Introduction

1. Overall Survival Since Initial Diagnosis Based on Initial Histology Overall Survival Since Initiation of PRDR Based on Histology at time of PRDR Pulsed reduced dose rate radiotherapy (PRDR): A novel reirradiation strategy for large volume recurrent glioma. Jarrod B. Adkison, Wolfgang A. Tomé, H. Ian Robins, Songwon Seo, Karl Rassmussen, James S. Welsh, Peter A. Mahler, and Steven P. Howard. Overall Survival Since Initiation of PRDR Based on Initial Histology • Results • Median survival from time of initiation of PRDR was 11.4 months for low grade, 5.4 months for grade 3, and 5.3 months for grade 4 astrocytoma based on histology at time of initial diagnosis. • Median survival for all-comers was 5.8 months. • Median survival for Karnofsky Performance Status (KPS) ≥ 70 was 6.2 months compared to 2.4 months for KPS < 70 (p<0.0001) . • Although age < 50 vs. ≥ 50 was not statistically significant (p=0.08), the median survivals were 6.3 months and 4.8 months, respectively. • There were no grade 4 or 5 toxicities. • Introduction • Combined modality therapy including maximal safe surgical resection followed by adjuvant radiotherapy and chemotherapy is standard treatment for high-grade glioma. The Stupp regimen represents the most significant treatment breakthrough in the last decade, improving median survival from 12.1 months to 14.6 months with temozolomide given concurrently and adjuvantly following radiotherapy. Despite aggressive treatment, median survival remains poor due to recurrence near the primary tumor in 90% of cases. • Chemotherapy has been largely ineffective for patients who have progressed after radiotherapy due to limited drug distribution and toxicity. • RT delivered below standard dose rates can preferentially protect normal tissue while producing almost identical tumor cell kill. This can occur due to the superior repair capacity of late responding normal tissue compared to tumor cells. In conventional radiation therapy a dose of 2 Gy is delivered at a dose rate of 4-6 Gy/min. By reducing the effective dose rate and increasing the treatment time for each individual fraction, cellular repair processes can occur during irradiation. • Low dose hyper-radiosensitivity (LDHRS) is a phenomenon that results in considerably lower cell survival when cells are treated with low doses of radiation (<0.3 - 0.5 Gy). • PRDR theoretically takes advantage of: • LDHRS by delivering 0.2 Gy sub-fractions, providing therapeutically advantageous tumor cell killing. • Increased intrafraction sublethal damage repair by delivering the radiation at a reduced dose rate, allowing therapeutically advantageous repair in the normal surrounding tissues. • In order to retreat large volumes of recurrent disease, a new paradigm has been explored to allow for repair of normal tissues while continuing to provide radiation damage to tumor cells using pulsed reduced dose-rate radiation therapy. Here we describe our early experience with PRDR in 103 previously irradiated primary CNS glioma patients. Median survival from time of initiation of PRDR based on initial histology is 11.4 months from low grade, 5.4 months for grade 3, and 5.3 months for grade 4. Median survival from time of initial diagnosis is 6.4 years for low grade tumors, 4.1 years for Grade 3, and 1.6 years for Grade 4. Overall Survival Since Initiation of PRDR Based on Performance Status WHO Grade at Retreatment WHO Grade at Initial Diagnosis A 37 year old man underwent subtotal resection of a WHO criteria Grade II astrocytoma in July 2000. Serial MRs demonstrated lesion stability until June 2001 at which time he received 54 Gy to the gross tumor volume (GTV) in 1.8 Gy per fraction. He patient underwent a second subtotal resection in June 2004. Pathology verified transformation to a WHO Grade IV astrocytoma. Temozolomide chemotherapy was administered from June through November 2004, when progression of disease was observed on follow-up brain MR (left). Retreatment consisted of 50 Gy delivered in 2 Gy fractions with PRDR. Treatments were administered in 20 cGy pulses at a dose rate of 100MU/min every three minutes for a time averaged dose rate of 6.67 cGy/min. Follow-up Brain MR four weeks after completion of therapy demonstrated interval regression of the nodular enhancement along the anteromedial aspect of the right temporal lobe resection cavity (right). The nodular enhancement along the resection cavity remained stable, but subsequent brain MRs demonstrated nodular enhancement thought to represent intracranial metastatic disease involving the cerebellar white matter adjacent to the fourth ventricle, pontine tegmuntum, and medulla. Additional drop mets were seen at C2, S2 and S3. The patient died 6 months after the completion of his pulsed reduced dose rate radiotherapy. He had no evidence of brain necrosis at autopsy. Kaplan Meier curves for overall survival since initiation of PRDR. The last available histology at time of reirradiation was the initial surgical specimen for 44 patients who did not have further surgical resection. Many of the low and grade 3 patients may have had more aggressive histology. Patients with KPS<70 had a median survival of 2.4 months from initiation of PRDR compared to 6.2 months for patient s with KPS≥70. • Methods • Between January 1999 and August 2007, 103 patients with recurrent glioma were reirradiated using PRDR (mean dose 50 Gy) delivered in 1.8-2.0 Gy fractions. Prior to the initiation of PRDR, all patients had received conventional radiotherapy, 59 had multiple surgeries, 14 radiosurgery, 4 GliaSite brachytherapy and 82 received conventional chemotherapy and/or one or more experimental therapies. • The median time from completion of initial radiotherapy to initiation of PRDR was 18.5 months (range 2 - 230 months). • MRI-CT fusion with 3-dimensional planning was used for all patients. The mean treatment volume was 336 cc, and the median treatment volume was 388 cc. The PTV included the volume of the contrast enhancing lesion and surrounding edema on pre-treatment MRI scan plus a 2 cm margin. • PRDR is a reirradiation technique at the University of Wisconsin which delivers a series of 0.2 Gy pulses separated by 3-minute time intervals, creating an apparent dose rate of 0.0667 Gy/min. The dose rate of the linear accelerator is reduced to ~100 cGy/minute during each pulse of 0.2 Gy. • Due to complexities of MRI interpretation, overall survival was used as the study endpoint. • Conclusions • This cohort of heavily previously treated patients obtained a palliative benefit from PRDR. • Our average PTV is considerably larger than other previously report reirradiation series. • Despite doses > 100 Gy, there was no clinical evidence of necrosis. • Although the tendency is to minimize both total dose and treatment volume when reirradiating brain tissue, our results suggest that the utilization PRDR may allow for the safe re-treatment of larger target volumes to higher doses potentially realizing a greater palliative benefit.

2. Introduction • Combined modality therapy including maximal safe surgical resection followed by adjuvant radiotherapy and chemotherapy is standard treatment for high-grade glioma. The Stupp regimen represents the most significant treatment breakthrough in the last decade, improving median survival from 12.1 months to 14.6 months with temozolomide given concurrently and adjuvantly following radiotherapy. Despite aggressive treatment, median survival remains poor due to recurrence near the primary tumor in 90% of cases. • Chemotherapy has been largely ineffective for patients who have progressed after radiotherapy due to limited drug distribution and toxicity. • RT delivered below standard dose rates can preferentially protect normal tissue while producing almost identical tumor cell kill. This can occur due to the superior repair capacity of late responding normal tissue compared to tumor cells. In conventional radiation therapy a dose of 2 Gy is delivered at a dose rate of 4-6 Gy/min. By reducing the effective dose rate and increasing the treatment time for each individual fraction, cellular repair processes can occur during irradiation. • Low dose hyper-radiosensitivity (LDHRS) is a phenomenon that results in considerably lower cell survival when cells are treated with low doses of radiation (<0.3 - 0.5 Gy). • PRDR theoretically takes advantage of: • LDHRS by delivering 0.2 Gy sub-fractions, providing therapeutically advantageous tumor cell killing. • Increased intrafraction sublethal damage repair by delivering the radiation at a reduced dose rate, allowing therapeutically advantageous repair in the normal surrounding tissues. • In order to retreat large volumes of recurrent disease, a new paradigm has been explored to allow for repair of normal tissues while continuing to provide radiation damage to tumor cells using pulsed reduced dose-rate radiation therapy. Here we describe our early experience with PRDR in 103 previously irradiated primary CNS glioma patients.

3. A 37 year old man underwent subtotal resection of a WHO criteria Grade II astrocytoma in July 2000. Serial MRs demonstrated lesion stability until June 2001 at which time he received 54 Gy to the gross tumor volume (GTV) in 1.8 Gy per fraction. He patient underwent a second subtotal resection in June 2004. Pathology verified transformation to a WHO Grade IV astrocytoma. Temozolomide chemotherapy was administered from June through November 2004, when progression of disease was observed on follow-up brain MR (left). Retreatment consisted of 50 Gy delivered in 2 Gy fractions with PRDR. Treatments were administered in 20 cGy pulses at a dose rate of 100MU/min every three minutes for a time averaged dose rate of 6.67 cGy/min. Follow-up Brain MR four weeks after completion of therapy demonstrated interval regression of the nodular enhancement along the anteromedial aspect of the right temporal lobe resection cavity (right). The nodular enhancement along the resection cavity remained stable, but subsequent brain MRs demonstrated nodular enhancement thought to represent intracranial metastatic disease involving the cerebellar white matter adjacent to the fourth ventricle, pontine tegmuntum, and medulla. Additional drop mets were seen at C2, S2 and S3. The patient died 6 months after the completion of his pulsed reduced dose rate radiotherapy. He had no evidence of brain necrosis at autopsy.

5. Methods • Between January 1999 and August 2007, 103 patients with recurrent glioma were reirradiated using PRDR (mean dose 50 Gy) delivered in 1.8-2.0 Gy fractions. Prior to the initiation of PRDR, all patients had received conventional radiotherapy, 59 had multiple surgeries, 14 radiosurgery, 4 GliaSite brachytherapy and 82 received conventional chemotherapy and/or one or more experimental therapies. • The median time from completion of initial radiotherapy to initiation of PRDR was 18.5 months (range 2 - 230 months). • MRI-CT fusion with 3-dimensional planning was used for all patients. The mean treatment volume was 336 cc, and the median treatment volume was 388 cc. The PTV included the volume of the contrast enhancing lesion and surrounding edema on pre-treatment MRI scan plus a 2 cm margin. • PRDR is a reirradiation technique at the University of Wisconsin which delivers a series of 0.2 Gy pulses separated by 3-minute time intervals, creating an apparent dose rate of 0.0667 Gy/min. The dose rate of the linear accelerator is reduced to ~100 cGy/minute during each pulse of 0.2 Gy. • Due to complexities of MRI interpretation, overall survival was used as the study endpoint.

6. Overall Survival Since Initial Diagnosis Based on Initial Histology Median survival from time of initial diagnosis is 6.4 years for low grade tumors, 4.1 years for Grade 3, and 1.6 years for Grade 4.

7. Overall Survival Since Initiation of PRDR Based on Initial Histology Median survival from time of initiation of PRDR based on initial histology is 11.4 months from low grade, 5.4 months for grade 3, and 5.3 months for grade 4.

8. Overall Survival Since Initiation of PRDR Based on Histology at time of PRDR Kaplan Meier curves for overall survival since initiation of PRDR. The last available histology at time of reirradiation was the initial surgical specimen for 44 patients who did not have further surgical resection. Many of the low and grade 3 patients may have had more aggressive histology.

9. Overall Survival Since Initiation of PRDR Based on Performance Status Patients with KPS<70 had a median survival of 2.4 months from initiation of PRDR compared to 6.2 months for patient s with KPS≥70.

11. Results • Median survival from time of initiation of PRDR was 11.4 months for low grade, 5.4 months for grade 3, and 5.3 months for grade 4 astrocytoma based on histology at time of initial diagnosis. • Median survival for all-comers was 5.8 months. • Median survival for Karnofsky Performance Status (KPS) ≥ 70 was 6.2 months compared to 2.4 months for KPS < 70 (p<0.0001) . • Although age < 50 vs. ≥ 50 was not statistically significant (p=0.08), the median survivals were 6.3 months and 4.8 months, respectively. • There were no grade 4 or 5 toxicities.

12. Conclusions • This cohort of heavily previously treated patients obtained a palliative benefit from PRDR. • Our average PTV is considerably larger than other previously report reirradiation series. • Despite doses > 100 Gy, there was no clinical evidence of necrosis. • Although the tendency is to minimize both total dose and treatment volume when reirradiating brain tissue, our results suggest that the utilization PRDR may allow for the safe re-treatment of larger target volumes to higher doses potentially realizing a greater palliative benefit.