Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

Management of Continuous Glucose Monitors in Radiation Oncology Patients.

Continuous glucose monitors (CGMs) are an increasingly prevalent electronic medical device utilized by patients with diabetes, offering several advantages over "finger sticks". There is a resulting rise in patients with CGMs seen in radiation oncology clinics. Manufacturers specify that CGMs should not be exposed to radiation (both diagnostic and therapeutic), due to risk of device damage, creating challenges for patients and providers. We present a workflow for management of CGMs in radiation oncology patients, beginning with systematic screening by providers and staff. We propose options for CGM management together with the device prescriber, including removal of the CGM or keeping it in place with periodic finger sticks to confirm accuracy, and offer guidance to radiation oncology providers and staff.

An Automated, Dynamic Radiation Oncology Prescription Checking System.

PURPOSE: Despite serving as a critical communication tool, radiation oncology prescriptions are entered manually and prone to error. An automated prescription checking system was developed and implemented to help address this problem. METHODS AND MATERIALS: Rules defining clinically appropriate prescriptions were generated, examining specific types of errors: (1) unapproved dose per fraction for a given disease site; (2) dose per fraction too large for nonstereotactic treatment technique; and (3) dose per fraction too low. With a goal of catching errors as upstream as possible to minimize their propagation, a report was created and ran every 30 minutes to check all newly written or approved prescriptions against the 3 rules. When a prescription violated these rules, an automated email was immediately sent to the prescriber alerting them of the potential error. System performance was continuously monitored and the criteria triggering an alert adjusted to balance error detection against false positives. Alerts leading to prescription amendment were considered true errors. RESULTS: From June 2021 to November 2022, the system checked 24,047 prescriptions. A total of 241 email alerts were triggered, for an average alert rate of 1%. Of the 241 alerts, 198 (82.2%) were unapproved doses per fraction for the disease site, 14 (5.8%) were doses per fraction that were too low, and 29 (12%) were doses too large for nonstereotactic treatment technique. Thirty-one percent of alerts led to a change of prescription, suggesting they were true errors. The baseline rate of erroneous prescription entry was 0.3%. A regression model showed that trainee prescription entry and dose per fraction <150 cGy were significantly associated with true errors. CONCLUSIONS: Given the significant consequences of erroneous prescription entry, which ranged from wasted resources and treatment delays to potentially serious misadministration, there is significant value in implementing automated prescription checking systems in radiation oncology clinics.

Treatment of oropharyngeal squamous cell carcinoma with IMRT: patterns of failure after concurrent chemoradiotherapy and sequential therapy.

BACKGROUND: The optimal management of oropharyngeal squamous cell carcinoma (OPSCC) is controversial. Modern radiotherapy typically employs intensity-modulated radiation therapy (IMRT), and herein, we report the Dana-Farber Cancer Institute (DFCI) experience with IMRT-based treatment of OPSCC. DESIGN: Retrospective study of all patients treated at DFCI for OPSCC with definitive or adjuvant IMRT between 8/04 and 8/09. The primary end point was overall survival (OS); secondary end points were locoregional control (LRC) and freedom from distant metastases (FFDM). Propensity score matching was used to create concurrent chemoradiotherapy (CCRT) and sequential therapy (ST) cohorts equally balanced for patient and disease characteristics. RESULTS: One hundred and sixty-three patients were included with 75% presenting with stage IV disease. Fifty-six patients (34%) were treated with ST. The three-year actuarial OS, LRC, and FFDM rates for the entire cohort/ST subset were 86%/89%, 86%/87%, and 88%/93%, respectively. There were no differences in OS, LRC, or FFDM between CCRT and ST in the propensity-matched cohort. CONCLUSIONS: IMRT was associated with excellent OS, LRC, and FFDM. Although the results following ST were superb, there was no obvious benefit to ST after adjustment for selection bias. We recommend that ST be reserved for medically fit patients with a high risk of distant metastases.

Cost-effectiveness of CT and PET-CT for determining the need for adjuvant neck dissection in locally advanced head and neck cancer.

BACKGROUND: Patients with node-positive head and neck squamous cell carcinomas (HNC) have a significant risk of residual disease (RD) in the neck after treatment, despite optimal chemoradiotherapy (CRT). Adjuvant neck dissection (ND) after CRT has been considered standard treatment, but its morbidity has led investigators to consider using post-CRT imaging to determine the need for surgery. We analyzed the cost-effectiveness of computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) as predictors of the need for ND compared with ND for all patients. MATERIALS AND METHODS: We developed a Markov model to describe health states in the 5 years after CRT for HNC in a 50-year-old man. We compared three strategies: dissect all patients, dissect patients with RD on CT, and dissect patients with RD on PET-CT. Probabilistic sensitivity analyses were carried out to model uncertainty in PET-CT performance, up-front and salvage dissection costs, and patient utilities. RESULTS: ND only for patients with RD on PET-CT was the dominant strategy over a wide range of realistic and exaggerated assumptions. Probabilistic sensitivity analyses confirmed that the PET-CT strategy was almost certainly cost-effective at a societal willingness-to-pay threshold of $500,000/quality-adjusted life year. CONCLUSION: Adjuvant ND reserved for patients with RD on PET-CT is the dominant and cost-effective strategy.

Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck.

BACKGROUND: Panitumumab has the potential to improve the therapeutic ratio of concurrent chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase I dose-finding study investigated escalating doses of paclitaxel (Taxol) given concurrently with panitumumab, carboplatin and intensity-modulated radiotherapy (IMRT) for stage III-IVB SCCHN. Untreated patients with oral cavity, oropharynx, larynx, hypopharynx or unknown primaries were eligible. Additional eligibility criteria included measurable disease, good performance status and no contraindication to therapy. Patients received weekly fixed doses of panitumumab and carboplatin plus escalating doses of paclitaxel with IMRT. RESULTS: Nineteen patients were enrolled on to two dose levels (DLs): weekly paclitaxel 15 mg/m(2) (n = 3) and 30 mg/m(2) (n = 16). One dose-limiting toxicity occurred in DL 2, which was declared the maximum tolerated dose. All patients experienced mucositis, primarily grade 3 or more. Oral pain, xerostomia, dysphagia, weight loss, dermatitis, nausea and acneiform rash were frequent. All patients had partial response according to RECIST, whereas the overall complete clinical response rate was 95%. At median follow-up of 21 months, 18 of 19 patients (95%) remained disease free. CONCLUSIONS: Panitumumab, carboplatin, paclitaxel and IMRT are well tolerated and appear highly active in the treatment of SCCHN. Further study of this regimen in SCCHN is warranted.

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation.

BACKGROUND: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. PATIENTS AND METHODS: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. RESULTS: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31-not reached] versus 24 months (95% CI: 13-42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41-0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12-59) versus 11 months (95% CI: 8-14) for PF (HR: 0.66; 95% CI: 0.45-0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37-0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). CONCLUSIONS: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.

Options for combining altered fractionation with IMRT.

We set out to investigate IMRT-based concomitant boost. Eight patients with stage III/IV squamous cell carcinoma of the head and neck treated with once daily with chemoradiotherapy at the Dana-Farber/Brigham and Women's Hospital had their treatment plans reviewed with IRB approval. Each case was replanned for treatment with a a concomitant boost regimen. Plans delivered 1.9 Gy in 30 fractions to 57 Gy with a boost of 1.5 Gy in 10 fractions for a total dose of 72 Gy. The boost was planned with both IMRT and 3-D conformal, to compare the two techniques. For each patient, both plans (IMRT-IMRT and IMRT-3DCRT) were evaluated for target and avoidance coverage, monitor units and integral dose. Finally, we evaluated the plans for time to completion. The IMRT-IMRT and IMRT-3-DCRT techniques were equivalent for target coverage. 100% coverage of the GTV and PTV was achieved with 97% of the prescription dose. Hot spots were seen 104% to 108% with IMRT-IMRT plan and from 102-111% with the IMRT-3DCRT plans. The IMRT-IMRT boost had double the monitor units as the 3-DCRT boosts. When the total monitor units from both the initial and boost portions of the plans were e combined there was not a significant difference. There was a slight increase in integral dose with the IMRT-IMRT plans of mean 3.8%. Planning time was increased for the 3-DCRT boost as opposed to the IMRT boost (mean 3.5 hours vs. 1.5 hours). More time was needed for quality assurance of the IMRT-IMRT plans (3.0 hours vs. 1.5 hours for IMRT-3-DCRT). We found that both IMRT-based concomitant-boost strategies are achievable and produce good dosimetric results.

Taxol sensitizes human astrocytoma cells to radiation.

Taxol is a chemotherapeutic drug which acts by stabilizing microtubules, preventing normal mitosis and resulting in a block of the cell cycle at G2 and M. The drug is isolated from the yew, Taxus sp. L., and is currently being evaluated in a series of Phase II and Phase III clinical trials. Taxol blocks cells in the most radiosensitive phases of the cell cycle and thus could act as a cell cycle-specific radiosensitizer. We report the results of combined taxol-radiation exposures in the human Grade III astrocytoma cell line, G18. Taxol is a potent inhibitor of G18 cell division; a concentration of 10 nM is cytostatic for a cell population observed for at least two doubling times. Cell survival curves for G18 cells showed a significant concentration-dependent interaction between taxol and radiation. Treatment of G18 cells with a fixed taxol concentration and radiation dose showed the interaction to be dependent on the duration of taxol exposure and consequently the fraction of cells in the G2 or M phase of the cell cycle. The sensitizer enhancement ratio for 10 nM taxol at 10% survival is 1.8 and, for 1 nM taxol, it is 1.2. These results suggest that appropriate combinations of taxol have a more than additive interaction in human tissue culture and may have a role in clinical protocols.

Increases in sequence specific DNA binding by p53 following treatment with chemotherapeutic and DNA damaging agents.

We have investigated the effect of chemotherapeutic and DNA damaging agents on binding of the tumor suppressor phosphoprotein p53 to its consensus DNA sequence. Activation of p53-DNA binding was seen for treatment with radiation, hydrogen peroxide, actinomycin D, Adriamycin, etoposide, camptothecin, 5-fluorouracil, mitomycin C, and cisplatin. These results showed that DNA strand breaks were sufficient to lead to increased levels of p53. The protein synthesis inhibitor cycloheximide blocks the increase in p53 following DNA damage. The increase in p53 activation in camptothecin treated cells may result, at least in part, from an increased half-life of the protein and consequent increases in intracellular protein concentration.

Microtubule-active drugs taxol, vinblastine, and nocodazole increase the levels of transcriptionally active p53.

A range of DNA-damaging agents has been shown to increase cellular levels of the nuclear phosphoprotein p53 and to induce p53-dependent processes. We examined the ability of three microtubule-active agents, taxol, vinblastine, and nocodazole, to increase p53 levels and activate p53-dependent processes. When tested using a p53 DNA-binding assay, all three agents induced p53 in a dose-dependent manner. To varying degrees, these agents also induced p21WAF1/CIP1 mRNA and transcription in a chloramphenicol acetyl transferase reporter system. These data suggest there is an additional pathway for activating p53 and subsequent p53-dependent processes.

Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases.

PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival. PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range. RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%. CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

The role of induction chemotherapy in the curative treatment of squamous cell cancer of the head and neck.

Induction chemotherapy is appropriate for the treatment of locally advanced squamous cell carcinoma of the head and neck because it allows organ preservation without compromising survival and improves survival in unresectable disease. Radiation therapy, not surgery, should immediately follow induction chemotherapy in potentially resectable patients to prevent tumor repopulation. The results of three phase II studies of docetaxel-based regimens as induction therapy of patients with locally advanced squamous cell carcinoma of the head and neck are reviewed and reported. Overall response rates ranged from 93% to 100%, with complete response rates of 40% to 63%. The primary toxicities were neutropenia and febrile neutropenia. A North American phase III trial, randomizing patients to docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil sequentially followed by chemoradiotherapy is being performed to determine whether docetaxel improves the complete response rate, organ preservation rate, and survival of patients treated with induction chemotherapy.

Correlation of sensitizer enhancement ratio with bromodeoxyuridine concentration and exposure time in human cervical carcinoma cells treated with low dose rate irradiation.

The effect of a range of bromodeoxyuridine concentrations and exposure times on the sensitizer enhancement ratio of two human cervical carcinoma cell lines treated with low rate irradiation was evaluated. Both cell lines show a linear, though different, dose response to low dose rate irradiation at dose rates up to 0.62 Gy/hr. Cells were pre-incubated with 0, 1, 5, or 10 microM bromodeoxyuridine for 0, 24, or 48 hr prior to low dose rate irradiation. Based on the survival of cells exposed to 4 Gy, delivered at 0.62 Gy/hr, a slope was determined for an exponential survival curve for each bromodeoxyuridine concentration and exposure time. Sensitizer enhancement ratios were calculated as the ratio of the slopes of the treated and untreated cells from a particular exposure time. Ratios increased linearly initially with a plateauing at higher levels with respect to the product of bromodeoxyuridine concentration and time of exposure for both cell lines with similar degrees of enhancement. A linear relationship has been noted previously for acute irradiation of hamster cells over a similar range of sensitizer concentrations and exposure times. At the highest dose-time points (540 microM-hr) ratios of greater than 2 were attained, which were comparable to results obtained following acute radiation exposures of V-79 cells. These results demonstrate that significant sensitizer enhancement ratios with low dose irradiation can be obtained in human tumor cells after exposures of 2 to 3 doubling times using relatively low concentrations of sensitizer.

Low dose rate irradiation and halogenated pyrimidine effects on human cervical carcinoma cells.

The response of two human cervical carcinoma cell lines to the combination of bromodeoxyuridine (BrdUrd) incorporation and low dose rate irradiation (LDRI) was assessed. Survival curves were generated following both acute (67.2 Gy/hr) and low dose rate (0.11-0.62 Gy/hr) 137Cs gamma-ray irradiation. The two cell lines exhibited markedly different radiation responses, but for the chronic irradiation, there was no significant difference in response between the low dose rates for either cell line. In all cases, the low dose rate radiation response could be described using a single exponential y = e-alpha D. The sensitizer enhancement ratio (SER) at 10% survival was determined and for the first cell line the low dose rate slope (alpha) was approximately 0.7 Gy-1 with an SER of 1.3-1.5 and an SER of approximately 1.6 for the acute response. In contrast, the second cell line had a low dose rate slope (alpha) of approximately 0.4 Gy-1, an SER of 1.3-1.5, and an SER of approximately 1.7 for the acute response. The similarity of the SER's is notable in light of the marked differences between the intrinsic radiation response of the cells. As the concentration and/or time of exposure to BrdUrd increased, both cytotoxicity and the degree of sensitization also increased. This study demonstrates that SER's with BrdUrd and LDRI are comparable to those obtained for acute exposures in two cervical carcinoma cell lines. The results suggest that this combination of modalities may have clinical applications.

Taxol: a novel radiation sensitizer.

The investigational antineoplastic agent, taxol, a natural product from the yew, Taxus sp. L., is currently being evaluated in a series of Phase II clinical trials. To date, the drug has shown activity against ovarian cancer, lung cancer, and melanoma. Taxol is a potent microtubule stabilizing agent that selectively blocks cells in the G2 and M phases of the cell cycle and is cytotoxic in a time-concentration dependent manner. It is well known from radiobiological principles that G2 and M are the most radiosensitive phases of the cell cycle. On the rationale that taxol could function as a cell-cycle selective radiosensitizer, we examined the consequences of combined drug-radiation exposures on the human grade 3 astrocytoma cell line, G18. Survival curve analysis shows a dramatic interaction between taxol and ionizing radiation with the degree of enhanced cell killing dependent on taxol concentration and on the fraction of cells in the G2 or M phases of the cell cycle. The sensitizer enhancement ratio (SER) for 10 nM taxol at 10% survival is approximately 1.8. These results obtained with cycling aerated radioresistant brain tumor cells indicate that significant advantage may derive from appropriate time-concentration dependent interactions in combined modality protocols.

Tolerance of cranial nerves of the cavernous sinus to radiosurgery.

PURPOSE: Stereotactic radiosurgery is becoming a more accepted treatment option for benign, deep seated intracranial lesions. However, little is known about the effects of large single fractions of radiation on cranial nerves. This study was undertaken to assess the effect of radiosurgery on the cranial nerves of the cavernous sinus. METHODS AND MATERIALS: We examined the tolerance of cranial nerves (II-VI) following radiosurgery for 62 patients (42/62 with meningiomas) treated for lesions within or near the cavernous sinus. Twenty-nine patients were treated with a modified 6 MV linear accelerator (Joint Center for Radiation Therapy) and 33 were treated with the Gamma Knife (University of Pittsburgh). Three-dimensional treatment plans were retrospectively reviewed and maximum doses were calculated for the cavernous sinus and the optic nerve and chiasm. RESULTS: Median follow-up was 19 months (range 3-49). New cranial neuropathies developed in 12 patients from 3-41 months following radiosurgery. Four of these complications involved injury to the optic system and 8 (3/8 transient) were the result of injury to the sensory or motor nerves of the cavernous sinus. There was no clear relationship between the maximum dose to the cavernous sinus and the development of complications for cranial nerves III-VI over the dose range used (1000-4000 cGy). For the optic apparatus, there was a significantly increased incidence of complications with dose. Four of 17 patients (24%) receiving greater than 800 cGy to any part of the optic apparatus developed visual complications compared with 0/35 who received less than 800 cGy (p = 0.009). CONCLUSION: Radiosurgery using tumor-controlling doses of up to 4000 cGy appears to be a relatively safe technique in treating lesions within or near the sensory and motor nerves (III-VI) of the cavernous sinus. The dose to the optic apparatus should be limited to under 800 cGy.