The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases

We have demonstrated that tumor irradiation enhanced the therapeutic effect of interleukin 2 (IL-2) on pulmonary metastases from a murine renal adenocarcinoma, Renca. To investigate the mechanism of interaction between tumor irradiation and IL-2 therapy, we have histologically evaluated the effects of each therapy alone or in combination on Renca pulmonary metastases. Following treatment of established lung metastases with irradiation and IL-2 therapy, lung sections were processed for H&E or immunohistochemical staining. We found that tumor irradiation or IL-2 therapy locally induced vascular damage, resulting in multifocal hemorrhages and mononuclear cell mobilization in the lung tissue. This effect was amplified in lungs treated with the combined therapy. Immunohistochemistry showed that irradiation produced a macrophage influx into irradiated tumor nodules, and systemic IL-2 therapy induced T-cell infiltration in tumor nodules. Lungs treated with the combined therapy exhibited massive macrophage, T-cell, and natural killer cell mobilization in disintegrating tumor nodules and in the lung tissue. This combined therapy caused a decrease in the number of proliferating tumor cells and an increase in the number of apoptotic cells, which were more marked than with either therapy alone. We suggest that the macrophages mobilized by radiation-induced tissue injury could play a role in phagocytosis of apoptotic tumor cells, processing and presenting of tumor antigens for a systemic immune response activated by IL-2. Tumor destruction may result from the concomitant action of activated T cells, natural killer cells, and macrophages infiltrating the tumor nodules.     

Epinephrine or peplomycin combined with hyperthermia in irradiated Lewis lung carcinoma: effects on tumor growth, skin reaction, and lung metastasis

Although hyperthermia potentiates the effect of radiation, the combined effect decreases as the time between irradiation and hyperthermia increases. The purpose of this study was to prevent the rapid loss of efficacy by the local injection of epinephrine or peplomycin(PEP), two agents known as hyperthermic potentiators. In this study, Lewis lung carcinoma implanted in the foot of BDF1 mice was used for the assessment of tumor growth, skin reactions, and lung metastasis. The tumors were irradiated, then warmed in a water bath for 45 min. The retarding effects of hyperthermia on tumor growth and skin reactions were lost 2 days after irradiation. However, when PEP or epinephrine was injected before hyperthermia, tumor growth was distinctly delayed. The effect of epinephrine was greater than PEP and still showed enhancement 8 days after irradiation. For skin reactions, no significant enhancing effect was observed. Lung metastasis was significantly inhibited by the addition of epinephrine either 0 or 2 days after irradiation. In conclusion, the local administration of epinephrine combined with hyperthermia significantly retarded tumor growth without an increase in skin reactions or lung metastases. Possible mechanism underlying this phenomenon was discussed.     

Radiation therapy in renal adenocarcinoma (author's transl)

Sole irradiation treatment for renal carcinoma or its metastases has to be regarded as only a palliative therapy, whereas postoperative radiation therapy brings about a distinct diminution of the frequency of local recurrences, and, at least in advanced tumor stages, an improvement of the 5-year survival rate. Long-term preirradiation (ca 3000 rd TD within 3 weeks, and operation after another three weeks) or short-term pre-irradiation (ca 1200 to 2000 rd TD within 2 or 4 days, and operation the next day) are tolerated well and do involve no disturbances of the wound healing. Surgical treatment is not complicated by short-term irradiation, but often is easier following long-term irradiation; beyond this, the latter may just render possible a radical extirpation of the renal tumor. It appears from first results that decrease of distant spread and improvement of recovery rates in advanced tumor stages may be within reach, particularly in connection with post-operative irradiation.     

Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain

BACKGROUND: A retrospective study of patients undergoing stereotactic radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma (NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven patients underwent radiosurgery during a 7-year interval; 71 also underwent whole brain radiation therapy. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. RESULTS: The overall median survival was 10 months after radiosurgery, and 15 months from the diagnosis of brain metastases. Five factors significantly affected survival: extent of systemic disease, presence of a neurologic deficit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary tumor of the chest. Median survival time was 26 months in a subgroup of patients with no extracranial metastases, no neurologic deficits, and a small tumor without necrosis. The authors evaluated 91 tumors with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery for NSCLC brain metastases is effective and is associated with few complications. The early detection of brain metastases and treatment with radiosurgery combined with radiation therapy provide the opportunity for extended high quality survival.     

Pharmaco-economic aspects of antibiotic therapy in hospitals

The prognosis of lung cancer patients is generally poor even when they have undergone complete resection of primary tumors and systemic lymph node dissection. This is mainly attributed to micrometastases which have already developed by the time of surgery and the fact that local therapies cannot eliminate all cancer cells from the body. We developed a multimodality combination therapy for primary non-small cell lung cancer consisting of surgery, chemotherapy, and adoptive immunotherapy using interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells. The results of a randomized study indicated that the survival rate of the IL-2, LAK adoptive immunotherapy group was significantly higher than that of the control group. In conclusion, IL-2, LAK adoptive immunotherapy is an effective and promising modality which will compensate for the deficiencies of other therapies.     

Combination therapy with suicide and cytokine genes for hepatic metastases of lung cancer

Metastases of lung cancer are a major cause of treatment failure. To evaluate the therapeutic efficacy of gene therapy in metastatic lung cancer, we used adenoviral (ADV) mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene and the cytokine gene interleukin-2 (IL-2) to treat a murine model of metastatic lung cancer in the liver. Hepatic metastases were established by intrahepatic implantation of LL2 cells in syngeneic recipient mice. One week after tumor implantation, various replication defective ADV vectors were injected intratumorally. Treatment with a vector expressing the HSV-tk followed by ganciclovir administration with ADV.tk resulted in significant regression of tumor (p<0.01) as well as prolongation of survival (p<0.001). While a vector expressing mouse IL-2 ADV.IL-2 alone was ineffective, combination therapy with HSV-tk resulted in further tumor regression and improvement of animal survival (p<0.05). These results demonstrate that suicide and cytokine genes can be utilized in combination to treat metastatic lung cancer in vivo.     

Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy

We investigated the antitumor effects of human recombinant interleukin-6 (hrIL-6) on the highly metastatic B16 melanoma clone F10.9. These tumor cells were found to have very low levels of IL-6 receptors and in vitro IL-6 had no effect on cell proliferation or on the expression of MHC class I antigens. However, in vivo IL-6 was active against the metastatic growth of this tumor in mice, presumably through indirect immune effects. Low-dose IL-6 (1-10 micrograms/day), in three daily injections, 4 days a week, for 3 weeks, strongly inhibited the formation of experimental lung metastases following intravenous tumor cell inoculation. IL-6 therapy could be started even 10 days after tumor injection, when metastases are already established. Moreover, IL-6 treatment of mice bearing F10.9 tumors in the footpads resulted in complete protection against pulmonary spontaneous metastasis and in long-term survival. Histology confirmed the absence of micrometastases in most of the IL-6-treated animals. Analysis of the cytolytic activity of splenocytes at different times during therapy of tumor-bearing mice revealed significant lysis (up to 42%) of the melanoma F10.9 cells in the mice receiving IL-6 but not in the control mice.     

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.     

Tumor therapy with an antibody-targeted superantigen generates a dichotomy between local and systemic immune responses

Repeated injections of a fusion protein containing the superantigen staphylococcal enterotoxin A (SEA) combined with a Fab fragment of a tumor-specific antibody is a highly efficient immunotherapy for mice expressing lung melanoma micrometastasis. In the present study, the systemic and local immune responses generated by this therapy were analyzed at a cellular level. Two distinct but coupled immune reactions occurred after repeated therapy. Tumor necrosis factor and macrophage inflammatory protein-1 alpha and -1 beta were immediately synthesized, in the absence of T lymphocytes, at the local tumor site in the lung. This was followed by the induction of VCAM-1 adhesion molecule expression on pulmonary vascular endothelial cells. Concurrently, the early response in the spleen was characterized by the induction of selective T cells producing interleukin (IL)-2. The primed and expanded SEA-reactive V beta 3- and V beta 11-expressing T lymphocytes accumulated to the tumor area only after Fab-SEA therapy and were not present in the lung when SEA, Fab fragment, or recombinant IL-2 was injected. The tumor-infiltrating T cells produced large amounts of interferon-gamma, but no IL-2 or Th2 type of lymphokines were detected at the tumor site in the Fab-SEA-targeted antitumor immune response. These results emphasize the necessity to investigate several sites of antigen presentation to elucidate the effects of immunotherapy.     

Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review

BACKGROUND: The limited efficacy of current approaches to the treatment of patients with hepatic cancer, including external beam radiation therapy and cytotoxic chemotherapy, has reawakened interest in the use of internal radiation therapy. METHODS: The authors reviewed series of patients with liver metastases or hepatocellular carcinoma (HCC) treated with 1) interstitial irradiation and direct intratumoral injection of 90Y microspheres, 2) intraarterial infusion of (131)I-Lipiodol, 3) intraarterial infusion of 90Y microspheres, or 4) parenteral administration of radiolabeled monoclonal antibodies. RESULTS: High dose rate interstitial irradiation with afterloading of (192)Ir resulted in local control of hepatic metastases for a median of 8 months and complete tumor eradication in 2 patients. Direct intratumoral injection of 90Y microspheres reduced the size of 90.6% of tumors and completely destroyed them in 8 patients. Treatment with arterial (131)I-Lipiodol resulted in a 17-92% response rate as well as a case of complete remission of unresectable HCC. It was found to be most effective against small tumors. No response was observed with liver metastases from colorectal carcinoma. Partial response was commonly achieved when patients with unresectable liver metastases or HCC were treated with intraarterial 9OY microspheres. Among four patients whose HCC became resectable following treatment with 90Y microspheres, two cases of complete remission were documented. In a prospective randomized trial, (131)I-antiferritin combined with chemotherapy was no more effective than chemotherapy alone. CONCLUSIONS: The different approaches to internal radiation therapy that are reviewed in this article represent several ways in which radiation can be selectively targeted to hepatic tumors without undue radiation to the nontumorous liver. However, the efficacy of each of these therapies still needs to be evaluated in randomized controlled trials.     

Human cytotoxic T-cells suppress the growth of spontaneous melanoma metastases in SCID/hu mice

Mice with severe combined immunodeficiency (scid) provide an excellent model for studying interactions between human tumor cells and effector cells of the immune system. Because these animals lack functional B and T lymphocytes, they can accept human tumor xenografts and transfer of human effector cells. Here, we determined the ability of a human melanoma-specific, cytotoxic T-cell line (CTL) in suppressing the growth of spontaneously metastasizing human melanoma cells M24 met (HLA-A11, A33) in scid mice. This CTL line was highly cytotoxic and restricted by HLA-A11 against M24 met melanoma cells in vitro but poorly cytotoxic when tested against a human melanoma cell line that did not express HLA-A11. In order to evaluate the efficacy of this CTL line against M24 met melanoma cells in vivo, randomized groups of animals were given injections of either RPMI culture medium, interleukin 2 (IL-2), CTLs, or CTLs + IL-2. IL-2, per se, did not significantly reduce tumor metastases; however, injection of melanoma-specific, HLA-A11 restricted CTLs into scid mice, 1 day postexcision of the previously induced primary tumor, markedly reduced the number of metastatic foci in the lung and decreased metastatic involvement in lymph nodes. The combination of these CTLs with IL-2 proved even more effective, since almost all lung metastases were eradicated and metastatic involvement in both axillary and inguinal lymph nodes was substantially reduced. Our results indicate that these human CTLs maintain their ability for specific killing of metastasizing melanoma cells in scid mice. Our data suggest that reconstitution of scid mice with a specific group of effector cells (step-wise scid/hu) may be helpful for in vivo evaluation of potentially useful cancer immunotherapy modalities.     

Molecular and pharmacological characterization of recombinant rat/mice N-methyl-D-aspartate receptor subtypes in the yeast Saccharomyces cerevisiae

PURPOSE: To assess the local control and survival in patients who received pelvic irradiation for locally recurrent rectal carcinoma. METHODS AND MATERIALS: The records of 519 patients with locally recurrent rectal carcinoma treated principally with external-beam radiation therapy between 1975 to 1985 at a single institute were retrospectively reviewed. These included 326 patients who relapsed locally following previous abdominoperineal resection, 151 after previous low anterior resection, and 42 after previous local excision or electrocoagulation for the primary. No patients had received adjuvant radiation therapy or chemotherapy for the primary disease. Concurrent extrapelvic distant metastases were found in 164 (32%) patients at local recurrence and, in the remaining 355, the relapse was confined to the pelvis. There were 290 men and 229 women whose age ranged from 23 to 91 years (median = 65). Median time from initial surgery to radiation therapy for local recurrence was 18 months (3-138 months). Radiation therapy was given with varying dose-fractionation schedules, total doses ranging from 4.4 to 65.0 Gy (median = 30 Gy) over 1 to 92 days (median = 22 days). For 214 patients who received a total dose > or = 35 Gy, radiation therapy was given in 1.8 to 2.5 Gy daily fractions. RESULTS: The median survival was 14 months and the median time to local disease progression was 5 months from date of pelvic irradiation. The 5-year survival was 5%, and the pelvic disease progression-free rate was 7%. Twelve patients remained alive and free of disease at 5 years after pelvic irradiation. Upon multivariate analysis, overall survival was positively correlated with ECOG performance status (p = 0.0001), absence of extrapelvic metastases (p = 0.0001), long intervals from initial surgery to radiation therapy for local recurrence (p = 0.0001), total radiation dose (p = 0.0001), and absence of obstructive uropathy (p = 0.0013). Pelvic disease progression-free rates were positively correlated with ECOG performance status (p = 0.0001), total radiation dose (p = 0.0001), and previous conservative surgery for the primary (p = 0.02). CONCLUSIONS: Survival is poor for patients who develop local recurrence following previous surgery for rectal carcinoma. Pelvic radiation therapy provides only short-term palliation, and future efforts should be directed to the use of effective adjuvant therapy for patients with rectal carcinoma who are at high risk of local recurrence.     

Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with interleukin 4

We have previously demonstrated that IFN-gamma causes cell growth inhibition and up-regulation of MHC antigens in human renal cell carcinoma cell lines. In this study, we have investigated the therapeutic potential of IFN-gamma for the treatment of 5-day established pulmonary metastases induced by i.v. injection of Renca cells, a murine renal adenocarcinoma. We found that systemic injections of IFN-gamma significantly reduced the number of lung metastases in a dose-dependent manner and increased mouse survival. Histological evaluation of IFN-gamma-treated lungs showed residual small tumor nodules containing extensive necrosis and mononuclear infiltrates. Immunohistochemistry studies on lung sections showed macrophage infiltration into tumor nodules, and in vivo depletion of macrophages partially inhibited IFN-gamma antitumor effect, suggesting a role for the macrophages in tumor destruction. Lymphocyte depletion of either natural killer (NK) cells or CD4+ or CD8+ T-cell subsets or both T-cell subsets did not affect the IFN-gamma effect, whereas depletion of both NK and T cells decreased the antitumor activity of IFN-gamma. These data indicate that neither T cells nor NK cells are essential for this activity but that either lymphocyte population can contribute to the IFN-gamma effect. An optimal dose of IFN-gamma inhibited by 60% the growth of Renca cells treated for 3 days in vitro, but this effect was transient and less pronounced in a long-term colony assay, suggesting that IFN-gamma direct growth inhibition may play a role but may not be sufficient to mediate its antitumor effect in vivo. In vitro, IFN-gamma caused up-regulation of class I MHC antigens and induction of class II antigen expression in Renca cells, an effect that may enhance Renca immunogenicity but may be relevant only when a T-cell response is elicited. A sequential administration of IFN-gamma followed by interleukin 4 was therapeutically better than IFN-gamma alone for the treatment of advanced pulmonary metastases, probably due to different antitumor mechanisms induced by these two cytokines.     

Human working memory capacity is 7+/-2 in a radial maze with distracting interruption: possible implication for neural mechanisms of declarative and implicit long-term memory

PURPOSE: To evaluate the long-term results of the treatment of anal canal carcinoma (ACC) with a combined concomitant radiochemotherapy (CCRT) treatment using fluorouracil (5 FU) and cisplatinum (CDDP) with a high dose of radiation therapy. PATIENTS AND METHODS: Between 1982 and 1993 a series of 95 patients were treated. Staging showed a majority of advanced squamous ACC, i.e. 6 T1, 47 T2, 28 T3, 14 T4, 53 NO, 32 N1, 6 N2 and 4 N3. Irradiation was done with high dose external beam radiation therapy (EBRT) followed by a boost with 192 Iridium implant. During EBRT all patients received one course of 5 FU continuous infusion (1 g/m2/day, days 1-4) and CDDP (25 mg/m2/day, bolus days 1-4). RESULTS: The median follow-up time was 64 months. At 5 and 8 years the overall survival was 84 and 77%, the cancer specific survival was 90 and 86% and the colostomy-free survival was 71 and 67%, respectively. The stage and the response of the tumor after EBRT were of prognostic significance. Patients with pararectal lymph nodes had an overall 5-year survival of 76% (versus 88% for non-N1). Among 78 patients who preserved their anus, the anal sphincter function was excellent or good in 72 (92%). CONCLUSION: According to these results and recent randomized trials, CCRT appears as the standard treatment of ACC. Radical surgery should be reserved for local recurrence or persisting disease after irradiation. High dose irradiation in a small volume with concomitant 5 FU-CDDP appears to give a high rate of long-term local control and survival. Careful evaluation of pararectal nodes is essential for a good staging of the disease.     

Multimodality therapy: radiation and continuous concomitant cis-platinum and PKC inhibition in a cervical carcinoma model

The addition of chemotherapy to radiation therapy has the potential to sterilize micrometastases and tumor foci adjacent and peripheral to the treatment field, so as to enhance local control of malignancy and improve primary and salvage therapy. Studies were done to investigate the effects of combining cisplatin (CP), the most active single agent in squamous-cell cancer of the cervix, with irradiation and the addition of a protein kinase C (PKC) inhibitor. This initial report of these studies describes our experience in exposing human cervical carcinoma (HeLa-S3) cells grown in culture as multicellular tumor spheroids to continuous CP combined with radiation in an attempt to mimic both clinically achievable serum concentrations of CP and a weekly fractionated-dose environment. Radiation-dose-dependent delays of spheroid growth were not significantly increased in the presence of the PKC inhibitor 7-OH-staurosporine (UCN-01) at 1.0 nM and 10.0 nM concentrations. When dose comparisons at 8 Gy alone (2 Gy x 4 fractions) were made for combined therapy with either CP alone (1.0 microgram/ml) or UCN-01 alone, absolute delays in spheroid growth at the highest concentrations used were comparable (range: 37-41 days). Although these data alone would not support minimal chemotherapeutic interaction, it appears that the overall effects observed for combination therapy were predominately radiation-dose dependent. The combination of UCN-01 plus CP (0.5 and 1.0 mu/ml, respectively) was effective in increasing the cytostatic and cytotoxic effects of irradiation at 4 Gy (2 Gy x 2 fractions). Observations made as early as day 4 and day 7 posttreatment were indicative of > or = 40% and 60%, respectively, of morphological damage. Spheroid growth was essentially static at these doses over the evaluation time of 60 days. Intracellular junctions were disorganized, and spheroid swelling was evident and contributed to the modest dimensional changes observed after treatment. No surviving fractions could be generated from spheroids that were mechanically disrupted, trypsinized, and plated at day 7 after the initiation of treatment. At 2 months, 88% (14/16) and 94% (15/16) of the multimodality treatment groups (4 Gy + UCN-01 + CP [0.5 and 1.0 mu/ml], respectively) had sterilized spheroids, indicating that the CP concentration dependence may not be a sole determinant of efficacy. Our therapeutic strategy for combining irradiation with CP was based on the contemporary use of CP as the most successful agent in producing high survival rates in gynecological malignancy. The combination of UCN-01 with CP and irradiation may, however, represent a more effective strategy for enhancing future cisplatin-based chemotherapy regimens.     

Potentiation of murine MCa-4 carcinoma radioresponse by 9-amino-20(S)-camptothecin

9-Amino-20(S)-camptothecin (9-AC) has demonstrated efficacy against several human cancer xenografts, including cancers of the colon, breast, lung, ovary, and stomach and malignant melanoma, and is currently undergoing Phase I clinical trials. In vitro data indicate that the addition of topoisomerase I inhibitors shortly after irradiation causes conversion of single-strand breaks to double-strand breaks, resulting in synergistic lethality to cultured log-phase or quiescent malignant cells. In our study, the efficacy of 9-AC as a potential radiosensitizing agent in vivo was assessed in C3Hf/Kam female mice bearing 7.6-8-mm MCa-4 mammary tumors implanted i.m. into the right posterior thigh. In one series of experiments to determine the dose dependence of 9-AC, mice were injected twice a week with either 0.5, 1.0, or 2.0 mg/kg 9-AC (total doses of 2, 4, and 8 mg/kg, respectively) either alone or 1 h before irradiation. In a second series of experiments, the schedule dependence of 9-AC was determined by giving a constant total dose of 4 mg/kg 9-AC once (2 mg/kg), twice (1 mg/kg every third day), or four (0.5 mg/kg every other day) times per week for 2 weeks, either alone or combined with radiation. The same radiation regimen was used in all experiments: 2-Gy fractions daily for 14 consecutive days, giving a total dose of 28 Gy to the tumor-bearing leg only. Tumor response was assessed by regrowth delay and dose modification factors (DMFs) obtained by comparing regrowth delay in the groups given 9-AC alone with those given the same dose of 9-AC and radiation. 9-AC significantly delayed tumor growth when combined with radiation, and this effect was dependent on drug dose; DMFs of 2.4 [95% confidence interval (CI), 2.0-3.1], 3.7 (95% CI, 3.1-4.6), and 3.3 (95% CI, 2.7-4.1) were obtained for groups treated with total drug doses of 2.0, 4.0, and 8.0 mg/kg 9-AC, respectively. In addition, the same total dose of 4 mg/kg 9-AC was more effective when given either twice or four times a week compared with once a week, giving DMFs of 2.8 (95% CI, 2.2-3.9), 2.6 (95% CI, 2.0-3.6), and 1.7 (95% CI, 1.3-2.4), respectively. The effect of 9-AC and radiation on normal tissue toxicity was assessed in two normal tissues, jejunum and skin, in separate groups of mice. Jejunal crypt cell survival was decreased in those mice given single doses of 9-AC ranging from 0.5-4.0 mg/kg and 12.5 Gy of total body radiation compared with those given 12.5 Gy of total body irradiation alone. The same regimen of drug and radiation did not modify acute skin reactions. These results suggest that 9-AC is an effective in vivo radiosensitizing agent when given in divided doses with fractionated irradiation. In addition, the gastrointestinal tract but not skin could be a critical target tissue for the use of 9-AC combined with radiation.     

Control of local tumor growth with combined fractionated radiotherapeutic and chemotherapeutic regimens

A treatment concept for the control of tumor growth utilized weekday radiotherapy and weekend chemotherapy. Mice were given sc injections of P815X2 mastocytoma cells on the lower back (day 0) and separated into the following treatment groups: 5-day/week X-irradiation, adriamycin alone at either 5 mg/kg body wt (days 6 and 13) or 2 mg/kg (days 5, 12, and 19), and combined radiotherapy and chemotherapy. Untreated controls had a mean tumor volume of 2.77 cm-3 and a mean survival time of 24 days. Adriamycin alone at 5 mg/kg resulted in an eventual tumor of 70 percent of the control value at death, whereas at 2mg/kg the tumor volume was 60 percent of control. After radiotherapy only, tumor size was 52 percent of control. Irradiation plus either 5 or 2 mg drug per kg body wt resulted in tumor volumes of 23 and 30 percent, respectively, of control values. Although no treatment regimen prolonged survival, the marked reduction in local tumor growth with combination therapy indicates that it may be a useful concept in future cancer therapy.     

Analysis of prognostic factors and patterns of failure in dogs with malignant oral tumors treated with megavoltage irradiation

OBJECTIVE: To determine quality and duration of progression-free survival (PFS) time in dogs with malignant oral tumors after definitive megavoltage irradiation, to analyze prognostic factors for PFS time and patterns of failure, and to analyze the influence of tumor recurrence and development of metastasis on survival. DESIGN: Prospective clinical trial. ANIMALS: 105 dogs with squamous cell carcinoma, fibrosarcoma, or malignant melanoma of the oral cavity without evidence of metastasis. PROCEDURE: Dogs were treated with 48 Gy over 4 weeks on an alternate-day schedule of 4 Gy/fraction. Multivariate analysis was done by use of Cox's regression model to determine significant prognostic factors and by use of a competing risk model to determine the differential effects of prognostic factors on type of, and time to, failure. In 8% of the dogs, severe acute radiation reactions in the final week of treatment resulted in treatment discontinuation. In 7.6% of the dogs, chronic radiation reactions, including bone necrosis and fistula formation, developed. RESULTS: Prognostic factors that independently affected PFS time were histologic type and tumor T stage. Histologic type significantly influenced pattern of failure, but not time to failure, whereas clinical stage significantly influenced time to failure, but not type of failure. CLINICAL IMPLICATIONS: Irradiation was a safe and effective treatment of malignant oral tumors. Because the local efficacy of radiation was influenced only by tumor size, early treatment of oral tumors should improve the prognosis. In dogs without tumor recurrence, systemic metastases, rather than regional metastases, limited long-term survival after radiation therapy.     

Radiotherapy of salivary gland carcinomas (results from 80 patients)

Of 102 patients irradiated because of a tumor of the salivary glands between 1952 and 1973, 80 cases are evaluated in this paper. 67 tumors were localized in the parotid gland. We found 12 tumors in the submandibular gland, one tumor in the sublingual gland. The tumors turned out to be benign in 17 cases, whereas the remaining 63 tumors evidently proved to be malignant. 28 patients underwent either sole irradiation, or radiation therapy was performed after a subtotal operation the number of the patients only irradiated being very small. In 29 cases radiation therapy followed a radical operation; the remaining 23 patients were sent to us for radiation therapy not earlier than after a single or repeated recurrences following surgical treatment. In 23 patients a local recurrence developed after irradiation. Metastases to the lymph nodes were observed in 24 patients, in 17 cases being already manifest at the beginning of the irradiation. Distant metastases were found in 30 patients, six of these existing already at the beginning of the radiation therapy. Till now, thirty patients died because of their cancerous disease, 13 patients because of intercurrent diseases. The five-year survival recovery rate amounted to 50%, the rate of seven-year survival to 42%. The results of surgery for malignant tumors of the salivary glands are distinctly improved by radiation therapy. Especially the high percentage of recurrences after sole surgical treatment reveals the necessity of postsurgical radiation therapy. For the prevention of local recurrences, however, very high doses have to be delivered to the tumor generally. We recommend 6500 rd as a minimal dose to be applied within five to six weeks. In certain cases, with particularly radioresistant tumors, a local dose of up to 7500 rd may be delivered to a small volume. Irradiation of the highly malignant tumors of salivary glands should encompass the regionary lymph nodes too, even if they are not affected metastatically.     

Effect of clarythromycin on the distant metastases of human lung cancer cells in SCID mice

Recently, the use of macrolides is suggested to be therapeutically effective in prolonging the survival of patients with inoperable non-small cell lung cancer. The purpose of this study was to examine therapeutic effects of a macrolide, clarythromycin (CAM) on the metastastic developments of two different human non-small cell lung cancers (squamous cell lung carcinoma RERF-LC-AI, and adenocarcinoma PC-14) in severe combined immunodeficient (SCID) mice depleted or undepleted of natural killer (NK) cells, respectively. CAM, injected subcutaneously at doses of 5 and 10 mg/kg body weight/day from day 7 to 41 after i.v. inoculation of human lung cancer cells, was not effective in inhibiting their distant organ metastases in SCID mice. CAM at concentrations of less than 10 micrograms/ml did not have a direct influence on the proliferation of these tumor cells in vitro. Although CAM alone was not effective in augmenting NK activity, it augmented the IL-2-induced killer (LAK) activity against Daudi cells in vitro. These results suggest that CAM alone may not be enough to control the spread of non-small cell lung cancer in the patient with T cell dysfunction.