The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy

The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy has been controversial. In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting, we reviewed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy. Patients with four or more positive nodes or at least one positive apical node were randomized to receive either five or ten cycles of cyclophosphamide/Adriamycin (Adria Laboratories, Columbus, OH) (CA) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were randomized to receive eight cycles of either cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) or methotrexate and 5-FU (MF) chemotherapy. Two hundred six of these patients were subsequently rerandomized to receive either no further treatment or adjuvant radiotherapy. Thirty-five patients withdrew after randomization, including 34 who declined to receive radiotherapy. Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes. Median follow-up from chemotherapy randomization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm. The crude rate of local failure (chest wall or draining lymph node areas) as first site of failure for patients randomized to receive chemotherapy only was 14%; for those randomized to receive both chemotherapy and radiotherapy it was 5% (P = .03). For patients in the CMF/MF arm, the rate of local failure as the first site of failure was nearly the same for patients randomized to chemotherapy only as for those randomized to adjuvant radiotherapy as well (5% v 2%). For patients in the CA arm, the crude rate of local failure was 20% for patients randomized to receive chemotherapy only, and 6% for those randomized to both types of adjuvant treatment (P = .03). Among the 43 patients treated with CA who actually received radiotherapy, there was only one local failure, compared with 12 local failures among the 59 patients (20%) who actually did not receive radiotherapy (P = .007). No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients randomized to receive radiation therapy and those randomized to no further treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Radiation therapy in the management of rectal cancer

For many years, rectal carcinoma has been treated by surgery alone. However, survival rates have not improved historically and local recurrence remains a problem. Adjuvant radiation therapy does have a role in this disease. While the optimal scheduling and dose are not determined yet, it can certainly prevent local recurrence and potentially increase survival. There are advantages to delivering radiation therapy preoperatively and postoperatively and the combination of low-dose preoperative radiation therapy and postoperative radiation therapy in selected patients ("sandwich" therapy) appears promising. The use of chemotherapy in combination with radiation therapy may further improve survival rates. Care must be taken in patients treated with rectal carcinoma to minimize the normal tissue irradiated to decrease complications and deliver tumoricidal doses to the areas at risk. Techniques are available to both the surgeon and the radiation oncologist to minimize the amount of small bowel irradiated. Radiation therapy also has a role in the treatment of very early rectal cancers as part of a sphincter-saving procedure and in the treatment of advanced or recurrent rectal cancers. In the latter, intraoperative radiation therapy plays an important role in controlling recurrent or residual rectal cancer.     

Pacemaker failure resulting from radiation damage

The authors present a case of radiation-induced pacemaker failure. After 2,000 rad (20 Gy) of photon irradiation for metastatic bronchogenic carcinoma, the pulse generator circuitry failed, producing a "runaway" rhythm. This suggests that present pacemaker circuitry may be more susceptible to irradiation than previously believed, and that even modest radiation doses can induce life-threatening arrhythmias.     

In vivo measurement of microvasculature: a method for repeated and reproducible quantitation during long-term experiments.

A method for long-term, reproducible observation of mature microvasculature is proposed using Sandison-Clark rabbit ear chambers. Forty-nine high-magnification (320 ×) in vivo photomicrographs, reproducible in position to a 10-μm accuracy with no overlap, are taken on each data-point day. They cover 1.617 mm² of vascular membrane of a standard 0.025-mm thickness. For the purpose of analysis, vessels are divided into two groups: vessels > 10 and ⩽ 10 μm in diameter. Vascular lengths and surface areas are measured directly from the photomicrographs projected at a fixed distance. These parameters are measured on Days 1, 5, 10, 20, and 30. Vascular length (> 10 μm, 8.35 mm ± 0.66; ⩽ 10 μm, 11.99 mm ± 1.31) and vascular surface area (> 10 μm, 0.168 mm² ± 9.88 × 10⁻³; ⩽ 10 μm, 0.079 mm² ± 4.21 × 10⁻³) obtained over a 30-day observation period indicate the reproducibility of the method. The intervascular supportive tissue area is calculated by subtracting the total microvascular surface area from the total tissue area. A dilatation factor has been derived which allows a comparison of the ratios of total microvascular surface area per unit vascular length over time. From the measured parameters, a number of important morphometric values can be calculated, e.g., vascular and supportive tissue volumes. Physiological changes are expressed as functions of masured parameters over time, with each specimen serving as its own control. These quantitative measurements are made possible by high-magnification photomicrography, which simultaneously allows qualitative analysis at the cellular level. This method should prove useful as a tool for quantitative and qualitative determination of changes in the microvasculature due to various local and systemic injuries.     

Alteration of a model antigen by Au(III) leads to T cell sensitization to cryptic peptides

Certain metal ions are known to be potent sensitizers, but the self proteins modified by metal ions and the self peptides recognized by ‘metal-specific’ T cells are unknown. In humans and mice treatment with gold anti-rheumatic drugs, containing Au(I), may lead to allergic and autoimmune side effects. Human and murine T cells do not react to Au(I), however, but to the reactive metabolite Au(III). Here we show that alteration by Au(III) of a model antigen, bovine ribonuclease (RNase) A, results in T cell sensitization to cryptic peptides of this protein. Upon immunization of mice with Au(III)-pretreated RNase [RNase/Au(III)], CD4⁺ T cell hybridomas specific for RNase/Au(III) were obtained in addition to those recognizing the immunodominant peptide RNase 74–88; the latter also were obtained after immunization with native RNase. RNase/Au(III)-specific T cell hybridomas reacted against RNase/Au(III) and RNase denatured by S-sulfonation of cysteine residues, but not against native RNase, or RNase pretreated with Au(I), Al(III), Cu(II), Fe(II), Fe(III), Ni(II), Mn(II), or Zn(II). Using a panel of overlapping, synthetic RNase peptides which were devoid of gold or gold-induced modifications, epitope mapping revealed that RNase/Au(III)-specific T cell hybridomas recognized the cryptic peptides 7–21 and 94–108, respectively. Comparison of the proliferative response of bulk CD4⁺ T cells, prepared from splenocytes after immunization with either RNase/Au(III) or native RNase, revealed that Au(III) pretreatment of RNase led to a markedly enhanced response to the two cryptic peptides while it did not influence the response to the immunodominant peptide. The cryptic peptides were also presented after preincubation of bone marrow-derived macrophages with RNase and Au(I), but not with RNase alone, suggesting that oxidation of Au(I) to Au(III) and subsequent protein alteration by Au(III) can happen in mononuclear phagocytes. We conclude that Au(III) alteration of proteins alters antigen processing and, thus, leads to presentation of cryptic peptides. This mechanism may shed light on the development of allergic and autoimmune side effects of Au(I) anti-rheumatic drugs. In addition, it might provide a general mechanism of how metal ions act as T cell sensitizers.     

Carcinoma of the nasopharynx an optimization of radiotherapeutic management for tumor control and spinal cord injury

A series of 131 patients with carcinoma of the nasopharynx were seen at the University of Chicago between 1949 and 1977. Within this series a subset of 96 patients received initial radiation treatment with curative intent at our institution, and comprises the basis of this report. Treatment doses to both the primary tumor site and the cervical spinal cord were converted to nominal standard doses (NSD). The patients were categorized into NSD intervals from 1200 to greater than 2 100 ret with corresponding incidence of complication: radiation induced cervical cord myelitis and recurrence at the primary site. Paired dose-response curves are presented that show tumor ablation and cervical myelitis as a complication of treatment versus NSD. The 5 % and 10 % incidence levels of radiation induced cervical myelitis are 1450 and 1750 ret, respectively. The therapeutic operating characteristic (TOC) curve of probability of tumor ablation versus the probability of cervical myelitis is developed and shown. A 10 % complication rate resulted from tumor control rates of 53% and 33% for T1, T2 and T3, T4 primary lesions, respectively. An additional 5% increase in cervical myelitis resulted from a 15 % gain in tumor ablation within all levels of primary tumor extension. Because of the higher tolerance of the cervical spinal cord and the poor prognosis for those patients who developed a recurrence at the primary site, the more aggressive treatment approach to all stages of nasopharyngeal carcinoma is proposed.     

Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data

In this paper, we propose a quantitative risk assessment methodology for skin sensitization aiming at the derivation of 'safe' exposure levels for sensitizing chemicals, used e.g., as ingredients in consumer products. Given the limited number of sensitizers tested in human sensitization tests, such as the human repeat-insult patch test (HRIPT) or the human maximization test (HMT), we used EC3 values from the local lymph node assay (LLNA) in mice because they provide the best quantitative measure of the skin sensitizing potency of a chemical. A comparison of LLNA EC3 values with HRIPT and HMT LOEL, and NOEL values was carried out and revealed that the EC3, expressed as area dose, can be used as a surrogate value for the human NOEL in risk assessment. The uncertainty/extrapolation factor approach was used to derive (a) an 'acceptable non-sensitizing area dose' (ANSAD) to protect non-allergic individuals against skin sensitization and (b) an 'acceptable non-eliciting area dose' (ANEAD) to protect allergic individuals against elicitation of allergic contact dermatitis. For ANSAD derivation, interspecies, intraspecies and time extrapolation factors are applied to the LLNA EC3. For ANEAD derivation, additional application of a variable sensitization-elicitation extrapolation factor is proposed. Values for extrapolation factors are derived and discussed, the proposed methodology is applied to the sensitizers methylchloroisothiazolinone/methylisothiazolinone, cinnamic aldehyde and nickel and results are compared to published risk assessments.     

A dosimetric comparison of MammoSite high-dose-rate brachytherapy and Xoft Axxent electronic brachytherapy

PURPOSE: Over 20,000 patients have been treated with partial breast irradiation (PBI) using the MammoSite balloon brachytherapy applicator (IBB). Recently, a new form of balloon-based PBI, Xoft Axxent electronic brachytherapy (KVB), which uses a 50-kV x-ray source, has been introduced. This analysis was undertaken to dosimetrically compare the results of treatment using these two methods of PBI. METHODS AND MATERIALS: The study population consisted of 15 patients previously treated with IBB. The planning CT scans from these 15 patients were used to construct hypothetical treatment plans using the source characteristics of the KVB device. The plans were then compared using the dosimetric parameters discussed below. RESULTS: The mean %V(90) was 99.6% vs. 99.0% (p=nonsignificant [ns]), the mean %V(100) was 96.5% vs. 96.5%, the mean %V(150) was 41.8% vs. 59.4% (p<0.05), the mean %V(200) was 11.3% vs. 32.0% (p<0.05), and the mean %V(300) was 0.4% vs. 6.7% (p<0.05) for the IBB and KVB methods, respectively. The mean ipsilateral breast %V(50) was 19.8% vs. 13.0% (p<0.05), the mean ipsilateral lung %V(30) was 3.7% vs. 1.1% (p<0.05), and the mean heart %V(5) was 59.2% vs. 9.4% (p<0.05) for the IBB and KVB methods, respectively. CONCLUSIONS: The IBB and KVB methods of PBI offer comparable target volume coverage; however, the KVB method is associated with an increased volume of breast tissue in the high-dose regions and a decreased dose to the adjacent normal tissues.     

Characterization of the sensitizing potential of chemicals by in vitro analysis of dendritic cell activation and skin penetration

Development of in vitro models to identify sensitizing chemicals receives public interest since animal testing should be avoided whenever possible. In this article we analyze two essential properties of sensitizing chemicals: skin penetration and dendritic cell (DC) activation. Activation of immature DC derived from peripheral blood monocytes was evaluated by flow cytometric analysis of CD86 positive cells and quantitative measurement of interleukin-1beta and aquaporin P3 gene expression. The sensitizer 2,4,6-trinitrobenzenesulfonic acid induced a concentration-dependent response for all parameters, whereas the irritant sodium lauryl sulfate did not. When two related aromatic amines, p-toluylenediamine (PTD) and hydroxyethyl-p-phenylenediamine (HE-PPD) were tested, both induced substantial DC activation indicating their potential sensitizing properties. These findings contrasted with in vivo results: in murine local lymph node assays (LLNA) PTD, but not HE-PPD, was sensitizing using acetone/aqua/olive oil as vehicle. Skin penetration measurement revealed that this was due to bioavailability differences. On retesting HE-PPD in the LLNA using the penetration enhancer dimethylsulfoxide as vehicle, it induced a specific response. We conclude that in vitro analysis of DC activation capability of the two selected chemicals demonstrates that prediction of skin sensitization potential is possible provided that skin penetration data indicate sufficient bioavailability of the test compound.     

Small-cell carcinoma of the lung: a five-year experience with combined modality therapy

In the past five years, we have treated 89 patients with small-cell carcinoma of the lung with radiotherapy plus one of three chemotherapy programs. The 24 patients with disease confined to the chest (Stage IIIMO) had an 87% response rate to the combined modalities (79% complete responses) and a median survival of 18 months; 13 patients with disease confined to the chest and ipsilateral supraclavicular nodes (Stage IIIMOSCN +) had an 84% response rate (69% complete responses) and 11-month median survival; the 52 patients with distant metastases (Stage IIIMI) had a 71% response rate (15% complete responses) and eight-month median survival. Survival was not affected by adding prophylactic cranial irradiation to the latest regimen, although the CNS relapse rate was reduced. We conclude that our three chemotherapy programs to date differ very little in their effect on survival of patients with metastatic disease. New and more vigorous approaches, possibly including surgery, need to be tested for the management of disease confined to the chest. The designation of patients as Stage IIIMOSCN + is valid because such patients have better survival rates than patients with distant metastatic disease.