Hyperfractionated Cyclophosphamide and Dexamethasone Alone or in Combination with Daratumumab and/or Carfilzomib for the Treatment of Relapsed or Refractory Multiple Myeloma: A Single-Center Retrospective Analysis.

BACKGROUND: Hyperfractionated cyclophosphamide and dexamethasone (HyperCd) alone, or with carfilzomib(K) and/or daratumumab(D), represents a potential treatment option when rapid disease control is needed for patients with aggressive presentations of relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: This is a single-center, retrospective analysis of adult patients with RRMM who received HyperCd with or without K and/or D between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Center. We here report treatment response and safety outcomes. RESULTS: Data from 97 patients, 12 with plasma cell leukemia (PCL), were reviewed in this analysis. Patients had had a median of 5 prior lines of therapy and received a median of 1 consecutive cycle of hyperCd-based therapy. The overall response rate (ORR) of all patients was 71.8% (HyperCd 75%, HyperCdK 64.3%, D-HyperCd 73.3%, and D-HyperCdK 76.9%). Median progression-free survival and overall survival among all patients was 4.3 months (HyperCd 3.1 months, HyperCdK 4.5 months, D-HyperCd 3.3 months, and D-HyperCdK 6 months) and 9.0 months (HyperCd 7.4 months, HyperCdK 9.0 months, D-HyperCd 7.5 months, and D-HyperCdK 15.2 months), respectively. Grade 3/4 hematologic toxicities were common, thrombocytopenia being the most frequent at 76%. Notably, 29-41% of patients per treatment group had existing grade 3/4 cytopenias at initiation of hyperCd-based therapy. CONCLUSION: HyperCd-based regimens provided rapid disease control among MM patients, even when heavily pre-treated and with few remaining treatment options. Grade 3/4 hematologic toxicities were frequent, but manageable with aggressive supportive care.

Randomized trial of combined modality therapy with and without thymosin fraction V in the treatment of small cell lung cancer.

A randomized trial of thymosin fraction V (60 mg/m2 s.c. twice weekly) given during induction chemotherapy and radiation therapy was performed in 91 patients with small cell carcinoma of the lung. Induction chemotherapy consisted of four cycles of an alternating combination of drugs (cyclophosphamide/Adriamycin/vincristine and cisplatin/etoposide). Radiation to the primary complex was given to patients with limited disease. All patients received prophylactic cranial irradiation. There were 35 patients with limited disease (18 randomized to thymosin and 17 to no thymosin) and 56 with extensive disease (28 thymosin and 28 no thymosin). Pretreatment immunological parameters were comparable between the two groups. For limited disease patients the overall response rate was 100%, including 66% (21 of 32) complete responders. The median duration of response was 19 mo (range, 5-57 mo) and survival 21 mo (range, 4 days to 57 mo). The 3-yr survival was 32%. For ED patients the overall response rate was 95% with 29% (13 of 48) complete. The median duration of response was 10 mo and the median duration of survival 12 mo with 13% alive at 2 yr. A comparison of the thymosin-versus no thymosin-treated patients revealed no difference in response rate, response duration, or survival whether analyzed as a whole or by extent of disease. An analysis based on pretreatment immune function and total white blood cell and absolute lymphocyte count revealed no difference in the survival distributions. No differences in the pattern of toxicity were observed between the thymosin- versus no thymosin-treated patients. The addition of thymosin fraction V during induction chemotherapy and consolidation radiotherapy did not alter outcome.

Autologous bone marrow transplantation for patients with poor-prognosis lymphoma.

Review of prognostic factors at Memorial Hospital in New York City has shown that adult patients with large-cell lymphoma (diffuse histiocytic lymphoma by Rappaport classification) who have high lactic dehydrogenase (LDH) and/or bulky mediastinal or abdominal disease are destined to do poorly with conventional combination chemotherapy, with a 2-year disease-free survival of about 20%. Patients who relapse after conventional combination chemotherapy have a similar poor prognosis. Thirty-one such patients with lymphoma were studied to evaluate the efficacy of intensive radiotherapy (hyperfractionated total body irradiation [TBI] [1,320 rad]), and cyclophosphamide (60 mg/kg/d for two days) followed by autologous bone marrow transplantation (ABMT). Our results show a disease-free survival advantage (P = .002) for 14 patients who underwent ABMT immediately after induction of remission with 79% surviving at a median follow-up 49.2+ months, compared with a median survival of 5.2 months for 17 patients administered ABMT while in relapse and/or after failing conventional treatment. Our results support the use of aggressive therapy as early treatment for patients with poor prognostic features.

Combination cyclophosphamide, Adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 in treatment of small cell lung cancer.

Forty-four patients with small cell lung cancer were treated with an intensive chemotherapy induction program consisting of combination cyclophosphamide, Adriamycin, and vincristine rapidly alternating with combination cisplatin and VP-16 followed by prophylactic cranial radiotherapy. After chemotherapy induction and cranial radiotherapy, patients with limited disease received multiple-field radiotherapy consolidation to the primary tumor site and mediastinum using thoracic computed tomographic scanning for field planning, and patients with extensive disease received chemotherapy maintenance. Patients with limited disease in complete remission following radiotherapy consolidation received no further treatment unless disease recurred. It was found that cyclophosphamide, Adriamycin, and vincristine could be alternated with cisplatin plus VP-16 at two-week intervals in 80 percent of patients on an outpatient basis and that two thirds of patients achieved clinical complete remission after two courses of each regimen. Locoregional radiotherapy delivered via multiple fields was effective in increasing the complete remission rate in patients with limited disease and was well tolerated. The median survival time was 18.5 months in 24 patients with limited disease and 12.2 months in 20 patients with extensive disease. Four patients with limited disease who received chemotherapy induction and radiotherapy consolidation without maintenance chemotherapy and one patient with extensive disease remain alive and disease-free at more than five years.

Is a fourth year necessary? The need for subspecialization: total body irradiation.

Although the number of radiation oncologists performing TBI procedures has increased in the last decade and there exists a significant body of unique medical knowledge pertinent to its use, there is little cohesiveness as a discipline within radiation oncology. There are no specific societies, journals, and no hospital divisions devoted to this area. Therefore, I content that subspecialty accreditation is not justified at this time. However, there are many fascinating scientific questions at the cellular, tissue, and clinical level which remain to be answered with regard to TBI, making it an exciting area for both laboratory and clinical research. Specialized training should be offered by institutions with expertise as a possible research year for residents and/or fellows who have a particular interest in pursuing an academic career along these lines.

Techniques of magna-field irradiation.

Total body irradiation (TBI) techniques have evolved over the years, with the basic goals remaining adequate immunosuppresion and/or tumor eradication. TBI technique variables include: machine type and energy, prescription parameters (dose, number of fractions, dose/fraction, dose rate), patient position, therapy room and machine constraints (field size, distance) and beam modifiers (bolus, compensators, shields). Related variable include chemotherapy agents and schedules, and 'boost' radiotherapy. Seven representative insitutions that treat a large number of TBI patients were surveyed for these variables. Homogeneity has been achieved generally within +/- 10% with the use of these techniques. One 'sentinel' effect is disucssed, namely interstitial pneumonitis, as a measure of normal tissue effects with varying techniques. There is an indication that more fractionated methods, used either daily or in a hyperfractionated fashion, are leading to a decreased incidence of pneymonitis.

Cell survival kinetics in peripheral blood and bone marrow during total body irradiation for marrow transplantation.

Cell survival kinetics in both peripheral blood and in bone marrow have been studied over the time course of hyperfractionated total body irradiation (TBI) for bone marrow transplantation. Our unique TBI regimen allows the study of the in vivo radiation effect uncomplicated by prior cyclophosphamide, since this agent is given after TBI in our cytoreduction scheme. Peripheral blood cell concentrations were monitored with conventional laboratory cell counts and differentials. Absolute bone marrow cell concentrations were monitored by measuring cell concentrations in an aspirate sample and correcting for dilution with blood by a cell cycle kinetic method using cytofluorometry. In the entire group of patients, time to engraftment with donor marrow was found to be 16.6 +/- 4.4 days and more rapid when a nucleated donor cell dose of greater than or equal to 4.0 X 10(8) cells/kg was given. For lymphocytes in peripheral blood in patients in remission, the effective D0 ranged from 373 rad in 10 children less than or equal to 10 y old, to 536 rad in the four patients between 11-17 y old, while n = 1.0 in all groups. There was no trend observed according to age. Granulocytes had a much higher effective D0, approximately 1000 rad in vivo. Absolute nucleated cell concentration in marrow dropped slowly initially, due to an increased lymphocyte concentration in marrow during a concurrent drop in lymphocyte concentration in peripheral blood, but eventually fell on the last day of TBI ranging from 7-44% of the initial marrow nucleated cell concentration. Marrow myeloid elements, however, dropped continuously throughout the course of TBI.

Total lymphoid irradiation, high-dose chemotherapy and autologous bone marrow transplantation for chemotherapy-resistant Hodgkin's disease.

Seventeen patients with advanced stage Hodgkin's disease who relapsed or failed to respond to multiple regimens of combination chemotherapy (mostly Mechlorethamine, Vincristine, Procarbarzine, Prednisone and Adriamycin, Bleomycin, Vinblastine, Dacarbazine) were treated with accelerated hyperfractionated total lymphoid irradiation (TLI) and high-dose chemotherapy followed by autologous bone marrow transplantation (AuBMT). Candidates for the protocol did not have prior radiation therapy and had no evidence of bone marrow involvement. Their bone marrow was initially harvested and cryopreserved. The treatment protocol consisted of reinduction with conventional doses of combination chemotherapy followed by boost local field irradiation to areas of residual disease (1500 cGy within 5 days) and total lymphoid irradiation (2004 cGy given in 12 fractions of 167 cGy each t.i.d. delivered within 4 days). The patients were treated with Etoposide (250 mg/m2/day I.V. X 3 days) and high-dose Cyclophosphamide (60 mg/kg/day I.V. X 2 days). Cryopreserved (unpurged) autologous bone marrow was infused 48 hr after completion of chemotherapy. Of the 17 patients treated, four were in relapse and 13 refractory to multiple regimens of combination chemotherapy. Four patients died during the immediate peritransplant period (2--septicemia, 2--pulmonary complications). Of the 13 surviving patients, 12 entered a complete remission and one had a partial remission and died of disease 6 months later. One patient relapsed 5 months after treatment and is currently alive with disease. Eleven patients (65%) are alive with no evidence of disease 4-35 months (median 20 months) following completion of therapy. Treatment with this protocol results in a high rate of complete remission and a potential for long-term disease-free survival in previously unirradiated patients with advanced stage refractory or relapsed Hodgkin's disease who have exhausted conventional modes of chemotherapy.

The patients perception of her breast following radiation and limited surgery.

Seventy-four patients followed from 1 to 8 years post completion of breast-conserving surgery and radiation for early-stage breast cancer were asked to answer a questionnaire exploring their perception and awareness of the treated breast. The questionnaire was divided into several sections, including "Daily Activities", Pre-menstrual Changes", "Sexual Activities", and a summary "Satisfaction Index" section; when appropriate, comparisons were sought between the treated and untreated breasts. Preliminary results from this study indicate that 70% of all patients are aware of their treated breast in some way during everyday activities. The "Satisfaction Index" of this patient group is very high, with 75% rating their cosmetic result, and 81% their functional result "8" or higher on a scale of "0" to "10","10" indicating "best" or "normal".

The 1993-94 patterns of care process survey for breast irradiation after breast-conserving surgery-comparison with the 1992 standard for breast conservation treatment. The Patterns of Care Study, American College of Radiology.

PURPOSE: To determine the patterns of evaluation and treatment in the U.S. of women with early breast cancer treated with breast-conserving surgery and irradiation in 1993-94, and to compare these with a similar survey in 1983 and with the 1992 Standard for Breast Conservation Treatment. METHODS AND MATERIALS: In 1995-96, 727 randomly selected records of eligible patients treated from 1993-94 at 62 facilities representative of 3 practice types were reviewed. RESULTS: Compared with the Process Survey (PS) in 1983, patients in the 1993-94 study had an older age distribution. In the current study, 70% of patients were > or = 50 years of age, and 69% were post-menopausal, compared with 59% > or = 50 years of age and 49% post-menopausal in 1983 (p = 0.0087 and < 0.001, respectively). Work-up and evaluation in the 1993-94 PS were closely aligned with the standard and were considerably improved compared with 1983. In the 1983 study, 77% of patients underwent mammography, as compared to 97% in the 1993-94 study. In 1983, pathological size documentation was performed in 83% of patients; in 1993-94, this was performed in 95% of patients. An estrogen receptor evaluation was performed in 36% of patients in 1983; in 1993-94, that increased to 76%. In 1983, 28% of patients underwent progesterone receptor evaluation; in 1993-94, this increased to 72%. Only 3% of patients in 1993-94 were enrolled in a clinical trial. Radiation treatment parameters closely adhered to standard recommendations, improving substantially from 1983. In 1983, wedge or compensator use was recommended for 64% of patients; in 1993-94, for 95% of patients. In 1983, 4-8 MV photons were recommended for breast treatment in 67% of patients; in 1993-94, 90%. In 1983, bolus was avoided in 75% of patients; in 1993-94, in 94%. In 1983, the recommended breast dose for 89% of patients was 45-50 Gy (44-51 Gy in PS); in 1993-94 this had increased to 99% of patients. In 1983, electrons were recommended for primary site boost in 70% of patients; in 1993-94, for 94% of patients. CONCLUSION: There was an extensive shift to adherence to the 1992 standard in 1993-94, compared with the 1983 PS, although there is room for improvement in some areas.

Improved survival of poor prognosis diffuse histiocytic (large cell) lymphoma managed with sequential induction chemotherapy, "boost" radiation therapy, and autologous bone marrow transplantation.

From 1981 to 1985, 33 patients with the diagnosis of diffuse histiocytic (large cell) lymphoma (DHL) with a poor prognosis received induction multi-drug chemotherapy followed by autologous marrow cryopreservation. Thirty patients who had residual disease after chemotherapy were given "boost" irradiation to these sites, followed immediately by hyperfractionated total body irradiation, 1320 to 1375 cGy in 11 fractions over 4 days, then cyclophosphamide (60 mg/kg/d) for 2 days. All patients received an autologous bone marrow transplant (ABMT), with 15 patients receiving marrow purged with 4-hydroperoxycyclophosphamide. Patients were transplanted either as part of a planned induction-transplant approach (Group I), or as salvage after relapse on the same induction regimen (Group II), or other conventional chemotherapy regimens (Group III). In the entire group, 16 of 33 patients (48%) are alive free of lymphoma with a median follow-up of 32 months (11 to 53 mo). Actuarial (Kaplan-Meier) survival is 51% at 2 years and 46% at 3 years, with only 1 patient dying after 2 years out of 11 at risk. Eight patients (24%) succumbed to early treatment related complications. Nine patients (27%) died from relapse. Patients receiving ABMT as planned sequential therapy post-induction (Group I) did significantly better than patients given ABMT as salvage therapy after relapse on prior chemotherapy (Groups II and III) and better than the historical group of patients treated with chemotherapy alone. At 2 years, the survival in Group I is 79% versus 0% for Group II versus 48% for Group III. Historically, this group of high risk patients had a 2-year disease-free survival of 20% or less with chemotherapy alone.

Immunosuppression prior to marrow transplantation for sensitized aplastic anemia patients: comparison of TLI with TBI.

From May 1980 through July 1986, 26 patients with severe aplastic anemia, sensitized with multiple transfusions of blood products, were treated on either of two immunosuppressive regimens in preparation for bone marrow transplantation from a matched donor. There were 10 patients treated with total body irradiation (TBI), 200 cGy/fraction X 4 daily fractions (800 cGy total dose), followed by cyclophosphamide, 60 mg/kg/d X 2 d. An additional 16 patients were treated with total lymphoid irradiation (TLI) [or, if they were infants, a modified TLI or thoracoabdominal irradiation (TAI)], 100 cGy/fraction, 3 fractions/d X 2 d (600 cGy total dose), followed by cyclophosphamide, 40 mg/kg/d X 4 d. The extent of immunosuppression was similar in both groups as measured by peripheral blood lymphocyte depression at the completion of the course of irradiation (5% of initial concentration for TBI and 24% for TLI), neutrophil engraftment (10/10 for TBI and 15/16 for TLI), and time to neutrophil engraftment (median of 22 d for TBI and 17 d for TLI). Marrow and peripheral blood cytogenetic analysis for assessment of percent donor cells was also compared in those patients in whom it was available. 2/2 patients studied with TBI had 100% donor cells, whereas 6/11 with TLI had 100% donor cells. Of the five who did not, three were stable mixed chimeras with greater than or equal to 70% donor cells, one became a mixed chimera with about 50% donor cells, but became aplastic again after Cyclosporine A cessation 5 mo post-transplant, and the fifth reverted to all host cells by d. 18 post-transplant. Overall actuarial survival at 2 years was 56% in the TLI group compared with 30% in the TBI group although this was not statistically significant. No survival decrement has been seen after 2 years in either group. There was less long-term morbidity in the TLI group compared with TBI although the numbers of surviving patients are small. With no difference in engraftment or survival, it is suggested that, for sensitized severe aplastic anemia patients, who are to receive a non-T cell-depleted marrow from a matched donor, prudent cytoreduction should include a fractionated, moderate dose irradiation regimen with maximum organ sparing, that is either TLI or TAI.

Local control with pre-operative radiotherapy alone versus "sandwich" radiotherapy for rectal carcinoma.

Forty-nine patients with primary adenocarcinoma of the rectum, clinically localized to the pelvis were treated with pre-op radiotherapy (RT) 1500 cGy/5 fx with AP/PA fields, followed by immediate curative resection. Patients staged as Astler-Coller B2, C1, or C2 were considered for post-op RT, 4140 cGy/23 fxs with a 4-field technique. There were 47 evaluable patients in this non-randomized study. Two groups of patients were analyzed, namely pre-op RT only (24 patients) and combined pre- and post-op ("sandwich") RT (23 patients). Two patients with pre-op RT only were considered inevaluable for recurrence because they died NED at 1 and 7 mo. All patients have been followed for greater than 1 year; 77% have been followed for greater than 2 yr. There has been only one local recurrence (LR), surprisingly in a Stage A pre-op RT patient who had no residual tumor in the final operative specimen. In the pre-op group which included 10 B2s, and 1 C2, 1500 cGy in 5 days (equivalent to 1940 cGy by the NSD formulation) was associated with no local recurrence. No distant metastases (DM) have developed in this group. In the "sandwich" RT group, which included 3 B2s, 1 C1, 17 C2s, and 1 D (localized to the pelvis, i.e. ovary), there were no LRs and 7 DMs (1 B2 and 6 C2s). Actuarial survival is 92% in the pre-op RT group at 2 and 3 yr, and 82% in the "sandwich" group at 2 and 3 yr. There have been no serious early or late complications related to RT in our pre-op group. The use of 1500 cGy in 5 days as pre-op RT with immediate surgery may prove, upon longer follow-up, to be sufficient for increasing local control, with minimum morbidity, in patients with B2 disease. Patients with C2 disease are being controlled locally with the "sandwich" regimen, but it is not clear whether pre-op RT alone may be adequate in this group as well. We are now addressing this question in a randomized study.

The use of lymphoscintigraphy in treatment planning of primary breast cancer.

A technique is described for the use of lymphoscintigraphy in treatment planning of primary breast patients. During simulation of the treatment fields, the positions of the internal mammary nodes are projected back toward the source onto the patient skin surface and are marked by radio-opaque markers for visualization on films. Exact solutions for the coordinates of these surface projection points are derived. Approximate solutions are also given which are independent of the isocenter location and primarily dependent on the treatment field gantry angle. If a typical couch angle and field size are assumed, the projection points can be calculated for various gantry angles prior to simulation. Generally, a decision can then be made beforehand whether it would be better to use deep tangents or a separate field to treat the internal mammary nodes. During simulation, the surface projection points serve as visual and fluoroscopic guides to field design and optimization. A method is also presented for projecting the internal mammary node positions onto a single transverse patient contour for conventional 2-dimensional treatment planning. By accurately showing the projected location of the node with respect to the field edge, adequate treatment margin can be assured.

Remote afterloading intraluminal brachytherapy in the treatment of rectal, rectosigmoid, and anal cancer: a feasibility study.

From 1981 to 1986, 28 patients (27 evaluable) were treated with intraluminal brachytherapy (ILBT) using a remote afterloading technique for persistent or recurrent anal, rectal and rectosigmoid cancers. Eighty-nine percent underwent previous surgery for colorectal cancer. Seventy-seven percent of the patients received external beam irradiation (ERT) as a part of the present treatment. Intraluminal brachytherapy was given with a 2 cm diameter cylinder and the dose per fraction ranged from 440 cGy to 840 cGy at 0.5 cm from the surface of the cylinder. Follow-up ranged from 1 to 74 months with a median of 12 months. Patients were divided into two groups. Group I consisted of 15 patients receiving elective ILBT; Group II: 13 patients with recurrent disease. Seventy-one percent of the patients in Group I and 39% of the patients in Group II achieved local control. The majority of patients tolerated treatment well with only transient reactions. However, three patients (11%) developed grade 3 (G3) complications requiring surgical intervention. Eight patients developed moderate complications--grade 2 (G2)--requiring only conservative treatment. This study has identified several factors which appear to influence the risk of developing complications with this combined treatment, using remote afterloading apparatus, among which are technique of previous external beam irradiation, treatment length, anatomical location, intraluminal brachytherapy fractionation, and total cumulative dose (ERT + ILBT). This experience suggests that intraluminal brachytherapy appears to be an acceptable form of treatment, as a boost to external beam radiation therapy, in the management of rectal and colorectal cancers.

Arbitrary oblique image sections for 3-D radiation treatment planning.

Methods for selecting and computing arbitrary image sections for displaying anatomic and isodose information for three-dimensional treatment planning are investigated. Selection of the desired plane may be made by defining a plane that is perpendicular to an existing image section (called the base image) and passing through a line on the base image. Alternatively, the anatomic structures displayed perspectively in three dimensions as a series of contours that can be rotated and translated may be used to define an arbitrary plane for image reconstruction. The viewing screen is considered to be the plane of interest. As a typical three-dimensional image of 30 to 60 sections requires considerable computer storage (on the order of 25 megabytes), a reconstruction algorithm may need extensive memory space or CPU and disk I/O time. Of the schemes examined, we believe the following is the most efficient. One pair of images is read from the disk at a time in sequence and intersections of the rows of the cutting plane with the box formed by the consecutive images are computed. Pixel values of all points between the given images are computed by interpolation. Special cases, such as the cutting plane being parallel to or coincident with an existing image, must be considered separately.

Limited resection for breast cancer: a study of inked specimen margins before radiotherapy.

This is an analysis of tumor margins of 108 patients who underwent a limited resection for infiltrating breast cancer, prior to starting radiation therapy. This represented the initial resection (IR) in 75 patients, and a re-excision (RE) after biopsy elsewhere in 33 patients. All specimens were processed by the India ink method prior to frozen and paraffin section analysis. Overall, the incidence of involved margins was 28% for the IR group, and 15% for the RE group. No correlation was found with the axillary node status, or with the type of prior surgery in the RE group. The data suggest a correlation between increasing tumor size and margin involvement. Further surgery in the IR group with involved margins yielded negative margins in all cases; the finding of residual carcinoma was correlated with the type of secondary surgery, that is, further re-excision or mastectomy.

Tolerance of normal tissue to therapeutic irradiation.

The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.

Three-dimensional treatment planning for postoperative treatment of rectal carcinoma.

The role of three-dimensional (3-D) treatment planning for postoperative radiation therapy was evaluated for rectal carcinoma as part of an NCI contract awarded to four institutions. It was found that the most important contribution of 3-D planning for this site was the ability to plan and localize target and normal tissues at all levels of the treatment volume, rather than using the traditional method of planning with only a single central transverse slice and simulation films. There was also a slight additional improvement when there were no constraints on the types of plans (i.e., when noncoplanar beams were used). Inhomogeneity considerations were not important at this site under the conditions of planning, i.e., with energies greater than 4 MV and multiple fields. Higher beam energies (15-25 MV) were preferred by a small margin over lower energies (down to 4 MV). The beam's eye view and dose-volume histograms were found quite useful as planning tools, but it was clear that work should continue on better 3-D displays and improved means of translating such plans to the treatment area.

Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.

PURPOSE: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. METHODS AND MATERIALS: From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). RESULTS: One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. CONCLUSION: Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.