Radiotherapy with 6-megavolt photons for early glottic carcinoma: potential impact of extension to the posterior vocal cord.

PURPOSE: Radiation therapy has a high success rate in the treatment of early glottic carcinoma. Excellent outcomes have been reported from centers using cobalt-60 or relatively low-energy (< or = 4 MV) radiation therapy to achieve these results. Whether similar outcomes can be achieved with a 6 MV linear accelerator has been less rigorously evaluated. This study assesses the efficacy of 6 MV radiation therapy for early stage glottic cancer and identifies prognostic factors for local control and overall survival in this common disease. MATERIALS AND METHODS: One hundred twenty-eight consecutive cases of Tis, T1, and T2 squamous cell carcinomas of the glottis from 1982 to 1996 were retrospectively analyzed with regard to local control and survival. All patients were treated with definitive radiation therapy with a 6-MV linear accelerator. Potential prognostic factors for local control and survival were evaluated with univariate and multivariate models. Median follow-up of locally controlled patients was 65 months. RESULTS: The overall 3-year actuarial local control rates for T1 and T2 carcinomas were 86% and 68%, respectively. Patients with lesions involving the posterior third of the vocal cord had significantly worse 3-year local control (76% vs. 86%, P =.038). Radiation therapy technique and overall treatment time did not significantly affect local control. For patients with Tis and T1 lesions, factors associated with significantly worse local control included cordectomy-ineligible disease (P =.024), dose less than 6,600 cGy (P =.024), and lesions limited to the posterior third of the vocal cord (P =.004). Three-year local control was 76%, with doses less than 6,600 cGy and 90% with higher doses. High rates of second primary malignancies were observed and represented the major cause of death. Five-year overall survival was 84%. CONCLUSIONS: The use of 6-MV photons for treatment of early glottic cancer seems to achieve local control similar to that reported with lower-energy photons. However, patients with posterior third involvement had a poorer local control rate with standard radiation therapy, thereby suggesting that alternative approaches be considered.

Concurrent chemotherapy and radiation for breast conservation treatment of early-stage breast cancer.

PURPOSE: The optimal sequencing of chemotherapy and radiation therapy in patients with early-stage breast cancer undergoing breast-conservation treatment remains controversial. The purpose of this study is to evaluate the outcome of patients treated with one specific sequence of concurrent chemoradiation followed by additional chemotherapy. METHODS: Between 1977 and 1992, 210 patients with stage I and II breast cancer underwent lumpectomy and axillary lymph node dissection followed by treatment with concurrent chemotherapy and radiation therapy, followed by further chemotherapy. Chemotherapy consisted of two 28-day cycles of CF (oral cyclophosphamide, 100 mg/m2 day 1 to 14, and intravenous 5-fluorouracil, 600 mg/m2 days 1 and 8) during radiation therapy, followed in general by six cycles of CMF (CF doses as above plus intravenous methotrexate 40 mg/m2 days 1 and 8) after the completion of radiation therapy. Fifty patients also received hormonal therapy, predominantly tamoxifen. One hundred ten patients had clinical T1 lesions, and 100 had T2 lesions. Fifty-three patients were pathologic N0, and 157 patients were pathologic N1 (123 patients had one to three positive nodes, and 34 patients had four or more positive nodes). Median follow-up for node-negative patients (5.2 years) is shorter than for node-positive patients (7.6 years). Therefore, outcome is reported at 5 and 10 years for node-positive patients but only at 5 years for node-negative patients. RESULTS: For node-positive patients, outcomes at 5 and 10 years, respectively, were 86% and 70% for overall survival, 78% and 67% for no evidence of disease survival, and 82% and 69% for freedom from distant metastases. For node-negative patients, outcomes at 5 years were 94% for overall survival, 94% for no evidence of disease survival, and 94% for freedom from distant metastases. Pathologic nodal status was predictive of outcome after treatment. Local failure in the treated breast was 5% at 5 years and 13% at 10 years for all patients. CONCLUSIONS: Concurrent CF with radiation therapy followed by six cycles of CMF after radiation therapy results in excellent survival, freedom from distant metastases, and local control for both node-negative and node-positive patients. This regimen of concurrent chemotherapy and radiation therapy is one option for sequencing, and it avoids the delays in administration of either modality that are associated with other sequencing regimens.

The effects of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy.

PURPOSE: Chemotherapy plays an increasingly important role in the treatment of both node-negative and node-positive breast cancer patients, but the optimal sequencing of chemotherapy and radiation therapy is not well established. The purpose of this study is to evaluate the interaction of sequence and type of chemotherapy and hormonal therapy given with radiation therapy on the cosmetic outcome and the incidence of complications of Stage I and II breast cancer patients treated with breast-conserving therapy. METHODS AND MATERIALS: The records of 1053 Stage I and II breast cancer patients treated with curative intent with breast-conserving surgery, axillary dissection, and radiation therapy between 1977-1991 were reviewed. Median follow-up after treatment was 6.7 years. Two hundred fourteen patients received chemotherapy alone, 141 patients received hormonal therapy alone, 86 patients received both, and 612 patients received no adjuvant therapy. Patients who received chemotherapy +/- hormonal therapy were grouped according to sequence of chemotherapy: (a) concurrent = concurrent chemotherapy with radiation therapy followed by chemotherapy; (b) sequential = radiation followed by chemotherapy or chemotherapy followed by radiation; and (c) sandwich = chemotherapy followed by concurrent chemotherapy and radiation followed by chemotherapy. Compared to node negative patients, node-positive patients more commonly received chemotherapy (77 vs. 9%, p < 0.0001) and/or hormonal therapy (40 vs. 14%, p < 0.0001). Among patients who received chemotherapy, the majority (243 patients) received concurrent chemotherapy and radiation therapy with two cycles of cytoxan and 5-fluorouracil (5-FU) administered during radiation followed by six cycles of chemotherapy with cytoxan, 5-fluorouracil and either methotrexate (CMF) or doxorubicin(CAF). For analysis of cosmesis, patients included were relapse free with 3 years minimum follow-up. RESULTS: The use of chemotherapy had an adverse effect on cosmetic outcome compared to no chemotherapy, which was of borderline significance at 3 years (92% excellent or good cosmetic outcome vs. 96% respectively, p = 0.057); however, cosmesis was not different at 5 years (91 vs. 93% respectively, p = 0.67). Cosmesis was not significantly different between patients treated sequentially and those treated concurrently (3 year: 87 vs. 93% respectively, p = 0.33), nor was it different between patients who received CMF vs. CAF (3 year: 92 vs. 93% respectively, p = 0.89). Hormonal therapy did not influence cosmetic outcome (p = 0.78). The incidence of Grade 4 or 5 arm edema (> or = 2 cm difference in arm circumference) was 2% without chemotherapy vs. 8% with chemotherapy (p = 0.00002). However, the incidence of arm edema was not affected by sequencing or type of chemotherapy (all p > or = 0.52). Patients treated sequentially had a 10% incidence of Grade 4 or 5 arm edema vs. 7% in the patients treated concurrently (p = 0.52). The incidence was 7 vs. 9% in patients treated with CMF vs. CAF (p = 0.73). The incidence of clinical pneumonitis and rib fracture was not influenced by use of chemotherapy, sequence of chemotherapy or use of hormonal therapy (all p > or = 0.06). CONCLUSIONS: Chemotherapy can be given concurrently with radiation therapy in the treatment of Stage I and II breast cancer with breast-conserving therapy without seriously compromising cosmetic outcome or incidence of complications compared to patients receiving other sequences of chemotherapy. Hormonal therapy did not affect cosmesis or complications. The chemotherapeutic regimen of cytoxan and 5-FU concurrent with radiation therapy followed by more chemotherapy is one reasonable option for breast conservation therapy in patients requiring chemotherapy.

Regulation of radiation-induced apoptosis in oncogene-transfected fibroblasts: influence of H-ras on the G2 delay.

Primary fibroblasts, after serum withdrawal or after irradiation, do not undergo apoptosis. Myc-transfected fibroblasts, in contrast, undergo apoptosis upon serum withdrawal and after irradiation. We have studied the relationship of apoptosis induction to effects on the G2 phase cell cycle in a series of rat embryo cells transformed by rasH plus myc or immortalized by myc alone. In this system, while the presence of rasH had little effect on the extent of apoptosis induction by serum withdrawal, rasH greatly suppressed the apoptotic response of myc-transfected cells to X-rays. The cells into which rasH had been introduced showed a profound G2 arrest associated with suppression of cyclin B1 mRNA expression. In contrast, cells with myc alone had a minimal G2 delay after irradiation and no suppression of cyclin B1 mRNA expression. We hypothesize that rasH, by influencing the G2 response of cells to X-rays, exerts an anti-apoptotic effect. In support of this hypothesis; we found that treatment of cells with caffeine, an agent that relieves the G2 delay after irradiation resulted in increased apoptosis in the irradiated cells, but not in control cells.

Decreased acute toxicity by using midline mucosa-sparing blocks during radiation therapy for carcinoma of the oral cavity, oropharynx, and nasopharynx.

PURPOSE: To determine whether midline mucosa-sparing blocks (MSBs) protecting the aerodigestive tract can statistically significantly reduce acute toxicity during radiation therapy for carcinoma of the head and neck, without compromising tumor control. MATERIALS AND METHODS: Radiation records and simulation films were reviewed in 125 patients with carcinoma of the oral cavity, oropharynx, or nasopharynx. Patients with and without MSBs were compared. Measures of acute toxicity during radiation therapy were weight loss (> or = 5%), hospitalization for nutritional support, and unplanned treatment interruptions (> or = 5 days). Actuarial local-regional tumor control was compared. RESULTS: Patients with MSBs had significantly less weight loss (26 of 50 vs 37 of 47 patients, P = .006), fewer hospitalizations for nutritional support (one of 61 vs seven of 64 patients, P = .04), and a trend toward fewer treatment interruptions (10 of 61 vs 19 of 64 patients, P = .07) than patients without MSBs. The 3-year actuarial tumor control rates in the neck were similar. CONCLUSION: Midline MSBs decrease acute toxicity during radiation therapy for carcinoma of the oral cavity, oropharynx, and nasopharynx without compromising tumor control.

MRI of carotid angiopathy after therapeutic radiation.

OBJECTIVE: Our goal was to assess whether significant secondary atherosclerotic changes from radiation can be detected on SE MR of the neck. MATERIALS AND METHODS: Pre- and postradiation MR scans of 16 patients with head and neck malignancies were studied randomly, independently, and blindly by two readers to determine the frequency of narrowing of the carotid arterial lumen and obliteration of the carotid space within the carotid sheath. RESULTS: Interval narrowing of either the common, internal, or external carotid artery lumen was seen in 108 of 192 (56%) of vessels evaluated on postradiation MR scans compared with preradiation studies. The differences in the grades of vessel luminal diameter were statistically significant (p < 0.05 for one reader and p < 0.0001 for the other reader). Among the 16 patients, 3 patients had vessels with a critical degree of stenosis, newly appearing on postradiation scans. Seven of 16 patients had diffuse obliteration of the planes within the carotid space. CONCLUSION: The incidence of accelerated atherosclerosis from therapeutic radiation may be greater than expected in nonirradiated patients. Magnetic resonance scans are an effective, noninvasive method for this type of follow-up.

The effects of radiation on the expression of a newly cloned and characterized rat cyclin B mRNA.

PURPOSE: To evaluate the hypothesis that the radiation induced G2 delay in the cell cycle is associated with radiation induced effects on cyclin B expression in a rodent cell system. METHODS AND MATERIALS: Two rodent, rat and Chinese hamster, cyclin B cDNAs were cloned and characterized. The two rodent species were 85% and 86% identical, respectively, when compared to the human cyclin B, indicating that they are the rodent homologous of cyclin B. 3.7 cells (rat embryo cells transformed by H-ras and v-myc) were synchronized and then irradiated. Flow cytometry and Northern blots were performed to evaluate the effects of radiation on cyclin expression in relation to phase of the cell cycle. RESULTS: Examination of the rodent cyclin B sequences revealed only two regions with significant divergence to the human sequence, one in the lysine rich region adjacent to the cyclin destruction box, which is the putative site for ubiquitination, and one at the C terminal end. Although many of the amino acids diverged in the lysine rich region, the positions of the lysines themselves were virtually invariant suggesting their potential importance in ubiquitination. Both rodent species were also noted to have a PEST-like sequence which occurs in the human, but not in non-mammalian cyclins cloned to date and could also potentially contribute to rapid destruction. The rat and Chinese hamster mRNAs contain much longer 3' untranslated regions than the published human sequence with multiple AUUUA and AUUU motifs which are seen in other mRNAs with rapid turnover times. This feature has not been previously found in cyclin mRNAs. In addition we have found that in the 3' region of the rodent cDNAs we find two potential polyadenylation sites suggesting that this gene may have several transcripts. Our studies suggest that multiple mechanisms of control of mammalian cyclin B destruction exist, both at the mRNA and protein level. Evidence is also provided that the levels of rat cyclin B mRNA peaks during G2/M. Irradiation is shown to induce a G2 delay in synchronized 3.7 cells, compared to unirradiated controls, and the delay is temporally related to decreased levels of cyclin B mRNA expression. Since the G2 delay induced by ionizing radiation may contribute to the ability of cells to survive irradiation, cyclin B expression may be a key component in the determination of sensitivity or resistance to radiation therapy. CONCLUSION: The isolation and characterization of two rodent cyclin B's confirm that multiple mechanisms of control of mammalian cyclin B destruction exist. Our studies show that rat cyclin B expression is influenced by radiation and is temporally related to the delay in the G2 phase induced by radiation.

Orbital lymphoma. Role of CT and MRI.

CT and MRI have made it possible to make a strongly presumptive diagnosis of orbital lymphoid tumors. Orbital lymphomas are usually homogeneous masses of relatively high density and sharp margins. The lesions mold themselves to pre-existing structures without eroding the bone. On MR imaging, they appear as relatively hypointense images, particularly in T1-weighted MR scans.