Kenneth J. Russell

Combined 5-fluorouracil and irradiation for transitional cell carcinoma of the urinary bladder

Thirty-four patients have completed treatment on a bladder-preservation protocol using primary irradiation combined with infusion 5-fluorouracil (5-FU). 4,000 cGy pelvic irradiation was delivered in 5 weeks, with 1,000 mg/m2/day of 5-FU administered as a 96 hr infusion on days 1-4 of week 1 and 4. After a 3-week rest period, patients eligible for cystectomy underwent cystoscopy and biopsy. Those with residual tumor underwent cystectomy, and those without tumor received an additional cycle of chemotherapy and irradiation. Patients ineligible for cystectomy for reasons medical, surgical, or refusal received a third cycle without the 4-week delay or re-evaluation. With a median follow-up of 18 months (range 2-45 months), and with 25/34 patients having T3 (16) or T4 (9) tumors, 17 patients are NED, 4 have died of intercurrent deaths, 7 have died with bladder cancer, and 6 are alive with tumor (2 confined to the bladder). The actuarial cancer-specific survival for the entire group of patients is 64% (+/- 12%) at 45 months, with a freedom from relapse of invasive cancer of 54% (+/- 10%). Twenty-four of the 34 patients retained intact bladders, with 20/24 reporting entirely normal voiding. Of 18 potential surgical candidates, 13/16 (81%) who underwent pathologic re-staging after 2 cycles of chemoradiotherapy had no histologic evidence of residual cancer. Of these 13 patients, 8 remain NED and 2/13 have locally recurrent non-invasive tumors only. Treatment was well-tolerated, with 28/34 patients having received 100% of the planned 5-FU and 34/34 having received greater than 80%. This regimen appears more successful than radiotherapy alone in achieving complete tumor responses, and is an attractive alternative for patients who are unable to receive more aggressive chemotherapy/radiation combinations.

Preferential radiosensitization of G1 checkpoint-deficient cells by methylxanthines

PURPOSE To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. METHODS AND MATERIALS A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. RESULTS Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. CONCLUSION This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.

Effect of pentoxifylline on radiation-induced lung and skin toxicity in rats☆

PURPOSE There is currently substantial clinical interest in pentoxifylline as an inhibitor of radiation-related normal tissue injury. To further assess this drugs potential toxicity-sparing effects, pentoxifylline was studied in rats using a radiation-induced lung injury model. METHODS AND MATERIALS Adult male rats were exposed to either sham irradiation or a single fraction of 21 Gy delivered to the left hemithorax. Four study groups were defined: those that received neither radiation nor pentoxifylline, those that received pentoxifylline (500 mg/L in drinking water) but no irradiation, those that underwent irradiation without pentoxifylline, and those that received both pentoxifylline and radiation. Lung injury was measured by changes in relative left:right lung perfusion ratios derived from quantitative gamma camera imaging of 99mTechnetium-macroaggregated albumin uptake in the pulmonary circulation. Serial scans were done over a 40-week period following radiation. Skin toxicity was also assessed. After 40 weeks, the animals were killed, and lung tissue was assayed for angiotensin converting enzyme activity as a marker for endothelial cell damage. RESULTS Both groups of radiated (with or without pentoxifylline) rats showed equivalent acute sharp decreases in left:right lung perfusion ratios compared to the nonirradiated groups, reaching a mean nadir value of 0.29 at week 4. Irradiated lung perfusion in subsequent weeks in the radiation-only group showed minimal recovery, with a plateau mean ratio of 0.37 (0.36-0.39). However, there was apparent later recovery of lung perfusion in the radiation with pentoxifylline group from weeks 14 through 40, to a mean ratio of 0.47 (0.43-0.52) (p < 0.01 compared to the radiation-only group). Angiotensin converting enzyme activity correlated closely with lung perfusion data. No effect of pentoxifylline on acute or late skin toxicity was detected. CONCLUSIONS This study suggests that pentoxifylline does not have any measurable effect on acute lung injury following hemithoracic irradiation in rats, but does result in sparing of later lung toxicity.

Clinical trials of neutron radiotherapy in the United States

The development of clinical neutron facilities in the 1980s, capable of delivering high energy neutrons spurred full scale phase III testing of neutron beam radiotherapy in a number of tumors including salivary gland, head and neck, prostate, and non small-cell lung cancer. The Radiation Therapy Oncology Group (RTOG) and the Medical Research Council (MRC) jointly sponsored a randomized trial for the treatment of advanced stage salivary gland tumors comparing neutron to conventional photon and/or electron radiotherapy. Although no improvement in survival was seen, the study demonstrated a striking and statistically significant difference in the local-regional control of unresectable salivary gland tumors (56 vs 17%), favoring neutron beam irradiation. Subsequent clinical trials of neutron beam irradiation were initiated by the Neutron Therapy Collaborative Working Group (NTCWG) sponsored by the National Cancer Institute (NCI). A phase III trial comparing neutron to photon radiotherapy for inoperable regional non-small cell lung cancer showed no overall improvement in survival. However, a statistically significant improvement in survival was observed in the subset of patients with squamous cell histology. The NTCWG trial comparing fast-neutron therapy versus conventional photon irradiation in the treatment of advanced squamous cell carcinomas of the head and neck showed a statistically significant improvement in initial complete response (70 vs 52%) favoring neutrons. However, subsequent failures erased any difference in ultimate local-regional control rates and survival curves were essentially the same in both arms. The randomized study of the NTCWG for locally advanced prostate cancer demonstrated a significant decrease in local-regional failure (11 vs 32%) at 5 years, favoring the neutron arm. Furthermore, biochemical measures of disease control also favored the neutron arm with prostate specific antigen (PSA) levels elevated in 17% of the neutron-treated patients compared to 45% of the photon-treated patients at 5 years. At the 5-year analysis, no significant difference in survival was observed between the two arms; however, longer follow-up is necessary to assess the ultimate impact of improved local-regional control on survival. An analysis of complications in this series revealed the importance of beam shaping and treatment planning capabilities in maintaining long-term sequelae following neutron irradiation at an acceptably low level.

Fast Neutron Radiation Therapy: Results of phase III randomized trials in head and neck, lung, and prostate cancers

The results of phase III trials comparing neutrons to photons for head and neck squamous cell cancers, non-small cell lung cancers, and prostate adenocarcinomas are reviewed, with emphasis given to the most recent U.S. National Cancer Institute sponsored randomized clinical studies in which fast neutrons were delivered using modern, hospital-based, high-energy, isocentric-capable cyclotrons. In locally advanced squamous cell head and neck cancers, neutrons showed no convincing advantage over photons. Fast neutron radiotherapy may have provided a therapeutic benefit in selected patients with inoperable non-small cell lung cancers. For locally advanced prostate adenocarcinomas, neutron therapy resulted in significantly superior clinical and histological loco-regional tumor control, which may translate to improved survival with additional follow-up. In general, severe late complications were more frequent with neutrons, especially in patients treated on older physics laboratory-based equipment. Even with modern state-of-the-art neutron generators, careful beam collimation and treatment planning are required to minimize side effects.

Fast Neutrons in Prostatic Adenocarcinomas: Worldwide Clinical Experience

Primary tumor control remains a major problem in the treatment of locally advanced prostate carcinoma. Clinical local failure rates approach 30-40% and may be significantly higher when results of prostatic biopsy or prostate-specific antigen (PSA) levels are considered. The low growth rate and cycling fraction of prostate adenocarcinoma suggest potential therapeutic advantage for the high linear energy transfer (LET) of neutrons. The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional randomized trial (RTOG 77-04) comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) compared pure neutron irradiation to standard photon irradiation. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Future analysis of the larger NTCWG trial at the 10-year point should confirm whether or not improved locoregional control translates into a survival advantage. These findings have significant implications for all local treatment strategies including dose-escalated conformal photon irradiation, prostate implantation, and neutron radiation. Given the large numbers of patients afflicted with this disease, a positive survival advantage for neutrons or mixed beam therapy would provide a strong incentive for the development of economically feasible clinical neutron facilities.

Combined 5-Fluorouracil and Irradiation for the Treatment of Invasive Bladder Cancer

Extensive clinical experience has demonstrated the efficacy of external beam radiotherapy for selected patients with radioresponsive bladder cancers. Patients who achieve a complete clinical response within 6 months of completion of radical radiotherapy enjoy a 45%–69% survival at 5 years, as opposed to 6%–14% for patients with unresponsive tumors (Bloom et al. 1982; Quilty and Duncan 1986; Hope-Stone et al. 1984). This relationship between tumor radioresponsiveness and prognosis also holds true for patients undergoing combined preoperative radiation followed by planned cystectomy.