Biomedical subjects

D C Ihde

Publications and source records attributed to D C Ihde.

At least 91 records · Page 5Linked to original sources

PubMed1986

Non-small-cell lung cancer. Major cause of late mortality in patients with small cell lung cancer.

Among 360 patients with small cell lung cancer treated in National Cancer Institute therapeutic trials from 1973 to 1982, 40 were two-year cancer-free survivors. Of these 40 patients, six had later development of non-small-cell lung cancer at 3.5 to 8.0 years (median 5.1) after the diagnosis of small cell lung cancer. Three had the second malignant tumor in the contralateral lung, one in a different lobe, and two in the same lobe as the initial small cell lung cancer. Ten patients had relapses of small cell lung cancer at 2.1 to 6.2 years (median 3.2) from diagnosis. Three recurrences were in the same site or lobe as the initial lesion, four in the same lobe and in sites outside the thorax, and three solely in sites outside the thorax. It is concluded that these non-small-cell lung cancers usually represent second primary lung tumors and that most late small cell lung cancers represent relapses occurring up to 6.2 years from diagnosis. In this study, the risk of development of non-small-cell lung cancer after two years of disease-free survival following small cell lung cancer is 4.4 percent per person-year, approximately 10 times higher than the rate of 0.5 percent previously determined in screening studies of men at high risk for lung cancer. Non-small-cell lung cancer represents more than a third of lung cancer deaths in patients with small cell lung cancer surviving beyond two years from diagnosis and more than half of lung cancer deaths beyond three years. It is recommended that all patients treated for small cell lung cancer discontinue smoking.

Adult↗

PubMed1986

The effect of combined modality therapy on local control and survival.

The systemic component of combined modality therapeutic programs has influenced both the selection of the approach to local control and survival in a number of tumor types. The more effective systemic therapy is against metastatic cancer by itself, the greater the impact on local control and survival. This observation is consistent with the invariable inverse relationship between curability and tumor cell number. For some common cancers, local control is good, but survival remains poor because of the inability to deal effectively with micrometastases. Improved systemic treatment is likely to have an impact on survival may shift local control measures, in some cases, to radiation therapy or lesser surgery without radiation therapy. There remains a substantial number of tumor types where both local control and survival is poor. In these tumors, improvement in local control by itself is not likely to improve survival because of the presence of micrometastases, but such improvements must occur before we can have a true evaluation of the systemic treatment of micrometastases in these tumors. The recent understanding that the metastatic process is under genetic control and the cloning of metastases genes offers a substantial opportunity to control this process and influence both local control and survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1986

Molecular genetic analysis reveals chromosomal deletion, gene amplification, and autocrine growth factor production in the pathogenesis of human lung cancer.

These studies of lung cancer suggest that a number of molecular mechanisms may be important in the pathogenesis of lung cancer, especially SCLC. An inherited predisposition to develop SCLC may correlate with a nonfunctional, recessive allele for a gene (McKusick #18228, McKusick 1986) that maps to chromosome region 3p(14-23). Individuals at risk would be heterozygous for this allele in their germ line, carrying one copy of a normal functional gene and one mutant, recessive allele. Exposure to carcinogens, in particular cigarette smoke, can produce somatic genetic changes such as chromosomal deletion or gene mutation in the functional allele of this gene, unmasking the nonfunctional allele. Loss of this normal gene may alter the regulation of cell growth, perhaps by allowing the deregulated expression of proto-oncogenes of the myc family, or autocrine growth factors such as GRP and/or its receptor. Alternatively, loss of this gene may result in the cell returning to a less differentiated developmental state where growth regulation is less stringent. Persons with this mutant gene should be at increased risk to develop SCLC, and further RFLP analysis of the 3p region in SCLC may allow identification of specific haplotypes with increased risk of developing lung cancer. If this notion is correct, one might expect to find an increased frequency of second tumors in lung cancer patients and the presence of similar chromosomal deletions in second tumors arising in SCLC patients. In this regard, cured lung cancer patients, including those with SCLC, have a tenfold increased risk of developing a second lung cancer (Fontana 1977; Cortese et al. 1983; Johnson et al. 1986b). In fact, a chromosome 3p deletion along with other chromosomal abnormalities was identified in acute erythroleukemia cells arising in a long-term survivor of SCLC (Bradley et al. 1982), implicating this same region in the pathogenesis of both tumors. Other predictions include the correction of at least a portion of the defect by introducing a normal chromosome 3 into SCLC cells. While c-myc is expressed in many fetal and adult tissues, high-level expression of N- and L-myc is very restricted as to tissue and stage in the developing mouse, with N-myc expressed in the fetal but not adult lung, whereas the lung was the only adult tissue where L-myc expression was detected (Zimmerman et al. 1986). Could these patterns provide a clue to the differential expression of c-, N-, and L-myc found in different lung cancers (Nau et al. 1986)?(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Differentiation↗

PubMed1986

Late intensive combined modality therapy followed by autologous bone marrow infusion in extensive-stage small-cell lung cancer.

To attempt to improve the poor prognosis of extensive-stage small-cell lung cancer (SCLC) patients, we tried to administer late intensive combined modality therapy (LICMRX) to patients with good tumor regression after 12 weeks of conventional chemotherapy. Twenty-nine consecutive extensive-stage SCLC patients received 6 weeks of cyclophosphamide, methotrexate, and lomustine (CMC) induction therapy, followed by 6 weeks of vincristine, doxorubicin, and procarbazine (VAP). After restaging for assessment of tumor response, autologous bone marrow (ABM) was collected in patients in good medical condition with complete response (CR) or partial response (PR) and no tumor on marrow examination. LICMRX consisted of irradiation with 2,000 rad in five fractions for five days to sites of initial tumor involvement, followed by cyclophosphamide, 60 mg/kg for 2 days, and etoposide, 200 mg/m2 for 3 days and then by ABM infusion. Prophylactic cranial irradiation (PCI) was administered thereafter, but no further chemotherapy was used. Due to lack of tumor regression or poor medical condition, only ten of the original 29 patients were eligible for LICMRX; two refused, so only eight (28%) received therapy. Three patients who began LICMRX in CR developed recurrence of SCLC after an additional 4, 8, and 15 months. Of five patients with PR, one attained CR but relapsed at 3 months, two remained in PR and progressed at 2 and 4 months, and two died of infection without recovery from LICMRX. Mean time from ABM infusion to recovery of granulocyte count to 500/microL was 15.8 days in the six surviving patients (range, 12-22). The major non-hematologic toxicity of LICMRX was severe esophagitis. Among all 29 patients, there were six CRs (21%) and no 2-year survivors, compared with a CR rate of 36% and 10% 2-year survivors in 78 extensive-stage patients previously treated with CMC plus VAP without LICMRX. We conclude that the LICMRX given in this study can be administered to only a minority of extensive-stage SCLC patients and is very unlikely to yield substantial improvement in the fraction of 2-year survivors (95% confidence limits for 2-year survival 0% to 10%).

Adult↗

PubMed1986

Etoposide (VP-16) and cisplatin in previously treated small-cell lung cancer: clinical trial and in vitro correlates.

Treatment of patients with relapsed small-cell lung cancer (SCLC) has been uniformly unsuccessful. Recently, the combination of etoposide (VP-16) and cisplatin in this setting has been reported to result in up to 50% response rates. We treated 29 patients with relapsed SCLC with this combination and found only a 12% response rate. The discrepancy between our results and those of others is most likely due to differences in prior treatment of the patients, although the effect of dose and schedule modifications are considered. Our patients had received a six-drug regimen over a median of 7 months and had a median drug-free interval before this treatment of only 3 weeks. Evidence is presented that suggests that this aggressive initial therapy affected both host tolerance to further treatment and the development of tumor resistance at the cellular level.

Adult↗

PubMed1986

Combined modality treatment of cutaneous T cell lymphoma: results of a 6-year follow-up.

Thirty-nine patients with cutaneous T cell lymphoma (CTCL; including mycosis fungoides or the Sezary syndrome) with no previous treatment other than topical therapy or oral corticosteroids, received total skin electron beam irradiation (TSEB) and either sequential or simultaneous systemic chemotherapy. Median follow-up, measured from the time of initiation of therapy to the time of analysis, is in excess of 6 years and extends to 100+ months. Thirteen patients with stage I disease (limited to skin with no adenopathy) received 3,000 rad total skin electron beam irradiation followed by three 2-week courses of daily intravenous (IV) mechlorethamine. Twenty-six patients with advanced disease (stage II-IV) received 2,400 rad of TSEB and simultaneous chemotherapy with two alternating three-drug regimens: vinblastine, doxorubicin, and bleomycin (VAB) alternating with cyclophosphamide, methotrexate, and prednisone (CMP) administered over 54 weeks. The overall response rate was 92% with 16 of 39 patients (41%) achieving a histologically documented complete response (CR). Stage I patients had a significantly increased CR rate (77%) compared with stage II-IV (P less than .01). The overall 6-year survival was 92% for stage I patients and 26% for stage II-IV patients (23%) (P less than .001). Among ten completely responding stage I patients, six remain alive and disease-free in excess of 72 months. The median disease-free survival is 26 months for completely responding stage II-IV patients (P = .04), but none are continuous disease-free survivors after protocol treatment. We conclude that combined modality treatment can be safely administered and produces prolonged disease-free survival in some stage I patients, but not in more advanced stage patients.

Adult↗

PubMed1986

A trial of combination chemotherapy followed by hormonal therapy for previously untreated metastatic carcinoma of the prostate.

We administered combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin to 25 previously untreated patients with metastatic prostate cancer in order to assess the efficacy of chemotherapy before any hormonal manipulation. Hormonal therapy was administered only after progression of disease to chemotherapy. All 25 patients were followed until time of death and all were able to receive hormonal therapy. We did not find substantially improved response rates when combination chemotherapy was applied before endocrine treatment since the 33% objective response rate to chemotherapy was only minimally higher than the response in our patients who had failed hormonal therapy and then received identical or similar chemotherapy. Furthermore, the introduction of intensive combination chemotherapy before hormonal therapy in our study did not result in any striking improvement in overall survival compared with patients who received initial hormonal therapy in many other studies. Responses to chemotherapy were not attributable to suppression of serum testosterone since all 12 patients with partial response (PR) or stable disease (SD) and four of seven patients with no response (NR) had normal testosterone levels at the time of response assessment. The initial use of chemotherapy did not adversely affect the expected high percentage of objective responses (68%) to subsequent hormonal manipulation. The frequency, duration, and quality of responses to hormonal therapy exceeded the responses to chemotherapy. The disappointing responses to chemotherapy reflect the very modest efficacy of even aggressively delivered cytotoxic agents.

Adenocarcinoma↗

PubMed1986

Excess prevalence of Pneumocystis carinii pneumonia in patients treated for lymphoma with combination chemotherapy.

A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.

Adult↗

PubMed1985

The role of radiation therapy in the treatment of small cell lung cancer.

Patients with small cell lung cancer (SCLC) are candidates for aggressive therapy because of their potential for long-term survival, especially patients with limited-stage disease. Although no treatment protocol can be considered "standard", the best results in limited-stage SCLC appear to be produced by a combination of chemotherapy and thoracic irradiation. Ongoing protocols testing the efficacy of thoracic irradiation should be able to settle question of the optimal treatment approach in limited-stage SCLC over the next 1 to 2 years. Careful attention to volume treated and the use of shrinking fields produce the best results with the minimum of toxicity. Treatment of extensive-stage SCLC has not been substantially improved to date with the addition of local or systemic irradiation. Prophylactic cranial irradiation reduces the incidence of CNS failure in SCLC and should be given, at a minimum, to patients achieving complete response status. Whether patients with partial response should also receive prophylactic cranial irradiation remains controversial. Finally, half-body radiation in SCLC is an experimental research technique that has shown some promise but remains quite toxic when combined with systemic chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1985

Phase I and pharmacokinetic study of tiazofurin (TCAR, NSC 286193) administered by continuous infusion.

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M2. Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 +/- 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.

Adult↗

PubMed1985

Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Identification of two groups of patients with prospects for prolonged survival.

Among 37 patients with hepatocellular carcinoma given systemic chemotherapy, 12 (32 percent) lived 14 to 37 months from initiation of treatment whereas the remainder died within five months. Individual factors associated with improved survival included fully ambulatory performance status, lack of jaundice, response to chemotherapy, the fibrolamellar carcinoma pathologic variant, absence of cirrhosis, and normal serum alpha-fetoprotein levels. Patients living longer than 12 months fell into two groups. Seven patients with fibrolamellar carcinoma lacked evidence of hepatitis B serum markers or cirrhosis and had normal alpha-fetoprotein levels and surprisingly frequent extrahepatic metastases. All but one were Caucasians aged 25 years or less. The other five "long-term" survivors were all fully ambulatory without jaundice, and the majority were older non-Caucasians with tumor confined to the liver at the time of diagnosis and with hepatitis B markers, elevated alpha-fetoprotein levels, or cirrhosis. All patients without fibrolamellar carcinoma who were less than fully ambulatory or who had jaundice died quickly. Patients with fibrolamellar carcinoma have homogeneous clinical features, and their disease follows a relatively indolent course. In other patients with hepatocellular carcinoma, assessment of ambulatory status and serum bilirubin determination can identify those with some prospect of prolonged survival.

Adolescent↗

PubMed1985

Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer.

In order to evaluate the relationship between neurologic function and cranial irradiation, 20 patients treated on National Cancer Institute (NCI) small-cell lung cancer (SCLC) trials who were alive and free of cancer 2.4 to 10.6 years (median, 6.2) from the start of therapy were studied. All were tested with a neurologic history and examination, mental status examination, neuropsychologic testing, and review of serial computed cranial tomography (CCT) scans. Fifteen patients had been treated with prophylactic cranial irradiation (PCI), two patients with therapeutic cranial irradiation, and three received no cranial irradiation. All patients but one were ambulatory and none were institutionalized. Fifteen patients (75%) had neurologic complaints, 13 (65%) had abnormal neurologic examinations, 12 (60%) had abnormal mental status examinations, 13 (65%) had abnormal neuropsychologic testing, and 15 (75%) had abnormal CCT scans. Compared with those given low-dose maintenance chemotherapy during PCI using 200 to 300 rad per fraction, patients who were given high-dose induction chemotherapy during the time of cranial irradiation or large radiotherapy fractions (400 rad) were more likely to have abnormal mental status examinations (6/6 v 4/9) and abnormal neuropsychologic tests (6/6 v 4/9), but no major difference in CCT findings was present. CCT scans in the majority of cases (11/18) showed progressive ventricular dilatation or cerebral atrophy up to 8 years after stopping therapy. We conclude neurologic abnormalities are common in long-term survivors of SCLC, and may be more prominent in patients given high-dose chemotherapy during cranial irradiation or treated with large radiotherapy fractions. The CCT scan abnormalities are common and progressive years after prophylactic cranial irradiation and chemotherapy are stopped.

Adult↗

PubMed1985

Patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. Data on potential cures, chronic toxicities, and late relapses after a five- to eleven-year follow-up.

We assessed the outcome in 252 patients with small-cell lung cancer 5 to 11 years after treatment with combination chemotherapy, with or without chest and cranial irradiation, in National Cancer Institute therapeutic trials from 1973 through 1978. Twenty-eight patients (11%) survived free of cancer for 30 months or more. Fourteen patients remain alive without evidence of cancer beyond 5 years (range, 6.4 to 11.3 years), and 7 patients have returned to a lifestyle similar to that before diagnosis. The other 14 patients who were cancer-free at 30 months have developed cancer or died; 6 patients had a relapse, 4 developed or died from non-small-cell lung cancer, and 4 died of unrelated causes. A few patients with small-cell lung cancer (5.6%) may be cured. Thirty-month, cancer-free survival is insufficient to show a cure. Although late toxicities are troublesome, they do not outweigh the benefits of prolonged survival and potential for cure with modern aggressive therapy in small-cell lung cancer.

Adult↗

PubMed1985

Assessment of serum radioimmune and enzymatic prostatic acid phosphatase and radioimmune creatine kinase BB for monitoring response to therapy in metastatic prostatic carcinoma.

Objective documentation of tumor response in patients with metastatic prostatic cancer is difficult. To evaluate a radioimmunoassay for creatine kinase BB, two commercial radioimmunoassays for prostatic acid phosphatase, and an enzymatic acid phosphatase measurement in monitoring the status of advanced prostatic carcinoma, we assayed sera from 34 patients with Stage D-2 disease prior to and during systemic treatment with combination chemotherapy or hormonal manipulation. Prior to treatment, the creatine kinase BB level was elevated less often (48%) than all three assays for acid phosphatase (83 to 91%). During therapy, all four test results both increased and decreased whether the patients were responding to or progressing on therapy. Test results usually declined when patients had documented responses to therapy, particularly when hormonal therapy was used. However, when patients progressed on therapy, test results also declined at least as often as they increased. No test was consistent enough to serve as a sole indication of tumor response. The three acid phosphatase assays performed similarly, with no evident advantage of radioimmunoassay over the enzymatic assay. Creatine kinase BB was generally inferior to all three acid phosphatase assays.

Acid Phosphatase↗

PubMed1984

Current status of therapy for small cell carcinoma of the lung.

Small cell carcinoma of the lung (SCCL) is distinguished from other types of lung cancer by its propensity for early development of distant metastases and its rapidly fatal clinical course in the absence of treatment. The introduction of chemotherapy into the management of SCCL has led to a four- to five-fold improvement in median survival and to the cure of a small proportion of patients with this disease. Employment of three- or four-drug regimens with or without chest irradiation in moderately intensive doses for periods of 12 months or less has proven to be the optimal therapeutic strategy with currently available agents. Despite these substantial gains, it is obvious that the vast majority of SCCL patients are continuing to die from their cancer, and a slowing in the pace of treatment advances has become apparent over the past 5 years. This article reviews current areas of active clinical investigation in SCCL and some information developed in the cell biology laboratory that may have eventual application in the clinic.

Antineoplastic Agents↗

PubMed1984

Small cell lung cancer 1973-1983: early progress and recent obstacles.

The recognition that the vast majority of patients with small cell lung cancer have distant metastatic disease at the time of diagnosis led to the use of systemic chemotherapy and consequent major improvements in survival in the early to mid-1970's. In the past five years, however, the pace of therapeutic advances has slowed. Recently evaluated treatment strategies, including more intensive induction chemotherapy, "late intensive" therapy of responding patients, alternation of chemotherapeutic regimens, integration of chest irradiation with drug therapy, large field irradiation, and reappraisal of the value of surgical resection, are discussed in this review. Advances in understanding of the cell biology of small cell lung cancer which may eventually lead to new forms of treatment are summarized.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

Combination chemotherapy with doxorubicin and mitomycin C in non-small cell bronchogenic carcinoma. Severe pulmonary toxicity from q 3 weekly mitomycin C.

Forty-five patients with advanced, measurable, or evaluable non-small bronchogenic carcinoma (NSCBC) were treated with doxorubicin and mitomycin C combination chemotherapy. The first 27 patients received doxorubicin 50 mg/m2 I.V. every 3 weeks and mitomycin C 10 mg/m2 I.V. every 3 weeks. Because of severe cardiopulmonary toxicity in seven patients, with four otherwise unexplained deaths, the next 18 patients were treated with the mitomycin C dose reduced to 10 mg/m2 every 6 weeks. Overall, 11 patients (25%) responded, with one complete and 10 partial remissions. Eight responses (30%) were observed in the patients who received mitomycin C every 3 weeks and three responses (17%) were found in those given mitomycin C every 6 weeks (p less than 0.5), with no cardiopulmonary toxicity in the latter group. The median survival was 21 weeks for the entire group of patients, with the group receiving mitomycin C every 3 weeks living a median of 15.5 weeks and those given mitomycin C every 6 weeks surviving 35.5 weeks (p less than 0.025). We conclude that there is a higher tumor response rate but more cardiopulmonary toxicity and shorter survival among the group receiving mitomycin C every 3 weeks compared to those receiving mitomycin C every 6 weeks. Future studies should consider this toxicity of mitomycin C administered on an every-3-week schedule.

Adult↗

PubMed1984

Diagnosis and significance of liver metastases in small cell carcinoma of the lung.

One hundred fifty-seven consecutive patients with small cell lung cancer seen at the National Cancer Institute over a four-year period underwent a series of pretherapy liver staging procedures to determine optimal means of detection and prognostic implications of hepatic metastases. Liver evaluation included physical examination, liver function tests, and liver scan (radionuclide or computerized tomography [CT]), as well as percutaneous and/or peritoneoscopy-directed liver biopsy when possible (74%). Liver metastases were detected in 26% of patients. Peritoneoscopy was the most sensitive method of liver evaluation and increased the detection of liver metastases when done in a sequential fashion after percutaneous liver biopsy from 18 to a total of 27 patients. Of the noninvasive procedures, radionuclide and CT liver scan were the most accurate concurring with liver biopsy in 87% of patients but permitting correct discrimination of stage in excess of 96% of patients. The accuracy of this noninvasive procedure was enhanced by an algorithm combining the results of radionuclide liver scan with liver function tests to detect patients with high or low likelihood of liver involvement. The survival and response of patients with liver metastases was significantly worse than those without such metastases with no three-year disease-free survivors among patients with liver metastases.

Actuarial Analysis↗