Radiosensitization produced in vivo by once- vs. twice-weekly 2'2'-difluoro-2'-deoxycytidine (gemcitabine).

PURPOSE: Gemcitabine (2'2'-difluoro-2'-deoxycytidine, dFdCyd) is a potent radiosensitizer of rodent and human tumor cells. Our Phase I clinical trial using once-weekly dFdCyd as a radiosensitizer in the treatment of patients with Stage IV squamous cell head and neck cancer has produced a high rate of tumor response and significant normal mucosal toxicity. These findings raised the question of whether we are using dFdCyd in the optimal dose and schedule. In vitro studies suggest that twice-weekly dFdCyd has the potential to be more effective than once-weekly dFdCyd when administered in combination with radiation (RT) given 5 days per week. Therefore, we have used a mouse model to assess whether the therapeutic ratio of combined modality therapy may be improved by using a twice-weekly drug regimen. We asked two questions: 1) Does a once-weekly or twice-weekly dFdCyd regimen cause more normal tissue radiosensitization? 2) Does a once-weekly or twice-weekly dFdCyd + RT regimen produce a better therapeutic index? METHODS AND MATERIALS: To assess normal tissue toxicity, C3H mice underwent mouth (60)Co RT (27.5 Gy in 5 daily fractions) +/- dFdCyd delivered intraperitoneally (IP) either once or twice weekly 6 hours prior to irradiation. Acute lip reactions were quantified according to a standard scoring system, and weight loss was measured. We measured tumor control using squamous cell carcinoma (SCC) VII murine squamous cell flank tumors (50-125 mm(3)) treated with the same regimens used in the mouth irradiation model. RESULTS: We found that dFdCyd delivered 800 mg/kg once weekly or 150 mg/kg twice weekly caused similar (and maximal tolerable) weight loss; therefore these regimens were chosen to test which schedule produced more acute lip radiosensitization. Twice-weekly dFdCyd + RT was somewhat more toxic by weight loss (800 mg/kg once weekly: 11.9%; 150 mg/kg twice weekly: 17.7%; p = 0.09). To assess therapeutic index, we treated SCC VII flank tumors with RT combined with isotoxic drug/RT regimens (dFdCyd 800 mg/kg once weekly or 100 mg/kg twice weekly). Tumors treated with twice-weekly dFdCyd + RT were significantly smaller than tumors treated with once-weekly drug + RT at 28 days from the start of treatment (p < 0.03). CONCLUSIONS: These findings demonstrate that equitoxic once- versus twice-weekly dFdCyd regimens cause differing levels of oral mucosal radiosensitization. This would suggest that each radiation-dFdCyd schedule will require its own dFdCyd dose escalation trial (which cannot be determined by the maximum tolerated dose (MTD) for dFdCyd alone using that schedule). In addition, our findings suggest that for head and neck cancers twice-weekly dFdCyd may have a higher therapeutic index compared with once-weekly dFdCyd when combined with daily RT.

Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing.

PURPOSE: Conformal treatment using static multisegmental intensity modulation was developed for patients requiring comprehensive irradiation for head and neck cancer. The major aim is sparing major salivary gland function while adequately treating the targets. To assess the adequacy of the conformal plans regarding target coverage and dose homogeneity, they were compared with standard irradiation plans. METHODS AND MATERIALS: Fifteen patients with stage III/IV head and neck cancer requiring comprehensive, bilateral neck irradiation participated in this study. CT-based treatment plans included five to six nonopposed fields, each having two to four in-field segments. Fields and segments were devised using beam's eye views of the planning target volumes (PTVs), noninvolved organs, and isodose surfaces, to achieve homogeneous dose distribution that encompassed the targets and spared major salivary gland tissue. For comparison, standard three-field radiation plans were devised retrospectively for each patient, with the same CT-derived targets used for the clinical (conformal) plans. Saliva flow rates from each major salivary gland were measured before and periodically after treatment. RESULTS: On average, the minimal dose to the primary PTVs in the conformal plans [95.2% of the prescribed dose, standard deviation (SD) 4%] was higher than in the standard plans (91%, SD 7%; p = 0.02), and target volumes receiving <95% or <90% of the prescribed dose were smaller in the conformal plans (p = 0.004 and 0.02, respectively). Similar advantages of the conformal plans compared to standard plans were found in ipsilateral jugular nodes PTV coverage. The reason for underdosing in the standard treatment plans was primarily failure of electron beams to fully encompass targets. No significant differences were found in contralateral jugular or posterior neck nodes coverage. The minimal dose to the retropharyngeal nodes was higher in the standard plans. However, all conformal plans achieved the planning goal of delivering 50 Gy to these nodes. In the conformal plans, the magnitude and volumes of high doses in noninvolved tissue were significantly reduced. The main reasons for hot spots in the standard plans (whose dose calculations included missing tissue compensators) were photon/electron match line inhomogeneities, which were avoided in the conformal plans. The mean doses to all the major salivary glands, notably the contralateral parotid (receiving on average 32% of the prescribed dose, SD 7%) were significantly lower in the conformal plans compared with standard radiation plans. The mean dose to the noninvolved oral cavity tended to be lower in the conformal plans (p = 0.07). One to 3 months after radiation, on average 60% (SD 49%) of the preradiation saliva flow rate was retained in the contralateral parotid glands and 10% (SD 16%) was retained in the submandibular/sublingual glands. CONCLUSIONS: Planning and delivery of comprehensive irradiation for head and neck cancer using static, multisegmental intensity modulation are feasible. Target coverage has not been compromised and dose distributions in noninvolved tissue are favorable compared with standard radiation. Substantial major salivary gland function can be retained.

Dose escalation for non-small cell lung cancer using conformal radiation therapy.

PURPOSE: Improved local control of non-small cell lung cancer (NSCLC) may be possible with an increased dose of radiation. Three-dimensional radiation treatment planning (3D RTP) was used to design a radiation therapy (RT) dose escalation trial, where the dose was determined by (a) the effective volume of normal lung irradiated, and (b) the estimated risk of a complication. Preliminary results of this trial were reviewed. METHODS AND MATERIALS: A graph of the iso-normal tissue complication probability (NTCP) levels associated with a dose and effective volume (V(eff)) was derived, using normal tissue parameters derived from the literature. This led to a dose escalation schema, where patients were sorted into 1 of 5 treatment bins, determined by the V(eff) of the best possible treatment plan. The starting doses ranged from 63 to 84 Gy. Each treatment bin was then escalated separately, as in Phase I dose escalation fashion, with Grade > or = 3 radiation pneumonitis defined as dose limiting. To allow for dose escalation, we required patient follow-up to be > or = 6 months for at least three patients. 3D treatment planning was used to irradiate only the radiographically abnormal areas, with 2.1 Gy (corrected for lung inhomogeneity)/day. Clinically uninvolved lymph nodes were not treated prophylactically. RESULTS: A total of 48 NSCLC patients have been treated (Stage I/II: 18 patients; Stage III: 28 patients; mediastinal recurrence postsurgery: 2 patients). No radiation pneumonitis has been observed in the 30 patients currently evaluable beyond the 6-month time point. All treatment bins have been escalated at least once. Current doses in the five treatment bins are 69.3, 69.3, 75.6, 84, and 92.4 Gy. None of the 15 evaluable patients in any bin with > or = 30% NTCP experienced clinical radiation pneumonitis, implying that the actual risk is < 20% (beta error rate 5%). Despite the observation of the clinically negative lymph nodes at high risk, there has been no failure in the untreated mediastinum as the sole site of first failure. Three of 10 patients receiving > or = 84 Gy have had biopsy proven residual or locally recurrent disease. CONCLUSION: Successful dose escalation in a volume-dependent organ can be performed using this technique. By incorporating the effective volume of irradiated tissue, some patients have been treated to a total dose of radiation over 50% higher than traditional doses. The literature-derived parameters appear to overestimate pneumonitis risk with higher volumes. There has been no obvious negative effect due to exclusion of elective lymph node radiation. When completed, this trial will have determined the maximum tolerable dose of RT as a single agent for NSCLC and the appropriate dose for Phase II investigation.

Impact of differences in ultrasound and computed tomography volumes on treatment planning of permanent prostate implants.

PURPOSE: Both ultrasound (US) and computerized tomography (CT) images have been used in the planning of prostate interstitial therapy. Ultrasound images more clearly define the apex and capsule of the prostate, while CT images define seed positions for postimplant dosimetry. Proper registration of the US volume with the CT volume is critical to the assessment of dosimetry. We therefore compared US and CT prostate volumes to determine if differences were significant. METHODS AND MATERIALS: Ten consecutive patients entered in an interstitial implant program were studied by pretreatment US. In addition, pretreatment CT scans were obtained and three physicians independently outlined the dimensions of the prostate on these images. The patients subsequently underwent placement of radioactive 125I or 103Pd. Postimplant CT images were obtained the next day and the postimplant prostate volumes were outlined by the same three physicians. Seven of 10 patients underwent late CT scans 9-14 months postimplant for comparison of preimplant and immediate postimplant CT studies. RESULTS: There were differences between US and CT volumes. Although the physician-to-physician variation was significant, the trends were consistent, with US prostate volume typically smaller (47%) than the preimplant CT volume and markedly smaller (120%) than the postimplant CT volume. Prostate volumes derived from late CT images did not consistently return to preimplant levels. CONCLUSIONS: Significant differences in volume of the prostate structure were found between US and CT images. The data suggests that: (a) Implants planned on CT tend to overestimate the size of the prostate and may lead to unnecessary implantation of the urogenital diaphragm and penile urethra. (b) Registration of initial US and postimplant CT prostate volumes required for accurate dosimetry is difficult due to the increased volume of prostate secondary to trauma. (c) Further study to determine the optimal time for the postimplant CT is necessary.

Current status of radiation sensitization by fluoropyrimidines.

Numerous clinical studies suggest that the combination of the fluoropyridimine fluorouracil and radiation is a more effective treatment for many cancers, especially gastrointestinal tumors, than is either modality alone. Also, the combination of fluorouracil and radiation has greatly expanded the possibilities for organ-preserving treatments, for example, in patients with bladder cancer. Another fluoropyridimine, floxuridine, administered via the hepatic artery, has been used in combination with irradiation in the treatment of patients with intrahepatic cancers and may prolong survival in patients with unresectable hepatobiliary malignancies. The beneficial effects of combining fluoropyrimidines and radiation are thought to be due to radiosensitization. More studies are needed to clarify the mechanism(s) of radiosensitization so as to optimize regimens in which the fluoropyrimidines are used.

Low grade gliomas: preliminary analysis of failure patterns among patients treated using 3D conformal external beam irradiation.

PURPOSE: The pattern of failure of low grade gliomas following radiotherapy is less well known than that of the high grade gliomas. Stereotactic histologic studies have suggested that tumor cells extend beyond imaging abnormalities, and that large margins would be required for radiotherapy target volumes to encompass all of the neoplasm. Our experience using computerized tomography (CT)- and magnetic resonance (MR)-planned irradiation of low grade gliomas was reviewed to determine the pattern of tumor recurrence, in an effort to clinically define the minimum margin required. METHODS AND MATERIALS: Forty-six patients with low grade supratentorial gliomas were treated between April 1985 and November 1992 using three-dimensional (3D) conformal CT- or MR-planned external beam radiotherapy. Fields were designed to encompass a target volume created by adding a margin to the tumor in three dimensions. Generally, patients were treated using shrinking fields with an initial target (tumor plus a 1 to 3 cm margin) treated to a dose of 45 to 50.4 (median 50.4) Gy, and a boost (tumor plus a 0 to 2 cm margin) treated to a total of 54 to 59.4 (median 59.4) Gy. Median follow-up was 32.9 months. RESULTS: There have been 11 failures; all of these occurred within the radiographic abnormality (either T2 prolongation or CT hypodensity) visualized at the time of treatment planning (i.e., all failures were within the boost volume). Median time to failure was 53 months. Because all failures were local, there was no relationship between the amount by which the tumor volumes were expanded to create target volumes and the eventual outcome. CONCLUSION: Despite pathologic data suggesting that low grade glioma cells can be found outside the MR T2-signal abnormality in many cases, our results demonstrate that conformal external beam radiotherapy, in which the high dose volume is limited, does not result in increased marginal or out-of-field failures. Until control of tumor within the radiographically abnormal volume can be achieved, the need for large fields to treat prophylactically microscopic disease beyond the visualized tumor volume is questionable. The use of conformal fields might be associated with reduced toxicity, and thereby allow delivery of higher total doses to the central tumor.

In vivo and in vitro enhanced antitumor effects by pentoxifylline in human cancer cells treated with thiotepa.

Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, we studied combination treatments with alkylating agents and pentoxifylline or other methylxanthines. With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to 10-fold (P less than 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic p.o. doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produced no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly, systemic therapy of other malignancies.