Palliative chemo-radiotherapy for abdominal recurrence of esophageal carcinoma--case report

A 71-year-old man with stage IV esophageal carcinoma was treated by chemo-radiotherapy (5-FU 500 mg/day + CDDP 10 mg/day for 4 weeks and 67.6 Gy of RT). The esophageal tumor showed a complete response to the treatment. Six months later, he had obstructive jaundice due to an abdominal recurrent mass. A secondary (palliative) CRT was performed (5-FU 500 mg/day + CDDP 10 mg/day for 3 weeks and 45 Gy of RT). The abdominal tumor became remarkably smaller and jaundice disappeared. Though the patient died from pulmonary carcinomatous lymphangitis, the primary lesion showed CR. CRT was very effective for local treatment and for palliative therapy.     

Cost effectiveness of chemoradiotherapy with cisplatin/fluorouracil and nedaplatin/fluorouracil for patients with esophageal cancer

OBJECTIVE: To assess the cost-effectiveness of chemoradiotherapy (CRT) regimens for patients with esophageal cancer, we compared two regimens consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) or 5-FU and nedaplatin (CDGP) with radiotherapy. METHODS: Medical records of 108 patients with esophageal cancer who received CRT of 5-FU+CDDP (CDDP group) or 5-FU+CDGP (CDGP group) were analyzed. In both groups, most of the patients were men with a pathological diagnosis of squamous cell carcinoma. A Markov model was used to show the clinical courses of esophageal cancer after the CRT therapy. An outcome used for economic evaluation was life year gained (LYG). We calculated the cost per-effectiveness ratio (CER) and incremental cost effectiveness ratio (ICER). Clinical effectiveness and costs in this model were investigated retrospectively, and the costs were estimated from the perspective of the medical institution. Sensitivity analysis was used to check the robustness of this model. RESULTS: In CDDP and CDGP group, LYG was 18.23 and 16.31 years and CER was 270,373 and 406,264 yen/LYG, respectively. As a result, ICER was .883,999 yen/LYG. The sensitivity analysis showed that this model was definitely robust. CONCLUSION: Our results suggested that CDDP could prolong LYG with less cost than CDGP and that CRT of 5-FU and CDDP was markedly cost effective treatment.     

A successful resected case of advanced esophageal cancer with early gastric cancer responding to neoadjuvant chemotherapy of docetaxel, CDDP and 5-FU

A 72-year-old male with a chief complaint of dysphagia was admitted to our hospital. Upper gastrointestinal endoscopic examination showed double cancers with thoracic esophageal cancer in the middle esophagus and gastric cancer in the antrum. Pathological examinations of the double cancer revealed the first one to be moderately-differentiated squamous cell carcinoma and the second to be well-differentiated adenocarcinoma. Computed tomography (CT) of the chest and abdomen showed no distant or lymph node metastases. Clinical stagings of the double cancer were stage II (T2N0M0)in esophageal cancer and stage I A (T1N0M0) in gastric cancer. The patient received neoadjuvant chemotherapy using docetaxel, CDDP and 5-FU. After 2 courses of chemotherapy, the adverse event was grade 2 in leucopenia and grade 2 in alopecia. Repeated macroscopic and histological examinations after chemotherapy revealed that the esophageal cancer had significant reductions in the size of tumors, leading to a partial response, and the gastric cancer had disappeared, leading to a complete response. He underwent thoracoscopy-assisted esophagectomy in the prone position, and laparoscopy-assisted gastric tube reconstruction. This neoadjuvant chemotherapy of docetaxel, CDDP and 5-FU might be effective and tolerable as with patients with double cancer of esophageal and gastric cancers.     

A case of nonresectable scirrhous type gastric cancer successfully treated by low-dose cisplatin (CDDP), 5-fluorouracil (5-FU) and pirarubicin (THP)

There have been few effective chemotherapeutic regimens for scirrhous type gastric cancer. Recently, the usefulness of combined cancer agent chemotherapy based on the concept of biochemical modulation has been reported. For example sequential MTX and 5-FU therapy, low-dose CDDP plus 5-FU, and the like. In this paper, we report the usefulness of low-dose CDDP plus 5-FU therapy in combination with pirarubicin (THP) for inoperable scirrhous type gastric cancer. A 32-year-old man who was suffering from scirrhous type gastric cancer with pyloric stenosis was treated with this regimen. Eight weeks after the start of therapy, his gastric capacity and lumen diameter had clearly increased, and he was taking ordinary meals. Ascites had also completely disappeared. CR has now been continued about 7 months. This regimen is considered to be promising for scirrhous type gastric cancers with a poor prognosis.     

Successful management of the recurrent esophageal cancer following esophagectomy at a different time with combined local treatment of chemoradiotherapy and hepatic arterial infusion chemotherapy

A 63-year-old man who underwent radical resection for esophageal cancer (cStage III)was diagnosed with metastasis of the paraaortic lymph node 5 months after the surgery. He was treated with concomitant chemoradiotherapy (CRT)with low-dose FP(5-FU, CDDP)and 60 Gy of irradiation. The effect of CRT was a complete response. Seven months later, there was a metastasis to the liver(S4). He received systemic chemotherapy(5-FU, ADR, CDDP: FAP), but it was not effective, so hepatic arterial infusion chemotherapy(FAP)was performed. Hepatic artery infusion therapy( 5-FU 1,000 mg/3.5 h x ADR 10 mg/1 h x CDDP 10 mg/1 h)was given for 1 day at an interval of 2 weeks for 18 months. Since ADR reached the maximum dose, hepatic artery infusion of 5-FU(1,000 mg/3.5 h)and CDDP(10 mg/ 1 h)was continued for 14 months at an interval of 4 weeks. The recurrent lesion disappeared completely 9 months after beginning hepatic artery infusion therapy. The patient is alive 69 months after surgery without any evidence of recurrence. Most cases with recurrent esophageal cancer have multiple metastases, and the treatment is mainly systemic therapy. However, in a patient with recurrent tumors at different times, it is possible to achieve a complete response and long-time survival by local treatment with fewer side effects as in this case. Combined local treatments could be the second treatment option after failed systemic chemotherapy for recurrent tumors in patients with esophageal cancer. Further investigations are necessary.     

Chemoradiotherapy with low-dose cisplatin and 5-FU for advanced esophageal cancer

We evaluated the efficacy of chemoradiotherapy (CRT) for advanced esophageal cancer, from the view point of response. The relationship between chemo-radiosensitivity and dihydropyridine dehydrogenase (DPD), thymidylate synthase (TS), and p53 was investigated immunohistochemically. Thirteen patients with inoperable advanced esophageal cancer were involved in this study. CDDP of 10 mg/m2/day and 5-FU of 335 mg/m2/day were infused intravenously (day 1-5, day 15-19). Radiation was delivered concomitantly at a total dose of 30 Gy. Expressions of p53, DPD and TS were detected using immunohistology in the biopsy samples taken before CRT from 8 patients. Partial response was observed in 8 cases, no change in 4 cases, and progressive disease in one case. The overall response rate was 62%. The reduction rate was higher in tumors positive for p53 expression than in negative ones. The same was true for DPD and TS. The Treatment effect was more precisely predicted by combination of p53, DPD and TS. CRT with low-dose CDDP + 5-FU chemotherapy was effective and combination with p53, DPD, and TS might be a predictive marker for CRT in patients with advanced esophageal cancer.     

A difficult case of esophageal and gastric double cancer with pleural and pericardial effusion following chemo-radiotherapy (CRT)

A 70-year-old man was presented with esophageal and gastric cancer pointed by his personal doctor in November 2002. Both of the esophageal and gastric cancer were diagnosed as multiples with cStage II and cStage IA, respectively. In consideration of the patient's quality of life (QOL), chemo-radiotherapy (CRT) for esophageal cancer was preceded, and then total gastrectomy was done. Although esophageal cancer was responded as being complete response (CR), 14 courses of FP therapy were added as supportive chemotherapy. Ten months following CRT, pericardial effusion was noticed, so that pericardiocentesis was performed. Also diuretic has been administered up to the present. Nineteen months following CRT, pleural effusion was noticed and thoracentesis was performed several times into both of the pleural cavities, and that was depending on the degree with OK-432 infusion. Consequently, the patient has been controlled well. As a treatment for esophageal and gastric double cancer, we chose CRT rather than esophagectomy because of the excessive invasiveness. Despite of CR, we have had a difficulty with pleural and pericardial effusions due to the late toxicity of radiotherapy. We need to pay attention to the late toxicity in the case of long-term survival following CRT.     

Long-term results of chemoradiation therapy for the patients with locally advanced (T4) esophageal cancer

The prognosis of patients with advanced esophageal cancer is still poor. Recently, concurrent chemoradiation therapy for esophageal cancer is being utilized with increasing frequency. In this study, we reported concurrent chemoradiation for patients with T4 esophageal cancer. From July 2000, we treated 21 consecutive patients with radiation and concurrent chemotherapy using intermittent low-dose FP chemoradiation (40 Gy radiation, 2 Gy/day, for 4 weeks 280/m(2) 5-FU intermittent 24 continuous, CDDP 8 mg/m(2)/intermittent). All patients who underwent the treatment with concurrent CRT completed the planned chemoradiation. Out of 21 patients, 2 (9.5%) showed a complete response and 9 patients (42.8%) showed a partial response. The 5-year survival rate of the T4 patients with CRT was almost the same as for those who underwent surgery alone. Concurrent chemoradiation therapy for T4 esophageal cancer patients is feasible and seems to be a standard treatment for T4 esophageal cancer patients. The results indicated that CRT is an effective therapy for advanced esophageal cancer.     

A case of advanced gastric cancer that responded to docetaxel with low-dose 5-FU and cisplatin combination chemotherapy after becoming chemoresistant to M-FLP

We report a case of advanced gastric cancer that responded to docetaxel with low-dose 5-FU and cisplatin combination chemotherapy after becoming chemoresistant to M-FLP. A 52-year-old male was diagnosed with type 3 gastric cancer of angulus (poorly differentiated adenocarcinoma) with left neck, Virchow, mediastinal and abdominal lymph nodes metastases. The patient was treated with 5 courses of M-FLP (MTX + 5-FU + LV + CDDP), and the effect of this therapy was PR, but the tumor was chemoresistant to the sixth course of this therapy. After 7 courses of M-FLP, docetaxel (TXT) with low-dose FP (5-FU + CDDP) was administered to the patient as second-line chemotherapy. After 2 courses of TXT with low-dose FP, the gastric cancer and metastatic lymph nodes were remarkably reduced and the effect of this therapy was PR. The toxic events were anemia (grade 2) and leukopenia (grade 3), which were treated with G-CSF. CDDP and 5-FU based regimens are considered as the first-line chemotherapy for metastatic advanced gastric cancer in Japan; however, a second-line chemotherapy has not been established. As in this case, a TXT based regimen is effective and well tolerated therapy as a second-line chemotherapy for metastatic gastric cancer after prior exposure to CDDP and 5-FU.     

A case of complete response to S-1 plus CDDP in early-stage mucosal esophageal cancer

We report a case of early-stage mucosal esophageal cancer, showing a complete response to S-1 and cis-diamminedichloplatinum (CDDP). The patient was a 67-year-old man with synchronous double primary early-stage mucosal esophageal and advanced gastric cancer. We planned neoadjuvant chemotherapy with S-1 and CDDP for the advanced gastric cancer and endoscopic mucosal resection for the early-stage esophageal cancer. After the first course of chemotherapy, the endoscopy revealed that the esophageal cancer had become a normal mucosal lesion, and the biopsy was negative for cancer. We diagnosed a complete response to S-1 and CDDP in early-stage esophageal cancer. After two courses of chemotherapy, distal gastrectomy was performed. The patient is still alive with no sign of recurrence at 16 months after the disappearance of the original tumor. These results suggest that chemotherapy with S-1 plus CDDP may be effective in early-stage esophageal cancer.     

Phase II study of 5-fluorouracil, pirarubicin and low-dose consecutive administration of cisplatin for advanced and recurrent gastric cancer

BACKGROUND: The FAP regimen was modified and low-dose consecutive daily administration of cisplatin (CDDP) and continuous infusion of 5-fluorouracil (5-FU) and pirarubicin were employed to reduce the toxicity and achieve synergy. Patients with advanced and recurrent gastric cancer were treated with this regimen as early phase II trial and its efficacy and toxicity were assessed. METHODS: Twenty-nine patients with advanced or recurrent gastric cancer were treated with intravenous 5-FU, 360 mg/m2, continuous infusion, on days 1-5 and 8-12, CDDP, 10 mg/body, drip infusion, on days 1-5 and 8-12 and pirarubicin, 20 mg/body, on days 1 and 8, which was repeated every 4 weeks. RESULTS: One complete (CR) and 10 partial (PR) responses were observed. Eleven patients showed no change (NC) and seven had progressive disease (PD). The overall response rate (CR and PR) was 37.9%. The response rates of lymph node metastatic lesions and primary gastric lesions were 47 and 44%, respectively. The major toxicity was bone marrow suppression, which was well tolerated. Grade 3/4 nausea/vomiting did not occur. The median survival of all patients was 30 weeks, that of those who responded was 48 weeks and that of those showing NC or PD was 24 weeks. CONCLUSIONS: This modified FAP regimen was considered useful with a moderate response and less severe toxicity, but further investigation is necessary.      

The evaluation of gastric cancer sensitivity to 5-FU/CDDP in terms of induction of apoptosis: time- and p53 expression-dependency of anti-cancer drugs

Clinical in vivo and in vitro studies have revealed pronounced gastric cancer activity using the combination of 5-fluorouracil (5-FU) and cisplatin (CDDP). In addition, the combination of 5-fluorouracil plus cisplatin (FP treatment) possesses synergistic cytotoxicity against gastric cancer. Sensitivity of two gastric cancer cell lines to anti-cancer drugs, 5-fluorouracil (5-FU) and/or cisplatinum (CDDP), was evaluated by use of either flow cytometric analysis (FACS) or morphological observation in terms of induction of apoptosis. In morphological observation, a new experimental technique was used in which cancer cells were distributed in thin collagen gel as one or two cell layers, and cultured with anti-cancer drugs. Thereafter, cells were stained with fluorescent Hoechst 33258 (Ho) and photographed, then stained with hematoxylin and eosin (H&E) and photographed again. Cell death patterns were determined by combining observations of Ho- and H&E-stained cells. While combined administration of 5-FU and CDDP did not induce apoptosis of MKN-28 (mutant-type p53), apoptotic cells were markedly observed in the case of MKN45 (wild-type p53). In addition, consecutive administration of CDDP for 3 h and 5-FU for 21 h effectively induced apoptosis of MKN45. These results indicated that the type of p53 expression in cancer cells could be a promising factor in predicting response to FP therapy and the administration of CDDP prior to 5-FU may be more effective in inducing apoptosis of gastric cancer cells with wild-type p53 expression. These data may provide evidence to support the idea that p53 expression is related to multidrug resistance (MDR) in FP therapy of gastric cancer cell lines.     

A case of advanced gastric cancer responding to combination chemotherapy with low-dose 5-FU plus CDDP

A 56-year-old man presented with dysphagia, and was found to have a type 3 advanced gastric cancer with bilateral multiple lung metastases. This patient was treated with low-dose 5-FU plus CDDP chemotherapy. In the first course, CDDP (6 mg/m2/day) plus 5-FU (300 mg/m2/day) were infused for 5 successive days a week, but a tumor response was not achieved. Therefore, in the second course, CDDP (6 mg/m2/day) plus 5-FU (600 mg/m2/day) were infused every other day (3 days a week). In response to the treatment, both the gastric tumor and the lung metastases almost completely disappeared (reduction rate 95%), and PR was achieved. The CEA level markedly decreased, from 260.3 to 1.4 ng/ml and the patient's symptoms disappeared. Following this treatment, low-dose CDDP plus UFT therapy was performed and the PR was maintained for 12 months. This report shows a case of advanced gastric cancer that responded to low-dose 5-FU plus CDDP.     

A case of stage IV (A3) cervical and upper thoracic esophageal adenocarcinoma successfully treated with concurrent chemoradiotherapy

We report a case of cervical and upper thoracic esophageal adenocarcinoma with tracheal stenosis and bilateral recurrent nerve palsy. A 64-year-old man with unresectable esophageal cancer (A3, N1, M0) was treated with concurrent chemoradiotherapy. A dose of 67.4 Gy was irradiated to the cervical and upper thoracic area where the primary tumor and lymph node metastases were located, and six courses of 5-FU (250 mg/24 h/day 1-5) and CDDP (5 mg/1 h, just before radiation/day 1-5) were delivered concurrently. The esophageal tumor showed a complete response (CR), and the paratracheal lymph node metastases showed partial responses (PR). The reason these therapies were more effective against the tumor than the lymph node metastases is uncertain. The patient is no longer required to stay in the hospital, and his QOL has been improving. His condition has been maintained for 4 months, so this type of concurrent chemoradiotherapy may be recommended for cervical and upper thoracic esophageal adenocarcinoma.     

A retrospective review of 15 years of radical radiotherapy with or without concurrent cisplatin and/or 5-fluorouracil for the treatment of locally advanced cervical cancer

Radiation therapy is the standard of care treatment for locally advanced cervical cancer in the United States. In 1999 the addition of concomitant chemotherapy to radical radiotherapy became standard. The addition of cisplatin (CDDP) with or without 5-fluorouracil (5-FU) chemotherapy to radiation therapy was based on the near simultaneous reporting of five randomized, controlled clinical trials which all showed an improvement in survival with a magnitude of approximately 35%. The purpose of our study was to test the hypothesis that the addition of chemotherapy improved survival in our patients. We identified 291 patients treated with primary 'intent-to-cure' radiation therapy for locally advanced carcinoma of the cervix between 1985 and 2000. We analyzed patients using a stepwise Cox regression, including as possible predictors: clinical stage, age at diagnosis, use of concurrent chemotherapy with radiation and method of teletherapy delivery. We also examined survival as a function of CRT with a CDDP and/or 5-FU containing regimen using the Kaplan-Meier estimates of overall survival. The use of concurrent CDDP and/or 5-FU chemotherapy with radiation (CRT) was not associated with an increase in disease free survival (p=0.734) or overall survival (p=0.989). In this retrospective study there was no disease free or overall survival benefit from the addition of CDDP and/or 5-FU chemotherapy to radical radiotherapy for the treatment of locally advanced cervical carcinoma, although there was a trend favoring CRT.     

Immunohistochemical study of dihydropyrimidine dehydrogenase (DPD) and p53 in biopsied specimens of esophageal cancer before chemoradiotherapy]

We studied whether the immunohistochemical status of dihydropyrimidine dehydrogenase (DPD) and p53 can be used to predict the sensitivity to chemoradiotherapy (CRT) in patients with esophageal cancer. In 19 patients who did not undergo preoperative CRT, the immunoreactivity of DPD and p53 in biopsied specimens correlated well with those in surgically resected specimens (DPD: 100%, p53: 73%). Fifteen patients were treated with 5-FU (250-300 mg/body/day: day 1-5, 8-12), low-dose cisplatin (10 mg/body/day: day 1, 8) and radiotherapy (30-40 Gy). The response rate (CR + PR) for CRT in these patients was 40%. All tumors that showed CR or PR demonstrated low expression of DPD. However, all tumors with high DPD expression showed MR or NC. However, the expression of p53 did not correlate with the response rate for CRT. Therefore, the effect of CRT for esophageal cancer may be predicted by immunohistochemical examination of DPD in biopsied tumor specimens.     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

In-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing of cisplatin treatment

Abstract. Background: To date, we have few effective chemotherapeutic agents against advanced and recurrent gastric cancer. 5-Fluorouracil (5-FU) and cisplatin (CDDP) are the most widely used drugs, and their combination has demonstrated favorable outcomes. However, the method (especially the timing) of CDDP administration is not well established. Methods: We examined the in-vitro effect of a combination of 5-FU and CDDP on four human gastric cancer cell lines: MKN-1, MKN-28, MKN-45, and MKN-74. The cell lines were exposed to 50% of the inhibitory concentrations of 5-FU and CDDP for 72 h and 8 h, respectively. CDDP was applied before, simultaneously with, and after the start of treatment with 5-FU. Results: When CDDP was applied after 5-FU, the cytotoxic activity against MKN-28, MKN-45, and MKN-74 was significantly potentiated. Against MKN-1, the earlier the initiation of CDDP treatment, the stronger was the cytotoxic effect. Conclusion: Our results suggest that the cytotoxicity of a combination of 5-FU and CDDP against human gastric cancer cells is both cell-line- and schedule-dependent and is especially affected by the timing of the CDDP treatment. Received: August 22, 2001 / Accepted: December 7, 2001     

Chemoradiotherapy using platinum analogs/5-FU for advanced esophageal cancer

We evaluated the efficacy of concurrent chemoradiotherapy (CRT) using cisplatin/nedaplatin and 5-FU for advanced esophageal cancer. Thirteen patients with locally advanced esophageal cancer (T4 cases) and 3 with recurrence of esophageal cancer were treated with radiotherapy (40-70 Gy) and 5-FU combined with cisplatin/nedaplatin concurrently. T4 patients who obtained down-staging by CRT also underwent esophagectomy. A complete response was obtained in one case, partial response in 8 cases, and no change in 7 cases. The overall response rate was 56.3%. A pathological complete response was obtained in one case in which curative resection was performed after CRT. Bone marrow suppression was observed in 68.8% and grade 3 and 4 bone marrow suppression was observed in 43.8%. Concurrent CRT using cisplatin/nedaplatin and 5-FU for advanced esophageal cancer has a high response rate and patients obtaining down-staging by CRT as a neoadjuvant therapy have a chance for long survival after curative resection in locally advanced cases.     

A case of recurrent esophageal cancer with tracheal invasion treated by chemo-radiotherapy (CRT) after placement of tracheal stent that maintained complete response (CR) for two years

Frequently advanced or recurrent esophageal cancer was invasive trachea and often causing hemoptysis, stenosis and dyspnea. Occasionally, these cases were treated by a placement of tracheal stent. The placement effect was quickly and a main symptom of dyspnea was improved dramatically. However, the most of the cases were in poor prognosis with advanced cancer treated by chemo-radiotherapy (CRT). We experienced a case of recurrent esophageal cancer with tracheal invasion treated by placement of tracheal expandable metallic stent (EMS). A case was a 73-year-old man (at first admission). He was performed esophagectomy with tracheotomy against esophageal carcinoma at cervical portion. Eighteen month later, a local recurrence with tracheal invasion was appeared. The tracheal covered stent was inserted at the recurrent site. After stenting, CRT was performed with 5-FU and docetaxel. The effect of CRT was complete response (CR). Hence, a stent was removed from trachea. No recurrence was observed at the site and maintained a CR condition for two years after CRT.