Multigene assays in early breast cancer: Insights from recent phase 3 studies.

Multigene assays (MGAs) guide treatment in early-stage breast cancer (ESBC) enabling selective and effective use of adjuvant chemotherapy (CT). Support for all MGAs had previously been derived from retrospectively-analyzed, prospective studies. Only 2 ESBC MGAs, the 70-gene signature (MammaPrint®) and the 21-gene Recurrence Score (RS) assay (Oncotype DX®), are now supported by entirely prospective randomized phase 3 trials. These studies varied in their primary objectives, design, and eligibility. The MINDACT study provided the first level 1 evidence for the 70-gene signature, identifying a prognostic capability irrespective of lymph node (LN) or hormone receptor (HR) status. However, the study did not support predictive value for the assay regarding adjuvant CT utility. The second prospective study, WSG-PlanB, confirmed the prognostic value of the 21-gene RS assay in HR-positive tumors with RS ≤ 11. A 5-year disease free survival (DFS) of 94% was identified in this group when treated with endocrine therapy (ET) alone regardless of N0 or N1 nodal status. The final new prospective study, TAILORx, confirmed the prognostic value of the 21-gene assay in N0 HR-positive disease, demonstrating a lack of CT benefit in patients with midrange RS. The information from these phase 3 studies confirms that MGAs are not interchangeable and that each provides different information for differing patient populations. Prognosis-only is supported for the 70-gene signature while both prognosis and the predictive value of CT are provided by the 21-gene assay. This review assesses and contrasts these phase 3 studies in the context of target populations and clinical utility.

Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.

BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.

Correlations among p53, Her-2/neu, and ras overexpression and aneuploidy by multiparameter flow cytometry in human breast cancer: evidence for a common phenotypic evolutionary pattern in infiltrating ductal carcinomas.

Human solid tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. We sought to determine whether there are specific sequences of occurrence of these progressive evolutionary changes in human breast cancers by performing correlated cell-by-cell measurements of cell DNA content, p53 protein, Her-2/neu protein, and ras protein by multiparameter flow cytometry in 56 primary tumor samples obtained at surgery. In addition, p53 allelic loss and Her-2/neu gene amplification were determined by fluorescence in situ hybridization in cells from the same samples. We reasoned that if there is a specific order in which genetic changes occur, the same early changes would be found consistently in the cells with the fewest abnormalities. We reasoned further that late-developing abnormalities would not occur alone in individual cells but would almost always be found together with the early changes inherited by the same cells. By these criteria, abnormalities involving p53 generally occurred early in the course of development of invasive breast cancers, whereas ras protein overexpression was found to be a late-occurring phenomenon. Within individual tumors, cellular p53 overexpression was often observed alone in individual cells, whereas ras protein overexpression was rarely observed in the absence of p53 overexpression and/or Her-2/neu overexpression in the same cells. Furthermore, the intracellular level of each abnormally expressed protein was found to increase progressively as new abnormalities were acquired. Infiltrating ductal carcinomas exhibited characteristic phenotypic patterns in which p53 allelic loss and/or p53 protein overexpression, Her-2/neu amplification and/or overexpression, aneuploidy, and ras overexpression accumulated within individual cells. However, this pattern was not a prominent feature of lobular breast cancers. All six lobular breast cancers studied were diploid. p53 allelic loss and/or early p53 overexpression, and late ras cooverexpression in the same cells were less common in lobular breast cancers than in infiltrating ductal carcinomas. Although Her-21neu overexpression was a common finding in lobular breast cancers, Her-2/neu amplification was not observed in these tumors.

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05.

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.

erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer.

BACKGROUND: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis. METHODS: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided. RESULTS: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P=.02), lack of estrogen receptors (P=.008), and the number of positive lymph nodes (P=.0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors--DFS: relative risk of failure (RR)=0.60 (95% confidence interval [CI]=0.44-0.83), P=.001; survival: RR=0.66 (95% CI=0.47-0.92), P =.01; RFS: RR=0.58 (95% CI=0.42-0.82), P=.002; DDFS: RR=0.61 (95% CI=0.44-0.85), P=.003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR=0.96 (95% CI=0.75-1.23), P=.74; survival: RR =0.90 (95% CI=0.69-1.19), P=.47; RFS: RR=0.88 (95% CI=0.67-1.16), P=.37; DDFS: RR=1.03 (95% CI=0.79-1.35), P=.84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P=.02) and DDFS (P=.02) but not for survival (P= .15) or RFS (P=.06). CONCLUSIONS: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.

A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients undergoing preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.

Characterization of a putative retroviral env-related human protein.

In this study, we developed a rabbit polyclonal antibody to a fusion protein containing the envelope (env) transmembrane (TM) region from the human endogenous retroviral family, HERV-E. We used this reagent to document the expression of TM-related protein by Western blot in endothelial, colon and prostate carcinoma and seminoma cell lines and in peripheral blood mononuclear cells from a healthy donor. We detected a 58-kD protein (as compared to murine TM of 15 kD) that had specificity for the env-related antibodies of the polyclonal antiserum.

Laparoscopic splenectomy by the lateral approach: a safe and effective alternative to open splenectomy for hematologic diseases.

BACKGROUND: The purpose of this study was to compare the clinical outcomes and expense of laparoscopic splenectomy by the lateral approach with open splenectomy for the treatment of hematologic diseases. METHODS: Medical records of 20 matched patients undergoing open splenectomy and lateral approach laparoscopic splenectomy were retrospectively reviewed detailing perioperative course, clinical outcome, and hospital charges. RESULTS: Patients undergoing laparoscopic splenectomy (n = 10) experienced longer anesthesia (324 versus 176 minutes; p < 0.05) and operative times (261 versus 131 minutes; p < 0.05) than those undergoing open splenectomy (n = 10). No difference was noted in both intraoperative and postoperative packed red blood cells transfused. Laparoscopic splenectomy resulted in a shorter duration of nasogastric decompression (1.2 versus 2.6 days), more rapid resumption of normal oral intake (1.9 versus 4.4 days), and earlier hospital dismissal (3.0 versus 5.8 days). Although hospital charges were not significantly higher in the laparoscopic group ($17,071.00 versus $13,196.00; p > 0.05), operative charges were always significantly higher. CONCLUSIONS: When compared with open splenectomy, lateral approach laparoscopic splenectomy allows a more rapid return of normal gastrointestinal function and shorter hospital stay. The operative expense of laparoscopic splenectomy is significantly higher; however, the overall hospital expense is not. If costs can be decreased, the lateral approach laparoscopic splenectomy will be the preferred operative approach.

Expression of a putative immunosuppressive protein in human tumors and tissues.

Tumor-induced immunosuppression by murine retrovirus-induced tumors and nonviral murine and human tumors has been shown to be mediated by the transmembrane (TM) envelope (env) protein p15E. This in vitro activity is inhibitable by anti-(murine)p15E antibodies, implying that a TM-like protein is produced by such tumors. The leading candidate genes that might encode such proteins in human tumors are human endogenous retroviral (HERV) sequences. We have utilized immunohistochemistry to determine what tissues may express HERV env proteins. We subcloned a restriction fragment from the putative TM human env gene of a type C-related HERV (clone-4-1) into a fusion protein gene construct. Using a rabbit polyclonal antiserum against the fusion protein, we observed staining in a variety of human tumor and nontumor tissues.

Esophageal heterotopic pancreas presenting as an inflammatory mass.

A 47-year-old female presented with complaints of epigastric pain, poor appetite, and dysphagia. Abdominal CT and esophagogastroduodenoscopy revealed a 9-cm mass extrinsic to the distal esophagus. Esophagogastrectomy was performed. The distal esophagus contained multiple foci of heterotopic pancreatic tissue. There was associated inflammation and fat necrosis in the surrounding periesophageal soft tissue. Heterotopic pancreas is uncommon in the esophagus, with only a few reports appearing in the English literature. The clinical features of heterotopic pancreas, and the pathophysiology of the associated inflammatory lesion is discussed.

A Monte Carlo simulation model for radiation dose to metastatic skeletal tumor from rhenium-186(Sn)-HEDP.

UNLABELLED: A Monte Carlo model has been developed for simulation of dose delivery to skeletal metastases by the bone surface-seeking radiopharmaceutical 186Re (Sn)-HEDP. METHODS: The model simulates: (1) the heterogeneous small scale geometry of the soft tissue/bone-spicule structure in the lesions as determined by histomorphometric measurements of histologic specimens, (2) the small scale spatial distribution of the radiopharmaceutical on the lesion bone spicule surface as determined by autoradiography, and (3) the 186Re beta and conversion electron decay spectrum and the associated charged particle transport within the modeled geometries. The results are compared with the commonly employed uniform lesion model, which assumes: (1) homogeneous lesion morphology, (2) uniform distribution of radioactivity within the lesion, and (3) complete energy deposition by charged particles within the lesion due to decay of this activity. Gamma and x-ray photons from the 186Re spectrum were assumed to escape from the lesion volume in both models. RESULTS: Results show a significant dependence on the bone volume fraction and hence on the histology of the lesion (lytic, blastic or mixed). The uniform lesion model calculations underestimate the radiation dose to blastic lesions by as much as a factor of 1.8. However, for lytic lesions with low bone volume fractions, both models provide similar dose values. CONCLUSIONS: These new model calculations provide a mechanism for optimizing treatment planning and dose response evaluations of therapeutic bone-seeking radiopharmaceuticals.

Comparison of postoperative wound complications and early cancer recurrence between patients undergoing mastectomy with or without immediate breast reconstruction.

The incidence of postoperative wound complications and early cancer recurrence was studied in 289 patients who had mastectomy alone and in 113 patients who underwent immediate reconstruction following mastectomy. Patients undergoing immediate reconstruction were younger and had less advanced disease than patients who had mastectomy alone. The postoperative hospital stay was 3.8 days and 4.4 days (p < 0.05) in patients with and without reconstruction, respectively. The overall incidence of postoperative complications was similar in the two groups of patients: 31% and 28% in patients with and without reconstruction, respectively. The incidence of postoperative seroma was higher among patients with mastectomy alone (19% versus 3%, p < 0.05), whereas the incidence of other wound complications was similar in the two groups of patients. Prosthesis-specific complications occurred in 17%. Eight prostheses were removed because of complications. During the relatively short follow-up period (approximately 20 months), local recurrence was noted in 16 patients (6%) who had mastectomy alone and in 1 patient (1%) who had immediate reconstruction after mastectomy (p < 0.05). There was no significant difference in the incidence of distant metastases between the two groups of patients. The results suggest that immediate breast reconstruction can be performed following mastectomy for cancer without increased risk for overall postoperative complications, prolonged hospital stay, or local recurrence. However, patients who choose to have immediate reconstruction need to be informed about risks for specific complications associated with the procedure, especially if an implant is used.

Cell cycle parameters and DNA ploidy in colorectal carcinomas.

Seven patients with colorectal adenocarcinoma and one with squamous cell carcinoma of anorectal region were infused preoperatively with iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU) in sequence (100 mg/m2 x 1 hr each with 1-hr interval in between) to label S-phase cells. The tumor biopsy specimens were embedded in glycol-methacrylate and 2-microns thick sections were treated with two monoclonal antibodies which permitted the identification of cells which incorporated IUdR only, BrdU only, both IUdR and BrdU, or neither IUdR or BrdU. The labeling index of tumors varied from 17.3 to 35.6% (mean = 25.78 +/- 6.162), duration of S-phase ranged from 14.0 to 23.9 hr (mean = 18.73 +/- 3.712), and total cell cycle time ranged from 39.4 to 123.4 hr (mean = 76.78 +/- 24.165). The architecture of the tumor was well preserved and a variable number of DNA synthesizing mononuclear cells were identified within and around the tumor. Image analysis of Feulgen-stained smears of the tumors was done to measure the DNA content of seven tumor samples. Each tumor was found to be hyperdiploid with multiple modal values. The studies described here demonstrate the feasibility of performing cell cycle kinetic measurements on gastrointestinal tumors which have been labeled in vivo. The ability to perform these measurements on tumor biopsies allows the avoidance of artifacts introduced when solid tumors are disaggregated in vitro for study.

Simultaneous immunohistochemical detection of IUdR and BrdU infused intravenously to cancer patients.

Cell cycle kinetics of solid tumors in the past have been restricted to an in vitro labeling index (LI) measurement. Two thymidine analogues, bromodeoxyuridine (BrdU) and iododeoxyuridine (IUdR), can be used to label S-phase cells in vivo because they can be detected in situ by use of monoclonal antibodies (MAb) against BrdU (Br-3) or IUdR (3D9). Patients with a variety of solid tumors (lymphoma, brain, colon cancers) received sequential intravenous IUdR and BrdU. Tumor tissue removed at the end of infusion was embedded in plastic and treated with MAb Br-3 and 3D9 sequentially, using a modification of a previously described method. Clearly single and double labeled cells were visible, which enabled us to determine the duration of S-phase (Ts) and the total cell cycle time (Tc), in addition to the LI in these tumors. Detailed control experiments using tissue culture cell lines as well as bone marrow cells from leukemic patients are described, including the comparison of this double label technique with our previously described BrdU-tritiated thymidine technique. We conclude that the two methods are comparable and that the IUdR/BrdU method permits rapid and reliable cell cycle measurements in solid tumors.

Radioimmunotherapy of human colon carcinomatosis xenograft with 90Y-ZCE025 monoclonal antibody: toxicity and tumor phenotype studies.

Monoclonal antibody ZCE025 recognizes an epitope of the carcinoembryonic molecule (CEA). We have shown that when linked to 90Y, its localization in the tumor was sufficient to result in a significant tumoricidal effect in human colon carcinomatosis grown in the peritoneum of athymic mice. Intraperitoneal tumors were present 7 days after inoculation of the CEA-producing human colon carcinoma cell line LS174T, when the mice received i.p. injections with 40 to 160 microCi of 90Y-labeled ZCE025 or 96.5c (nonspecific monoclonal antibody). The animals that were autopsied 12 days after treatment displayed a significant (P less than 0.001) inhibition of tumor growth when compared to the control animals that received no treatment or similar doses of nonspecific monoclonal antibody. Microscopically, the treated tumors showed extensive radiation effect and they became progressively necrotic until only a rim of viable tissue remained in the periphery of the nodules. CEA expression was practically absent on the newly grown nodules that began to appear 3 weeks after therapy, and remained so 6 weeks thereafter. In contrast, over 80% of the tumor cells from the untreated animals expressed CEA. There was no mortality due to treatment; however, the hematopoietic organs were markedly depleted at the higher doses. The marrow and the spleen recovery began 2 weeks after treatment, and it was completed by the 4th week. No evidence of toxicity was present in any of the other organs examined. These studies suggest that 90Y-ZCE025 therapy results in clonal selection of cells lacking or minimally expressing CEA. The inherent implications of these findings are discussed.

Evaluation of a short-stay program for patients undergoing mastectomy.

Two hundred twenty-eight patients were included in a retrospective study to evaluate the morbidity and feasibility of early discharge after mastectomy. Group I (early discharge, n = 75) patients were given pre- and postoperative instruction related to wound and drain care. Group II (concurrent control, n = 44) was given similar postoperative instruction, but received no preoperative teaching. Group III (historical controls, n = 109) underwent surgery during a period of more liberal hospitalization and discharge policies. The groups were similar in age, cultural background, operations performed, and pathologic diagnosis. Length of stay for groups I, II, and III was 5.5 +/- 0.4, 3.5 +/- 0.2, and 8.6 +/- 0.3 days, respectively. Groups I and II had a significantly shorter stay than group III. There was no difference among the groups for the presence of wound erythema, rate of primary healing, seroma formation, or wound infection. The practice of same-day admission and early discharge to limit length of stay for patients undergoing mastectomy is safe and effective.

Effect of yttrium-90-labeled anti-carcinoembryonic antigen monoclonal antibody on the morphology and phenotype of human tumors grown as peritoneal carcinomatosis in athymic mice.

Grossly visible peritoneal carcinomatosis resembling that seen in man was produced in athymic mice 7 days after intraperitoneal injection of 8 x 10(5) cells of the carcinoembryonic antigen (CEA)-producing human colon carcinoma cell line LS174T. The mice received intraperitoneal injections of 40 to 160 microCi of yttrium-90 (90Y)-labeled anti-CEA monoclonal antibody (MAb). When the mice were killed 12 days after injection, a significant inhibition of tumor growth, ranging from 40% to 95%, was observed in the treated animals when compared to the growth of tumors in the untreated animals (P less than 0.001). No mortality secondary to the therapy was seen. The bone marrow was depleted significantly at the higher doses of labeled MAb, but total recovery was observed 4 weeks after treatment. Histologically, the treated tumors showed extensive radiation effects early in the posttherapy period and massive necrosis at later times. Minute foci of viable tumor remained in the periphery. New tumor outgrowths with histologic features similar to those in the untreated controls began to appear 3 weeks after therapy. The CEA expression of the treated tumors was similar to that of the untreated controls during the early posttreatment period, diminishing progressively as the tumors became necrotic. Newly grown tumor nodules in the treated animals lacked significant CEA expression both initially and at later times. Our studies suggest that therapy with 90Y-anti-CEA MAb therapy results in selection of tumor clones lacking CEA, and that a single large dose of 90Y-MAb should be more effective than multiple fractions of smaller doses.