A recurrent ovarian cancer patient who achieved a complete response following irinotecan plus CDDP therapy

A 78-year-old patient had abdominal bloating since October 2002, and visited a GP, who noticed ascites, and referred the patient to our hospital. An exploratory laparotomy was performed and stage IIIc ovarian cancer was diagnosed. Six courses of docetaxel-carboplatin (DJ) chemotherapy were administered; however, the lesion was assessed as progressive disease (PD), and 24 courses of weekly paclitaxel were then administered. During the follow-up as an outpatient, a tumor marker increased again. Weekly paclitaxel was not effective this time, and the lesion was assessed as PD. The patient therefore received treatment with irinotecan and cisplatin (CPT-11+CDDP). These drugs have different mechanisms of action. The CA 125 level returned to normal following four courses of CPT-11+CDDP. The patient received a total of six courses, and thus far, no obvious recurrent lesion has been observed. These results suggest that CPT-11+CDDP may be effective against recurrent ovarian cancer, which is difficult to treat due to its resistance to platinum drugs and taxane drugs.     

A case of recurrent sigmoid colon cancer successfully treated with 5-FU and UFT

A 57-year-old female patient with recurrent sigmoid colon cancer was successfully treated with 5-FU and UFT for 8 years. The patient, with cancer recurrence in the para-aortic lymph nodes, which were palpated in the abdomen, was given oral 5-FU at a daily dose of 200 mg. During the second week of administration, the mass showed a remarkable decrease in size, and complete disappearance was achieved within one month. However, 5 years and 2 months after discontinuation of 5-FU administration, recurrence in the supra-clavicular lymph nodes and para-aortic lymph nodes was recognized. After administration of UFT at a daily dose of 600 mg, complete disappearance of para-aortic lymph node recurrence was observed. At present, the patient is under observation as an outpatient at our hospital. This case suggests the effectiveness of 5-FU and UFT for lymph node metastases of sigmoid colon cancer.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

Oxaliplatin and UFT combination chemotherapy in patients with metastatic colorectal cancer

A phase II study was performed to evaluate the clinical efficacy and toxicity of oxaliplatin combined with uracil and tegafur (UFT) in patients with advanced colorectal cancer previously treated with a fluoropyrimidine-based regimen. From January to December 1999, 34 patients were enrolled in this study. Patients received intravenous oxaliplatin 130 mg/m2 on day 1 and daily oral UFT 350 mg/m2 in 3 divided doses for 21 days and repeated every 21 days. Thirty-one of 34 patients were assessable for response and 32 patients for toxicity. Partial response was observed in four patients and stable disease in six patients. The response rate was 12.9% (95% CI, 3.6-29.8%) and median duration of response was 17 weeks. The median overall survival and progression-free survival of all patients were 26 weeks (range, 3-90+ weeks) and 9 weeks (range, 3-56 weeks), respectively. Sensory neuropathy was the most common toxicity, but there was no severe toxicity (>grade II) except for a case of grade III neutropenia. We conclude that oxaliplatin and UFT combination chemotherapy was well tolerated without significant toxicities. The results of this trial will serve as the basis for designing new clinical trials with a different dose or schedule.     

UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.     

Two cases with a long-term survival following multidisciplinary treatment for recurrent breast cancer after surgery

Recurrent breast cancer (BC) tends to show an aggressive behavior and the number of cases of long-term survival is limited. Two rare cases of recurrent breast cancer were treated with a multidisciplinary approach. The outcome of the two cases indicated an excellent survival period of more than 13 years after recurrence. These findings suggest that patients who experience a recurrence after tumor resection have a chance of achieving long-term survival when treated with aggressive therapy, even in the presence of extensive metastases involving multiple organs.     

Two patients with ovarian cancer refractory to cisplatin-based chemotherapy managed by a new combination chemotherapy with irinotecan hydrochloride and mitomycin-C

Two women with ovarian cancer refractory to cisplatin-based chemotherapy were managed by a new combination chemotherapy consisting of 2 courses of irinotecan hydrochloride and mitomycin-C (CPT-M therapy). One course of therapy consisted of irinotecan hydrochloride (100 mg/m²) and mitomycin-C (5 mg/m²) given 3 times at 2-week intervals. The second course was started 4 weeks after completion of the first course. Treatment effects, as well as disease conditions, were evaluated with imaging studies and by serially monitoring serum carcinoembryonic antigen or carbohydrate antigen-125 levels. The first patient was a 61-year-old woman who underwent surgery for stage IIIc mucinous cystadenocarcinoma, and whose residual tumor in the retroperitoneal lymph nodes after surgery did not respond to 2 types of cisplatin-based chemotherapy. The second patient was a 47-year-old woman treated for stage IIIc serous cystadenocarcinoma, whose multiple liver metastases failed to respond either to combination chemotherapy with irinotecan hydrochloride and cisplatin, or to transcatheter arterial chemoembolization, CPT-M therapy showed some usefulness for ovarian cancer refractory to cisplatin-based chemotherapy when used as third-line chemotherapy in these 2 patients who achieved partial responses with tolerable toxicities, although the duration of the response was short. Further studies on the effectiveness of the CPT-M therapy, including dose escalation, are needed.     

in vitro synergistic antitumor activity of a combination of 5-fluorouracil and irinotecan in human colon cancer

The combination of irinotecan and a fluoro-pyrimidine is widely accepted as a treatment for advanced colorectal cancer. However, evaluable data on the feasibility of these combinations has not been presented, and an optimal sequence for administration has not been experimentally and clinically determined. The sequential effect of a combination of 5-FU and CPT-11 in the human colon cancer cell line LoVo was evaluated by WST-8 colorimetric assay. The cytotoxicity and cell cycle distributions of each drug were analyzed by apoptosis assay and flow cytometry. Further, the potential mechanisms of the sequence-dependent effects were investigated by a microarray technique, and confirmed by Western blot analysis. The cytotoxicity of 5-FU (10, 100, 1000 microM) followed by CPT-11 (1 microM) was significantly greater than that of CPT-11 (1 microM) followed by 5-FU (10, 100, 1000 microM) (p<0.05). In cell cycle distribution, 5-FU exposure for 24 h increased the S phase fraction in a dose-dependent manner; though there was no significant difference in cell cycle distribution in 24 h CPT-11 (0.01-1 microM) exposure. Microarray analysis revealed that expressions of some apoptosis related genes such as Bcl-2 changed, and were correlated with sequence-dependent cytotoxicity of the 5-FU --> CPT-11 sequence. Western blot analysis confirmed that the Bcl-2/Bax ratio was lower after 5-FU --> CPT-11 sequence than before. The sequence-dependent cytotoxic effect may depend on the sensitizing effect of 5-FU pretreatment on CPT-11 cytotoxicity. 5-FU followed by CPT-11 administration may be an optimal sequence for IFL treatment of advanced colon cancer.     

化疗后再使用EGFR-TKI治疗晚期非小细胞肺癌的临床研究

  目的  表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)虽疗效显著,且安全性好,但最终都会发生耐药。EGFR-TKI耐药机制复杂,应对困难,本研究旨在探讨EGFR-TKI治疗晚期NSCLC获得性耐药的患者,化疗后再次应用EGFR-TKI的疗效。  方法  前瞻性对EGFR-TKI治疗晚期NSCLC长期获益后获得性耐药的27例患者,先化疗,后再次应用EGFR-TKI治疗,吉非替尼250 mg qd或厄洛替尼150 mg qd至疾病进展;依据RECIST标准评价疗效,比较再使用原EGFR-TKI与另一种EGFR-TKI的疗效。  结果  27例患者全为晚期肺腺癌,完全缓解(CR)为1例(3.7%)、部分缓解(PR)为8例(29.6%)、稳定(SD)为14例(51.9%)、进展(PD)为4例(14.8%),有效率(RR)为33.3%,疾病控制率(DCR)为85.2% (95% CI为62~94),mPFS为6个月。13例再用原EGFR-TKI (同药组) CR为1例(7.6%),PR为2例(15.4%)、SD为8例(61.5%),RR为23%,PD为2例(15.4%),DCR为86.4%,其mPFS为5个月;14例再用另一种EGFR-TKI (换药组) CR为0例,PR为6例(42.8%),SD为6例(42.8%),进展为2例(14.3%),RR为42.8%,其mPFS为9.5个月,DCR为85.7%,两组DCR比较无显著性差异(P>0.05),两组的mPFS比较有显著性差异(P < 0.05);mPFS换药组明显长于同药组。  结论  EGFR-TKI治疗晚期NSCLC长期获益后获得性耐药的患者,先化疗、后再次应用EGFR-TKI,大部分患者仍能取得一定疗效。      

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant di     

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy

Purpose The efficacy and safety of a combined regimen of topotecan and etoposide was tested in patients with relapsed or refractory small-cell lung cancer. Patients and methods From October 2003 to May 2005, 23 patients who have failed to the previous irinotecan and platinum chemotherapy received intravenous topotecan 1 mg/m² (day 1–5) and etoposide 80 mg/m² (day 1–3). Treatment was repeated every 21 days for a maximum of 6 cycles. Results Twelve patients were refractory to first-line chemotherapy. Seventeen patients (73.9%) were male and the median age was 63 years. ECOG performance status was 0–1 in 13 (56.5%) patients. The median cycles of chemotherapy was three. Twenty-one patients were assessable for response evaluation. The overall response rate was 17.4% (0 CR, 4 PR, 7 SD, 10 PD) under the intent-to-treat analysis. Two sensitive case patients and two refractory case patients achieved partial response. After a median follow-up of 20.8 months, median progression free survival was 4.7 months and median overall survival was 9.5 months. The estimated 1-year survival rate was 38.7%. All patients were assessable for toxicity and major toxicities were myelosuppression. Grade 3/4 neutropenia and thrombocytopenia occurred in 18 (78.3%) and 12 (52.2%) patients, respectively. Grade 3/4 febrile neutropenia occurred in two patients (8.7%) and infection in three patients (13.0%). There was one treatment-related death due to pneumonia. Conclusion This salvage regimen showed modest efficacy and manageable toxicities. Further study will be required in recurrent SCLC patients pretreated irinotecan and platinum.     

Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma

The prognosis for patients with recurrent malignant glioma is poor. Both temozolomide and irinotecan have been shown to be active in this disease. A study was performed combining temozolomide 200 mg/m2 daily for 5 days and irinotecan 125 mg/m2 on days 6, 13, and 20 initially (Schedule A) and then changed to (Schedule B) temozolomide 200 mg/m2 daily for 5 days and irinotecan 350 mg/m2 on day 6. Each cycle was 28 days. All patients with recurrent tumor had to complete two cycles of therapy to be evaluable. Six cycles of treatment were provided for all responders. Thirty-two patients were treated, 6 with schedule A, 24 with schedule B, and 2 initially schedule A and then switched to schedule B. Eighteen patients (56%) had glioblastoma and 14 patients and anaplastic glioma (AOA 8, anaplastic astrocytoma 4, AO 2). Eighty-three percent (15/18) of patients with glioblastoma responded (complete response [CR] 2, partial response [PR] 3, stable disease [SD] 10). Median duration of response was 24 weeks, and 6-month progression-free survival (PFS) was 39% (7/18). Fourteen patients with anaplastic glioma were treated and all responded (CR 3, PR 2, SD 9). Median duration of response was 29 weeks and 6-month PFS was 71% (10/14). Grade IV leukopenia occurred in one patient and grade IV thrombocytopenia in two patients. Two patients were admitted to the hospital for neutropenic fever. Nonhematologic toxicity was mild and mostly gastrointestinal. These results demonstrate a favorable response and low toxicity with combined irinotecan and temozolomide therapy and warrant further clinical evaluation.