Patricia McManus

Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone☆

PURPOSE Following a thorough Phase I/II study, we evaluated by a Phase III trial high versus conventional dose external beam irradiation as mono-therapy for patients with Stage T3-T4 prostate cancer. Patient outcome following standard dose radiotherapy or following a 12.5% increase in total dose to 75.6 Cobalt Gray Equivalent (CGE) using a conformal perineal proton boost was compared for local tumor control, disease-free survival, and overall survival. METHODS AND MATERIALS Stage T3-T4, Nx, N0-2, M0 patients received 50.4 Gy by four-field photons and were randomized to receive either an additional 25.2 CGE by conformal protons (arm 1--the high dose arm, 103 patients, total dose 75.6 CGE) or an additional 16.8 Gy by photons (arm 2--the conventional dose arm, 99 patients, total dose 67.2 Gy). Actuarial overall survival (OS), disease-specific survival (DSS), total recurrence-free survival (TRFS), (clinically free, prostate specific antigen (PSA) less than 4ng/ml and a negative prostate rebiopsy, done in 38 patients without evidence of disease) and local control (digital rectal exam and rebiopsy negative) were evaluated. RESULTS The protocol completion rate was 90% for arm 1 and 97% for arm 2. With a median follow-up of 61 months (range 3 to 139 months) 135 patients are alive and 67 have died, 20 from causes other than prostate cancer. We found no significant differences in OS, DSS, TRFS or local control between the two arms. Among those completing randomized treatment (93 in arm 1 and 96 in arm 2), the local control at 5 and 8 years for arm 1 is 92% and 77%, respectively and is 80% and 60%, respectively for arm 2 (p = .089) and there are no significant differences in OS, DSS, and TRFS. The local control for the 57 patients with poorly differentiated (Gleason 4 or 5 of 5) tumors at 5 and 8 years for arm 1 is 94% and 84% and is 64% and 19% on arm 2 (p = 0.0014). In patients whose digital rectal exam had normalized following treatment and underwent prostate rebiopsy there was a lower positive rebiopsy rate for arm 1 versus arm 2 patients (28 vs. 45%) and also for those with well and moderately differentiated tumors versus poorly differentiated tumors (32 and 50%). These differences were not statistically significant. Grade 1 and 2 rectal bleeding is higher (32 vs. 12%, p = 0.002) as may be urethral stricture (19 vs. 8%, p = 0.07) in the arm 1 versus arm 2. CONCLUSIONS An increase in prostate tumor dose by external beam of 12.5% to 75.6 CGE by a conformal proton boost compared to a conventional dose of 67.2 Gy by a photon boost significantly improved local control only in patients with poorly differentiated tumors. It has increased late radiation sequelae, and as yet, has not increased overall survival, disease-specific survival, or total recurrence-free survival in any subgroup. These results have led us to test by a subsequent Phase III trial the potential beneficial effect on local control and disease-specific survival of a 12.5% increase in total dose relative to conventional dose in patients with T1, T2a, and T2b tumors.

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

PURPOSE Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >or=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. METHODS AND MATERIALS Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewings sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. RESULTS A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. CONCLUSIONS Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

Late rectal bleeding following combined x-ray and proton high dose irradiation for patients with stages T3–T4 prostate carcinoma

PURPOSE Dose escalation for prostate cancer by external beam irradiation is feasible by a 160 MeV perineal proton beam that reduces the volume of rectum irradiated. We correlated the total doses received to portions of the anterior rectum to study the possible relationship of the volume irradiated to the incidence of late rectal toxicity. METHODS We have randomized 191 patients with stages T3 and T4 prostatic carcinoma to one of two treatment dose arms. These were: 1) 75.6 Cobalt-Gy-equivalent (CGE), 50.4 Gy delivered by 107-25 MV photons followed by 25.2 CGE delivered perineally by protons (Arm 1) or 2) 67.2 CGE delivered by 10-25 MV photons (Arm 2). RESULTS With a median follow-up of 3.7 years, post-irradiation rectal bleeding (grades 1 and 2 only, none requiring surgery or hospitalization) from telangiectatic rectal mucosal vessels has occurred in 34% of 99 Arm-1 patients and 16% of 92 Arm-2 patients (p = 0.013). Dose-volume histograms (DVHs) for the anterior rectal wall, the posterior rectal wall and the total rectum in 41 patients treated on Arm 1 were calculated from the three dimensional dose distributions. Rectal bleeding has occurred in 14 or 34% of the 41 DVH-analyzed subset of Arm-1 patients. Both the fractional volume of the anterior rectum and the total dose received by fractional volumes of the anterior rectum significantly correlate with the actuarial probability of bleeding. CONCLUSIONS Clinicians planning dose escalation to men with localized prostate cancer should approve with caution treatment plans raising more than 40% of the anterior rectum to more than 75 CGE without additional effort to protect the rectal mucosa because this late sequela data indicate that more than half of these men will otherwise have rectal bleeding.

Base of skull and cervical spine chordomas in children treated by high-dose irradiation

PURPOSE To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. METHODS AND MATERIALS Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. RESULTS The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. CONCLUSION Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity.

LATE NORMAL TISSUE SEQUELAE IN THE SECOND DECADE AFTER HIGH DOSE RADIATION THERAPY WITH COMBINED PHOTONS AND CONFORMAL PROTONS FOR LOCALLY ADVANCED PROSTATE CANCER

PURPOSE We determined the long-term normal tissue effects of 77.4 Gy. delivered to the prostate in patients with locally advanced prostate cancer. METHODS AND MATERIALS Between 1976 and 1992, 167 men with stages T3 to 4 prostate cancer were treated on protocol with 50.4 Gy. photons at 1.8 Gy. per fraction using a 4-field box arrangement, followed by a conformal perineal proton boost of 27 Gy. (cobalt Gy. equivalent) in 11 fractions. The chart was reviewed and 39 of the 42 surviving patients were interviewed. Median followup was 13.1 years (range 7 to 23). Normal tissue morbidity was recorded using Radiation Therapy Oncology Group criteria and the late effects normal tissue scale. RESULTS The actuarial incidence of grade 2 or greater genitourinary morbidity was 59% at 15 years. However, these grade 2 or greater problems persisted to the time of the interview in only 7 of 39 cases. The actuarial incidence of grade 2 or greater hematuria was 21% at 5 years and 47% at 15. For grade 3 or greater hematuria the risk was 3% and 8% at 5 and 15 years, respectively. No patient required cystectomy but 1 required diversion for morbidity. Urethral stricture and urinary incontinence with pads needed developed in 4 and 3 men, respectively. This particular morbidity was strongly associated with previous or subsequent prostate surgery. The actuarial incidence of grade 2 or greater gastrointestinal morbidity was 13% at 5 and 15 years, while grade 1 rectal bleeding occurred in another 41%. CONCLUSIONS High dose conformal radiation to the prostate is followed by a high rate of low grade rectal bleeding but a low rate of grade 2 or higher gastrointestinal morbidity. This rate is stable and does not increase beyond 5 years. Genitourinary morbidity continues to develop well into the second decade after treatment, although high grade morbidity is uncommon. These findings do not suggest that the modern trend toward high dose prostate treatment with conformal techniques will result in a high incidence of serious and permanent late sequelae but it appears that hematuria will be common.

Biopsy after External Beam Radiation Therapy for Adenocarcinoma of the Prostate: Correlation with Original Histological Grade and Current Prostate Specific Antigen Levels

We obtained post-irradiation biopsies in 37 men with initially stage T3 prostatic adenocarcinoma treated by external beam radiotherapy. Eligibility for post-irradiation biopsy included no clinical local failure, interval since treatment of 24 months or more and no endocrine therapy. Of the 37 patients 23 (62%) had negative biopsies while 14 (38%) had positive biopsies. Of 23 patients whose original cancer was well or moderately differentiated 18 (78%) had negative biopsies, compared to only 5 of 14 (36%) of those with poorly differentiated cancer (p less than 0.03). Among 19 patients whose current serum prostate specific antigen (PSA) value is less than 2.5 ng./ml. 15 (79%) had negative biopsies, compared to only 4 of 14 (29%) with a PSA level of greater than 2.5 ng./ml. (p less than 0.02). These results strongly suggest that there is a low probability of positive post-irradiation biopsy regardless of its significance in men with a normal prostate by palpation and a normal serum PSA value. However, short followup since biopsy precludes analysis of the predictive value of post-irradiation biopsy on long-term local and distant disease status.

Fractionated Proton Radiation Therapy of Cranial and Intracranial Tumors

Since 1973 fractionated proton radiation therapy has been used in the treatment of malignant disease. Protons have favorable physical characteristics that yield dose distributions superior to those of photons in certain clinical situations. As of December 31, 1987, 1,678 patients had been treated. Of these, 110 had chordomas or low-grade chondrosarcomas of the base of skull. The first 68 patients have a minimum follow-up of 17 months. The median dose was 69 Cobalt Gray Equivalent (CGE). (CGE is the dose in proton Gray multiplied by 1.1, which is the relative biological effectiveness for protons relative to 60Cobalt.) The actuarial 5-year local control rate is 82%, and the disease-free survival rate is 76%. Thirteen patients with meningiomas have been treated, following subtotal resection. The median dose was 59.4 CGE. With a median follow-up of 26 months, no patient has had tumor progression. In addition, nine patients with gliomas and 12 with craniopharyngiomas have been treated.

136 Skull base chordomas: Treatment outcome and prognostic factors in adult patients following conformal treatment with 3d planning and high dose fractionated combined proton and photon radiation therapy

Methods & Materials: From 1975 through 1993, 132 adult patienls with skull base chordomas were treated with fractionated combined proton and photon radiation therapy. Seventy five patients (57%) were mate and 57 (43%) female. Age ranged from 19 to 80 years (median 45.5 years). All pathology was verified at MGH by a single pathologist Ninety six had non-chondroid (NCC) and 36 chondroid chordomas (CC), respectively. Median prescribed dose was 68.7 CGE (CGE, Cobalt Gray-equivalent: proton Gy X RBE 1.1 + photon Gy), ranging from 36 to 79.2 CGE; 95% received >_ 66.6 CGE. Between 70 and 100% of the close was given with the 160 MeV proton beam at the Harvard Cyclotron. 3D CT-based treatment planning has been employed in all patients treated since 1980. Median follow-up was 46 months (range 2-158 months).