Spatially fractionated (GRID) radiation therapy using proton pencil beam scanning (PBS): Feasibility study and clinical implementation.

PURPOSE: GRID therapy is an effective treatment for bulky tumors. Linear accelerator (Linac)-produced photon beams collimated through blocks or multileaf collimators (MLCs) are the most common methods used to deliver this therapy. Utilizing the newest proton delivery method of pencil beam scanning (PBS) can further improve the efficacy of GRID therapy. In this study, we developed a method of delivering GRID therapy using proton PBS, evaluated the dosimetry of this novel technique and applied this method in two clinical cases. MATERIALS/METHODS: In the feasibility study phase, a single PBS proton beam was optimized to heterogeneously irradiate a shallow 20 × 20 × 12 cm3 target volume centered at a 6 cm depth in a water phantom. The beam was constrained to have an identical spot pattern in all layers, creating a "beamlet" at each spot position. Another GRID treatment using PBS was also performed on a deep 15 × 15 × 8 cm3 target volume centered at a 14 cm depth in a water phantom. Dosimetric parameters of both PBS dose distributions were compared with typical photon GRID dose distributions. In the next phase, four patients have been treated at our center with this proton GRID technique. The planning, dosimetry, and measurements for two representative patients are reported. RESULTS: For the shallow phantom target, the depth-dose curve of the PBS plan was uniform within the target (variation < 5%) and dropped quickly beyond the target (50% at 12.9 cm and 0.5% at 14 cm). The lateral profiles of the PBS plan were comparable to those of photon GRID in terms of valley-to-peak ratios. For the deep phantom target, the PBS plan provided smaller valley-to-peak ratios than the photon GRID technique. Pretreatment dose verification QA showed close agreement between the measurements and the plan (pass rate > 95% with a gamma index criterion of 3%/3 mm). Patients tolerated the treatment well without significant skin toxicity (radiation dermatitis grade ≤ 1). CONCLUSIONS: Proton GRID therapy using a PBS delivery method was successfully developed and implemented clinically. Proton GRID therapy offers many advantages over photon GRID techniques. The use of protons provides a more uniform beamlet dose within the tumor and spares normal tissues located beyond the tumor. This new PBS method will also reduce the dose to proximal organs when treating a deep-seated tumor.

Targeted chemoradiation for advanced head and neck cancer: analysis of 213 patients.

BACKGROUND: To determine the survival results, patterns of relapse, and organ preservation effects of a targeted chemoradiation protocol for patients with advanced (stage III-IV) carcinoma of the head and neck. METHODS: Analysis of 213 patients with stage III-IV squamous cell carcinoma treated at UT Memphis between June 1993 and March 1998. Treatment included weekly intra-arterial infusions of cisplatin (150 mg/m(2)/ week x 4) rapidly delivered to the tumor bulk, simultaneous intravenous thiosulfate for systemic drug neutralization, and conventional external-beam irradiation (180-200 cGy/fraction) to a total dose of 68-72 Gy. RESULTS: Tumor response, toxicity, disease control above the clavicle, pattern of relapse, and survival. There were 89 events of grade III-IV toxicity and 6 treatment-related deaths (grade V). Complete response in the primary and regional sites was obtained in 171 of 213 (80%) and 92 of 151 (61%), respectively. The rate of clearance of regional disease after neck dissection was 98%. There were 51 of 195 recurrences (26%): 11 local (5.6%), 5 regional (2.6%), and 35 distant (17.9%). The Kaplan Meier plot projections for overall and cancer-related 5-year survival was 38.8% and 53.6%, respectively, whereas disease control above the clavicle was 74.3%. CONCLUSIONS: We believe this chemoradiation protocol represents an effective management scheme for patients with advanced head and neck cancer with a high rate of organ preservation and possibly improved survival.

Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer.

PURPOSE: To determine the efficacy of targeted chemoradiation with the radiation plus platinum (RADPLAT) protocol and planned selective neck dissection in patients with N2 to N3 nodal disease associated with upper aerodigestive tract carcinoma. METHODS: Analysis of 52 patients with N2a, N2b, or N3 disease involving 60 heminecks treated with intraarterial cisplatin, 150 mg/m2, and intravenous sodium thiosulfate, 9 g/m2, on days 1, 8, 15, and 22; radiation therapy, 180 to 200 cGy per fraction for 35 fractions (total dose, 68-74 Gy); and planned neck dissection (33 of 35 procedures were selective). RESULTS: Of the 56 evaluable heminecks, a clinical complete response was achieved in 33 (59%). Within this group, 16 neck dissections were performed, none of which yielded disease on pathological examination. A clinical partial response was obtained in 21 heminecks, of which 18 subsequently had a neck dissection, yielding disease on pathological examination in 14. In all cases, it was possible to completely excise all adenopathy with clear margins on pathological examination. The rate of regional disease control among the 56 evaluable heminecks was 91% (51/56) (median follow-up, 36 months). Four failures were associated with uncontrolled disease at other sites, and 1 was an isolated neck recurrence. CONCLUSION: Selective neck dissection appears to be an effective adjunct to targeted chemoradiation in controlling N2 to N3 neck disease.

Review of eye plaque dosimetry based on AAPM Task Group 43 recommendations. American Association of Physicists in Medicine.

PURPOSE: AAPM Task Group 43 recently revised the dosimetry recommendations for 125I seeds. We reviewed these guidelines and studied the effects of the recommendations on the prescription absorbed dose for patients who have undergone eye plaque therapy in our clinic. METHODS AND MATERIALS: 95 consecutive patients were chosen for this study. Absorbed doses at various points of clinical interest were computed based on conventional dose calculation algorithm (3, 4, 7) and TG-43 recommendations. For three representative plaques chosen, the seeds are approximated by isotropic point and line sources, respectively, and absorbed doses were calculated at all points on the central axis of the plaque. RESULTS: For apical heights shorter than 5 mm, treatment plans using model 6711 seeds delivered 10-13% lower absorbed doses than that calculated previously. For lesions with apical heights 5 mm or larger, the absorbed dose was 6-12% lower than prescribed. Calculations for model 6702 seeds indicated that TG-43 recommendations would produce 0-6% lower absorbed doses. Point doses calculated along the central axis of the plaque and isodose distributions at various levels showed that point source approximation of the seeds was clinically acceptable. CONCLUSIONS: TG-43 recommendations, if implemented, would result in lower absorbed doses unless the dose prescription is modified. The clinicians need to be aware of the dosimetric implications of these recommendations. The seeds may be approximated by isotropic point sources.

Patterns of failure in children with medulloblastoma: effects of preirradiation chemotherapy.

PURPOSE: To evaluate the effects of preirradiation chemotherapy on patterns of failure in children with medulloblastoma. METHODS AND MATERIALS: Fifty-three patients (pts) with medulloblastoma were given preirradiation chemotherapy as initial postoperative treatment at St. Jude Children's Research Hospital from November 1984 to September 1993. Patients < or = 3 years of age (n = 23) received chemotherapy (CH) with delayed craniospinal irradiation (CSI). Children > or = 3 years with more advanced disease (T3b-T4, M+ or measurable residual after resection) were given CH followed by CSI (30 patients). Chemotherapy regimen depended on protocol, but usually included cis- or carboplatin and etoposide, +/- cyclophosphamide and vincristine. RESULTS: Actuarial overall survival and event-free survival rates are 60% (95% confidence interval [41,79]) and 37% [19,55] at 5 years. Children < or = 3 at diagnosis: six of 23 pts completed CH without progression and received consolidative CSI; all six are alive with no evidence of disease (NED) at 2.4-9.1 years. Seventeen patients progressed during CH and were then given CSI. Sites of progression during CH were posterior fossa (PF) in 11 patients, neuraxis (NEUR) in 4, and PF+NEUR in 2. Following CSI, 7 patients are alive NED at 2.0-8.6 years; 10 patients died of progressive disease. Eleven patients had M0 disease at diagnosis; 8 (73%) progressed during CH, 3 in the neuraxis. Children > or = 3 at diagnosis: 20 of 30 patients completed pre-CSI CH without progression; 15 are alive NED at 1.3-9.2 years, and 5 showed post-CSI progression in the PF (n = 3), in the NEUR (n = 1) and in bone marrow (n = 1). Ten of the 30 (33%) patients progressed on CH (6 in NEUR, 4 in PF); 5 are alive and NED or with stable disease. Seventeen patients had M0 disease at diagnosis; 3 out of 17 (18%) progressed during CH, 2 in NEUR and 1 in an extraneural site. In the total group of 30 patients, 11 have had disease recurrence after completion of XRT. The actuarial rate of failure was 23 +/- 9% for the patients < or = 3 years of age and 21 +/- 8% for the older children when evaluated at 4 months after diagnosis (at the completion of chemotherapy in the older children but during the ongoing chemotherapy in the younger children). CONCLUSIONS: In patients presenting with M0 disease and receiving pre-CSI chemotherapy, the risk of neuraxis progression seems to increase with duration of chemotherapy. The sites of progression during preirradiation chemotherapy are nearly equally divided between posterior fossa and other neuraxis sites. CSI salvage of patients progressing on chemotherapy is possible in approximately 50% of patients. Following CSI, neuraxis progression is more frequent than posterior fossa relapse.

Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience.

PURPOSE/OBJECTIVE: To evaluate the feasibility, response rates, and toxicity of a Phase II study using targeted supradose cisplatin and concurrent radiation therapy in unresectable Stage III-IV head and neck squamous cell carcinoma. METHODS AND MATERIALS: Sixty patients presenting between 6/93-9/94 were enrolled, 44 (73%) of whom had T4 and/or N2-N3 nodal disease. All patients were treated with rapid targeted superselective intraarterial infusions of cisplatin (150 mg/m2 weekly x 4) and simultaneous sodium thiosulfate intravenously (9 g/m2) for systemic neutralization of cisplatin. Concurrent (day 1) daily radiation therapy was delivered to the primary tumor and overt nodal disease to 66-74 Gy while the uninvolved lower neck received 50 Gy, at 2.0 Gy/fraction. RESULTS: Fifty-one (85%) patients completed the full RADPLAT protocol as planned. Fifty-seven of 60 patients were evaluable for response. Histological (n = 50) or clinical (n = 7) assessment of primary site revealed a complete response (CR) in 52 patients, partial response (PR) in 4, and stable disease (SD) in 1. Of the 40 patients presenting with nodal metastases, pathological (n = 31) or clinical (n = 6) assessment revealed a CR in 25, PR in 11, and SD in 1, while 3 were unevaluable. Overall, for both primary site and nodal disease, CR was attained in 44 (75%), PR in 12 (23%), and SD in 1 (2%) of the 57 evaluable patients. Only 2 (4%) of 57 evaluable patients have recurred above the clavicle, 1 in the primary site and 1 in the regional lymph nodes. Twelve patients (23%) have failed in distant sites. Grade III/VI toxicity has included gastrointestinal in 6, hematologic in 6, mucosal in 12, vascular in 4, and neurological in 4 patients. CONCLUSION: Concurrent radiation therapy and targeted supradose cisplatin (i.e., RADPLAT) can be safely delivered with high response rates and excellent loco-regional control in advanced Stage III/IV head and neck squamous cell carcinoma.

Integration of surgery in multimodality therapy for esophageal cancer.

BACKGROUND: While adding chemotherapy to radiation for the treatment of esophageal cancers has been shown to be beneficial, surgery usually follows treatment or is omitted. In either case, regional control remains problematic. The purpose of this study was to test the feasibility of using chemotherapy and radiation following surgery in the treatment of of esophageal cancer and to assess the impact of this approach on regional control and survival. PATIENTS AND METHODS: Twenty-five patients with esophageal cancer were treated in a phase I pilot protocol consisting of initial esophagectomy with gastroesophagostomy and subsequent combined chemotherapy and radiation. Chemotherapy consisted of cisplatin given on day 1 and 5-fluorouracil (FU) on days 1-5 by continuous infusion. Radiation therapy was administered in varying fractionation schedules of once or twice daily concomitantly with the chemotherapy. Treatment was repeated every other week for two to four cycles. Median follow-up was 42 months. RESULTS: Acute toxicities (mucositis and cytopenias) were common but not worse than grade 3. Higher doses of 50 Gy with 2 Gy b.i.d. hyperfractionation caused late complications in four of 10 patients, (two lethal). Control of local disease for all patients was excellent with only two known and two possible local recurrences (16%) but distant metastases were common (46%). Disease-free survival was 58 and 30% at 1 and 2 years, respectively. Survival was 58 and 32% at 1 and 2 years, respectively (median survival, 19 months). CONCLUSION: The local control rate and survival were better than those in our historical experience with cisplatin and 5-FU chemotherapy and radiation given prior to surgery. A dose-fractionation schedule of < 2 Gy up to a total of 50 Gy b.i.d. is recommended to avoid late adverse effects. The role of surgery will be defined by randomized studies. Better systemic therapy is needed to impact on systemic failure.

The dilemma of delayed cellulitis after breast conservation therapy.

OBJECTIVE: To determine the clinicopathologic characteristics of patients with breast cancers in whom delayed breast cellulitis developed after conservation therapy (lumpectomy, axillary dissection, and radiation). BACKGROUND: Breast cellulitis developing after conservation therapy represents a difficult diagnostic and management dilemma because determination of its origin may be necessary before further treatment decisions can be made. METHODS: In this retrospective evaluation of 184 sequential patients with breast cancers who underwent conservation therapy, 10 study patients (5%) in whom breast cellulitis developed 3 or more months after surgery were compared with the 174 patients in whom cellulitis did not develop. RESULTS: There was no significant difference in clinicopathologic characteristics of the study patients compared with control patients. The cellulitis resolved in 5 patients (50%) and persisted from 4 months to more than 1 year in 5 patients (50%). The cellulitis recurred in 1 patient who responded to repeated therapy. The 5 patients with persistent cellulitis underwent biopsies, and recurrent cancer was found in 1 patient. Recurrent cancer did not develop in the patients whose cellulitis resolved within 4 months with a minimum follow-up of 24 months. CONCLUSIONS: Delayed-onset cellulitis occurs in a small percentage of patients with breast cancers treated by conservation therapy. The cellulitis may take several weeks to clear, and/or it may recur or persist. If the condition persists after 4 months of therapy, a biopsy should be performed to rule out recurrent cancer.

Dose to contralateral breast: a comparison of four primary breast irradiation techniques.

PURPOSE: Contralateral breast dose from primary breast irradiation has been implicated in the risk of second breast malignancies. It has been previously shown that the use of half-beam blocking can increase the opposite breast dose by a factor of five. This study evaluates four different breast treatment techniques to compare the radiation dose to the contralateral breast. METHODS AND MATERIALS: Dose measurements were made using thermoluminescent dosimeters (TLD) capsules, which were placed in the Rando phantom in the following locations in the contralateral breast: seven along the central axis plane, on at 5 cm superior to, and one 5 cm inferior to the central axis plane. One TLD capsule was placed in the midcenter of the treated breast. The following radiation techniques were used: (a) half-beam with a custom block (HB+CB), (b) half-beam using asymmetric collimator jaw (HB/AJ), (c) half-beam using asymmetric collimator jaw with custom block (H/AJ+CB), and (d) isocentric technique with nondivergent posterior borders [Joint Center for Radiation Therapy (JCRT) techique]. For each technique, isodose distributions for the Rando phantom were optimized using (a) 15 degree medial and lateral compensating wedges, and (b) a single 30 degree lateral compensating wedge. The phantom was treated with 6 MV photons. Each technique was repeated six times, and the TLD readings were averaged. RESULTS: The custom cerrobend half-beam block technique gives the highest contralateral breast dose, regardless of wedge. The remaining techniques give results in a similar range, with the asymmetric jaw with no medial wedge technique giving the lowest total dose (p = not significant). The use of a medial wedge increases the opposite breast dose for all techniques. The asymmetric half-beam technique gives significantly less dose than the cerrobend half-beam technique, due to decreased transmission through the asymmetric collimators. The asymmetric jaw vs JCRT technique results in similar contralateral breast dose. CONCLUSIONS: As expected, dose to the contralateral breast increases with the use of a medial wedge. Cerrobend half-beam blocking gives the highest opposite breast dose. The lowest contralateral breast dose is with the asymmetric jaw with no medial wedge and no block. The asymmetric jaw technique with block yields equivalent contralateral breast doses to the JCRT technique.

Delaying the initiation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recurrence.

BACKGROUND: The impact of delaying irradiation to the intact breast for patients receiving chemotherapy for lymph node positive breast cancer is controversial. METHODS: From 1974 to 1989, 474 patients underwent lumpectomy and intact breast irradiation for early stage invasive breast cancer. Chemotherapy was administered to 84 patients (1 patient with bilateral breast cancer) because of positive axillary lymph nodes. Time from definitive breast surgery (lumpectomy or reexcision) to the initiation of breast irradiation was 21-314 days, with a median of 124 days. Forty-two patients began receiving radiation therapy before 120 days (early) and 42 more than 120 days after surgery (delayed). In the early group, cyclophosphamide/methotrexate/5-fluorouracil (CMF) was administered to 32 patients, doxorubicin, cyclophosphamide or cyclophosphamide, doxorubicin, 5-fluorouracil (AC or CAF) to 6 patients, and other regimens to 4 patients; in the delayed group, CMF was given to 29 patients, CAF to 12 patients, and L-PAM/5-fluorouracil to 1 patient. RESULTS: Median follow-up was 62 months. There was one breast recurrence in the early group, compared with six in the patients receiving delayed irradiation. The actuarial relapse rates for these groups at 5 years were 2% and 14%, respectively (P = 0.05). Survival and distant disease free survival were not significantly different between the two groups. CONCLUSIONS: Delays in the initiation of irradiation are associated with increased risk of relapse in the breast. When possible, the interval between definitive breast surgery (lumpectomy or reexcision) and the initiation of radiation therapy should be fewer than 120 days.

Omission of axillary lymph node dissection in early-stage breast cancer: effect on treatment outcome.

PURPOSE: To determine the effect omission of axillary lymph node dissection has on outcome in patients treated with breast-conserving therapy for early-stage invasive breast cancer. MATERIALS AND METHODS: The authors evaluated 492 patients with breast cancer treated with (n = 32) and without (n = 456) axillary lymph node dissection. The primary tumor characteristics of the two groups were similar, though the median age was different. All patients received whole-breast radiation (mean dose, 50 Gy); additional tumor bed boosts and nodal irradiation were used more often in patients without dissection. RESULTS: Median follow-up in patients without and with dissection was 60 and 52 months, respectively. The 5-year survival was 88% and 93%, respectively. There were no regional failures in the group treated without dissection. Crude rates of local and distant failure were similar for both groups. CONCLUSION: Omission of axillary lymph node dissection should be considered in patients whose pathologic nodal status will not influence decisions regarding adjuvant therapy.

Tandem peripheral blood progenitor cell transplants as initial therapy for metastatic breast cancer.

PURPOSE: To investigate the use of two sequential courses of high-dose chemotherapy and peripheral blood progenitor cell (PBPC) transplant as initial therapy for patients with untreated metastatic breast cancer. The goal of the study was to maximize treatment intensity through the use of two non-cross-resistant regimens, each equal in intensity to that used in single transplants. METHODS: PBPC were collected after a course of granulocyte colony-stimulating factor (G-CSF) only or of cyclophosphamide, etoposide, and G-CSF. The first transplant regimen consisted of thiotepa (600 mg/m2), cyclophosphamide (6000 mg/m2), and carboplatin (800 mg/m2). After recovery from the first transplant, responding patients received a second course of therapy consisting of busulfan (16 mg/kg) and etoposide (60 mg/kg). RESULTS: Forty-four patients were enrolled. Five patients did not proceed to transplantation due to tumor progression during PBPC mobilization. Five patients achieved complete response after the first transplant, and 14 were in complete remission at the end of the therapy. Six patients remain free of disease after a median followup of 22 months (range 12-27+ months). The 2-year event-free survival for complete responders is 25.4% (standard error 14.4%). Engraftment was prompt, with a median of 8 and 13 days, respectively, to reach a neutrophil count of 500/mm3 and a platelet count of 50,000/mm3. As a result of the gastrointestinal toxicity of the first course, the median interval between transplants was 68 days. The toxicities of the second transplant course were principally hepatic and muco-cutaneous. Hepatic veno-occlusive disease occurred in 12 patients and was a contributor to the death of three. CONCLUSIONS: Rapid hematologic recovery achieved with PBPC made possible the administration of two courses of high-dose chemotherapy without compromising the intensity of either transplant regimen. The adverse effects of the second course, however, were substantially higher than predicted. The outcome of patients achieving a complete response is promising. Overall, the antitumor benefit of this approach in patients with previously untreated metastatic disease was not superior to that achieved with single transplants in patients responding to standard-dose chemotherapy.

Using simulation data to predict lung geometry for inhomogeneity corrections in breast cancer treatments.

PURPOSE: To develop a statistical model based only on simulation measurement data, to predict the lung geometry in the central slice of the tangential radiation treatment fields for breast cancer. METHODS AND MATERIALS: A linear regression analysis was performed on 22 patients to determine the shape of lung in the central axis plane of the tangential radiation fields. Data collected include the greatest perpendicular distance (GPD) measured from the chest wall to the field border on computed tomography (CT) images, the central lung distance (CLD) measured from the posterior field border to the chest wall on the simulation portal images, and the lung contours digitized at 1 cm intervals. The lung contours of these patients were fitted to a parabolic curve through a polynomial regression model. A lung template based on the regression model is used to construct a "generic lung" contour on patients' external body contours for treatment planning. The accuracy of this technique was tested on another group of 15 patients for its ability to predict the shape of lung on the central axis plane and the accuracy of dose to the prescription point. RESULTS: The polynomial regression indicates that all the patients' lung contours in the tangential fields follow a parabolic curve: Y = -0.0808 X2 + 0.0096 X + 0.0326. The maximum lung involvement (GPD) can be determined from the value of CLD measured on the simulation film by the linear regression model with a determination coefficient of 0.712. The 15-patient test results indicate that our model predicts the lung separation on the central axis with an average deviation of 1.35 cm, and the average absolute dose deviation to the dose prescription point is 1.46%. CONCLUSION: The model presented in this article provides an efficient method to estimate the lung geometry for breast cancer treatment planning without the requirement of CT data. The lung contour predicted by our model is useful for calculating dose distributions with inhomogeneity correction and may potentially benefit patients at higher risk of pulmonary toxicity.