A course in medical research study design and analysis.
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Curriculum↗
Biomedical subjects
J D Cox
Publications and source records attributed to J D Cox.
The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies.
It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck. Two regimens of induction chemotherapy were studied in separate randomized, prospective trials over the last 6 years. Eighty-three patients with advanced disease were entered into the first study (43/chemotherapy; 40/control), and 60 into the second (27/chemotherapy; 33/control). Patient randomization was stratified by stage (III/IV) and site (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses). The first study utilized bleomycin, Cytoxan, methotrexate and 5-fluorouracil in two cycles (one cycle if no tumor response), followed by standard treatment which consisted of combined irradiation and surgery or, in some instances, primary irradiation alone. The second study utilized cisplatin and 5-fluorouracil in three cycles prior to standard treatment. An objective tumor response to chemotherapy was observed in 68% in the first study and 85% in the second. The patient survival in both studies (at 24 months in the first; at 19 in the second) was better in the control than that in the experimental groups (43% to 31%; 69% to 46%). In the second study, the average length of delay of standard treatment was longer than in the first study (95 days vs. 66 days; P less than .02). Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy. While toxicity to chemotherapy was not a factor in survival, the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups. Except for new drug regimens of exceptional promise, it is recommended that future studies be designed so that chemotherapy is given concurrent with, or following the completion of standard treatment.
Antineoplastic Combined Chemotherapy Protocols↗
The potential use of the discouraging random guessing (DRG) approach in multiple-choice exams in medical education.
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Education, Medical, Undergraduate↗
Prognostic significance of interval from preoperative irradiation to hysterectomy for endometrial carcinoma.
From 1965 through 1980, 193 patients with histologically proven endometrial carcinoma, FIGO-AJC Stage I-III, received preoperative radiation therapy. One hundred forty-two patients had Stage I (G1:41, G2:68, G3:33), 47 Stage II, and 4 Stage III endometrial carcinoma. All patients were treated with preoperative radiation therapy (intracavitary application, external pelvic irradiation or both) followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO). They were followed from 3 to 18 years (median, 6.2 years) after the completion of the treatment and none was lost to follow-up. Overall 5-year actuarial disease-free survival was 85%. The interval between the completion of radiation therapy and TAH-BSO ranged from 3 days to 123 days (median, 40 days). Five-year and 10-year survivals were 95% among 65 patients who did not have residual cancer in the hysterectomy specimen compared to 75% and 70%, respectively, among 128 patients who had positive hysterectomy specimens (P less than 0.01). The presence or absence of residual carcinoma in the surgical specimen after preoperative irradiation was the only important prognostic variable. The most significant factors associated with residual cancer cells were the interval from the completion of radiation therapy to TAH-BSO (P less than 0.001) and the method of preoperative irradiation in patients with Stage I Grade 3 and Stage II external pelvic irradiation was less frequently associated with residual cancer than intracavitary applications (P = 0.043). With one exception, all patients who failed had residual cancer in the hysterectomy specimen. The depth of myometrial invasion of residual tumor in the hysterectomy specimen after preoperative irradiation was correlated to the frequency of failures (P = less than 0.05). Failures were distributed equally among the pelvis, para-aortic nodes, and distant sites. Complications of treatment were infrequent (7%) and were mild; no fatal complications were seen. The data suggest an optimal interval for hysterectomy is 29 to 42 days after completion of radiation therapy in unfavorable carcinomas of the endometrium. These patients also benefit from external pelvic irradiation with or without intracavitary applications as this therapy provides the highest probability there will be no residual cancer cells in the surgical specimen.
Adenocarcinoma↗
Complications of radiation therapy and factors in their prevention.
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Animals↗
Prognostic influence of TNM staging and LDH levels in small cell carcinoma of the lung (SCCL).
To better define the prognostic factors influencing the response to therapy and survival in small cell carcinoma of the lung (SCCL), an expanded "TNM" type staging system was developed and investigated in a series of 73 protocol treated patients. Because serum LDH levels at disease presentation have been correlated to disease extent, response to therapy, and treatment outcome in a number of malignancies, including SCCL, these interrelationships were also analyzed in the protocol patients. The TNM system was found to be a more descriptive and specific "shorthand" for denoting sites of involvement and for indicating the body burden of tumor than the traditional limited-extensive disease (LD-ED) system. A clear statistical advantage could not be shown over the LD-ED system for predicting chemotherapy response or survival, although there were trends suggesting the TNM system could divide patients into three prognostic subgroups. Serum LDH proved to be a useful index of disease extent and therapy outcome. LDH levels at presentation were proportionately higher with more extensive tumor, measured by either the LD-ED or TNM staging. High LDH predicted poorer responses to chemotherapy and lower survival within similar stage subgroups compared to patients with normal LDH levels. The negative effect of elevated LDH was independent of hepatic involvement and did not predict subsequent hepatic failure in any consistent way. The SCCL TNM staging system proposed needs further refinement and should be tested with larger patient numbers. LDH, along with other tumor markers recently identified, need to be integrated into the staging system to form an overall prognostic index.
Aged↗
A randomized study of adjuvant chemotherapy for cancer of the upper aerodigestive tract.
A prospective, randomized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract (UAD) was conducted between July 1979 and September 1982. Eighty-three patients with locally advanced Stage III-IV tumors received standard treatment (STD RX; defined as preoperative irradiation and radical excision or irradiation alone), or induction chemotherapy (CTX) followed by STD RX. Chemotherapy consisted of two cycles of bleomycin (30 units/day by continuous infusions Days 1-4), cyclophosphamide (200 mg/m2 IV Days 1-5), methotrexate (30 mg/m2 Days 1 + 5), and 5-fluorouracil (400 mg/m2 IV Days 1-5). Response to CTX was complete in 2 and partial (greater than 50% reduction) in 27; the overall response rate was 68%. Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and/or surgery and in 24/43 CTX patients (17/29 responders, 7/14 non-responders). Freedom from local-regional disease was noted at 2 years in 53% STD RX and 35% CTX patients (p less than .06). CTX patients had a higher proportion of local-regional persistence and recurrence. The difference was apparent only in the subset of patients treated with primary irradiation; local-regional control following irradiation and surgery was equal in STD RX and CTX groups. Survival at 2 years was 43% STD RX and 31% CTX. Disease-free survival in those with clearance was 64% STD RX and 59% CTX. Induction chemotherapy did not improve tumor clearance or survival in this series. Caution regarding local-regional control with CTX and primary irradiation is noted.
Bleomycin↗
Is adenocarcinoma/large cell carcinoma the most radiocurable type of cancer of the lung?
Radiation therapy is widely considered the primary treatment for inoperable "non-small" cell carcinoma of the lung. In clinical investigations, distinction has been infrequent among the histopathologic subtypes of non-small cell carcinoma. Studies have shown significant differences between squamous cell carcinoma and adenocarcinoma/large cell carcinoma; adenocarcinoma/large cell carcinoma has a greater propensity for extrathoracic dissemination, especially to the brain, and it is less curable by resection when regional lymph node metastases are present. No differences have been documented between adenocarcinoma and large cell carcinoma. A retrospective study was undertaken to determine the results of definitive radiation therapy by histopathologic subtype of non-small cell carcinoma of the lung. Between July 1977 and April 1983, 134 patients with non-small cell carcinoma of the lung underwent definitive radiation therapy with curative intent. All patients had performance status scores of 80 to 100 (Karnofsky), and received minimum total doses within the tumor of 60 Gy in 6 to 7 weeks, five fractions per week. The median period of observation was 63 months. Ninety patients had squamous cell carcinoma; 44 had adenocarcinoma/large cell carcinoma. The two groups of patients were comparable in respect to age and Stage; there were significantly more women with adenocarcinoma/large cell carcinoma (27%) than with squamous cell carcinoma (13%). The median survival for patients with squamous cell carcinoma was 11.5 months; the 2 and 4 year survival rates were 21 and 7%, respectively. The median survival for patients with adenocarcinoma/large cell carcinoma was 18 months; 2 and 4 year survival rates were 38 and 23%, respectively. Comparison of the overall survival experience did not show a significant difference between the two cell types (p = .12 using Gehan's generalized Wilcoxon test). However, comparison of the proportion of patients with adenocarcinoma/large cell carcinoma surviving 18 months (50%) was significantly higher (p = .02) than that with squamous cell carcinoma (30%). A small body of data from the literature also suggests a better long-term prognosis for adenocarcinoma/large cell carcinoma. This observation requires confirmation from large trials with histopathologic review. If it is confirmed, there are important implications for therapeutic strategies in future clinical investigations of inoperable carcinoma of the lung.
Adenocarcinoma↗
Extended-field radiation therapy for prostatic carcinoma with para-aortic lymph node metastasis.
The finding of involvement of para-aortic lymph nodes in patients with adenocarcinoma of the prostate has been considered so ominous that further therapy has often only been palliative. What is the proportion of patients with carcinoma of the prostate with regional metastasis limited to the infra-diaphragmatic lymph nodes who might be cured or at least offered long-term progression-free survival by aggressive treatment? From June 1970 through March 1983, 114 patients were treated with curative intent for adenocarcinoma of the prostate, clinical Stage III, at the Medical College of Wisconsin Affiliated Hospitals. Twenty-three of these patients had evidence of metastasis to the para-aortic lymph nodes. These patients were treated aggressively with external radiation therapy to the entire pelvis and para-aortic region. The median dose to the prostate was 70 Gy, the pelvis 54 Gy, and the para-aortic region 50 Gy. The median period of observation after treatment was 53.5 months. The actuarial survival was 90% at 5 years and progression-free survival was 73% at 5 years. The rate of major complications was 4.3%. Although the number of patients is small, the data suggest that extended field radiation therapy can result in prolonged progression-free survival and perhaps cure many patients with juxtaregional dissemination of adenocarcinoma of the prostate.
Adenocarcinoma↗
Non-small cell lung cancer. Role of radiation therapy.
The most important role of radiation therapy for carcinoma of the lung is its contribution to cure. Important technical advances in radiation therapy have been made that, along with advances in understanding the natural history of cancer of the lung, permit treatment with a higher expectation of cure than previously. Studies of fractionation have defined the doses required for control of intrathoracic tumors, and ancillary studies have better defined the treatment volumes necessary. Operable patients benefit from postoperative irradiation only when there is involvement of regional lymph nodes. In inoperable cases, the greatest survival benefit from radiation therapy is found among those who have a high performance status. Patients with adenocarcinoma and large cell carcinoma have a greater probability of long-term survival than those with squamous carcinoma. Investigations of altered fractionation may lead to improved results in radiation therapy for all histopathologic types of carcinoma of the lung.
Adenocarcinoma↗
Treatment of cancer of the lung.
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Carcinoma, Small Cell↗
Cisplatin and etoposide before definitive radiation therapy for inoperable squamous carcinoma, adenocarcinoma, and large cell carcinoma of the lung: a phase I-II study of the Radiation Therapy Oncology Group.
A trial of "neoadjuvant" cisplatin-etoposide and radiation therapy was conducted by the Radiation Therapy Oncology Group for non-small cell carcinoma of the lung limited to the thorax. Thirty evaluable patients were studied: two achieved complete response and four achieved partial response after chemotherapy. All patients underwent radiation therapy as planned, with no unusual acute reactions. Sixteen patients had local failure, and 13 had distant metastasis. Twenty-seven patients are dead, two are alive with cancer, and one is clinically free of cancer at 145 weeks. Five of six patients who survived greater than or equal to 2 years after treatment had adenocarcinomas. There was no unexpected late toxicity. This combination of chemotherapy and radiotherapy is unlikely to improve results in the treatment of inoperable non-small cell carcinoma of the lung over those with radiotherapy alone.
Actuarial Analysis↗
Large-dose fractionation (hypofractionation).
Fractionation is a radiotherapeutic "modality" that may be manipulated to attempt to improve control of malignant tumors or to decrease effects on normal tissues. In addition, some fractionation regimen must be selected as the basis for addition of any other modality such as radiosensitizers or hyperthermia. Considerable literature derived from clinical experiences with reduced numbers of large fractions has become available in the last 15 years. A review of this literature is focused on tumor control and effects on normal tissues resulting from hypofractionation (fewer than five fractions/week), rapid fractionation (large daily fractions treated five times/week), and rapid split-course regimens that include a rest interval in the course of treatment. The evidence available indicates that a decrease in tumor control is associated with each of these large-dose fractionation approaches. At the same time, late effects on normal tissues are increased as the result of the large-sized fractions. The overall reduction in therapeutic ratio suggests that this avenue of clinical research should no longer be pursued and that such regimens should be adopted with caution for purposes of combining radiosensitizers or hyperthermia. Conversely, clinical research in radiotherapy justifiably can explore the effects of increased numbers of small fractions.
Clinical Trials as Topic↗
Combined methotrexate and high-dose vincristine chemotherapy with radiation therapy for small cell bronchogenic carcinoma.
The addition of methotrexate to a previously described regimen of cyclophosphamide, Adriamycin (doxorubicin), and high-dose vincristine (VAC) was tested in 50 evaluable patients with small cell bronchogenic carcinoma. Prophylactic whole brain radiation therapy was given during the first chemotherapy course and consolidation radiation therapy was given to the mediastinum and primary site after achieving partial or complete remission. The addition of methotrexate did not improve the incidence of complete remission as compared to a previous regimen without it. The addition of radiation therapy improved the local control rate. The high-dose vincristine in this and a previous CAV study improved the incidence of complete remission in both limited and extensive disease presentation as compared with the authors' previous experience and induced an acceptable and reversible neurotoxicity. Moderate dose consolidation radiotherapy to the lung primary and mediastinum was effective in improving local control. The distinction between limited and extensive disease was found to be vague, as 22% of the patients could be shifted from one group to the other depending on definition. The evaluation of the various staging procedures indicates that bone scan gave a small number of truly abnormal tests. Isotopic brain and liver-spleen scan could be duplicated by computerized axial tomography (CAT). CAT scan of abdomen disclosed unexpected extension to the retroperitoneal nodes and adrenals. It is concluded that radionuclide studies of brain, liver-spleen, and bone can be eliminated and can be replaced by CAT scan of brain, chest, and abdomen. Site of recurrence indicate that most intrathoracic recurrences took place outside the radiation therapy field and in the pleural space. An incidental finding was the high incidence of intramedullary spinal cord recurrence.
Adult↗
Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: preliminary report of a RTOG Pilot Study.
Patients with localized unresectable non-oat cell carcinoma of the lung were treated by supervoltage radiation therapy to the primary tumor, mediastinum and supraclavicular lymph nodes with 50.4 Gy, 42 fractions of 1.2 Gy, twice daily, 4 to 6 hours apart, 5 times a week. Small field treatment to the known involved areas of primary and lymph nodes was given from 9.6 to 24 Gy, also with 1.2 Gy, twice daily. One hundred twenty-five patients were entered, three of whom were cancelled and two were ineligible. Of the remaining 120 eligible patients, 10 patients received a dose of 50.4 Gy, 20 received 60.0 Gy, 79 received 69.6 Gy and 11 patients received 74.4 Gy. Of these, nine patients were unable to complete hyperfractionated radiation therapy for various reasons. Treatment was discontinued or stopped in 14 patients because of early death or deterioration of the patient's condition. Four additional patients were found to have unacceptable doses to tumor or normal tissues, for a total of 27 patients with protocol violations. Complete regression occurred in 19% of T1-T3, N0-N2 patients with 9% among T3.3b, T4 or N3 patients. Partial regression was 29 and 41%, respectively. There were six cases of severe and two of life-threatening toxicity, but there were no fatalities attributable to the treatment. Toxicity consisted mainly of pneumonitis and pulmonary fibrosis as well as esophagitis. Median survival of the entire group was 7.2 months, which is consistent with previous experience with the treatment of localized inoperable non-oat cell carcinoma of the lung by radiation therapy. Further study of this method of treatment is warranted.
Adenocarcinoma↗
Computed tomography in the staging of small cell lung cancer: implications for combined modality therapy.
Computed tomography of the thorax and abdomen, from the thoracic inlet to the renal hila, was performed as part of initial staging in 51 patients with small cell carcinoma of the lung (SCCL). The computed tomographic (CT) scans were repeated after completion of chemotherapy, as part of routine restaging and assessment of response to therapy. To identify the ways in which CT scanning uniquely benefited evaluation of initial disease extent in comparison to other diagnostic studies exclusive of CT scan, all diagnostic and clinical data were reviewed. CT scan identified more advanced intrathoracic disease than chest radiography in 82% of patients. Mediastinal node involvement not appreciated by chest radiography was seen in 61% of patients. Adrenal and retroperitoneal node involvement, not suspected by other studies, was identified by CT scan in 31% and 12% of patients, respectively. Thirty percent of the patients staged as limited disease (LD) were advanced to extensive disease (ED) by CT scan findings. While confirmation, by biopsy, of positive CT findings was not consistently accomplished, restaging CT scans provided indirect confirmation by displaying improvement or worsening that correlated with disease regression or progression. Thoraco-abdominal CT scanning more accurately identifies the extent of small cell carcinoma than other imaging procedures. This has important implications for reporting results by extent of disease. In addition, CT more accurately identifies the magnitude of intrathoracic primary and nodal tumors, which may influence the choice and conduct of local treatment--surgery and/or radiation therapy--in combination with systemic chemotherapy.
Carcinoma, Small Cell↗
Radiotherapy for lung cancer.
The role of radiation therapy in the management of lung cancer was reviewed at a workshop held in Cambridge, England, in June 1984. It was concluded that there was a continuing role for radiation therapy in the primary management of small cell lung cancer, including the loco-regional treatment for patients with limited disease. Radical radiotherapy for patients with non-small cell carcinoma could be curative for a proportion of patients with limited disease. Careful planning and quality control was essential. Palliative radiotherapy provided useful treatment for many other patients. Other related aspects of treatment are also presented.
Brain Neoplasms↗
Training in therapeutic radiology in the United States, 1984.
The 1984 survey of training programs in Therapeutic Radiology in the United States revealed little change in the number of training programs and the number of residency positions offered. However, there has been a striking increase in the number of residents in training since the survey of 1982. The numbers of residents training in the PG-II and PG-III years are more than 50% greater than any previous survey. The proportion of foreign medical graduates is smaller than reported in 1982, but the proportion of women in residency is unchanged.
Directories as Topic↗