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High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma.

PURPOSE: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. PATIENTS AND METHODS: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. RESULTS: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. CONCLUSION: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors.

Adolescent↗

Encouraging result of tamoxifen in a retinoblastoma patient with central nervous system metastasis.

Extraocular retinoblastoma occurs more frequently in developing countries as a delayed diagnosis and prognosis of patients with conventional therapy is very poor. Metastatic retinoblastoma, especially in the central nervous system (CNS), is a highly lethal disease. Tamoxifen has been used in some previous studies with variety of responses to therapy in patients with unresectable recurrent brain tumors. A 7-year-old girl with recurrent metastatic retinoblastoma received 60 mg/m2 tamoxifen in addition to chemotherapy and CNS radiotherapy. She was in remission until she has died in a traffic accident at week 114. The authors think that tamoxifen can be added to treatment protocols of metastatic retinoblastoma to provide longer and at least higher quality of life for these patients.

Angiogenesis Inhibitors↗

Second-line combination chemotherapy of oral S-1 with cisplatin and irinotecan for colorectal cancer resistant to 5-FU.

BACKGROUND/AIMS: A phase I clinical trial has been planned to determine the recommended dose and to assess the safety and efficacy of combination chemotherapy of S-1 with cisplatin and irinotecan (SCI regimen) as a second-line treatment in 5-fluorouracil (5-FU) resistant colorectal cancer (CRC). METHODOLOGY: Patients with unresectable recurrent or metastatic CRC were enrolled in this study for second-line treatment. On an outpatient basis, the patients received a treatment SCI regimen comprising S-1 oral administration for 28 days followed by withdrawal for 2 weeks, plus cisplatin and irinotecan were administered on days 1, 8, 15 and 22 by intravenous injection. These courses were repeated every 6 weeks. Starting doses were 70 mg/m2 S-1, 6 mg/m2 Cisplatin, and 60 mg/m2 Irinotecan. RESULTS: A total of 29 patients was enrolled. Dose-limiting toxicities were fatigue, nausea, and leucopenia. Twenty-three patients at recommended dose were evaluable for treatment response. The response rate was 21.7% (5 partial responses, 13 stable diseases, and 5 progressive diseases). The median progression-free survival rate was 4.3 months; the median survival time was 9.6 months. CONCLUSIONS: The SCI regimen is feasible in an outpatient setting and should be considered as second-line chemotherapy for patients with 5-FU resistant CRC.

Administration, Oral↗

Treatment of malignant pheochromocytoma.

Pheochromocytoma is a tumor derived from chromaffin tissue, which secretes catecholamines. Today, about 90 percent of patients with this tumor are cured by surgical procedures. In 8 to 15 percent of patients with this tumor there is unresectable, recurrent or metastatic disease, which causes significant morbidity and mortality. The natural history of metastatic disease includes long-term survivors; many, however, die early of disseminated disease. The most common site of metastatic lesions is the skeleton. Palliation for these lesions can often be achieved with the use of radiation therapy. Other sites are, in general, less responsive to radiation therapy. Chemotherapy has been used in combination with radiation therapy, but the results generally have been disappointing. Chemotherapy with doxorubicin hydrochloride and cyclophosphamide in combination with radiation therapy has provided good palliation for skeletal disease for about five months, when disease progression was again noted. Further information is needed concerning the optimal chemotherapeutic treatment of this unusual tumor.

Adrenal Gland Neoplasms↗

Head and neck malignant fibrous histiocytomas.

Malignant fibrous histiocytoma of the head and neck is a rare tumor with less than 50 total cases reported in the literature. Its rarity and complex histopathology combine to make it a difficult diagnosis. Two cases are described. Pathology characteristics are discussed. The traditional treatment of choice is wide surgical excision. Radiation therapy is usually reserved for recurrent, unresectable, or extremely aggressive tumors.

Adult↗

[Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma].

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.

Adenocarcinoma↗

Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group.

PURPOSE: To develop a tolerable regimen of fluorouracil (5-FU), low-dose leucovorin, and radiation, and to obtain an early estimate of therapeutic effectiveness. PATIENTS AND METHODS: Forty patients with locally unresectable or recurrent gastrointestinal carcinoma were studied (pancreas, n = 22; rectum and sigmoid, n = 10; gastric, n = 6; other, n = 2). Irradiation therapy was administered in 1.8-Gy fractions 5 days per week, with total doses ranging from 45 to 54 Gy. 5-FU 400 mg/m2/d plus leucovorin 20 mg/m2/d, both by rapid intravenous injection, were administered for 3 or 4 days during the first and fifth weeks of radiation. 5-FU 425 mg/m2/d plus leucovorin 20 mg/m2/d were administered for 4 days at 4 weeks following radiation and for 5 days at 9 weeks. RESULTS: Major toxicities with upper abdominal treatment were nausea, vomiting, weight loss, and leukopenia. A tolerable dosage regimen was radiation at 45 Gy with 4 days of 5-FU plus leucovorin during the first week and 3 days during the last week with postradiation chemotherapy. Major toxicities with pelvic radiation were diarrhea and leukopenia. A tolerable regimen was 54 Gy with 4 days of 5-FU plus leucovorin during the first and fifth week followed by the postradiation chemotherapy. Median survival durations for pancreatic and rectal/sigmoid carcinomas are 13 months and 31 months, respectively. Five patients have no evidence of disease from 38 to 50 months after the onset of therapy (rectal, n = 2; stomach, n = 2; pancreas, n = 1). CONCLUSION: We have developed patient-tolerable regimens for combined 5-FU plus leucovorin followed by radiation to the abdomen and to the pelvis. The favorable results observed in locally unresectable disease allow cautious optimism for possible effectiveness in the surgical adjuvant setting, a possibility currently being tested in national trials of rectal and gastric carcinoma.

Adenocarcinoma↗

Optimal dose-finding study of bi-weekly paclitaxel in unresectable advanced or recurrent gastric cancer.

BACKGROUND: Tri-weekly and weekly regimens of paclitaxel have been reported to be effective in unresectable advanced or recurrent gastric cancer. The present study was conducted to determine the optimal dose of bi-weekly paclitaxel and evaluate safety and antitumor effect. PATIENTS AND METHODS: The study included patients with a histologically confirmed diagnosis of advanced or recurrent gastric cancer. Paclitaxel was intravenously infused for 1 h bi-weekly. One cycle consisted of four weeks and at least two cycles were performed. Dose levels 1, 2, 3, 4 and 5 were 100, 120, 140, 160 and 180 mg/m2, respectively. RESULTS: Of the 21 patients enrolled, 18 patients (85.7%) had received prior treatment. The maximum tolerated dose was 160 mg/m2 (level 4) and dose-limiting toxicities included grade 3 fatigue, anorexia and neuropathy and grade 4 neutropenia and allergic reaction. The recommended dose was designated as to be 140 mg/m2 (level 3). At this dose level, only one patient experienced a dose-limiting toxicity of neutropenia. No patient had grade 3 or higher non-hematological toxicity. The response rate was 12.5% (2/16) and 14 patients (87.5%) had partial response or stable disease. The median number of treatment courses was four (up to 13 courses). The median survival time was 222 days and the time to progression was 76 days. CONCLUSION: In advanced or recurrent gastric cancer, bi-weekly paclitaxel may be safely administered at a recommended dose of 140 mg/m2. A phase II study is now underway.

Adult↗

A phase I dose escalation trial of gemcitabine with radiotherapy for breast cancer in the treatment of unresectable chest wall recurrences.

The purpose of this study was to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with standard radiotherapy for the treatment of chest wall recurrences, and to compare actuarial rates of local-regional control with those achieved in historical controls. Patients with unresectable chest wall recurrences were enrolled in a phase I trial of concurrent gemcitabine and radiotherapy. Gemcitabine was increased at 150 mg/m(2)/week increments, starting at 300 mg/m(2)/week. Radiotherapy was delivered to the chest wall and regional nodes to a total of 60 to 70 Gy in 2 Gy daily fractions. Treatment toxicity was assessed and a comparison of treatment outcome was performed between study patients and historical groups treated with either radiotherapy alone or excision followed by radiotherapy. The dose-limiting toxicities of neutropenia and thrombocytopenia occurred at the second planned dose of 450 mg/m(2)/week after accrual of only six patients, resulting in a MTD of 300 mg/m(2)/week. Myelosuppression and skin desquamation were commonly observed. Actuarial rates of local-regional control were 100%, 50%, and 90% at 2 years for the gemcitabine with radiotherapy, radiotherapy alone, and excision followed by radiotherapy groups, respectively (p = 0.105). The difference among the Kaplan-Meier curves for overall local-regional control was statistically significant at p = 0.007 in favor of combined gemcitabine and radiotherapy. The MTD of gemcitabine is 300 mg/m(2)/week when gemcitabine is delivered concurrently with radiotherapy for unresectable chest wall failures. This novel approach suggests excellent local-regional control when compared to historical controls. A phase II trial is warranted.

Actuarial Analysis↗

Integrated treatment with doxifluridine and radiotherapy in recurrent or primary unresectable rectal cancer. A feasibility study.

AIMS AND BACKGROUND: When combined with radiotherapy, fluoropyrimidines have been shown to have synergistic effects on various tumor types. Doxifluridine (5-dFUR) is a 5-fluorouracil (5-FU) prodrug that is transformed into 5-FU in neoplastic tissue, which suggests that it may improve the activity of radiotherapy. The aims of this study were to evaluate the feasibility and efficacy of the combination of radiotherapy and oral 5-dFUR plus l-leucovorin in terms of pathologically complete remissions in locally advanced rectal cancer. METHODS: Eleven patients with locally recurrent (n = 7) or primary unresectable rectal cancer (n = 4) were treated with three cycles of oral l-leucovorin 25 mg/dose followed by 5-dFUR 750 mg/m2 twice daily for four days every 12, in combination with pelvic radiation at a standard dose of 45 Gy over five weeks. The tumor burden was assessed by means of CT and endoscopic ultrasound at baseline and at least four weeks after the end of the treatment and before surgery. RESULTS: Four patients achieved an objective response, 6 disease stabilization and 1 had progressive disease. After a median time of five weeks from the end of treatment 8 patients underwent radical resection and a pathologically complete remission was documented in 2. Seven of these patients are still alive and disease free after a median follow-up of 18 months. The major side effects were grade 3 diarrhea in one case, and grade 1-2 nausea and vomiting in three cases. No significant hematological toxicity was observed. CONCLUSIONS: This combination of radiation and 5-dFUR plus l-leucovorin led to an interesting rate of resectability, with pathological downstaging being documented in two cases. These preliminary results show an encouraging local control of an otherwise unresectable disease. Combined preoperative therapy with oral fluoropyrimidine plus l-leucovorin together with radiation may be an attractive approach in patients with operable rectal cancer.

Adenocarcinoma↗

The role of particle therapy in the treatment of locally recurrent rectal cancer: a systematic review.

BACKGROUND: Colorectal cancer is a common malignancy. Advancements in multimodality treatment have improved outcomes. About 2-10% of patients will have a local recurrence even after optimal treatment. Salvage surgical treatment is the treatment of choice, however, in posterior and lateral recurrences, surgery is linked to a high rate of treatment-related morbidity. Some recurrences remain unresectable even after neoadjuvant treatment. MATERIALS AND METHODS: A systematic literature review was performed to search for studies on curative-intent radiation therapy (RT) with photons, stereotactic body radiation therapy (SBRT) and particle beam therapy. The aim of the literature search was to define the role of particle therapy in the treatment of patients with unresectable or inoperable local recurrences of rectal cancer where neoadjuvant treatment is unlikely to result in downstaging, leaving patients with RT as the only curative treatment option. RESULTS: 32 studies which fulfil the criteria were identified. In general, SBRT and particle beam therapy permitted the application of significantly higher doses to the target without a concomitant increase in treatment-related toxicities. CONCLUSIONS: For unresectable and inoperable locally recurrent rectal cancer ablative radiotherapy techniques such as SBRT and particle beam therapy offer a curative treatment approach as an alternative to surgery. SBRT can be offered for small local and nodal recurrences, while particle beam therapy can be offered for larger recurrences and complex shapes spanning several anatomical compartments as well. Further research is needed to stratify patients according to their need and eligibility for the different possible modalities of curative-intent RT.

Humans↗

The role of radiotherapy in the management of pelvic recurrence of rectal cancer.

Unresectable pelvic recurrence from carcinoma of the rectum becomes invariably symptomatic. While radiotherapy remains the most common antineoplastic modality used for palliation of symptoms, the optimal radiation dose and fractionation remains undefined. A systematic review of the literature was performed to determine the most effective dose fractionation schedule for the relief of symptoms in patients with pelvic recurrence. An expert panel reviewed and interpreted the data, with a special focus on indications, effectiveness, optimal dose fractionation, and toxicity of radiotherapy in this context. Only retrospective data (level V evidence) were available on this issue and were reviewed. Pain relief was the major indication for treatment, although bleeding and mucous discharge were also seen as indications for radiotherapy. Initial pain relief appeared to be achievable in 70-90% of patients. The median duration of pain relief was approximately three months, 23-50% of patients had symptom control at six months. The value of "local control" as a meaningful additional endpoint was discussed. There were no significant differences observable in initial symptom response and the proportion maintaining a response at six months, within the range of doses employed, comparing "lower" versus "higher" doses (using 45-50 Gy as the dividing dose). Toxicity was usually evaluated qualitatively and was deemed acceptable. The expert panel agreed that pelvic radiotherapy has a definite value in the relief of symptoms in patients with pelvic recurrence from rectal carcinoma. The optimal dose fractionation in this context could not be determined in view of the quality of the data available. Well designed, randomized studies with clinically relevant study arms and endpoints are necessary to define an optimal dose fractionation against which alternative strategies can be compared.

Humans↗

Unresectable primary and recurrent head and neck tumors: effect of hyperthermia and carboplatin--preliminary experience.

PURPOSE: To perform a single-arm study to determine the effectiveness of and potential toxic reactions to local hyperthermia and systemic carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II) for the treatment of advanced or recurrent squamous cell carcinomas of the head and neck. MATERIALS AND METHODS: Eight patients with squamous cell carcinoma of the head and neck and stage IV disease (N2 or N3 neck adenopathy) or recurrent local-regional disease and who were previously and definitively treated were included in the study. Thermochemotherapy was administered every 4 weeks. Recorded end points were tumor response, duration of response, incidence of distant metastases, survival, cause of death, and toxic reactions. RESULTS: One patient had a complete response to therapy, and two had a partial response. Five patients had no response or developed progressive disease during therapy. Six patients died after 4-13 months of progressive disease. Two long-term survivors received radiation therapy; one also underwent surgical resection for residual neck disease. Each thermochemotherapeutic session was well tolerated, with minimal discomfort. Toxic reactions included hypotension, vomiting, hyponatremia, anemia, thrombocytopenia, and infection at the site of administration. There were no life-threatening toxic reactions. CONCLUSION: The combined use of hyperthermia and carboplatin shows potential in the management of unresectable head and neck tumors and is safe and well tolerated. Further studies on thermochemotherapy are warranted to assess its potential.

Aged↗

Early results from a phase I/II radiation dose-escalation study with concurrent amifostine and infusional 5-fluorouracil chemotherapy for preoperative treatment of unresectable or locally recurrent rectal carcinoma.

To improve the resectability and long-term local control of locally advanced rectal cancer, we have initiated a radiation dose-escalation trial. It is hoped that the radioprotector amifostine will sufficiently reduce rectal morbidity (without also reducing tumor response) to permit increasing radiation doses. Only 6 patients have been treated at the first dose level (45 Gy with a 9-Gy boost and concurrent continuous infusion of 5-fluorouracil). During treatment, daily stool frequency improved or was stable. There was one case of transitory severe proctitis/enteritis. Four of the six patients achieved objective responses to preoperative treatment. These very early results suggest that the use of amifostine does not interfere with tumor response and that it may facilitate the delivery of higher boost doses to the rectum.

Adenocarcinoma↗

Rationale for a phase I/II radiation dose-escalation study with concurrent amifostine (Ethyol) and infusional 5-FU chemotherapy for preoperative treatment of unresectable or locally recurrent rectal carcinoma.

Rectal adenocarcinoma almost invariably requires extirpative surgery to be cured. Although radiation therapy and concurrent chemotherapy often will elicit dramatic responses, the treatment morbidity limits the tolerable dose of radiation to about 45 to 50 Gy. Strategies to reduce procto/enteritis may permit higher doses of radiation to be delivered. This report reviews a recently activated radiation dose-escalation study that combines the radioprotector amifostine (Ethyol, WR-2721) with 3-dimensionally planned radiation therapy and concurrent infusional 5-fluorouracil chemotherapy.

Adenocarcinoma↗

Concurrent interstitial radiotherapy and infusional chemotherapy for recurrent gynecologic malignancies.

Patients with unresectable locally recurrent gynecologic malignancies pose a difficult therapeutic challenge. Conventional therapies are frequently unsuccessful and offer only marginal palliation. In this study, interstitial 192iridium-needle implants and concomitant infusional 5-fluorouracil (5FU) and cisplatin (CDDP) or carboplatin (CBDCA) chemotherapy were used to treat 14 women with recurrent pelvic tumors. Malignancies of the cervix, endometrium ovary, tube and vulva are represented; all patients were heavily pretreated. Twenty interstitial implants were performed in these 14 patients. Needle distributions and doses were individualized to accommodate the recurrent tumor volumes. Tumor responses were seen in 12 patients (six complete and six partial responses). Four women remain clinically free of disease and four are alive with disease at 18-34 months of follow-up. There were no severe acute toxicities, however, four patients have subsequently developed fistulae associated with tumor progression. Although longer follow-up is required, the high response rate, wide applicability and acceptable toxicity observed in this heavily pretreated patient population warrant further study of combined interstitial radiation and chemotherapy.

Journal Article↗

Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs.

BACKGROUND: Bronchioloalveolar carcinoma (BAC) is a well-differentiated lung adenocarcinoma that has a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes and may therefore be amenable to local therapy. However, a high rate of local recurrence after lung transplantation was recently reported. We describe two patients with unresectable and recurrent extensive BAC limited to the lung parenchyma who underwent lung transplantation with curative intent. METHODS: Patients were chosen to receive lung transplants for BAC if they met the following criteria: (1) recurrent or unresectable BAC limited to the lung parenchyma without nodal involvement and (2) suitable candidate for lung transplantation. RESULTS: The first patient relapsed in the lungs at 9 months after transplantation. The pattern of disease suggested contamination of the new lungs at the time of implantation. Repeat lung transplantation was performed, with cardiopulmonary bypass and irrigation of the remaining upper airway. This patient has had no evidence of local or systemic tumor recurrence at more than 4 years since the second transplantation. The second patient underwent transplantation using the modified technique and expired 16 months after transplantation of other causes. An autopsy showed no evidence of recurrent BAC in the lungs or of metastatic lesions at any site. CONCLUSIONS: Lung transplantation may be an option for unresectable or recurrent BAC confined to the lungs. Isolation of the diseased lungs and the use of cardiopulmonary bypass during surgery may be important in this disease and should be studied further.

Adenocarcinoma, Bronchiolo-Alveolar↗