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Summary Objectives There is debate about the optimal clinical target volume (CTV) expansion and prophylactic nodal dose (PND) in head and neck IMRT. We evaluated our patterns-of-failure (POF) after helical tomotherapy-based concurrent chemoradiotherapy (CCRT) to assess the oncologic safety of reducing the CTV, PND, and bilateral parotid sparing (BPS). Materials and Methods All patients with locally advanced squamous cell carcinoma of the head and neck treated with curative intent CCRT between January 2007 and April 2013 at a single institution were included in this retrospective study. Locoregional recurrences (LRR) were overlaid on the treatment plan, and POF was determined relative to planned dose. Results One hundred and fourteen patients treated with CCRT were evaluated, 74% of whom underwent BPS. The median follow-up for surviving patients was 29.3 months. The 3-year cumulative incidence of locoregional failure, distant metastasis, progression-free and overall survival were 20%, 20%, 56% and 73% respectively. The local failures ( n = 12) were either entirely contained within or centered on the original gross tumor volume (GTV), and all but 2 regional recurrences were in GTV. There were no nodal failures in the low-dose or peri-parotid neck (including ipsilateral neck). Discussion Nearly all LRR were located within the GTV suggesting that minimal-to-zero margin is required for CTV 70. The nodal recurrence pattern suggests the safety of routine bilateral parotid sparing and relatively low biologically equivalent dose (54 Gy in 33fx) to the low-risk neck.

Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-alpha and TGF-beta in 41/46 and 40/46 cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-alpha and the incidence of PCD (p= 0.0015). Patients who showed high PCD also had an elevated TNF-alpha level. Thus, the expression of high amounts of TNF-alpha and TGF-beta and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-alpha drugs such as pentoxifylline.

The spectrum of clinical manifestations of multiple myeloma is usually related to the severity of osteolytic lesions and bone marrow invasion by the tumor. While extramedullary involvement is not an uncommon manifestation of multiple myeloma, it usually remains asymptomatic. The most frequent site of ext ramedullary myeloma is the reticuloendothelial system. The pancreas is only rarely involved by multiple myeloma and the diagnosis is often made postmortem. When symptoms do arise from myeloma of the pancreas, jaundice is the most frequent symptom. We report a patient with multiple myeloma that involved the head of the pancreas leading to bile duct obstruction and jaundice. The diagnosis was established by fine-needle aspiration under CT guidance. The biliary tract obstruction was t reated by placing an endoprosthesis during ERCP.

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

55 Background: The reported increased prostate cancer lethality in Af Ams has been attributed by some to altered androgen receptor (AR) signaling. We compared toxicity, PSA response, time-to-PSA progression (TTPP), and radiographic progression-free survival (rPFS) in Af Am vs non Af Am pts with CRPC treated with AA + prednisone (P) vs placebo + P. We hypothesized that differences in response to AA may be observed if differences in AR signaling exist in Af Ams. Methods: COU-AA-301 is a randomized double blind study of AA (1000 mg + P 5 mg po BID) vs placebo + P post-docetaxel. Results: TTPP, rPFS, and PSA response rate were higher with AA vs placebo. In Af Am pts, treatment emergent AEs (TEAEs) for AA vs placebo occurred in 96.4% vs 100.0% of pts (50.0% and 66.7%, respectively, grade 3/4); serious TEAEs occurred in 42.9% and 33.3% of pts (28.6% and 26.7%, respectively, grade 3/4). The safety profile of AA appears comparable between the Af Am and overall study populations. Conclusions: Although the small number of Af Am pts in this study precludes formal conclusions regarding efficacy and safety of AA in this pt population, the overall trend suggests these pts experienced clinical benefit from AA with a safety profile comparable to the overall study population. These findings do not appear to support the hypothesis that AR signaling accounts for the increased lethality of prostate cancer seen in Af Ams. Further studies of AA in Af Am pts are planned to understand the potential benefit in this population. Additional efforts are needed to increase participation of Af Am pts in clinical trials. [Table: see text]

PURPOSE To compare two published schedules of cisplatin plus fluorouracil (5-FU) infusion and radiation as either sequential or concomitant treatment for toxicity and efficacy in patients with unresectable head and neck cancer. PATIENTS AND METHODS This was a randomized trial between cisplatin 100 mg/m2 over 15 minutes on day 1 plus 5-FU 1.0 g/m2 by continuous infusion on days 1 to 5, repeated every 3 weeks for three cycles, followed by 70 Gy of radiation in 7 to 8 weeks, versus cisplatin 60 mg/m2 over 15 minutes on day 1 plus 5-FU 800 mg/m2 by continuous infusion on days 1 to 5 plus radiation 2 Gy on days 1 to 5, repeated every other week for seven cycles. Unresectable head and neck squamous cancer patients not previously treated with radiation or chemotherapy and with a performance status of 0 to 2 were stratified by tumor (T) and node (N) groupings and performance status and randomized. RESULTS Two hundred fifteen patients were entered and 214 analyzed, 107 on each arm. After all treatment, overall response rates were different (P = .003), with similar complete response rates, but more partial responses and fewer patients with no change or progression with concomitant treatment. Cox regression analysis for progression-free survival identified concomitant treatment (P = .003), Radiation Therapy Oncology Group (RTOG) stage III grouping (P < .0001), performance status (P = .0002), concomitant treatment (P = .003), and treating institution (P = .006) as significant. The sequential and concomitant treatments showed similar distant failure patterns (10% and 7%, respectively), but divergent regional failure rates (55% and 39%). Severe and worse toxic events were similar between the treatment programs, but radiation-induced mucositis combined with cisplatin-induced water-losing nephropathy, in the concomitant arm only, demanded more supportive care. Survival duration was similar between the treatment arms, but significantly more patients in the sequential arm died of their cancer (P = .011). CONCLUSION Concomitant treatment offered improved disease control, predominantly of regional disease, but benefit was dependent on the experience of the treating institution. Translation of this benefit into improved survival is not yet evident, with an excess of deaths from other causes in the concomitant arm.

To assess the ability of simultaneous cisplatin, 5-Fluorouracil, and radiation to substitute for surgery and radiation in advanced head and neck cancer, we have retrospectively selected from our phase II study a subgroup of 29 patients having primary disease requiring either more than a hemiglossec-tomy or a laryngectomy for control. Patients included 22 with stage IV and 7 with stage III disease, 12 tongue, 10 hypopharynx, and 7 larynx primaries. The treatment consisted of concurrent cisplatin, 5-Fluo-rouracil, and split-course radiation every other week for a total of 7 cycles within 13 weeks. With a median follow-up of 5 years, 86% of patients had preservation of speech and/or swallowing function. Median survival was 45 months, with 14 (48%) patients currently alive and disease free, 11 (38%) dead from their cancer, and 4 (14%) dead of other causes. The overall failure rate was 38%. Advanced-stage presence of N3 nodal disease and fewer than 7 cycles of chemotherapy received were significantly associated with increasing failure rates. This program of concomitant cisplatin, 5-Fluorouracil, and radiation produced control rates quite competitive with surgery and radiation and is appropriate for definitive testing in a randomized trial.

Patients with relapsed/refractory aggressive lymphoma have limited options for achieving long-term remission other than stem cell transplantation. ESHAP is active in aggressive NHL and has the added advantage of being a non-anthracycline regimen. However, the response rate and remission duration with ESHAP chemotherapy alone are low in this group of patients. Encouraged by the increased efficacy of chemo-immunotherapy combinations like CHOP + Rituximab (Rituxan) in untreated aggressive lymphoma, and the in vitro synergy of Rituximab with cisplatin, cyclophosphamide and steroids, we studied the safety and efficacy of ESHAP + Rituximab combination in this group of patients. Standard ESHAP regimen (Etoposide 40 mg/m2/d IV/2h day1–4; Methylprednisolone 500 mg/m2 IV days 1–4; Cytarabine 2 g/m2 IV/3h day 5 and Cisplatin 25 mg/m2/d CIV days 1–4) was administered. Rituximab 375 mg/m2 IV was administered in the following manner: 2 doses separated by one week prior to the first cycle of ESHAP and 2 doses administered similarly after completion of the sixth cycle of ESHAP; one dose of Rituximab each was also given 48 hours prior to the third and fifth cycle of ESHAP. Treatment cycles were repeated every 28 days x 6. GMCSF (Leukine) and Erythropoietin (Procrit) were used at the discretion of the investigator. 14 patients were enrolled in the study. Median age was 55.5 years (range 37–70); there were 12 males and 2 females. 11/14 (71%) of patients had advanced disease (stage III/IV). Extranodal disease sites included kidney, lungs and adrenals. Histology was Diffuse Large Cell: 13 (93%) and Mantle Cell Lymphoma: 1 (7%). All patients had prior therapy: 1st relapse 11, 2nd relapse 1 and 3rd relapse 2. Prior therapies included CHOP, modified CHOP, Fludarabine-based regimen, Rituxan and Bexxar. 7 patients (50%) achieved CR, 2 PR, 1 stable disease and 4 PD. Among the 6 patients who received all 6 cycles of therapy, 4/6 (67%) achieved CR and 2/6 (33%) PR, (ORR 100%). Duration of response in patients who received all 6 cycles: All Responders: 26.3 months (1–53.3) and Patients who achieved CR: 35 months (24.1–53.3). Significant toxicity included grade III/IV hematologic in 43% and grade III/IV infection/febrile neutropenia in 21%. Conclusion: ESHAP combined with Rituximab appears to be more active than ESHAP alone with no additional toxicity other than infusion-related adverse events in patients with relapsed/refractory aggressive lymphoma. Patients who achieved CR with this regimen appear to have longer remissions. Prospective, controlled trials are warranted.

The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.

• We evaluated postoperative complications in a randomized series of patients with head and neck cancer who received preoperative chemotherapy. Forty-two patients with advanced squamous carcinoma of the head and neck were randomized to receive either high-dose metho-trexate with leucovorin calcium rescue (23 patients) or no chemotherapy (19 patients) prior to definitive conventional treatment. The two groups of patients were balanced by sex, disease site, stage, histologic grade, and prior therapy. Sixteen of the 23 patients receiving preoperative chemotherapy had postoperative complications, whereas only eight of 19 patients not receiving chemotherapy had postoperative complications. Surgical complications included wound infections, orocutaneous fistulas, and flap necrosis. ( Arch Otolaryngol Head Neck Surg 1986;112:437-439)

Forty-four patients with predominantly inoperable or recurrent head and neck cancers were treated with combined chemotherapy (CT) and radiation therapy (RT) in a Phase I/II study. CT and RT were combined in a concomitant fashion to take advantage of radiosensitizing properties of the chemotherapeutic agents. Each treatment cycle consisted of cisplatin 60 mg/M2 on day 1, 5-FU infusion at a dose of 800 mg/M2 per day continuously for 5 days and RT at 200 cGy per day, days 1 through 5. The treatment cycle was repeated every 2 weeks for 7 cycles in patients treated curatively and for 2 to 6 cycles in patients treated palliatively due to prior radiation therapy or the presence of metastatic disease. Regional control was achieved in 98% of the patients. Regional control has persisted in 87% of the patients treated curatively with a minimum follow-up of 24 months. Distant failure occurred in 23% of this group. Actuarial survival of 2 years for the curative group is 66%. Concomitant combination of radiation with radiation potentiating chemotherapeutic agents shows promise of increase in local control.

Fifty-three patients with stage III (eight patients, 15%), stage IV (36 patients, 68%), or recurrent disease (nine patients, 17%) entered a study of simultaneous cisplatin, 60 mg/m2 day 1, fluorouracil (5-FU) infusion, 800 mg/m2 days 1 to 5, and radiation, 2 Gy days 1 to 5, every other week for a total of seven cycles (70 Gy in 13 weeks). Patient acceptance was high, with only two patients (4%) refusing to complete therapy. The median actual dose delivered was 88% of the planned dose for cisplatin, 78% for 5-FU, and 70 Gy for radiation. Weight loss of 10% or more and severe mucositis were the most common side effects (53% and 48% incidence, respectively). All patients were followed at least 1 year (median, 51 months). While the complete response rate (55%) seemed no better than that reported in other series, freedom of progression of regional disease (73%), and the survival of all patients (median, 37 months) were substantially improved. Only 33% of partial responders have failed regionally, while 15% of complete responders have failed regionally (P greater than .10), which indicates that clinical assessment of response was unreliable. Stage, the presence of N3 disease, and delivery of less than the median actual dose received of 5-FU (but not cisplatin) were significantly associated with failure. This regimen is feasible and tolerable in this difficult patient population. It generally requires no special forced feeding techniques. Survival results from this limited institution study appear better than those using sequential multimodality therapies. With such favorable regional control, this approach may offer an alternative in the future to radical surgery and radiation in resectable disease. More definitive evaluation seems warranted.

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

Forty-seven patients with recurrent or metastatic head and neck squamous cancer were entered into a prospectively controlled study comparing high-dose infusion methotrexate with leucovorin against standard-dose methotrexate without leucovorin. Patients were stratified for prior treatment and hematogenous metastases prior to randomization. Patients received either methotrexate (1,500 mg/m2) infused over 24 hours with leucovorin or 40 mg/m2 intramuscularly. Each treatment was given weekly for the first six weeks and followed a dose escalation schedule to toxicity. After six weeks patients received the high-dose regimen every two weeks and the low-dose schedule continued weekly. One patient was ineligible and four had inadequate follow-up to assess response (less than two weeks). Forty-two patients were evaluable for survival and 37 for response. Six of 19 patients (32%) treated with high-dose infusion responded (one complete response) and four of 18 patients (22%) receiving standard dosage responded (P = .52). Treatment with high-dose methotrexate resulted in an improved duration of disease control over standard dosage with the respective median times to progression of 11 weeks and five weeks (P = .04). These differences were most marked in good performance status patients (P = .007) and those without hematogenous dissemination (P = .02). Toxicity, however, was also significantly worse in the high-dose treatment group (P = .01) and survival was identical between treatments (4.2 months). The authors conclude that any treatment advantage to high-dose methotrexate may be attributable to its greater toxicity rather than to a selective therapeutic effect and this regimen does not result in improved patient survival. Good performance status patients may benefit from more aggressive therapy.