Intergenerational effects of racism on amygdala and hippocampus resting state functional connectivity.

Racism is an insidious problem with far-reaching effects on the lives of Black, Indigenous, and People of Color (BIPOC). The pervasive negative impact of racism on mental health is well documented. However, less is known about the potential downstream impacts of maternal experiences of racism on offspring neurodevelopment. This study sought to examine evidence for a biological pathway of intergenerational transmission of racism-related trauma. This study examined the effects of self-reported maternal experiences of racism on resting state functional connectivity (rsFC) in n = 25 neonates (13 female, 12 male) birthed by BIPOC mothers. Amygdala and hippocampus are brain regions involved in fear, memory, and anxiety, and are central nodes in brain networks associated with trauma-related change. We used average scores on the Experiences of Racism Scale as a continuous, voxel-wise regressor in seed-based, whole-brain connectivity analysis of anatomically defined amygdala and hippocampus seed regions of interest. All analyses controlled for infant sex and gestational age at the 2-week scanning session. More maternal racism-related experiences were associated with (1) stronger right amygdala rsFC with visual cortex and thalamus; and (2) stronger hippocampus rsFC with visual cortex and a temporo-parietal network, in neonates. The results of this research have implications for understanding how maternal experiences of racism may alter neurodevelopment, and for related social policy.

GLT-1 overexpression attenuates bladder nociception and local/cross-organ sensitization of bladder nociception.

Glutamatergic pathways mediate transmission of pain. Strategies to reduce glutamatergic neurotransmission may have beneficial effects to mitigate nociception. Recent work revealed that overexpression of the astrocytic glutamate transporter (GLT-1) by transgenic or pharmacologic approaches produced a diminished visceral nociceptive response to colonic distension. The purpose of this study was to determine the effect of GLT-1 overexpression on the visceromotor response to bladder distension. Increased glutamate uptake activity produced by 1-wk ceftriaxone (CTX) treatment attenuated 60-64% the visceromotor response to graded bladder distension compared with vehicle-treated mice. One-hour pretreatment with selective GLT-1 antagonist dihydrokainate reversed the blunted visceromotor response to bladder distension produced by 1-wk CTX, suggesting that GLT-1 overexpression mediated the analgesic effect of CTX. Moreover, sensitization of the visceromotor response to bladder distension produced by local bladder irritation (acrolein) was also attenuated by 1-wk CTX treatment. A model of cross-organ sensitization of bladder visceromotor response to distension was next studied to determine whether increased expression of GLT-1 can mitigate colon to bladder sensitization. Intracolonic trinitrobenzene sulfonic acid (TNBS) administered 1 h before eliciting the visceromotor response to graded bladder distension produced a 75-138% increase in visceromotor response compared with animals receiving intracolonic vehicle. In marked contrast, animals treated with 1-wk CTX + intracolonic TNBS showed no enhanced visceromotor response compared with the 1-wk vehicle + intracolonic vehicle group. The study suggests that GLT-1 overexpression attenuates the visceromotor response to bladder distension and both local irritant-induced and cross-organ-sensitized visceromotor response to bladder distension.

Antioxidants attenuate multiple phases of formalin-induced nociceptive response in mice.

An emerging theme in the study of the pathophysiology of chronic and persistent pain is the role of pro-oxidant substances. Reactive oxygen species (ROS) have been implicated in contributing to and/or maintaining conditions of chronic pain. Recent pre-clinical reports suggest that antioxidants are effective analgesics in neuropathic and inflammatory pain models. The present study extends this work by examining the effect of three antioxidants on tissue injury-induced nociception. C57BL6 mice (20-25 g) were pretreated with either phenyl-N-tert-butylnitrone (PBN; 50 mg/kg, i.p.), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy (TEMPOL; 200 or 50 mg/kg, i.p.), N-acetyl-L-cysteine (NAC; 200 or 100mg/kg, i.p.), or vehicle (0.5 ml/100 g), 5 min before intraplantar formalin (10%, 20 microl) injection. Nociceptive responding, indicated by licking or biting the affected hindlimb, was quantified for 30 min after formalin injection. Each drug was effective in attenuating two or more phases (acute, quiescent, and tonic) of the formalin response. To assess putative site of action, intrathecal TEMPOL (380 nmol/5 microl, i.t.) was given 5 min before intraplantar formalin. Intrathecal TEMPOL produced a 83% reduction in nociceptive responding in the tonic phase, but no significant attenuation of the acute phase response. To confirm that the antioxidant property of intrathecal TEMPOL was responsible for its analgesic effect on the formalin-induced pain response, intrathecal TEMPOL was coadministered with the free radical donor tert-butylhydroperoxide (tert-BuOOH). Tert-BuOOH coadminstration reversed the TEMPOL-induced analgesia in the tonic intraplantar formalin response reduction. The data suggest that pro-oxidant species may be important mediators of tissue injury-induced algesia in rodents, and that a spinal site of action is implicated in the tonic response.

Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study.

Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible, patients must have had one previous chemotherapy regimen, and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin, 13% with bisantrene, and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin, 66 days with bisantrene, and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin, 290 days for bisantrene, and 177 days for mitoxantrone (logrank P = .04), although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin, and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting, mucositis, and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction, as defined by moderate to severe Alexander grade changes, was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%, bisantrene-treated patients = 5%, and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents, but at a cost of increased toxicity.

The conformation of angiotensin II. II. The rates of peptide NH exchange with solvent for [Asn1, Val5]angiotensin II, angiotensin III and saralasin.

The amide hydrogen exchange rates in H2O of two angiotensin agonists (angiotensinamide and angiotensin III) and one angiotensin antagonist (saralasin) have been measured at room temperature by the transfer of solvent saturation method. The NH of His6 is observed to exchange more slowly than predicted for all three peptides, suggesting that it is a participant in an intramolecular hydrogen bond. The NH-C alpha H 1H-NMR coupling constants are measured and found to be constant over the pH range of 5.0 to 6.5. The results are compared with those previously obtained for human angiotensin II and interpreted in terms of a dominant three-dimensional structure common to all four molecules. Two models for this structure are evaluated using the observed NH-C alpha H coupling constants and the reported activity of conformationally restrained derivatives.

Proton NMR investigation of Ln3+ complexes of thymopoietin 32-36.

The pentapeptide Arg-Lys-Asp-Val-Tyr (TP5) is a biologically active fragment of thymopoietin, the thymic hormone that induces selective T-cell differentiation. The formation of lanthanide(III) complexes of TP5 is demonstrated through the observation of Tb3+ fluorescence enhancement. The equilibria, stoichiometry and solution conformation of the La3+, Pr3+ and Yb3+ complexes of TP5 have been investigated using NMR spectroscopy. In addition, the dissociation constants of two methyl ester analogs of TP5 have been studied. Evidence is presented supporting an interaction between the arginine guanidino N epsilon H and the aspartate carboxylate of TP5. Binding of Ln3+ appears to be accompanied by a disruption (or weakening) of this interaction and a concomitant increase in the 180 degrees rotamer population for the aspartate carboxylate group. The observed trends in the magnitudes of the dissociation constants and the rotamer populations appear to suggest that, although a significant amount of monodentate complexes may also exist, the metal ion binds predominantly to both carboxylates in a bidentate fashion.

Vindesine in patients with metastatic malignant melanoma: a Southwest Oncology Group study.

A phase II study using vindesine (3 mg/m2 by slow intravenous push at seven to 14 day intervals) was carried out in 42 patients with metastatic melanoma. There was one complete remission (2.5%) of greater than 12 months duration; seven partial remissions (17.5%) of two, three, three, four, five, six and eight months duration; 11 with no change (27.5%) of one to 10 months duration; and 21 (52.5%) patients with increasing disease. Toxicity included neutropenia, neurotoxicity, phlebitis and cellulitis at the site of injection, alopecia, fever and chills, myalgias, and gastrointestinal toxicity. It was concluded that vindesine does have activity in some patients with metastatic malignant melanoma. Further studies in previously untreated patients are warranted.

Objective antitumor activity of acivicin in patients with recurrent CNS malignancies: a Southwest Oncology Group trial.

Acivicin (AT-125) is a glutamine antagonist with dose-limiting, schedule-dependent CNS toxicity and predictable CSF penetration after intravenous administration. Because of these properties, a trial in CNS malignancies was initiated. Thirty-two patients with recurrent or residual malignant astrocytomas were treated with AT-125. The majority of patients had glioblastoma multiforme (24) and had received prior nitrosoureas (21). The median age was 50 years, and Southwest Oncology Group (SWOG) performance status was 2. The major determinant of response was based upon radiologic criteria using computed tomographic (CT) scanning and/or magnetic resonance imaging (MRI) scans. The tumor mass was measured in two perpendicular planes, which yielded the largest cross-sectional area. Standard solid tumor criteria for response were used. All responding patients also had a stable or tapered dose of corticosteroids with stable or improved performance status and neurologic examination. There were four objective responses (12%): one complete remission (3 1/2+ years) and three partial remissions (57, 86, and 322 days). Two patients had improvement in disease that did not meet requirements for a partial remission. Toxicity was mild and primarily consisted of nausea, vomiting, and lethargy. Two patients were removed from study due to neurotoxicity (depression and hallucinations). The strict response criteria used in this trial were not those that have been used in testing other active agents such as carmustine (BCNU). We conclude that AT-125 has objective antitumor activity in malignant astrocytomas and warrants further study.

Treatment of small-cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group pilot study.

We designed an intensive, weekly treatment regimen for patients with small-cell lung cancer (SCLC) using six of the most active chemotherapeutic agents for this disease (doxorubicin [DOX], cyclophosphamide [CTX], vincristine [VCR], etoposide [VP-16], cisplatin [CDDP], and methotrexate [MTX]). The goal of this program was to gain rapid, repetitive exposure to multiple, active drugs. Treatment was administered weekly for a total of 16 weeks. Seventy-six SCLC patients (limited disease, 34; extensive disease, 42) were treated. The overall complete plus partial response rate was 82%. Complete response rates of 47% and 38% were observed in patients with limited (LD) and extensive disease (ED), respectively. The median survivals for patients with LD and ED were 16.6 and 11.4 months, respectively. Toxicities were tolerable and were primarily hematologic. Twenty-six patients had one or more transient life-threatening toxicities, but only one patient developed a fatal toxicity. Eighty-four percent of the patients received 80% or greater of the intended protocol dosages over the entire 16-week treatment period. We conclude that this intensive, short-duration treatment regimen is at least as good as other "standard" regimens, and we are encouraged aged by the complete response rate and median survival in patients with ED SCLC.

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study.

PURPOSE: Previous reports of chemotherapy in patients with adrenal cancer have described responses to cisplatin (CDDP). Because of these reports of good results, a phase II trial that used CDDP with and without mitotane (o,p'DDD) was initiated. PATIENTS AND METHODS: Patients with metastatic or residual adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities were divided into good-risk and poor-risk categories. The latter received CDDP 100 mg/m2 intravenously, and the former received 75 mg/m2. o,p'DDD was administered at a 1,000-mg dose orally four times a day along with cortisone acetate and Florinef (fludrocortisone acetate; Bristol-Myers Squibb Co, Princeton, NJ). RESULTS: Of a total of 42 patients entered onto the study, 37 were eligible. Twenty-nine patients received good-risk and eight received poor-risk doses of CDDP. Functioning tumors were present in 45% of patients. Objective responses were noted in 30% (11 of 37) patients (95% confidence interval, 16% to 50%). Response duration was 7.9 months, and the median time to response was 76 days. The median survival of the 37 eligible patients was 11.8 months, and a significant survival advantage was found for patients who underwent prior surgical removal of their primary tumor or bulky disease, who had a performance status of 0 or 1, or who had synchronous metastatic disease. Toxicity of the CDDP and o,p'DDD combination was moderate to severe, and the most common side effects were gastrointestinal, renal, and neurologic. CONCLUSION: The regimen of CDDP and o,p'DDD has activity in patients with adrenocortical carcinoma; however, the toxicity of this treatment was moderate to severe.

A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.

Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung. A Southwest Oncology Group Study.

Using a randomized prospective trial design, chemotherapy with 5-fluorouracil, vincristine, and mitomycin C (FOMi) was compared with cyclophosphamide, doxorubicin, and cisplatin (CAP) and with FOMi alternating with CAP (FOMi/CAP) in 452 eligible patients with metastatic large-cell undifferentiated and adenocarcinoma of the lung. Objective responses were obtained in 26%, 17%, and 22% of patients treated with FOMi, CAP, and FOMi/CAP, respectively. The median survival was similar for FOMi, CAP, and FOMi/CAP therapies (20, 24, and 23 weeks, respectively), but the overall survival (log rank test), 1-year survival, and remission duration were longer for FOMi/CAP-treated patients. Survival was significantly longer for fully ambulatory FOMi/CAP-treated patients compared with either FOMi (P = .01) or CAP (P = .04). Younger patients treated with full doses of therapy responded more often than older patients receiving reduced drug doses (26% and 11%, respectively; P = .003). A prognostic factor regression analysis of all eligible patients indicates that sex, performance status, stage, and treatment assigned were important independent variables determining survival (P less than .05). Toxicity was comparable in each treatment group.

Pancreatic cancer treated with carmustine, fluorouracil, and spironolactone: a randomized study.

A prospective randomized trial between two drug regimens in 38 patients with advanced pancreatic carcinoma was performed. The two-drug regimen consisted of carmustine and fluorouracil. The survival rate and response to these two drugs was compared to a three-drug regimen consisting of these same two drugs plus spironolactone. Objective partial responses were rare in both groups, being 3/18 in the two-drug group and 2/20 in the three-drug group. Life table analysis in previously untreated patients from time of treatment shows longer survival for the three-drug group, but this difference was not statistically significant.

An evaluation of prostate-specific antigen as a screening test for prostate cancer.

Prostate cancer is the second leading cause of cancer death in men. Recently, there has been increased interest in the use of prostate-specific antigen (PSA) as a screening test for prostate cancer. The PSA test offers the benefit of a reproducible, objective value that is independent of the examiner's skill; however, it does not seem to be effective alone as a screening test for prostate cancer. Additionally, the efficacy of treatment for prostate cancer with radiation therapy or radical prostatectomy remains to be demonstrated. Thus, further studies demonstrating an improved mortality in prostate cancer with PSA screening need to be performed before universal screening with PSA can be recommended. Meanwhile, education of the patient regarding the risks, benefits, and costs of PSA screening and subsequent treatment should be addressed before performing a PSA test.

Geomelophagia. An unusual pica in iron-deficiency anemia.

A patient with lung cancer treated by radiation and in remission presented with a two-month history of compulsive eating of raw, chilled potatoes. Suspicion of a pica due to iron-deficiency anemia was confirmed after complete laboratory evaluation. The source of iron loss was found to be gastrointestinal bleeding. Therapy with iron sulfate was begun, with a subsequent increase in the hemoglobin level; the pica ceased within one week of initiation of therapy. If searched for, pica is a common manifestation of iron deficiency; however, this patient apparently represents the first report of geomelophagia. Appropriate investigation of compulsive eating habits might lead to the diagnosis of iron deficiency and also allay patients' anxieties toward their behavior.

Methotrexate cerebrospinal fluid pharmacokinetics in a patient with lymphoma treated with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone.

The role of "moderate-dose" systemic methotrexate in preventing central nervous system lymphomatous relapse is unknown. Certain patients with diffuse non-Hodgkin's histologic subtypes have an increased risk of relapse in the central nervous system, and it would be helpful to know if intravenous "moderate-dose" methotrexate might treat or possibly protect the meninges from involvement. In part, the rationale behind the recent regimen of methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), and dexamethasone (m-BACOD) is to protect the central nervous system, and the empiric proof of this protection awaits the follow-up results of trials currently underway. In the meantime, the systemic and cerebrospinal fluid pharmacokinetics of moderate-dose intravenous methotrexate were studied in one patient whose histologic subtype places him at high risk for central nervous system involvement. Although the central nervous system levels of methotrexate in this patient never reached 1 X 10(-6) M, the levels exceeded 1 X 10(-7) M for at least 24 hours. The implications of peak dose versus sustained exposure to a lower dose of methotrexate are discussed.

Long-term survival and toxicity in small cell lung cancer. Southwest Oncology Group study.

In the first study of combined chemotherapy and radiation therapy for small cell lung cancer by the Southwest Oncology Group, 17 patients survived more than five years after treatment was initiated (4.6 percent). Late relapse, or a second primary malignancy three to six years after diagnosis, accounted for death in five of these patients. Late recurrences involved the chest, bone, and liver; none occurred in the central nervous system. Disease-free survival continues in 10 patients (6 percent of those with limited disease and 1 percent of those with extensive-stage diseases) at a minimal follow-up in excess of six years. One definite case of chronic treatment-related toxicity occurred: congestive cardiomyopathy after 450 mg/m2 of doxorubicin, successfully managed with digitalis and diuretics. One severe neurologic problem (orthostatic hypotension with preterminal dementia) and two less severe neurologic complications (occasional falling episodes without documented cause and cerebrovascular accident) may be treatment-related. Progressive pulmonary disability, post-herpetic pain syndromes, organic brain syndrome, and hematologic abnormalities have not been observed to date. Nitrosourea administration and/or co-administration of a nitrosourea or methotrexate during the induction phase of treatment with radiotherapy to the brain may account for the higher incidence of complications observed by others in long-term survivors.

Simultaneous chemotherapy-radiotherapy with prophylactic cranial irradiation for inoperable adeno and large cell lung carcinoma: a Southwest Oncology Group Study.

From September 1980 to March 1983, 30 cases were registered in a Southwest Oncology Group Study. Twenty-four cases were evaluable and constitute the basis for this report. Patients were diagnosed with adenocarcinoma or large cell lung carcinoma. Tumors were considered inoperable but able to be encompassed in a single radiotherapy (RT) port. Seventy-two percent of measured tumors were 4 cm in diameter or bigger (range 2 cm to 10 cm). RT was given initially to the primary lung tumor and ipsilateral hilar, mediastinal, and supraclavicular nodes, at 2 Gy per day; total dose was 44 Gy. The areas involved by tumor were boosted with 10 Gy more. Prophylactic cranial irradiation (PCI) was started at the same time with 15 treatments of 2.75 Gy. A 2-week rest period was instituted after the first 11 treatments. Chemotherapy (CT) was given from day 1 which consisted of 5-Flourouracil, 500 mg./M2, (bolus day 1 and 8) Vincristine, 1 mg./M2, and Mitomycin C, 5 mg./M2 both given on day 1. Cycles were repeated at 28 day intervals for 3 cycles and at 6 week intervals for 5 more cycles, or until progression, with persistent disease. Eight cases (33%) achieved complete response (CR), and 5 (21%) partial response (PR). Overall median survival was 37 weeks and 2 years survival was 8%. CR patients had the best chance for long-term survival. Relapses were evenly distributed between extra and intrathoracic sites, with the latter even between the inside and outside the RT field. No patient died with clinical evidence of metastasis to the brain (MB), although one was found to have MB at autopsy. Toxicity was severe in 7 cases (29%) and 2 deaths are considered toxicity related. When comparing these results to those from the literature, we found this protocol has achieved a slightly higher CR rate than what is expected with RT alone, without survival improvement. As CR patients have the best prognosis, simultaneous CT-RT might offer some promise, but at the expense of increased toxicity. PCI was effective in preventing or delaying MB, and thus deserves further investigation. We should caution that the study of possible long-term effects of PCI could not be assessed because of the short median survival of the patients. It is possible that a less aggressive time-dose fractionation to the brain might be as effective as the one used in this protocol.