Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma.

BACKGROUND: We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL). PATIENTS AND METHODS: From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15-36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20-45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6-57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5-92 months). RESULTS: The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date. CONCLUSION: Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.

Protons safely allow coverage of high-risk nodes for patients with regionally advanced non-small-cell lung cancer.

Our objective was to determine if protons allow for the expansion of treatment volumes to cover high-risk nodes in patients with regionally advanced non-small-cell lung cancer. In this study, 5 consecutive patients underwent external-beam radiotherapy treatment planning. Four treatment plans were generated for each patient: 1) photons (x-rays) to treat positron emission tomography (PET)-positive gross disease only to 74 Gy (XG); 2) photons (x-rays) to treat high-risk nodes to 44 Gy and PET-positive gross disease to 74 Gy (XNG); 3) protons to treat PET-positive gross disease only to 74 cobalt gray equivalent (PG); and 4) protons to treat high-risk nodes to 44 CGE and PET-positive gross disease to 74 CGE (PNG). We defined high-risk nodes as mediastinal, hilar, and supraclavicular lymph nodal stations anatomically adjacent to the foci of PET-positive gross disease. Four-dimensional computed tomography was utilized for all patients to account for tumor motion. Standard normal-tissue constraints were utilized. Our results showed that proton plans for all patients were isoeffective with the corresponding photon (x-ray) plans in that they achieved the desired target doses while respecting normal-tissue constraints. In spite of the larger volumes covered, median volume of normal lung receiving 10 CGE or greater (V10Gy/CGE), median V20Gy/CGE, and mean lung dose were lower in the proton plans (PNG) targeting gross disease and nodes when compared with the photon (x-ray) plans (XG) treating gross disease alone. In conclusion, proton plans demonstrated the potential to safely include high-risk nodes without increasing the volume of normal lung irradiated when compared to photon (x-ray) plans, which only targeted gross disease.

External-beam radiation therapy for improved dialysis access patency: feasibility and early safety.

Rectenwald, J. E., Pretus, H. A., Seeger, J. M., Huber, T. S., Mendenhall, N. P., Zlotecki, R. A., Palta, J. R., Li, Z. F., Hook, S. Y., Sarac, T. P., Welborn, M. B., Klingman, N. V., Abouhamze, Z. S. and Ozaki, C. K. External-Beam Radiation Therapy for Improved Dialysis Access Patency: Feasibility and Early Safety. Radiat. Res. 156, 53-60 (2001).Prosthetic dialysis access grafts fail secondary to neointimal hyperplasia at the venous anastomosis. We hypothesized that postoperative single-fraction external-beam radiation therapy to the venous anastomosis of hemodialysis grafts can be used safely in an effort to improve access patency. Dogs (n = 8) underwent placement of expanded polytetrafluoroethylene grafts from the right carotid artery to the left jugular vein. Five dogs received single-fraction external-beam photon irradiation (8 Gy) to the venous anastomosis after surgery. Controls were not irradiated. Shunt angiograms were completed 3 and 6 months postoperatively. Anastomoses, mid-graft, and the surrounding tissues were analyzed. Immunohistochemistry for smooth muscle cell alpha-actin, proliferating cellular nuclear antigen (PCNA), and apoptosis was performed. Incisions healed well, though all animals developed wound seromas. One control suffered graft thrombosis 4 months postoperatively. Angiography/histology confirmed severe neointimal hyperplasia at the venous anastomosis. The remaining seven dogs developed similar amounts of neointimal hyperplasia. PCNA studies showed no accelerated fibroproliferative response at irradiated anastomoses compared to controls. Skin incisions and soft tissues over irradiated anastomoses revealed no radiation-induced changes or increase in apoptosis. Thus we conclude that postoperative single-fraction external-beam irradiation of the venous anastomosis of a prosthetic arteriovenous graft that mimics the situation in humans is feasible and safe with regard to early wound healing.

Breast-conserving therapy for early-stage breast cancer.

In most other organs (extremities, bladder, rectum, larynx, or eye), the acceptance of organ-conserving therapy into standard oncologic practice has required only the demonstration of feasibility and efficacy--not equivalency with the radical surgical alternative. BCT was not generally accepted as standard oncologic practice until the maturation of numerous prospective randomized trials that universally demonstrated equivalence in disease control outcomes and survival with mastectomy. In fact, the acceptance of BCT as standard therapy in many parts of the United States actually lagged more than a decade behind sentinel publications documenting proof of equivalency with mastectomy. Even today, investigators continue to search for a subset of breast cancer patients who will have better disease control with radical surgery. BCT stands as not only the best-studied example of organ-conserving therapy but one of the most rigorously tested therapies in all of medicine. Breast-conserving therapy requires a multidisciplinary approach with close coordination among team members from diagnosis through surveillance following treatment. The surgeon must be willing to assess and re-excise margins, to mark the tumor bed with clips, and to use sentinel node biopsy in appropriate patients. The radiation oncologist must be willing to use CT planning, paying close attention not only to coverage of target tissues but to avoidance of critical normal tissues. The medical oncologist must work closely with the surgeon and radiation oncologist to determine the optimal sequencing of therapies and selection of systemic agents. All must recognize special circumstances where genetic counselling may be beneficial, psychosocial support may be needed, or BCT may not be the best choice for patients. When used appropriately, BCT produces maximal disease control and quality of life while minimizing iatrogenic functional, cosmetic, and psychologic sequelae in patients with early-stage breast cancer. BCT serves as a model for the optimal combination of surgery and radiation in organ-preserving cancer therapy.

Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease.

BACKGROUND: Hodgkin disease commonly affects women of reproductive age. Total lymph node irradiation (TNI) typically delivers a dose of 2000-4000 centigray (cGy) to the ovaries, which invariably results in premature ovarian failure (POF) and infertility unless the ovaries are shielded. Transposition of the ovaries at staging laparotomy has had mixed success and may be remote in time from pelvic radiation. METHODS: A laparoscopic technique has been described that allows transposition of the ovaries just prior to pelvic radiation. This is a report of the outcome of 12 patients who underwent laparoscopic oophoropexy at the University of Florida from 1989 to 1995. Two were excluded from analysis, because one died and the other had a second malignancy for which radiation was aborted. RESULTS: At follow-up, five patients had evidence of ovarian function, and the four patients of these five who desired children achieved pregnancies. All five had zero to two courses of chemotherapy. Two patients who subsequently had pregnancies had staging laparotomy with oophoropexy 5 and 6 months, respectively, before laparoscopy. In both cases the ovaries had migrated back to their original positions, and their therapy would have resulted in ovarian failure had the repeat procedure not been performed. Five patients had ovarian failure at follow-up. Four of the five had received multiple courses of chemotherapy; the other had pelvic primary disease and received 3500 cGy to the femoral lymph nodes and pelvis, with little central shielding. CONCLUSIONS: Laparoscopic oophoropexy performed immediately prior to pelvic irradiation is effective in preserving ovarian function in nearly all patients who are to undergo TNI for Hodgkin disease and who receive minimal or no chemotherapy.

Non-physician practitioners in radiation oncology: advanced practice nurses and physician assistants.

PURPOSE: With changes in reimbursement and a decrease in the number of residents, there is a need to explore new ways of achieving high quality patient care in radiation oncology. One mechanism is the implementation of non-physician practitioner roles, such as the advanced practice nurse (APN) and physician assistant (PA). This paper provides information for radiation oncologists and nurses making decisions about: (1) whether or not APNs or PAs are appropriate for their practice, (2) which type of provider would be most effective, and (3) how best to implement this role. METHODS: Review of the literature and personal perspective. CONCLUSIONS: Specific issues addressed regarding APN and PA roles in radiation oncology include: definition of roles, regulation, prescriptive authority, reimbursement, considerations in implementation of the role, educational needs, and impact on resident training. A point of emphasis is that the non-physician practitioner is not a replacement or substitute for either a resident or a radiation oncologist. Instead, this role is a complementary one. The non-physician practitioner can assist in the diagnostic work-up of patients, manage symptoms, provide education to patients and families, and assist them in coping. This support facilitates the physician's ability to focus on the technical aspects of prescribing radiotherapy.

Squamous cell carcinoma of the nasal vestibule.

BACKGROUND AND METHODS: Sixty patients were treated with radiation therapy alone (56 patients) or followed by surgery (4 patients) between 1970 and 1995 for squamous cell carcinoma of the nasal vestibule. RESULTS: Local control rates at five years after irradiation alone in 56 patients were: T1-T2, 94%; T4, 71%; and overall, 85%. Multivariate analysis revealed that tumor size and bone invasion significantly influenced local control. All four patients with extensive T4 tumors treated with radiation therapy plus surgery were cured. Cause-specific survival rates at five years for 56 patients treated with radiation therapy alone were: T1-T2, 94%; T4, 86%; and overall, 91%. Multivariate analysis revealed that bone invasion and tumor size adversely influenced cause-specific survival. No patient treated with irradiation alone experienced a major complication, compared with three of four patients who underwent irradiation and surgery. CONCLUSIONS: Radiation therapy results in a high cure rate with good cosmesis. Patients with extensive T4 cancers have an improved chance of cure with radiation and surgery but more complications.

The optimal dose of radiation in Hodgkin's disease: an analysis of clinical and treatment factors affecting in-field disease control.

PURPOSE: The purpose of this study is to analyze the effect of radiation dose, as well as other clinical and therapeutic factors, on in-field disease control. PATIENTS AND MATERIALS: The study population comprised 232 patients with Stage I and II Hodgkin's disease (HD) treated with curative intent at the University of Florida with radiotherapy (RT) alone (169 patients) or chemotherapy and radiotherapy (CMT) (63 patients). Sites of involvement and radiation doses were prospectively recorded and correlated with sites of disease recurrence. RESULTS: Freedom from relapse and absolute survival rates at 10 years were as follows: 76% and 77%, entire group; 76% and 80%, RT group; 79% and 70%, CMT group; 85% and 78%, Stage I; and 71% and 77%, Stage II. Treatment failure occurred in 50 patients (22%) including in-field failure in 22 patients (9%). In-field failure was rare in electively treated sites. Multivariate analysis of clinical factors (tumor size, number of sites involved, B-symptoms, gender, histology, age, and site of involvement) and treatment factors (use of chemotherapy, number of cycles of chemotherapy, radiation dose, radiation treatment volume, and radiation treatment time) showed only tumor size (p = 0.0001) to be significantly correlated with in-field disease control. In RT patients, the in-field failure rate according to tumor size was as follows: 0% for < or = 3 cm; 4% for > 3 cm and < or = 6 cm; 23% for > 6 cm and < or = 9 cm; and 36% for > 9 cm. In CMT patients, the in-field failure rate was as follows: 0% for < or = 3 cm; 0% for > 3 and < or = 6 cm; 5% for > 6 cm and < or = 9 cm; and 26% for > 9 cm. In-field recurrence was not a predominant pattern of failure in RT patients with small tumors (< or = 6 cm); thus, the difference in in-field control in tumors < or = 6 cm between doses < or = 35 Gy (6%) and doses > or = 36 Gy (0%) was not statistically significant. In larger tumors (> 6 cm), in-field recurrence was a predominant pattern of failure; the in-field failure rate in RT patients with tumors > 6 cm of 30% for doses < or = 35 Gy was not significantly different from 25% for doses > 35 Gy. In moderately bulky tumors (> 6 cm and < or = 9 cm), the addition of chemotherapy did appear to increase in-field disease control; the in-field failure rate was 23% with RT and 5% with CMT (p = 0.07). CONCLUSION: Our data do not demonstrate statistically significant evidence of increasing tumor control in HD with doses > 30 Gy. The data do show that increasing tumor size is associated with increased rates of in-field failure, and the addition of chemotherapy may improve in-field disease control in tumors > 6 cm. In-field recurrence in large tumors remains a predominant pattern of failure, however, and the role of radiation doses higher than 30-35 Gy in this high-risk subset warrants further study.

The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma.

PURPOSE/OBJECTIVE: To assess local (in-field) disease control, identify potential prognostic factors, and elucidate the optimal radiotherapy dose in various clinical settings of Stage I and II non-Hodgkin's lymphoma (non-CNS). MATERIALS & METHODS: A total of 285 consecutive patients with Stage I and II non-Hodgkin's lymphoma were treated with curative intent, including 159 with radiotherapy (RT) alone and 126 with combined-modality therapy (CMT). Of these, 72 patients had low-grade lymphomas (LGL), 92 had intermediate or high-grade lymphomas (I/HGL), and 21 had unclassified lymphomas. Clinical and treatment variables with potential prognostic significance for in-field disease control, freedom from relapse (FFR), and absolute survival (AS) were evaluated by univariate and multivariate analyses. RESULTS: The 5-, 10-, and 20-year actuarial AS rates were 73%, 46%, and 33% for patients with LGL and 64%, 44%, and 18% for patients with I/HGL, respectively. The 5-, 10-, and 20-year actuarial FFR rates were 62%, 59%, and 49% for patients with LGL and 66%, 57%, and 57% for patients with I/HGL, respectively. Significant prognostic factors identified by the multivariate analysis were age, tumor size, and histology for AS; tumor size and treatment for FFR; and only tumor size for in-field disease control. There were 95 total failures, with only 12 occurring infield. Most failures (65%) were in contiguous unirradiated sites. All 4 in-field failures in patients with LGL occurred after RT doses < 30 Gy, although none occurred in 10 patients with small-volume LGL of the orbit treated with doses < 30 Gy. The 8 in-field failures in patients with I/HGL were distributed evenly throughout the RT dose range; 5 occurred in patients treated with CMT, all with tumors > 6 cm, and 4 with less than a complete response (CR) to chemotherapy. CONCLUSION: Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general, as well as for patients with nonbulky (< or = 6 cm) I/HGL treated with CMT who have a CR. However, patients with I/HGL treated with CMT for tumors > 6 cm and/or without a CR may benefit from doses > or = 40 Gy.

Radiotherapy in the management of orbital lymphoma.

PURPOSE: This retrospective study reviews the treatment technique, disease outcome, and complications of radiotherapy used in the management of lymphoma involving the orbits. PATIENTS & METHODS: Thirty-eight patients were treated between May 1969 and January 1995, with a median follow-up of 8.3 years. All patients had biopsy-proven orbital lymphoma. Twenty patients who had limited disease were treated with curative intent, and 18 patients who had known systemic disease were treated with palliative intent. Of the 20 patients treated with curative intent, 14 had low-grade and 6 had intermediate- or high-grade disease. None received chemotherapy. Most patients received treatment with 250 kVP or 60Co radiation, using either an en face anterior field or wedged anterior and lateral fields. Median treatment dose was 25 Gy. Lens shielding was performed if possible. For patients treated for cure, cause-specific survival and freedom from distant relapse were calculated using the Kaplan-Meier method. RESULTS: Control of disease in the orbit was achieved in all but 1 patient, who developed an out-of-field recurrence after irradiation of a lacrimal tumor and was salvaged with further radiotherapy. In the patients treated curatively, the 5-year rate of actuarial freedom from distant relapse was 61% for those with low-grade and 33% for those with intermediate/high-grade disease (p = 0.08). Cause-specific survival at 5 years was 89% for patients with low-grade and 33% for those with intermediate/high-grade disease (p = 0.005). Two patients with low-grade disease had contralateral orbital failures; both were salvaged with further irradiation. Acute toxicity was minimal. Cataracts developed in 7 of 21 patients treated without lens shielding and 0 of 17 patients treated with lens shielding. No patient developed significant late lacrimal toxicity. CONCLUSION: Radiotherapy is a safe and effective local treatment in the management of orbital lymphoma.

Non-Hodgkin's lymphoma of the head and neck: a 30-year experience at the University of Florida.

BACKGROUND: Outcome in previously untreated patients with non-Hodgkin's lymphoma of the head and neck needed to be assessed. METHODS: A retrospective review was performed of 79 patients with stage I or II non-Hodgkin's lymphoma of the head and neck treated between 1964 and 1994 with radiotherapy (RT) or combined modality therapy (CMT) at the University of Florida. Freedom from relapse, cause-specific survival, and absolute survival were analyzed by the Kaplan-Meier method. Patterns of failure were defined, and the relationship between dose and infield recurrence was studied. Histology was classified as low grade or intermediate/high grade. RESULTS: At 10 years, absolute survival for patients with low-grade lymphoma treated with RT was 45%; absolute survival for patients with intermediate/high-grade lymphoma was 41% for those treated with RT and 57% for those who received CMT. Twenty-seven patients had a recurrence of lymphoma after initial treatment. Twenty patients (74%) had recurrences outside the radiation treatment field; 90% of these failures were in predictable sites that would be included in comprehensive lymphatic irradiation fields (Waldeyer's ring, mantle, and whole abdomen). No clear dose response was observed. Multivariate analysis showed that patients with tumors <5 cm in diameter had improved cause-specific survival, absolute survival, and freedom from relapse compared with patients with tumors > or = 5 cm in diameter. CONCLUSIONS: Patients with non-Hodgkin's lymphoma in the head and neck with tumors > or = 5 cm in diameter appear to have a worse prognosis than those with smaller tumors. The patterns of failure suggest that initial treatment with comprehensive lymphatic irradiation fields could potentially eliminate the majority of treatment failures.

The role of radiation in the management of Hodgkin's disease: an update.

RT is the most effective single agent in HD, and it has many roles in the management of this disease. These roles include RT as the sole curative agent in early stage HD in adults and in limited nodal recurrences in patients previously treated with CT alone; RT as the primary treatment for clinical and subclinical disease in CMT regimens using minimal adjuvant CT; RT as an integral part of standard and high-dose CMT regimens used to consolidate CT responses in all sites of clinical involvement; and RT as an adjuvant to CT for areas of bulky disease or incomplete CT response. Its effectiveness depends on the clinical expertise of the treating physician, the adequacy of the staging studies, and the accuracy of the treatment technique.

Medulloblastoma: time-dose relationship based on a 30-year review.

PURPOSE: Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. METHODS AND MATERIALS: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (> or =T3b or > or =M1) or low (< or =T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. RESULTS: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p=0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p=0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was < or =45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p=0.01). Duration of treatment also affected freedom from relapse at 5 years: < or =45 days (76%) compared with >45 days (43%), p=0.004. CONCLUSION: Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.

Carcinoma of the skin metastatic to the parotid area lymph nodes.

BACKGROUND: We performed an analysis of treatment outcome at the University of Florida for 77 patients with previously untreated carcinoma of the skin metastatic to parotid area lymph nodes. METHODS: Seventy-seven patients with 79 parotid node metastases were treated with curative intent between 1966 and 1994. All patients had a minimum 2-year follow-up. Treatment consisted of radiotherapy alone in 18 patients, preoperative radiotherapy in 6 patients (7 parotids), and postoperative radiotherapy in 53 patients (54 parotids). RESULTS: Overall rate of disease control in the parotid area at 5 years was 82%. Parotid area disease control according to treatment group revealed: surgery and postoperative radiotherapy, 43 of 48 (90%); preoperative radiotherapy and surgery, 4 of 5 (80%); and radiotherapy alone, 8 of 15 (53%). Multivariate analysis of parotid disease control revealed the following: treatment method (p = .0037), N stage (p = .0726), cranial nerve involvement (p = .1851), fixation (p = .1820), skin involvement (p = .1771), and sex (p = .5782). Overall 5-year absolute and cause-specific survival rates were 54% and 68%, respectively. The 5-year cause-specific survival rate was 72% after surgery and postoperative radiotherapy and 59% following radiotherapy alone. Multivariate analysis of cause-specific survival revealed the following: skin involvement (p = .0215), cranial nerve involvement (p = .1549), fixation (p = .0347), N stage (p = .4302), sex (p = .6806), and treatment method (p = .9599). CONCLUSIONS: Our current policy is to treat patients with tumor that is initially resectable with surgery followed by radiotherapy, whereas those who have initially unresectable disease undergo preoperative radiotherapy followed by surgical resection if the tumor becomes resectable. If surgery cannot be performed for medical reasons, patients still have better than a 50% chance of being cured with radiotherapy alone.