Multiple Daily Fractionation Research Articles

Technical Note: Partial body irradiation of mice using a customized PMMA apparatus and a clinical 3D planning/LINAC radiotherapy system.

In vivo radiobiology experiments involving partial body irradiation (PBI) of mice are of major importance because they allow for the evaluation of individual organ tolerance; overcoming current limitations of experiments using lower dose, whole body irradiation. In the current study, the authors characterize and validate an effective and efficient apparatus for multiple animal PBI, directed to the head, thorax, or abdomen of mice. The apparatus is made of polymethylmethacrylate and consists of a rectangular parallelepiped prism (40 cm × 16 cm × 8 cm), in which five holes were drilled to accomodate standard 60 ml syringes, each housing an unanesthetized, fully immobilized mouse. Following CT-scanning and radiotherapy treatment planning, radiation fields were designed to irradiate the head, thorax, or abdomen of the animal. Thermoluminescent dosimeters (TLDs) were used to confirm the treatment planning dosimetry for primary beam and scattered radiation. Mice are efficiently placed into 60 ml syringes and immobilized, without the use of anesthetics. Although partial rotational movement around the longitudinal axis and a minor 2 mm forward/backward movement are permitted, this does not compromise the irradiation of the chosen body area. TLDs confirmed the dose values predicted by the treatment planning dosimetry, both for primary beam and scattered radiation. The customized PMMA apparatus described and validated is cost-effective, convenient to use, and efficient in performing PBI without the use of anesthesia. The developed apparatus permits the isolated irradiation of the mouse head, thorax, and abdomen. Importantly, the apparatus allows the delivery of PBI to five mice, simultaneously, representing an efficient way to effectively expose a large number of animals to PBI through multiple daily fractions, simulating clinical radiotherapy treatment schedules.

A rare case of clear cell carcinoma of the breast evaluated by 18F-FDG PET/CT

Stage IIIB includes patients with T4, any N, M0, and any T, N3, M0. Surgery may be indicated only for carefully selected T4N0M0 patients with or without neoadjuvant chemotherapy or chemoradiotherapy. Patients with N3 lymph node involvement are not considered as surgical candidates. For patients with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiotherapy has resulted in better survival than treatment with radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in improved survival compared with standard fractionation once daily. Concurrent chemoradiotherapy appears to be associated with improved survival compared with sequential chemotherapy and radiotherapy. Treatment of stage IIIB due to malignant pleural effusion is addressed in the section that deals with stage IV disease.

A fluence map optimization model for restoring traditional fractionation in IMRT treatment planning

One of the core problems in intensity modulated radiation therapy (IMRT) treatment planning is the fluence map optimization (FMO) problem, which determines a fluence map (or profile) for each beam used in the delivery of treatment. Radiation therapy is administered in multiple so-called daily fractions to allow for healthy tissue to recover from damage caused by the treatment. Before the advent of IMRT, the treatment was designed to ensure a constant dose to cells in the target (the areas in the patient where cancerous cells are present or suspected). In the presence of multiple targets with different prescribed doses, this design meant that treatment had to be delivered in a sequence of unequal fractions, one per prescription dose level. For example, in case of two targets treatment would consist of an initial plan aimed at treating both targets to a lower total dose, followed by a so-called boost plan aimed at delivering the additional dose at the target with higher prescribed dose. In contrast, IMRT treatment plans are often delivered with equal treatment plan for each fraction, which means that the dose per fraction cannot be the same for all targets. The important problem of restoring traditional fractionation to IMRT treatments has not yet received much attention in the literature. In this paper we propose a new optimization model that explicitly restores fractionation into the FMO problem, yielding an optimal set of fluence maps for each fraction. We illustrate the capabilities of our approach on clinical head-and-neck cancer cases.

WE-C-AUD B-08: Biologically Based Corrections for Interfraction Variations During Prostate Cancer Radiation Therapy

Purpose: The linear‐quadratic (LQ) survival model is used to calculate the doses required to correct for interfraction deviations from the planned doses arising from patient setup errors, organ deformation and organ movement after multiple daily fractions. Corrected dose distributions derived from isosurvival (biological) and isodose (physical) methods are compared to planned dose distributions for a representative prostate cancer case. Method and Materials: Voxel‐by‐voxel interfraction deviations from a planned prostate cancertreatmentdelivered using image‐guidedintensity modulated radiation therapy (IG‐IMRT) with a linac and CT‐on‐Rails combination (CTVision, Siemens) are determined using the XiO treatment planning system by CMS and an in‐house image deformable registration tool based on the CT‐of‐the‐day for multiple days. Dose distributions needed on the nth treatment day to correct for the accumulated interfraction variations in previous fractions are determined using methods expected to produce the same surviving fraction in all regions of diseased and normal tissue as the planned treatment.Results: After completing a series of 5 planned fractions of 1.76 Gy, dose corrections derived from the biological modeling ranged from a low of 1.391 Gy (reduced by 27%) to a high of 2.652 Gy (increased by 51%) in some regions of tissue.Dose corrections derived from isosurvival modeling always yields smaller corrected doses than isodose methods, although the differences in the two methods are nearly indistinguishable for planned doses ∼ 2 Gy per day. Conclusion:Doses required to correct for interfraction variations accumulated on multiple treatment days are smaller for isosurvival (biological) methods than for isodose (physical) methods. In the limit when the planned fraction size is small compared to α/β, interfraction corrections to dose distributions derived from the physical and biological methods are indistinguishable. For hypofractionated treatments,dose corrections derived from isosurvival modeling may be substantially smaller than the ones derived from isodose methods.

Nasopharyngeal Cancer: Advances in Radiotherapy

Nasopharyngeal Cancer: Advances in Radiotherapy

Treatment of Non-small Cell Lung Cancer, Stage IIIB: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

To develop evidence-based guidelines on best available treatment options for patients with stage IIIB non-small cell lung cancer (NSCLC). A review was conducted of published English-language (abstract or full text) phase II or phase III trials and guidelines from other organizations that address management of the various categories of stage IIIB disease. The literature search was provided by the Duke University Center for Clinical Health Policy Research and supplemented by any additional studies known by the authors. Surgery may be indicated for carefully selected patients with T4N0-1M0. Patients with N3 nodal involvement are not considered to be surgical candidates. For individuals with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy (RT) alone. Concurrent chemoradiotherapy seems to be associated with improved survival compared with sequential chemoradiotherapy. Multiple daily fractions of RT when combined with chemotherapy have not been shown to result in improved survival compared with standard once-daily RT combined with chemotherapy. The optimal chemotherapy agents and the number of cycles of treatment to combine with RT are uncertain. Prospective trials are needed to answer important questions, such as the role of induction therapy in patients with potentially resectable stage IIIB disease. Future trials are needed to answer the questions of optimal chemotherapy agents and radiation fractionation schedule. The role of targeted novel agents in combination with chemoradiotherapy is just starting to be investigated.

Early reoxygenation in tumors after irradiation: Determining factors and consequences for radiotherapy regimens using daily multiple fractions

To characterize changes in the tumor microenvironment early after irradiation and determine the factors responsible for early reoxygenation. Fibrosarcoma type II (FSaII) and hepatocarcinoma transplantable liver tumor tumor oxygenation were determined using electron paramagnetic resonance oximetry and a fiberoptic device. Perfusion was assessed by laser Doppler, dynamic contrast-enhanced MRI, and dye penetration. Oxygen consumption was determined by electron paramagnetic resonance. The interstitial fluid pressure was evaluated by the wick-in-needle technique. An increase in oxygen partial pressure was observed 3-4 h after irradiation. This increase resulted from a decrease in global oxygen consumption and an increase in oxygen delivery. The increase in oxygen delivery was due to radiation-induced acute inflammation (that was partially inhibited by the antiinflammatory agent diclofenac) and to a decrease in interstitial fluid pressure. The endothelial nitric oxide synthase pathway, identified as a contributing factor at 24 h after irradiation, did not play a role in the early stage after irradiation. We also observed that splitting a treatment of 18 Gy into two fractions separated by 4 h (time of maximal reoxygenation) had a greater effect on tumor regrowth delay than when applied as a single dose. Although the cell cycle redistribution effect is important for treatment protocols using multiple daily radiation fractions, the results of this work emphasize that the oxygen effect must be also considered to optimize the treatment strategy.

Guidelines on Treatment of Stage IIIB Non-small Cell Lung Cancer

Stage IIIB includes patients with T4, any N, M0, and any T, N3, M0. Surgery may be indicated only for carefully selected T4N0M0 patients with or without neoadjuvant chemotherapy or chemoradiotherapy. Patients with N3 lymph node involvement are not considered as surgical candidates. For patients with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiotherapy has resulted in better survival than treatment with radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in improved survival compared with standard fractionation once daily. Concurrent chemoradiotherapy appears to be associated with improved survival compared with sequential chemotherapy and radiotherapy. Treatment of stage IIIB due to malignant pleural effusion is addressed in the section that deals with stage IV disease.

Immobilization in stereotactic radiotherapy: the head and neck localizer frame

Stereotactic radiotherapy refers to multiple daily fractions of radiation, over days or weeks of treatment, with the patient in a relocatable stereotactic frame. The linear accelerator-based, couch-mounted system from Radionics utilizes the Gill-Thomas-Cosman (GTC) frame and the new Tarbell-Loeffler-Cosman (TLC) pediatric frame for accurate positioning reproducibility. Radionics has now made available the Head and Neck Localizer (HNL) frame to be used with its XPlan treatment planning system and the mini multileaf collimator (MMLC). This will extend the overall capability of stereotactic radiotherapy to the treatment of head and neck cancers. However, with no data available on the HNL frame, a study is being undertaken to assess the accuracy in patient position reproducibility using the frame. This report provides the preliminary findings of comparing depth-helmet readings with radiographic data, together with recommended modifications to the frame.

Multiple daily fractionation radiotherapy schedules in lung cancer.

Lung cancer is the number one worldwide cancer killer, and in spite of therapeutic advances, the overall impact on survival has remained very modest. For both small and non-small-cell lung cancer, treatment trends have shifted toward combined-modality approaches, chemotherapy for the control of systemic micrometastases, and radiotherapy for intrathoracic control. However, on both counts, rates of failure remain unacceptably high, and several novel strategies are currently being explored. The use of altered fractionation, including multiple daily fractions, reflects one approach for modifying radiotherapy. The two most common approaches are hyperfractionation and acceleration, the former designed to reduce late normal tissue toxicities and the latter to counteract accelerated tumor repopulation. Recent randomized trials suggest that such approaches may result not only in lowered rates of intrathoracic failure but also in improved survival.

Radiation survival of two human cervical carcinoma cell lines after multifraction irradiation

Purpose : Multifraction irradiation may contribute to radiation therapy treatment failure is selection of radiation resistant subpopulations occurs. We sought to determined whether surviving cells following daily fraction irradiation of two human cervical squamous cell carcinoma lines would express different radiation survival characteristics compared to the unirradiated parent. Methods and Materials : A late-passage line (HTB35) and an early-passage line 9RECA) received daily 2 Gy x-irradiation. Two stable HTB35 cell lines were extablished after 40 and 60 Gy (HTB3540 and HTB3560). A single line was established from RECA after 30 Gy (RECA-30). High dose rate (74 cGy/min) acute radiation survival curves were prepared from the three nre lines and the unirradiated parents. Potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) responses were detailed for HTB35, HTB3540 and HTB3560. Low dose rate (1.27 cGy/min) survival was measured dfor HTB35 and HTB3560. Clones were derived from HTB35 and from HTB3560 and the survivung fraction at 2 Gy (SF 2) values were determined. Results : The two parent lines (HTB35 and RECA) differed in acute radiation survival. The surviving lines following multifraction irradiation (HTB3540, HTB3560, and RECA) showed no change in acute radiation response compared to the appropriate parent. HTB3540 and HTB3560 were repair proficient, demonstrating similar PLDR anmd SLDR recovery ratios as the parent. Likewise, low dose rate survival of HTB35 and HTB3560 was similar. Nine clones derived deom HTB35 lacked a consistent difference in SF 2 compared to the original culture. A single clone of seven derived from HTB3560 was consistently radiation resistant (SF 2 = 0.81 ± 0.06 compared to the original culture (SF 2 = 0.50 ± 0.09). Conclusion : No evidence was obtained that cell lines generated following multiple daily fractions of x-irradiation in vitro possessed acute radiation survival or repair characteristics that were different from the unirradiated parent.

Reemergence of apoptotic cells between fractionated doses in irradiated murine tumors

Purpose : The purpose of this investigation was to follow up our previous studies on the development of apoptosis in irradiated murine tumors by testing whether an apoptotic subpopulation of cells reemerges between fractionated exposures. Methods and Materials : Mice bearing a murine ovarian carcinoma, OCa-I, were treated in vivo with two fractionation protocols: two doses of 12.5 Gy separated by various times out to 5 days and multiple daily fractions of 2.5 Gy. Animals were killed 4 h after the last dose in each protocol, and the percent apoptosis was scored from stained histological sections made from the irradiated tumors according to the specific features characteristic of this mode of cell death. Results : The 12.5+12.5 Gy protocol yielded a net total percent apoptosis of about 45% when the two doses were separated by 5 days (total dose = 25 Gy), whereas the 2.5 Gy per day protocol yielded about 50% net apoptotic cells when given for 5 days (total dose = 12.5 Gy). These values are to be compared to the value of 36% apoptotic cells that is yielded by large single doses (> 25 Gy). Thus, these results indicate that an apoptotic subpopulation of cells reemerged between the fractions in both protocols, but the kinetics appeared to be delayed in the 12.5+12.5 Gy vs. the multiple 2.5 Gy protocol. Conclusion : This reemergence of cells with the propensity for radiation -induced apoptosis between fractionated exposures is consistent with a role for this mode of cell death in the response of tumors to radiotherapy and may represent the priming of a new subpopulation of tumor cells for apoptosis as part of normal tumor homeostasis to counterbalance cell division.

New concepts in radiotherapy for advanced squamous cell carcinoma of the head and neck

This paper reviews two of the newer concepts—multiple daily fractions of radiotherapy, and concomitant chemotherapy and radiotherapy—in improving the treatment of squamous cell carcinoma of the head and neck.

Alternating chemotherapy and twice-daily thoracic radiotherapy in limited-stage small-cell lung cancer: a pilot study of the Eastern Cooperative Oncology Group.

This pilot study was undertaken to determine the efficacy and feasibility of alternating cisplatin and etoposide with multiple daily fractions of thoracic radiotherapy (TRT) in patients with limited-stage small-cell lung cancer (SCLC). Thirty-four SCLC patients received four courses of cisplatin (30 mg/m2/d x 3) plus etoposide (120 mg/m2/d x 3) (PE) every 3 weeks. TRT was administered twice daily (1.5 Gy per fraction) for 5 consecutive days in the week after cycles 1, 2, and 3 of chemotherapy (total TRT dose, 45 Gy). Patients who achieved a complete response (CR) received one course of late-intensification (LI) treatment consisting of cyclophosphamide (4 g/m2) and etoposide (900 mg/m2). Prophylactic cranial irradiation (PCI) was optional. Nineteen of 32 assessable patients achieved a CR (59%) and 12 had a partial response (38%), for an overall response rate of 97% (95% confidence interval [CI], 84% to 99%). Median survival was 18 months, while 2-year progression-free survival was 47%. Leukopenia < or = 1,000/microL occurred in 12% of induction treatment cycles. Severe esophagitis was uncommon. Pulmonary fibrosis that was asymptomatic or minimally symptomatic was observed in eight patients (25%). There was one episode of adult respiratory distress syndrome (ARDS) during LI chemotherapy. Life-threatening neutropenia (< or = 500/microL) developed in all patients who underwent LI chemotherapy, with a median duration of 10 days (range, 8 to 19). Two patients died of sepsis during LI chemotherapy. Alternating PE and TRT as performed in this trial is an effective brief induction regimen for limited-stage SCLC. However, this particular regimen did not appear to be substantially different in terms of efficacy or toxicity compared with regimens using concurrent chemotherapy and standard-fraction TRT. LI chemotherapy was associated with unacceptable toxicity and did not appear to have a favorable impact on survival.

New concepts in radiotherapy for advanced squamous cell carcinoma of the head and neck.

This paper reviews two of the newer concepts - multiple daily fractions of radiotherapy - in improving the treatment of squamous cell carcinoma of the head and neck.

Postoperative radiotherapy of carcinoma in bilharzial bladder: Improved disease free survival through improving local control

Two hundred thirty-six patients with T 3 bladder cancer who survived radical surgery and proved to have P 3a, P 3b, or P 4a tumors were randomized in two phases into three groups: (a) no further treatment (83 patients (b) postoperative radiotherapy multiple daily fractionation (MDF), using 3 daily fractions of 1.25 Gy each, with 3 hr between fractions, up to a total dose of 37.5 Gy in 12 days (75 patients); and (c) postoperative radiotherapy conventional fractionation (CF), for a total dose of 50 Gy/5 weeks (78 patients). The tolerance of the patients to postoperative radiotherapy was quite acceptable, with equal acute reactions in MDF and CF groups. The 5-year disease-free survival (DFS) rates amounted to 49 and 44% in MDF and CF postoperative radiotherapy groups, respectively, compared to 25% in the cystectomy-alone group. The 5-year local control rates were 87% and 93% for those treated with multiple daily fractionation and conventional fractionation while it was 50% in the surgery-alone group. The therapeutic benefit of postoperative irradiation was consistent for all tumor types, histological grades, and pathological stages for both the disease-free survival and local control. Patients with nodal metastases demonstrated lower recurrence rates in the postoperative radiotherapy groups, but this was not associated with improved disease-free survival. Multivariate analysis using the Cox Model confirmed these results. The independent prognostic factors affecting both disease-free survival and local control were the addition of postoperative radiotherapy, the nodal status, the pathological stage, and the tumor grade. Late complications of radiotherapy in the skin, small intestine, rectum, and the anastomotic site of the urinary division were lower with MDF than with conventional fractionation.

Extra lethal damage due to residual incompletely repaired sublethal damage in hyperfractionated and continuous radiation treatment

In the conventional linear-quadratic model of single-dose response, the alpha and beta terms reflect lethal damage created during the delivery of a dose, from two different presumed molecular processes, one linear with dose, the other quadratic. With the conventional one-fraction-per-day (or less) regimens, the sublethal damage (SLD), presumably repairing exponentially over time, is essentially completely fixed by the time of the next dose of radiation. If this assumption is true, the effects of subsequent fractions of radiation should be independent, that is, there should be little, if any, reversible damage left from previous fractions, at the time of the next dose. For multiple daily fractions, or for the limiting case, continuous radiation, this simplification may overlook damaged cells that have had insufficient time for repair. A generalized method is presented for accounting for extra lethal damage (ELD) arising from such residual SLD for hyperfractionation and continuous irradiation schemes. It may help to predict differences in toxicity and tumor control, if any, obtained with "unconventional" treatment regimens. A key element in the present model is the finite size and the dynamic character of the pool of sublethal damage. Besides creating the usual linear and quadratic components of lethal damage, each new fraction converts a certain fraction of the existing SLD into ELD, and creates some new SLD. The expressions developed by Thames [Int. J. Radiat. Biol. 47, 319-339 (1987)] for fractionated treatment (the IR model) and by Dale [Br. J. Radiol. 58, 515-528 (1985); 59, 919-927 (1986)] for protracted and fractionated treatment are found to be similar to our results in the limiting case where the pool of SLD is very large (infinite).(ABSTRACT TRUNCATED AT 250 WORDS)

Etoposide in the management of non-small cell lung cancer

Etoposide is a phase-specific, schedule-dependent derivative of podophyllotoxin that appears to act by inhibiting DNA-topoisomerase II. Early preclinical work demonstrated sharp activity in mouse leukemias and possible synergy with cisplatin. As a single agent (either orally or intravenously), it demonstrated limited benefit in non-small cell lung cancer (NSCLC), with response rates around 10%. In combination with cisplatin, it has become a mainstay of chemotherapeutic efforts, either as primary therapy or in conjunction with radiation. Response rates in advanced disease average around 30%, climbing to more than 50% in patients with Stage IIIA or IIIB disease. More recent work suggests that the issue of the true synergy of etoposide with cisplatin in NSCLC needs reassessment. The relative roles of etoposide and cisplatin in the combination are unclear, as several studies conflict. Pharmacokinetic data suggest that multiple daily fractions of etoposide are superior to prolonged infusions, warranting several future trials. The current major role for etoposide plus cisplatin would appear to be in multimodality therapy where the combination can be readily combined with radiation and/or surgery. Several other agents have been studied with etoposide or etoposide plus cisplatin (mitomycin, vindesine, doxorubicin, cyclophosphamide, ifosfamide, and carboplatin), but it is unclear whether the addition of any of them offers any response or survival advantage.

Fraction size-dependent acute skin reaction of mice after multiple twice-a-day doses

To study the effect of multiple daily fractions on acute murine foot reaction, the left feet of C3Hf/Sed mice were irradiated by a Cs-137 irradiator at intervals of 6 and 18 hr, alternately. Fraction sizes ranged from 1 to 12 Gy, and various numbers of fractions were given. At the end of fractionation, a top-up dose of 20 Gy was administered. The overall treatment time ranged from 2 to 21 days. The average skin reaction from 10 to 35 days after completion of irradiations was determined. The skin reactions started from 8 to 27 days following the completion of irradiations. The skin reaction after fraction sizes of 3.5 and 5 Gy was dependent on the total dose. The skin reaction after fraction sizes of 1.5 and 2 Gy showed a biphasic response; at lower total doses, the skin reaction was proportional to the total dose, but at higher total dose, the skin reaction reached a plateau. The average skin reaction at the plateau with fraction sizes of 1, 1.5, and 2 Gy were 0.79 ± 0.03, 1.12 ± 0.13, and 1.37 ± 0.06, respectively. The α β ratio for acute skin reaction following the twice a day scheme was 9.09 Gy (at dose/fraction ≥ 3.5 Gy). The plateau may be attributed to the effect of accelerated proliferation and a balance between cell depletion and proliferation during twice-a-day irradiations. It is also suggested that twice-a-day irradiations induce more proliferation in skin than once a day treatments.

Presidential address: Malignant glioma—A nemesis which requires clinical and basic investigation in radiation oncology

Malignant gliomas account for 40% of all central nervous system malignancies. These are essentially localized neoplastic tumors that have defied most treatment. In spite of improved techniques, surgery is unlikely to increase survival further since true cancer operations cannot be performed. Radiation therapy has made a significant difference in outcome. Investigation in radiation oncology is essential for further improvement in the treatment of these tumors. The pattern of failure is local tumor recurrence, but the method to overcome this resistance to treatment is not clear. Radiation therapy techniques and inherent radio-resistance have been considered as possible reasons for failure. With newer imaging procedures, the extent of tumor can be more accurately defined allowing improved treatment planning. Identifying an effective treatment program is more difficult. Studies have documented the beneficial effect of radiation therapy, but the optimal dose or fractionation schedule has not been determined. Whereas some studies have reported improved survival using higher radiation doses, others have reported no benefit. More recently, studies of multiple daily fractionation schedules have been conducted using two or three daily fractions. Equally confusing results have been reported. Histologically, these tumors have necrotic areas and may be radioresistant due to hypoxic cells. Treatment methods designed to overcome the radioprotective effect of hypoxia have yielded disappointing results. The addition of hypoxic cell sensitizers has not produced the expected improvement in outcome. Studies using neutron radiation therapy report tumor control but not improved survival. Radiobiologic information is now available which may contribute to our understanding of the response of these tumors to radiation. Further laboratory and clinical investigation is required. Carefully designed clinical trials are needed to test new treatment concepts, and all radiation oncologists should be prepared to participate in such clinical studies.