin (20 mg/m²/day,rapid infusion) and 5-FU (1000 mg/m², continuous 24-h infusion),given on days 1–5 and 29–34, were followed by aradical gastrectomy and a D2 lymphadenectomy. Patients havingR0 resections were to receive three cycles of i.p. FUdR (1000mg/m²) and LV (240 mg/m²), given on days 1–3, 15–17and 29–31. Intraperitoneal chemotherapy was begun 5–10days from surgery. Results: Thirty-eight patients were treated. Both preoperativeand postoperative chemotherapy were well tolerated. T stagedownstaging (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 operativemortality 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 associatedwith better survival (P = 0.053). Peritoneal and hepatic failureswere found in 22% and 9% of patients, respectively. Qualityof life seemed to be preserved. Conclusions: Neoadjuvant cisplatin/5-FU followed by postoperativei.p. FUdR/LV can be safely delivered to patients undergoingradical gastrectomy and D2 lymphadenectomy. The R0 resectionand the survival rates are encouraging. An association betweenpathologic response and patient outcome was suggested. Key words: locally advanced gastric cancer, neoadjuvant chemotherapy, intraperitoneal treatment     

Phase II Study of Chemoradiotherapy for Advanced Squamous Cell Carcinoma of the Thoracic Esophagus: Nine Japanese Institutions Trial

A phase II study of chemoradiotherapy for advanced squamouscell carcinoma of the thoracic esophagus was carried out cooperativelyby nine Japanese institutions. Forty-five patients with thoracicadvanced squamous cell carcinoma, who had T4 tumor or distantlymph node metastasis (M1_(LYM)), were enrolled in the studyfor treatment with cisplatin (70 mg/m²) on days 1 and 36, and5-fluorouracil infusion (700 mg/m²) on days 1–4 and 36–39sandwiched around external beam irradiation (60 Gy over 6 weeks).Of the 45 evaluable patients, 37 (84.1%) completed the treatment.The overall response rate was 64.4%, and the complete responserate 8.9%. The median duration of response was 125.0 days forpatients who achieved complete and partial response. The 50%median survival time was 215 days. There was one toxicity-relateddeath due to radiation pneumonitis. The major form of toxicityexceeding grade 2 was myelosuppression and anorexia, but grade4 toxicity was also observed (2 pulmonary, 1 severe hypoxemia,1 severe cardiac failure and 1 mental disturbance). The resultsshowed that this form of chemoradiotherapy had a satisfactoryeffect and might be useful for treatment of inoperable advancedesophageal cancer.     

Oxaliplatin and capecitabine in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction and gastric cardia: a phase II study from the North Central Cancer Treatment Group

Purpose: The synergic combination of oxaliplatin and capecitabinehas demonstrated activity against various gastrointestinal cancers,including colon cancer. We therefore undertook this phase IIstudy to test this first-line combination in patients with metastaticadenocarcinoma of the esophagus, gastroesophageal junction andgastric cardia. Patients and methods: Forty-three patients with histologic orcytologic confirmation of the above malignancy were recruited.The cohort had Eastern Cooperative Oncology Group performancestatuses of 0, 1 and 2 in 47%, 51%, and 2%, respectively. Medianage was 61 years (range 32–80). All had adequate organfunction. Initially, patients were prescribed 130 mg/m² intravenouslyon day 1 and capecitabine 1000 mg/m² orally twice a day, ondays 1–14 of a 21-day cycle. Four treatment-related deathsin the first 24 patients led to a reduction in capecitabineto 850 mg/m² orally twice a day, days 1–14, for the remainderof the cohort. Results: The tumor response rate was 35% [95% confidence intervals(CI) 23% to 50%]. All responses were partial; seven of 24 occurredbefore the capecitabine dose reduction, and eight of 19 after.Median time to tumor progression was 4 months (95% CI 3.1–4.6),and median survival 6.4 months (95% CI 4.6–10). To date,there have been 36 deaths. Four were treatment-related (oneinfection, two myocardial infarctions, one respiratory failure),and all occurred before the capecitabine dose reduction. Notablegrade 4 events from the entire cohort included diarrhea (twopatients), vomiting (three), dyspnea (one), thrombosis (two)and anorexia (two). Grade 3 events included nausea (12 patients),diarrhea (12), fatigue (10), abdominal pain (seven), vomiting(six), dyspnea (six), hypokalemia (six), dehydration (five),hypokalemia (five) and infection (four). Conclusions: Oxaliplatin and capecitabine in combination demonstratesactivity in metastatic adenocarcinoma of the esophagus, gastroesophagealjunction and gastric cardia. The lower dose (capecitabine 850mg/m² orally twice a day, days 1–14, and oxaliplatin 130mg/m² intravenously on day 1) yielded an acceptable toxicityprofile and merits further study. Key words: chemotherapy, esophageal cancer, metastatic, oral therapy, response rate     

Intensive Chemotherapy with Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide and Granulocyte Colony-stimulating Factor for Advanced Thymona or Thymic Cancer: Preliminary Results

A study was conducted to evaluate the impact of cisplatin, doxorubicin,cyclophosphamide and etoposide (PACE) with granulocyte colony-stimulatingfactor (G-CSF) on advanced thymoma or thymic cancer. BetweenAugust 1989 and December 1994, 14 patients with invasive, metastaticor recurrent thymoma or thymic cancer were treated with cisplatin(80 mg/m², on day 1), doxorubicin (45 mg/m², on day 1), cyclophosphamide(800 mg/m², on day 1) and etoposide (80 mg/m², on day 1–3)with G-CSF (90 mg/m², on day 5–18) at the National CancerCenter Hospital, Tokyo. Courses were repeated every 3 or 4 weeksfor a maximum of 4 cycles. Twelve patients were treated with2 or more courses of PACE. Two patients were treated with onlyone course, one refused and another required emergency thoracicradiotherapy after one course of PACE. Six patients had partialresponses (3 thymomas and 3 thymic cancers) but there were nocomplete remissions (response rates, 42.9%; 95% confidence interval,17.7% to 71.1%). Moderate hematological toxicities were observed:grade 3 or 4 leukopenia, neutropenia, anemia and thrombocytopeniain 10, 13, 8 and 6 patients, respectively. Six patients developedinfections that required antibiotics. Surgical resection orthoracic radiotherapy after PACE treatment was performed in2 and 7 patients, respectively. The overall median survivaltime was 14.7 months (range, 5.9 to 59.7 months). For 9 patientswho had received no prior treatment before chemotherapy, themedian survival time was 8.9 months, and one patient survivedfor 4 years and is still alive. In conclusion, PACE with G-CSFfrequently produces objective remissions in patients with advancedthymoma or thymic cancer. A large-scale intergroup study isnecessary to determine the impact of this regimen on advancedthymoma and thymic cancer.     

Neoadjuvant chemotherapy with carboplatin, ifosfamide, and peplomycin in advanced cervical squamous cell carcinoma

Background. To control advanced cervical squamous cell carcinoma more effectively and more easily, we used neoadjuvant chemotherapy, with three drugs carboplatin, ifosfamide, and peplomycin (PIP), in a study performed from July 1990 to October 1994 in nine Institutions. Methods. Sixty-five patients with untreated, inoperable squamous cell carcinoma of the cervix were treated with carboplatin (300 mg/m² IV; low-dose PIP regimen, or 400 mg/m² IV; high-dose PIP regimen) on day 1, ifosfamide (1000 mg/m², IV) on days 1–3, and peplomycin (5 mg/body, IM) on days 1–6. The low-dose PIP was given between July 1990 and April 1992, and the high-dose PIP from May 1992 to October 1994. Results. Response rates for the low- and high-dose PIP regimens were 42.9% (12/28) and 59.5% (22/37), respectively. Measurable lesions were recognized in the cervix, pelvic lymph node (PeN), paraaortic lymph node (PAN), lung, and supraclavicular lymph node. Response rates in these individual lesions to our low- and high-dose PIP regimens were 35.7% (10/28) and 55.6% (20/36), respectively in the cervical lesion and more than 50% for both regimens in the PeN and PAN metastatic lesions, while the supraclavicular lymph node metastatic lesions responded poorly to both regimens. After low-dose PIP, surgery was performed in 2 patients (2/28; 7.1%), while after high-dose PIP, 12 patients (12/37; 32.4%) underwent surgery. The 3-year survival rate of patients with high-dose PIP was significantly higher than that of those with low-dose PIP (P < 0.01). Conclusions. Neoadjuvant chemotherapy with PIP appears feasible and effective. The link between dosage and treatment response and achievable surgery rate and survival rates suggests that results might be further optimized by considering patients' renal function, and utilizing the Calvert formula for dosing analysis. Received: January 21, 1999 / Accepted: July 28, 1999     

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in pleural mesothelioma

BACKGROUND: In a previous phase II study with a dose-intensive weekly cisplatinschedule for six cycles, we observed a partial response in 5of 14 patients with pleural mesothelioma. However, responseduration was short (median 6 months). Since oral etoposide maytheoretically be synergis-tic to cisplatin, we performed a phaseII study with the combination of both drugs. PATIENTS AND METHODS: Twenty-five chemo-naive patients with pleural mesothelioma weretreated with cisplatin 70 mg/m² days 1–8–15 anddays 29–36–43 in combination with oral etoposide50 mg days 1–15 and days 29–43. Patients with stabledisease, or better, continued treatment with oral etoposide50 mg/m²/day days 1–21 every 28 days. RESULTS: All patients were evaluable for response and toxicity. Completeresponse was observed in one patient and partial responses in5 patients (RR% 24%; 95% Cl: 10%–45%) for a median durationof 30 weeks. Twelve patients had stable disease. The responsestatus never improved during maintenance treatment with oraletoposide. Most patients tolerated the regimen very well. Toxicitywas mainly haema-tologic with leukocytopenia causing treatmentdelays in 8 patients. Ototoxicity grade 1 or 2 was observedin 8 patients, neurotoxicity grade 1 in 9 patients and nephrotoxicitygrade 1 in 1 patient. CONCLUSION: Frequently administered cisplatin in combination with oral etoposidehas a moderate but definite activity in pleural mesothelioma pleural mesothelioma, cisplatin, oral etoposide, dose-intensity     

Concurrent Chemotherapy and Radiation Therapy for Locally Advanced Carcinoma of the Esophagus

A pilot study was undertaken to clarify the efficacy of concurrentchemoradiotherapy against locally advanced esophageal carcinoma.The 20 patients in this study had previously untreated esophagealcarcinoma with evidence of T4 disease and/or distant node metastases.Chemotherapy consisted of protracted infusion of 5-fluorouracilat a dose of 400 mg/m²/day on days 1–5 and 8–12,combined with a 2-h infusion of cisplatinum at 40 mg/m² on days1 and 8. Radiation treatment for the mediastinum was administered5 days per week for 3 wk at 2 Gy/day, along with chemotherapy.These schedules were repeated twice to give a total radiationdose of 60 Gy. For patients who responded, two additional coursesof chemotherapy were administered. Five of the 20 patients hadUICC stage III disease and 15 had stage IV. Seventeen (85%)of the 20 patients exhibited an objective response, including6 (30%) complete responses. Local control was excellent with10 (50%) complete responses. Toxic effects were severe. Majortoxicities were leukocytopenia of grade 3 or more in 45% ofthe patients and esophagitis, including four perforations. Therewere two treatment-related deaths. The median survival timewas 9 mo (range: 2 to 34+). Concurrent chemotherapy and radiotherapywas effective even for locally advanced esophageal carcinoma,but was associated with significant toxicity.     

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: A clinical and pharmacologic analysis

BACKGROUND:: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interactsbiochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU) PATIENTS AND METHODS:: IUdR was added to the previously studied regimen of continuousinfusion 5-FU at 300 mg/ m²/day for 5 days, HU 500 mg every12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days,all administered for 7 consecutive weeks to patients with malignantglioma. IUdR was administered as 5-day continuous intravenousinfusion during weeks 1 and 4. The IUdR dose was changed incohorts of patients. IUdR plasma concentrations were determinedduring weeks 1 and 4, and IUdR incorporation into the DNA ofgranulocytes was measured on weeks 2 and 5. RESULTS:: Two patients treated at the initial IUdR dose of 500 mg/m²/daydeveloped grade 3 or 4 myelosuppression and mucositis. Additionaldose levels of IUdR tested were 250 mg/m²/day and 125 mg/m²/day;at the latter dose, severe or life-threatening toxicity wasseen in only 3 of 8 patients treated. IUdR incorporation intoDNA of granulocytes was 10.5(± 2.3)% at an IUdR doseof 500 mg/mVday but decreased to 0.76(± 0.3)% at 125mg/m²/day. Similarly, lUdR plasma concentrations decreased from436 (± 114) ng/ml to 99(±29)ng/ml. CONCLUSIONS:: The addition of IUdR to 5-FU and HU results in significant systemictoxicity necessitating limitation of the IUdR dose to 125 mg/m²/day. There is a significant biochemical interaction betweenIUdR, 5-FU and HU leading to increased IUdR incorporation intoDNA and to substantial clinical toxicity. Further clinical studiesto exploit this interaction at more feasible schedules may beuseful. malignant gliomas, concomitant chemoradiotherapy, IUdR, fluorouracil, hydroxyurea     

A Case of Advanced Gastric Cancer Complicated by Severe Toxicity Induced by a Combination of Tegafur, Uracil and Mitomycin C, and Associated with Abnormal Pharmacokinetics

A 60-year-old female patient with gastric cancer and lymph nodeand liver metastases was treated with a combination of tegafurand uracil (UFT) (375 mg/m²/day) and mitomycin C (MMC) (5 mg/m²once weekly). On day 15, when diarrhea appeared, chemotherapywas stopped immediately. On day 21, the WBC decreased to 900/µland high fever developed. Despite treatment with granulocytecolony-stimulating factor and antibiotics, leukopenia persistedand the patient went into septic shock on day 26. On day 34,WBC increased to 5,400/µl and she recovered, with reductionin the size of the lymph node and liver metastases. Pharmacokineticexamination after intravenous injection of low-dose MMC (0.5mg/m²) showed a markedly high peak plasma concentration (PPC),a large area under the time-versus-concentration curve (AUC)and reduced clearance. Similarly, oral administration of UFT(tegafur 300 mg/body) produced a relatively higher PPC and alarger AUC of 5-fluorouracil (FU). The activity of dihydropyrimidinedehydrogenase, the rate-limiting enzyme in the metabolism ofFU, in peripheral mononuclear cells was within the normal range(0.265 nmol/min/mg). MMC is believed to have played a largepart in inducing the severe toxicity observed in this patient.Physicians should be aware of the possibility of severe toxicityduring treatment with UFT and MMC, although details of its incidenceand mechanism are unclear.     

Phase II study of a closely spaced ifosfamide--cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma

BACKGROUND:: Ifosfamide and cisplatin are frequently combined cytotoxic agents.Both have a dose-response relationship. In view of this it appearsattractive to study regimens with a higher dose intensity thanusual. One way to increase the dose intensity is to shortenintervals between chemotherapy cycles. As bone marrow toxicityis dose limiting in ifosfamide-cisplatin combinations we starteda phase II study with both drugs administered every 2 weeksin combination with G-CSF. PATIENTS AND METHODS:: Patients with advanced non-small-cell lung cancer or malignantmelanoma were eligible for the study. The treatment consistedof ifosfamide 2 gram/m²/day days 1–3 combined with mesna,and cisplatin 33 mg/m²/day days 1–3, administered in hypertonicsaline (3% NaCl). G-CSF was started on day 4 at a dose of 5µg/kg/day and was continued until day 12. The cycles wereto be repeated every 2 weeks for a maximum of 6 cycles. RESULTS:: Thirty-two patients were entered in the study; 30 patients wereevaluable for response and toxicity. Neutropenia (grade 4 in16 patients) and thrombocytopenia (grade 4 in 15 patients) werethe most common toxicities. Thrombocytopenia incidence and -durationincreased per cycle and was the main cause of treatment delaysespecially after the third cycle. Only 4 patients were ableto complete the planned treatment without any delay or dosereduction and reached the intended dose intensity of 3 gram/m²/weekof ifosfamide and 50 mg/m²/week of cisplatin. Non haematologictoxicities were generally mild. Out of 22 evaluable patientswith non-small cell lung cancer 6 responded (27%; 95% CI: 10%–48%)while only one out of 8 patients with melanoma responded. Themedian response duration was 26 weeks (range 16–36 weeks). CONCLUSION:: The planned high-dose intensity of ifosfamide and cisplatincould be reached only for the first 2–3 cycles. Haematologictoxicity, especially cumulative thrombocytopenia, necessitatedtreatment delays jeopardizing the dose intensity. The responserate in non-small-cell lung cancer and melanoma was not superiorto what can be expected from more conventional regimens. cisplatin, G-CSF, ifosfamide, phase II study     

Phase I/II trial of filgrastim (r-metHuG-CSF), CEOP chemotherapy and antiretroviral therapy in HIV-related non-Hodgkin's lymphoma

BACKGROUND:: A phase I/II trial determined the maximum tolerated dose (MTD)of CEOP for AIDS-related non-Hodgkin's lymphoma (NHL) with concurrentfilgrastim and antiretroviral therapy. PATIENTS AND METHODS:: Fourteen AIDS-NHL patients, chemotherapy-naïve and ECOGperformance status >2 received filgrastim 1.0 µg/kgs.c. daily for 3–7 days to assess neutrophil response,followed by CEOP with filgrastim support 10 µg/kg s.c.daily, day 2–14, continued if the absolute neutrophilcount (ANC) <1.2 x 10⁹/l. Two CEOP dose cohorts were used:cohort 1 (5 patients) - cyclophospharnide (C) 500 mg/m², epirubicin(E) 37.5 mg/m², vincristine (O) 2 mg and prednisolone (P) 75mg/m² daily on days 1–5; cohort 2 (9 patients) - C 750mg/m², E 50 mg/m², same doses of O and P. Antiretroviral therapywas maintained (zidovudine-10, ddI-3, both-1). RESULTS:: In cohort 1, 4/5 patients received at least 3 courses of CEOPwith one complete response after five cycles and four progressions.Four have died (3–21 months after entry) with 1 aliveat 40 months. Dose limiting toxicity (DLT - grade IV febrileneutropenia in cycle 1) occurred in 1 patient. In cohort 2,5/9 completed 5 cycles with 6 complete responses, 1 partialresponse and 2 progressions, 6 deaths and 3 alive at 33 months.DLT (evaluable in 8 patients) occurred in two patients. Mediansurvival for both cohorts was 17 months. Mean relative doseintensity was >85%. CONCLUSIONS:: The dosages of CEOP in cohort 1 defined the MTD however thecohort 2 doses with filgrastim and antiretroviral therapy gavean encouraging response, acceptable toxicities and merit furtherstudy. AIDS, antineoplastic agents, antiretroviral therapy, G-CSF, non-Hodgkin's lymphoma     

A phase I investigation of the sequential use of methotrexate and paclitaxel with and without G-CSF for the treatment of solid tumors

BACKGROUND: Paclitaxel is a novel agent with significant activity in severalsolid tumors. Preclinical data suggested that methotrexate priorto pacitaxel would be synergistic. To determine the qualitativeand quantitative toxicity of this regimen we performed a phaseI study in patients with solid tumors. PATIENTS AND METHODS: Patients with solid tumors previously treated with no more thantwo prior chemotherapy regimens were given methotrexate intravenouslyon day 1, followed by pacitaxel, as a 24-hour infusion on day2. The starting dose (level ‘0’) was 40 mg/m formethotrexate and 135 mg/m for paditaxel. RESULTS: After achieving a maximum tolerated dose, additional patientswere enrolled with the addition of G-CSF 5 µg/kg/d ondays 4–13. At the starting dose level, dose-limit ingtoxicity consisting of neutropenic fever occurred in 3 of 4patients. At dose level–1, methotrexate 30 mg/m² and paclitaxel110 mg/m² neutropenic fever occurred in 7 of 10 patients duringthe first course. At dose level–2, methotrexate 23 mg/m²and paclitaxel 85 mg/m² neutropenic fever occurred in 1 of 7patients. To abrogate the neutropenia we explored the same combinationwith the addition of G-CSF. Neutropenic fever remained the onlydose-limiting toxicity. At dose level ‘0’ with G-CSF,1 of 7 patients developed doselimiting toxicity. At dose level1 plus G—CSF, methotrexate 40 mg/m² and pacitaxel 170mg/m² dose-limiting neutropenic fever occurred in 4 of 6 patients.Partial responses occurred in 4 of 41 patients entered on thisstudy. Pharmacokinetic data suggested that methotrexate didnot increase pacitaxel levels. CONCLUSION: The combination of methotrexate and paci taxel is feasible,but neutropenic fever, even with the addition of G—CSFprevents further escalations of paclitaxel beyond 135 mg/m²following methotrexate. phase I, methotrexate, paclitaxel, solid tumors     

Effectiveness of doxifluridine (5′-DFUR)/docetaxel against advanced/recurrent gastric cancer showing resistance to various anticancer drug regimens

A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy, as well as D3 dissection, and received postoperative chemotherapy combining oral uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of multiple abdominal lymph node metastases around the aorta. He therefore received various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil); however, final results showed growth of lymph node metastasis and simultaneous worsening of his general condition. The patient then received combined administration of doxifluridine (5′-DFUR)/docetaxel (5′-DFUR, 1000 mg/body [666.7 mg/m ² ], given by consecutive daily administration, orally, for days 1–14; and docetaxel, 80 mg/body [60 mg/m ² ], on day 8, by venous drip, every 3 weeks). Three courses of this regimen resulted in approximately 90% reduction of the abdominal lymph node size, disappearance of the right cervical lymph node metastasis, reductions of the levels of two tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general condition. In total, seven courses of the regimen were carried out. The patient died on day 298 after starting this combined regimen and showed a response period of 126 days. The primary toxicity identified was neutropenia (grade 4), as well as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In the field of gastric cancer treatment, especially for patients showing multiple resistance to anticancer drugs, an effective therapy is critically needed. Received: January 15, 2002 / Accepted: July 8, 2002 Offprint requests to: A. Sato     

Myelo-ablative therapy with peripheral blood progenitor cell (PBPC support in patients with haematological malignancy

BACKGROUND: Myelo-ablative therapy with peripheral blood progenitor cell(PBPC) support is increasingly being used in patients with haematologicalmalignancy considered to be at high risk for recurrence. Theresults of this approach, in comparison with the previous experienceat St. Bartholomew's Hospital (SBH) using autologous bone marrowtransplantation form the basis of this report. PATIENTS AND METHODS: 42 patients (age range 18–63 years, median 42 years),deemed to have a poor prognosis with conventional therapy receivedmyelo-ablative therapy with PBPC support. Diagnoses comprised:non-Hodgkin's lymphoma (NHL): 16 patients, Hodgkin's disease(HD): 9, Multiple Myeloma (MM): 12, and solid tumours (ST):5. PBPC were mobilised using adriamycin: 35 mg/m² i.v. on day1 and etoposide 100 mg/m² orally, days 1–5, followed byG-CSF: 5 ng/kg, subcutaneously, for a median of 7 days (range6–9 days). RESULTS: A total of 67 PBPC collections were performed, 1 being ‘sufficient’(i.e. mononuclear cells > 1.5x10⁸/g and CD34+ cells >1x10⁶/kg)in 21 of the 42 patients. The median time to haematologicalrecovery following reinfusion of PBPC was 13 days for both neutrophils>0.5x10⁹/I and platelets >20x10⁹/I (ranges: 8–27,and 8–48 days, respectively) which is significantly shorterthan for patients in the historical control group. Supportivecare requirements were also significantly reduced, as was theduration of hospital stay i.e., median 19 days (range 12–73days) compared with 29 days (range 9–180 days). CONCLUSION: These results confirm rapid blood count recovery following myelo-ablativetherapy with PBPC support and the feasibility of this approach. myelo-ablative therapy, peripheral blood progenitor cells, haematological malignancy     

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors

BACKGROUND: In a previous phase I study we showed that single-agent cisplatincan be given weekly for six weeks at a dose of 80 mg/m²/wk.It has been suggested that etoposide has synergistic activitywith cisplatin and the drug can be given orally continuously.We therefore performed a phase I study with weekly cisplatincombined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were enteredin the study. Cisplatin was administered in hypertonic saline(NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m²for six weeks combined with daily oral etoposide at a dose of50 mg. At the maximum tolerable dose of cisplatin 75 mg/m²/wkand etoposide 50 mg/m² daily, leukocytopenia and thrombocytopeniawere dose-limiting toxic effects which resulted in frequenttreatment delays. Other toxicities were mild. Finally, a doseof cisplatin 70 mg/m²/wk weeks 1–2–3 and weeks 5–6–7in combination with etoposide 50 mg orally days 1–15 anddays 29–43 combined a high median cisplatin dose intensityof 52.5 mg/m²/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combinationwith oral etoposide. Leuko-cytopenia and thrombocytopenia aredose-limiting toxicities. The schedule will be explored furtherin phase n studies. phase I, cisplatin, etoposide, dose intensity     

Mitomycin C plus vindesine plus etoposide (MEV) versus mitomycin C plus vindesine plus cisplatin (MVP) in stage IV non-small-cell lung cancer: A phase III multicentre randomised trial

PURPOSE:: To compare mitomycin C plus vindesine plus etoposide (MEV) vs.mitomycin C plus vindesine plus cisplatin (MVP) in the treatmentof stage IV non-small-cell lung cancer. PATIENTS AND METHODS:: 204 patients were entered in a phase III multicentre randomisedtrial from June 1990 to December 1994 and stratified accordingto the ECOG performance status (0–1 vs. 2). MVP was givenin the following dosages: mitomycin C 8 mg/m² + vindesine 3mg/m² + cisplatin 100 mg/m² i.v. day 1 and vindesine 3 mg/m²i.v. day 8 with cycles repeated every 4 weeks. MEV was givenin the following dosages: mitomycin C 8 mg/m² + vindesine 3mg/m² i.v. day 1 and etoposide 100 mg/m² i.v. days 1 to 3 withcycles repeated every 3 weeks. For both treatments a maximumof 6 cycles was planned. Response and toxicity were evaluatedaccording to WHO. Subjective responses were assessed by numericalscales. Analyses were made on the basis of intent to treat. RESULTS:: The objective response rate was 21.4% (1 CR + 21 PR among 103patients) in the MEV and 28.7% (1 CR + 28 PR among 101 patients)in the MVP arm (P=0.48). Symptoms were similar in the two arms.196 patients progressed and 182 died. The median times to progressionwere 10 weeks (95% CI 9–12) and 12 weeks (95% CI 10–15)and median survivals were 29 weeks (95% CI 25–36) and28 weeks (95% CI 25–35) in the MEV and MVP arms, respectively.The relative risks of progressing and of dying were 0.89 (95%CL 0.66–1.20) and 0.96 CL 0.71–1.30), respectively,for patients receiving MVP as compared with those receivingMEV at multivariate analysis adjusted by sex, age, histologictype, number of metastatic sites, performance status at entry,and centre. CONCLUSIONS:: In the present study, no significant dfferences were observedin response rate, survival or palliation of symptoms betweenthe MEV and MVP regimens, while toxicity was significantly morefrequent and severe with MVP. Thus, MEV should be considereda reasonable alternative to the MVP regimen in the treatmentof stage IV NSCLC. chemotherapy, non-cisplatin-containing, regimen, stage IV NSCLC     

Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck

Purpose The aim of this study was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), methotrexate (MTX) and leucovorin (LV) (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods Seventy-seven patients with previously untreated stages III–IV SCCHN were included in this trial. Patients received two cycles of chemotherapy repeated every 4 weeks. The chemotherapy regimen consisted CDDP (60 mg/m², day 4), 5-FU (600 mg/m² given over 24 h for 5 days, days 1–5), MTX (30 mg/m², day 1) and LV (20 mg/m², days 1–5). Radiation was targeted to begin on the starting day of chemotherapy, day 1. The total radiation dose to the primary site and neck lymph nodes was 70.0 Gy. When grade ≥3 toxicities were observed frequently, radiotherapy and/or chemotherapy were delayed or reduced. Results The main toxicities were mucositis (grade ≥3, 39%), leukocytopenia (grade ≥3, 34%) and neutropenia (grade ≥3, 30%). The overall clinical response rate and the pathological complete response (CR) were 94% (72/77) and 71% (55/77). The primary site CR and neck lymph node CR were 79% (61/77) and 85% (44/52), and 3-year survival rate was 73%. Conclusions This concurrent chemoradiotherapy with PFML was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in locally advanced SCCHN patients.     

Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer

BACKGROUND:: FAMTX (5-fluorouracil, adriamycin, methotrexate) is one of themost effective drug combinations in gastric cancer. Therefore,modifications of FAMTX appear of interest and the FEMTX-P regimentwas conceived. PATIENTS AND METHODS:: Fifty patients with unresectable locally advanced and/or metastaticgastric carcinoma were treated with methotrexate 1500 mg/m²i.v. and 5-fluorouracil 1500 mg/m² i.v. on day 1; leucovorinrescue 15 mg/m² orally every 6 hours for 8 doses on days 2 and3; epirubicin 60 mg/ m² i.v. and cisplatin 50 mg/m² i.v. onday 15, q 4 weeks. RESULTS:: Of forty-seven patients evaluable for response, five (11%) achievedcomplete responses and seventeen (36%) partial responses (totalresponse rate 47%). The median duration of response was 8+ months(range: 5–25+ months). Four of 14 patients with locallyadvanced disease were successfully downstaged and subsequentlyresected. The median duration of survival of all patients was10 months (range: 1–25+ months). Leukopenia grade 4 occurredin 18% of patients and thrombocytopenia grade 4 and mucositisgrade 4 in 4% and 2%, respectively. Treatment postponement forhematologic toxicity was necessary in 54% of patients. CONCLUSIONS:: The FEMTX-P regimen is an active regimen in advanced gastriccarcinoma, with acceptable toxicity. chemotherapy, FEMTX-P, gastric cancer