Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas.

PURPOSE: To evaluate the effectiveness of combined intraoperative radiation therapy (IORT) and perioperative chemotherapy in the management of unresectable pancreatic cancer. MATERIALS AND METHODS: Forty-nine patients with localized unresectable adenocarcinoma of the pancreas were treated in a multimodality program of initial IORT and perioperative chemotherapy (fluorouracil [5-FU]/leucovorin) followed by combined external-beam radiation (40 to 55 Gy) and continued chemotherapy. Patients were evaluated for toxicity, pattern of failure, and survival. The follow-up times of these patients range from a minimum of 12 months to a maximum of 62 months, with a median of 28 months. RESULTS: The incidence of perioperative mortality was 0%. Early postsurgical morbidity (grade 3/4) was observed in seven of 49 patients (14%) and late treatment-related morbidity (grade 3/4) in eight of 43 patients (19%) alive beyond 6 months. Morbidity was primarily gastrointestinal (GI), with no hematologic toxicities observed. The median survival time in the total group of patients is 16 months, with a 2-year survival rate of 22% and a 4-year survival rate of 7%. Freedom from local progression of disease was achieved in 71% of patients. CONCLUSION: The patients who undergo IORT with electrons and treated with perioperative chemotherapy (5-FU leucovorin) followed by additional external-beam radiation and chemotherapy appear to have improved survival, with few early or late complications. Dose escalation of external-beam radiation and chemotherapy may further improve local control of disease and survival of patients.

Carcinoma of the pancreas--the Jefferson experience 1975-1988.

A retrospective review of 410 patients with carcinoma of the pancreas seen at Thomas Jefferson University from 1975-1988 was undertaken to provide a global view of the effectiveness of different modalities of treatment in the management of this disease. There were seven patients with Stage I disease, 141 patients with Stage II disease, 91 with Stage III, and 171 with Stage IV disease. The overall median survival was 7 months and a 1-year survival of 30% was observed. Median survival was 15 months for Stage I, 10 months for Stage II, 9 months for Stage III and 4 months for Stage IV patients. Several treatment approaches were utilized in these patients. Twenty-three patients underwent surgical resection. Five of these had Stage I tumor, and 18 patients had Stage II or III disease. Median survival in this group was 12 months with an operative mortality of 13%. No resected patients survived greater than 3 years. Eleven patients with Stage II and III disease received chemotherapy alone, 28 patients received external radiation alone, and 30 patients received Iodine-125 implantation plus external radiation. Median survival in all three groups was 7 months. Forty-five patients received combined chemotherapy plus external radiation for Stage II and III cancer with a median survival of 10 months and a 2-year survival of 14%. Eighty-one patients received combined Iodine-125 implantation+external radiation+chemotherapy and had a median survival of 13 months and a 2-year survival of 22%. Local control of disease was achieved in 74% of these patients. This combined modality approach appears to have the best potential for control of primary cancer and long-term survival of selected patients.

Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast.

BACKGROUND: Few women with locally advanced breast cancer remain disease-free, even for 2 years. Response to induction chemotherapy may be associated with longer disease-free and overall survival rates. The role of breast conservation in selected patients with response to induction chemotherapy was evaluated. METHODS: Since 1979, patients with Stages IIB and III breast cancer have undergone induction chemotherapy; patients with response continued chemotherapy until a plateau of regression was achieved. Before 1983, all patients having a response to chemotherapy underwent mastectomy; since 1983, selected patients have undergone breast conservation. Outcomes were tallied comparing these two groups of patients. RESULTS: The study group included 189 women, who were followed up for 12-159 months (median, 46 months) after diagnosis. Of the patients, 85% had a response to induction chemotherapy. Patients with no response were excluded from additional consideration in this study. One hundred three (64%) women underwent mastectomy; 55 (36%) were treated with breast conservation. The disease-free 5-year survival rate was 61% for all patients with a response to chemotherapy; 56% for those having mastectomy and 77% for those having breast conservation. The overall 5-year survival rate was 69% for all patients with a response to chemotherapy, 67% for those undergoing mastectomy and 80% for those having breast conservation. CONCLUSIONS: Induction chemotherapy achieves significant tumor regression in most women with locally advanced breast cancer, permitting subsequent breast conservation or mastectomy with a greater expectation of long-term success. Breast conservation is used more frequently with the same expectation of success as mastectomy, presuming careful selection based on response to chemotherapy.

Long-term results of combined modality treatment with I-125 implantation for carcinoma of the pancreas.

From 1981 to 1987, 81 patients with localized, unresectable carcinoma of the pancreas were treated at Thomas Jefferson University Hospital with a combination of intraoperative Iodine-125 implantation, external beam radiation, and peri-operative systemic chemotherapy. Fifty patients had Stage II disease and 31 patients had Stage III disease. Radioactive Iodine-125 seeds were implanted intraoperatively into the tumor to deliver a minimum peripheral dose of 12,000 cGy over one year. This was followed by external beam radiation (50-55 Gy) and systemic chemotherapy (5-FU, Mitomycin-C +/- CCNU). Incidence of peri-operative mortality was 5% (4/81). Early morbidity was observed in 34% of patients and late complications in 32%. A median survival of 12 months and 2- and 5-year survival rates of 21% and 7% were observed. The determinate 2- and 5-year survival rates were 28% and 13%, respectively. The overall 2- and 5-year survival rates with Stage II disease were 27% and 8% and for Stage III disease, 13% and 3%, respectively (p less than 0.05). The determinate 2- and 5-year survival rates were 34% and 19% for Stage II and 19% and 5% for Stage III disease, respectively (p = 0.08). Local control of disease was achieved in 71% of patients. This combined modality approach appears to have achieved satisfactory local control of primary cancer and long term survival of selected patients.

An evaluation of the potential cost reductions resulting from the use of clodronate in the treatment of metastatic carcinoma of the breast to bone.

The reported studies of clodronate in the management of osteolytic bone metastases suggest a significant palliative role for this drug. In this paper we report on analysis of the hospital costs associated with the management of osteolytic metastatic disease, and an estimate of the potential cost/benefit impact of clodronate therapy. Two separate patient populations were assessed retrospectively. The first, a sample of 120 patients with symptomatic bone metastases who had died from metastatic breast cancer over the period 1980-1990, was used to define the natural history of the disease. A second non-concurrent patient group of 337 patients was evaluated to determine the mean cost of all hospital admissions for patients with bone metastases from breast carcinoma. The length of stay and costs for hospital admissions related to the bone metastases were also assessed, in addition to the cost of out-patient radiation therapy. Our cost/benefit value analysis suggests that there are significant savings to be gained from the use of clodronate if a 20% or greater reduction occurs in the incidence of fractures, hypercalcaemia, and hospital-based treatment for pain control (via radiotherapy). We also speculate that the quality of life of patients with osteolytic bone metastases may be improved with this agent.

[Shortening diclofenac therapy by B vitamins. Results of a randomized double-blind study, diclofenac 50 mg versus diclofenac 50 mg plus B vitamins, in painful spinal diseases with degenerative changes]. / Verkürzung der Diclofenac-Therapie durch B-Vitamine. Ergebnisse einer randomisierten Doppelblindstudie, Diclofenac 50 mg gegen Diclofenac 50 mg mit degenerativen Veränderungen.

The use of nonsteroidal anti-inflammatory drugs (NSAID) such as diclofenac for treatment of degenerative rheumatic disorders of the lumbar spine is of great significance in orthopedic practice. Clinical studies have shown that concomitant treatment with vitamins B1, B6, B12 and diclofenac provides more efficient pain relief than treatment using diclofenac alone. This study was undertaken in order to determine whether the duration of treatment with diclofenac for lower back pain can be shortened by adding B-vitamins to the therapeutic regimen. From September through December of 1986, 256 patients participated in a multicenter, controlled, randomized double-blind trial which compared the clinical efficacy of diclofenac (50 mg) with a combined therapy of diclofenac (50 mg) and vitamins B1, B6, and B12 (thiamine nitrate, pyridoxine hydrochloride, and cyanocobalamine, resp.; in dosages of 50 mg, 50 mg, and 0.25 mg, resp.). Patients were treated with 3 X 1 capsule daily for a maximum of two weeks, having the option to terminate participation in the trial after 1 week in the event of total pain relief. The data of 238 patients were able to be included in the evaluation. 29 patients opted to discontinue therapy due to remission on symptoms. Nineteen (65.6%) of these patients belonged to the combined therapy group, the other 10 (34.4%) having taken diclofenac alone; this difference is statistically significant (p less than 0.05). An important aspect in the evaluation of therapy was the patient response regarding the improvement of painful symptoms which, in addition to their subjective feedback, was reflected in the test results of the "Hoppe Pain Questionnaire (HPQ)." All parameters used as a measure of pain relief indicated superior results with the B-vitamin supplemented therapy when compared with results obtained with diclofenac alone. Moreover, after 3 days of therapy the "sensory" pain factor "sharpness" improved significantly. Undesirable side-effects were documented with 39 patients, 14 of them having discontinued therapy for this reason. No statistically significant difference could be determined within this group with regard to therapy. The study results document the positive influence of B-vitamins on painful symptoms and indicate that less NSAID is needed for pain relief when combined with B-vitamins.

Combined modality treatment of localized unresectable adenocarcinoma of the pancreas.

Since 1978, 86 patients with unresectable localized adenocarcinoma of the pancreas have been treated with a combined modality program using radioactive iodine 125-Implantation, external beam radiation, and systemic chemotherapy. Three treatment approaches were used with sequential modifications of the technique based on the course of disease and patterns of failure. Group 1 was comprised of 13 patients treated with a combination of implantation followed by a planned external radiation dose of 5000 to 6000 cGy delivered in 6 weeks. Group 2 included patients treated as in Group 1 followed by adjuvant chemotherapy. The most recent group of 54 patients, Group 3, has been treated since 1981 with implantation into the tumor of radioactive Iodine 125 seeds (12000 cGy minimal peripheral dose), perioperative chemotherapy (5-FU, Mito-C), and external beam irradiation (5000-5500 cGy) followed by further chemotherapy. Incidence of perioperative mortality has been reduced from 31% (10/32) in Groups 1 & 2 to 7% (4/54) in Group 3. Clinical local control of tumor has been excellent in all three groups (84%). Analysis of the Group 3 results indicate that the problem of distant metastasis, in spite of adjuvant chemotherapy, still remains overwhelming (64%)--especially to the liver--and requires development of more effective regimens. Median survival in the three groups of patients is 5.5, 11.3, and 12.5 months. The 2-year survival is 0, 15, and 22%, retrospectively in the three groups.

Neoadjuvant chemotherapy before definitive treatment for stage III carcinoma of the breast.

One hundred women with American Joint Committee (AJC) stage III (T2, N2; T3, N0/1/2; T4, N0/1/2) carcinoma of the breast were treated with combination chemotherapy following biopsy to confirm the diagnosis and determine hormone receptor status before any other treatment of the local disease (so-called neoadjuvant chemotherapy). Response was assessed after three cycles of treatment, and responders were treated until the tumor and/or axillary nodes failed to show further regression. Definitive surgery was then performed, usually radical mastectomy. Chemotherapy was resumed following surgery for a total of 12 cycles. Ninety patients are assessable, and 70% have responded to chemotherapy. Outcomes of both responders and nonresponders were analyzed. Radical mastectomy without postoperative radiotherapy seems to be the preferable surgical treatment for the responders. Median follow-up of the assessable patients was 27 months; projected five-year disease-free survival of the responders is greater than 65%, and projected overall five-year survival of this group is greater than 85%. Because the follow-up of these patients suggests a marked improvement in outcome compared with similar patients treated traditionally with mastectomy or radiotherapy followed by adjuvant chemotherapy, we advocate more widespread use of combination chemotherapy before definitive treatment for stage III carcinomas of the breast.

Multimodality therapy of localized unresectable pancreatic adenocarcinoma.

Eighty-eight patients with localized unresectable carcinoma of the pancreas were treated at Thomas Jefferson University Hospital between 1974 and 1981. Four treatment regimens were used which were sequential modifications of the technique based on the experience in the preceding group of patients. Each treatment changed the course of the disease, and as patterns of failure were identified, the treatment was altered to deal with them. Initially, all patients were treated with external beam radiation. Subsequently, Iodine-125 implantation was added to improve local control; low-dose preoperative radiotherapy to reduce the risk of peritoneal seeding; and adjuvant chemotherapy to reduce the risks of distant metastases. The addition of 125I implantation increased the local control from 22% to 81%, but did not increase the median survival, which was unchanged from 7 months. The addition of adjuvant chemotherapy increased the median survival from 7 months to 14 months, but had no impact on the control of the pancreatic tumor. Adjunctive chemotherapy and low-dose preoperative radiotherapy appear synergistic in reducing the risk of peritoneal seeding. The combination of 125I implantation, external beam radiation, and adjunctive chemotherapy is safe and effective. This regimen produces excellent local control with acceptable morbidity. This regimen produced a 30% survival at 18 months. The patterns of failure among these patients suggest future modifications of the technique.

Thymidylate synthetase and dihydrofolic acid reductase in the stimulated human lymphocyte.

The phytohemagglutinin (PHA)-stimulated human lymphocytes demonstrated trace or no activity (dihydro) folate acid reductase using three methods including a radioassay, but demonstrated ample activity of thymidylate synthetase. This was true regardless of the day of harvest, (first through seventh) of the stimulated lymphocyte. The lymphocyte extracts revealed no inhibitor to the reductase enzyme when these extracts were added before the liver extracts to the assay system. When methotrexate (MTX) was added to the culture media of the lymphocytes, there was, as expected, an increase in the synthetase activity, but the expected rise in the reductase activity did not occur, it remained nil. On the other hand, MTX did influence the incorporation of nucleosides by the stimulated lymphocytes in a fashion similar to its action on the incorporation of the same nucleosides by other cells.