Neelam K. Patel, PharmD, BCOP

• Clinical Pharmacy Specialist—Breast Medical Oncology, Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas

Publication of the more recent Italian study of epirubicin and ifosfamide as adjuvant therapy for extremity sarcomas may clarify this situation further treatment 101 oxytrol 5mg generic. With clear definition of a population at high risk for metastatic disease medicine 0027 v generic 2.5mg oxytrol fast delivery, identification of relatively sensitive histologic subtypes of sarcoma treatment kitty colds buy oxytrol 5mg low cost, and use of combinations of active agents medicine while breastfeeding order oxytrol 5mg otc, it is hoped that future studies will delineate which clinical situations merit use of adjuvant chemotherapy medicine emblem buy oxytrol 5 mg online. Preoperative neoadjuvant chemotherapy can make subsequent surgery easier and potentially treats micrometastatic disease earlier before acquisition of resistance medicine man 1992 order 2.5 mg oxytrol. Treating with chemotherapy before surgery also leaves primary vasculature intact for drug delivery medications via endotracheal tube purchase oxytrol 2.5mg on line. In addition treatment 7th march cheap oxytrol 5 mg amex, preoperative chemotherapy can guide postoperative treatment based on pathologic review of the tissue after chemotherapy. In experimental models, preoperative chemotherapy eliminates a postoperative surge in growth of metastases noted after resection of primary tumors. Partial or complete responses were noted in over one-third of patients; not surprisingly, those patients who had a complete response by any means had a better overall survival than those who did not respond completely. Anderson Cancer Center examined preoperative chemotherapy using cyclophosphamide, doxorubicin, and dacarbazine. Only 1 of 29 patients demonstrated a clinical partial response, although liquefaction, cystic necrosis, and hemorrhage into the tumor were noted regularly in the resected specimen, with three tumors showing greater than 90% necrosis. Most patients did not elect to receive postoperative chemotherapy after surgery, and survival results from this study did not differ significantly from studies of adjuvant doxorubicin or of no chemotherapy. Assessing the response to preoperative chemotherapy in primary soft tissue sarcomas is difficult. In sum, preoperative chemotherapy is given to some patients with potentially sensitive sarcoma subtypes such as synovial sarcoma or other high-grade lesions. Nonetheless, preoperative chemotherapy may be considered during an attempt to maintain function of an extremity, with the possibility that more aggressive surgery could be performed later if needed. Selected patients have had responses that allow for a more conservative resection, avoid an amputation, or both. This infusional approach is to be differentiated from local limb perfusion, discussed later in the section Hyperthermia and Limb Perfusion. Intraarterial chemotherapy has the potential benefit of providing higher doses of chemotherapy to the limb in a first-pass effect. However, pharmacokinetic data have not shown an advantage over intravenous chemotherapy. Thereafter, a randomized trial by the same group examined preoperative intravenous versus intraarterial chemotherapy before radiation (28 Gy given over 8 days) followed by wide excision. There was no difference in local recurrence or survival between the 45 patients receiving intraarterial doxorubicin and the 54 patients receiving intravenous doxorubicin. Infusional chemotherapy has its attendant complications as well, including arterial thromboembolism, infection, gangrene, and problems with wound healing, itself requiring amputation. Pathologic fractures have been reported in patients receiving chemotherapy and relatively large doses of radiation. One study 283 reported ten major complications in 13 patients treated intraarterial chemotherapy with simultaneous radiation, emphasizing the investigational nature of this approach. Although there are situations in which such therapy should be considered, intraarterial chemotherapy at present has a limited role in the treatment of extremity sarcomas. The arterial and venous supply of the limb is connected to an extracorporeal circulation system to isolate the limb from the rest of the body. Recirculation of the blood from the limb is performed by a heart-lung machine to reoxygenate the blood. Care is taken after isolation of the limb to ensure no leakage of the circuit into the systemic circulation; technetium-labeled albumin is injected into the circuit and a probe is used over the heart to ensure isolation of the bypass circuit. Since mild hyperthermia may make chemotherapy more effective in some clinical settings (as mentioned in this section), the blood of the circuit is often warmed to 39° to 40°C. A number of chemotherapeutic agents have been used for limb perfusion, such as melphalan, nitrogen mustard, actinomycin D, and doxorubicin. Surgery to remove residual tumor was performed 2 to 4 months after limb perfusion. It is difficult to compare this approach with standard chemotherapy, given the heterogeneity of patients between the two types of studies. In aggregate, the response rate does appear higher in the perfusion studies than in the infusion studies. However, isolated limb perfusion requires substantial expertise and specialized dedicated equipment. Isolated limb perfusion does appear to hold promise for at least a subset of patients who would otherwise require amputation for local control and has been approved for such patients in Europe. Studies are underway to examine the utility of regional limb infusion, which would not require bypass machines, as a simplified means of treating otherwise unresectable extremity sarcomas. Hyperthermia has been used in other ways to enhance the effects of chemotherapy in patients with locally advanced disease. Whole body hyperthermia using extracorporeal heating of blood has been combined with ifosfamide and carboplatin intravenous chemotherapy, and responses have been seen in patients with otherwise refractory small cell sarcomas. The hyperthermia used in these protocols is more aggressive than that used with limb perfusion; higher temperatures have led to a higher rate of local complications. Isolated limb perfusion has not been compared directly with simultaneous hyperthermia and chemotherapy. In sum, isolated limb perfusion and hyperthermia-enhanced chemotherapy represent novel ways of attempting to preserve function of limbs in what otherwise would be situations in which amputation would be necessary. On occasion pain is present and, less commonly, gastrointestinal bleeding, incomplete obstruction, or neurologic symptoms relating to retroperitoneal invasion or pressure on neurovascular structures are present. In one report, 289 neurologic symptoms related primarily to an expanding retroperitoneal mass were identified in 27% of patients. Important issues of differential diagnosis, particularly in the young, are the presence of a germ cell tumor or a primary retroperitoneal tumor arising from the adrenal. Most of such lesions, however, are tumors of mesenchymal origin, either benign or malignant. For retroperitoneal lesions, the incidence of metastatic disease to the liver is possible but still low. Of the histopathologic types, leiomyosarcoma and liposarcoma predominate (see. Most retroperitoneal tumors are high-grade lesions because of the predominance of leiomyosarcoma in the visceral lesions. The retroperitoneal liposarcoma is often predominantly low grade and overall the more common tumor. Nevertheless, with increasing frequency we note the mixed cellularity and grade of some retroperitoneal sarcomas. Preoperative bowel preparation is important, not because of tumor invasion, but often because of the technical difficulty of resection without encompassing the intestine. Because many tumors involve the retroperitoneum, evaluation of renal function, particularly the establishment of contralateral adequate renal function, is important, to allow nephrectomy where appropriate. Although resection of adjacent organs is common289 proof that a more extensive resection of adjacent organs has an effect on long-term survival seems limited. It is clear that complete surgical resection is the primary factor in outcome (. Once complete resection is accounted for, the predominant factor in outcome is the grade of the lesion. Survival following resection of primary retroperitoneal sarcoma according to resection status in 155 patients aged 16 years or older admitted to Memorial Sloan-Kettering Cancer Center between July 1982 and July 1999 (P <. Thoracoabdominal incisions, rectus-dividing incisions, incisions extending through the inguinal ligament into the thigh, the availability of venovenous bypass, adequate and appropriate anesthetic, and blood replacement therapy are all important issues for many of these large lesions. Resectability rates vary widely, but seem independent of histologic type, grade, or size. Complete resection is usually possible in 60% to 70% of patients presenting with a second or subsequent recurrence. In our reviews, 289,290 although nephrectomy was commonly performed (in 46% of cases), the kidney itself was rarely involved. In the report by Jaques and coworkers289 only 2 of 30 nephrectomies showed true parenchymal invasion. Nevertheless, the encompassment of the kidney and the involvement of the hilar renal vasculature all make the resection of the kidney on occasions technically necessary. The overriding principle is not to be reticent about resection of adjacent organs should they be involved by tumor. Conversely, one should not resect uninvolved organs if they are not the limiting factor in the margins. For example, the resection of a kidney, when the vena cava is the closest margin, makes little oncologic sense. Overall, the use of debulking for recurrent lesions is rarely of significant value in terms of long-term survival. It is often difficult to decide how much can be palliated by incomplete removal of tumor. The concept, however, should be that unless palliation can be achieved, operation should be reserved for those patients for whom complete resection is at least possible, if not probable. The basis for unresectability is usually the presence of peritoneal implants or extensive vascular involvement. Most of these tumors are large, making it difficult to obtain adequate margins of resection. Compounding the problem, the presence of normal organ such as small bowel, large bowel, kidney, and liver make delivery of therapeutic doses of radiation therapy either difficult or impossible. One-half of the patients presented with liposarcoma, whereas 29% had leiomyosarcoma. Sixty-five percent of primary sarcomas underwent a complete resection, whereas approximately one-half the patients with recurrent retroperitoneal sarcomas could have a complete resection. Despite complete resection, local recurrence developed in approximately 40% to 50% of cases. Importantly, local recurrence is a problem for both high-grade and low-grade lesions: the local recurrence rate is similar, but the time to recurrence differs significantly. The median time for recurrence was 15 months for high-grade and 42 months for low-grade sarcomas. Fifty-three percent of patients required adjacent organ resection, and 40% of patients required more than one adjacent organ resection, in order to accomplish complete removal of disease. Adjuvant external-beam irradiation is limited because of the low tolerance of surrounding normal organs. However, there are data to suggest some improvement in local control with moderate doses of external-beam irradiation. Radiation dose appeared to influence tumor control, with only 30% of patients locally controlled at doses less than 5000 cGy and 83% of patients controlled with doses greater than 6000 cGy. Obviously, the total dose of radiation that is possible varies with the size and location of that lesion. With a median follow-up of 3 years, the 5-year local control and survival rates were 58% and 50%, respectively. The rate of peripheral neuropathy was 6% and the rate of gastrointestinal toxicity was 19%. They represent approximately 1% of all head and neck malignancies and 10% of all soft tissue sarcomas. Any histologic type of soft tissue sarcoma could originate in the head and neck area, but there is preponderance of angiosarcoma in this site. Multimodality approach is the cornerstone for most soft tissue sarcomas of the head and neck. Surgery is the main treatment for these tumors, and every attempt should be made to obtain at least gross total resection, otherwise the results are usually poor. However, unlike extremity sarcomas, head and neck sarcomas are not amenable to wide local excision with generous margin of normal tissue due to anatomic constraints. Therefore, the use of adjuvant radiation is more liberal in this site because local recurrence could be the cause of death in a substantial proportion of patients. The only independent prognostic factor for survival was surgery other than biopsy (P =. For local control the combined use of surgery and radiation as opposed to single modality was also an independent prognostic factor (P =. On multivariate analysis survival correlated with low grade, recurrent presentation, and lack of direct extension (P =. There was also a 15-fold increased risk of dying for patients whose tumor had recurred locoregionally, compared with controlled sarcomas (P =. On multivariate analysis the independent predictors of improved survival were age less than 55 (P =. In addition, they display a higher incidence of regional lymph node metastasis than other sarcomas with a reported rate of 10% to 15%. The 5-year overall and distant metastasis-free survival rates were 29% and 37%, respectively. The 5-year above clavicle local control rates were 24% for definitive radiation compared with 40% with adjuvant radiation (P =. They usually present as a painless mass with no distinctive findings on mammography. The main treatment is surgery and the extent of resection is debatable, but most authors believe that wide excision with generous negative margin is adequate. The 5-year overall survival rate was 61%, which did not vary significantly between those treated with wide excision compared with those who underwent mastectomy (P =. Five patients received adjuvant radiation and none of them developed local recurrence. Early studies defined the effects of doxorubicin and x-ray treatment on wound healing in animal models. They suggested that radiation or antineoplastic drugs delivered more than 7 days on either side of the wound were accompanied by minimal inhibition of wound healing. Conversely, the application of radiation or chemotherapy just before, or in close juxtaposition to , the time of wounding, resulted in significant impairment of wound healing as demonstrated by wound-breaking strength. This appeared to be due to inhibition of newly synthesized collagen as determined by hydroxyproline assays. A comprehensive review of the effect of chemotherapeutic agents on wound healing 310 emphasized the importance of the agents used and the timing of delivery. The other covariable that contributed to wound reoperation was the width of the excised skin. If the width was greater than 4 cm the rate was 10%, but if the width was less than or equal to 4 cm the rate was 1% (P =. Wound complications were defined as secondary wound surgery, hospital admission for wound care, and deep packing or prolonged dressings within 120 days following tumor resection. The investigators found that preoperative radiation had a significantly higher rate of wound complications (35% vs. Prognostic factors for local recurrence, metastasis, disease-specific survival, and overall survival may all be fine gradations of differing factors, all of which provide considerably different information. An analysis of long-term follow-up for over 1000 patients with localized soft tissue sarcoma of the extremity has been provided from our group. Factors that increased the risk of local recurrence were age greater than 50 years, recurrent disease at the time of presentation, positive histologic primary margins, histologic subtypes of fibrosarcoma (including desmoid), and malignant peripheral nerve tumors (Table 39. Relative Risk Influence on Recurrence of Localized Extremity Soft Tissue Sarcoma a Factors that increased distant recurrence rates were tumor size greater than 5 cm, high histologic grade, deep location, recurrent disease at the time of presentation, and histologic subtype leiomyosarcoma. Histology of liposarcoma was favorable for decreased distant recurrence rate when compared with other histologies. For disease-specific mortality, large tumor size, high histologic grade, deep location, recurrent disease at presentation, positive histologic margins at the time of resection of the primary, lower extremity site, and the histologic types of leiomyosarcoma and malignant peripheral nerve tumor were all factors. Postmetastasis survival for most patients is independent of factors involved in the primary presentation, although large tumor size has been associated. The determination of recurrence rates and survival rates can depend on which factor is examined. For example, high-grade lesions have a much greater cumulative hazard rate of developing a distant metastasis in the first 30 months. Low-grade lesions, however, have a continued slow but inexorable progression to a continuing long-term rate of metastasis. This raises the interesting biologic question of whether lack of recognition of the metastatic potential of low-grade sarcomas is caused by inherent sampling error in low-grade lesions, where small foci of potentially metastatic cells are not appreciated. Alternatively, all soft tissue sarcomas may be inherently imbued with metastatic potential. An analysis of patients who were disease-free 5 years after the diagnosis and treatment of extremity lesions showed 9% would go on to have a further recurrence in the next 5 years (. Survival in patients with extremity soft tissue sarcoma who were metastasis-free at 5 years. This issue is obviously of great significance in patients with soft tissue sarcoma of the extremity who are being treated with conservative surgery and adjuvant therapy in order to preserve function and potentially improve the overall quality of life. However, in order to determine the effect of adjuvant therapy it is important to look at other potential contributing factors as well. The effect of adjuvant radiation and some of its parameters on functional outcome have been studied more extensively. But there was a correlation between volume irradiated to greater than or equal to 55 Gy and poorer functional score, strength, fibrosis, and skin changes. Local recurrence, however, remains a significant factor in long-term morbidity and mortality. In cases in which surgical resection can be achieved, then adjuvant radiation therapy should be considered in the vast majority of patients with recurrent disease. In patients undergoing systemic recurrence, again surgical resection should be considered.

The gastrohepatic ligament is divided close to the liver up to the gastroesophageal junction medicine zantac oxytrol 2.5 mg amex. Once near the celiac axis medicine 8 soundcloud buy 5 mg oxytrol mastercard, the lymph node­bearing tissue is dissected until the left gastric artery is visualized and can be divided at its origin medicine cards best oxytrol 5 mg. The proximal peritoneal attachments of the stomach and distal esophagus can then be incised treatment locator buy 5mg oxytrol overnight delivery, and the proximal extent of resection is chosen medicine 968 2.5 mg oxytrol otc. For tumors of the mid- and proximal stomach symptoms hyperthyroidism purchase oxytrol 5 mg amex, dissection of the lymph nodes along the splenic artery and splenic hilum is important symptoms 0f brain tumor buy discount oxytrol 2.5 mg. This technique is not indicated for antral tumors symptoms vaginal cancer safe 2.5mg oxytrol, given the low rate of splenic hilar nodal metastases seen with these tumors. The stomach is then divided 5 cm proximal to the tumor, which dictates the extent of gastric resection. Despite the fact that the entire blood supply of the stomach has been interrupted, a cuff of proximal stomach invariably shows good vascularization from the feeding distal esophageal arcade. When feasible, most surgeons prefer to anastomose jejunum to stomach versus esophagus because of the technical ease and excellent healing. Reconstruction using a variety of techniques has been described and is a matter of personal choice (. Variations in types of reconstruction after total or subtotal gastrectomy include (left to right) the Roux-en-Y, Braun, and Lawrence techniques. Patients with early-stage gastric cancer (Tis; T1N0M0; or shallow penetrating T2N0M0) have a good to excellent prognosis, with cure rates exceeding 70% to 80% after operation alone. After curative surgery, however, patients with locally advanced cancers without nodal metastases (T3N0 gastric cancers) have an at least 50% chance of dying within 5 years; lymph node metastases have an even more ominous prognosis. Although 80% to 90% of American patients fall in the high-risk group, preoperative identification of patients at low risk for recurrence is difficult. Newer preoperative staging techniques, such as laparoscopy, have been demonstrated to be highly sensitive and specific in identifying patients with intraabdominal metastatic tumor, particularly in the peritoneal cavity. However, these techniques still have a relatively low sensitivity for separating deeply penetrating T2 from T3 tumors, as well as a low sensitivity for identifying metastatic lymphadenopathy. Therefore, for patients who have more than early-stage gastric cancer (deeply penetrating T2 or T3 tumors and patients with lymph node metastasis), the use of systemic therapy early in the treatment plan is rational in a disease in which a high propensity is seen for systemic failure with or without local recurrence. Neoadjuvant chemotherapy (also known as preoperative or primary chemotherapy) is an attractive concept in diseases such as gastric cancer for which complete resection of the primary tumor is often difficult or impossible, and because systemic dissemination at the time of diagnosis is common. A more traditional approach to adjuvant therapy is the use of postoperative treatment. A third study by the Veterans Administration Surgical Oncology Group using the same agents on a different schedule was also negative. Mitomycin -Containing Regimens A series of trials have involved the use of mitomycin (see Table 33. One Spanish trial investigated the use of high-dose mitomycin C alone after surgical resection. In this study, only 33 patients received chemotherapy; 37 patients were in a control group. A striking difference in survival was noted (seven relapses in the treatment arm, 23 in the control arm; P <. The chemotherapy dose schedule was mitomycin C, 20 mg/m2 once every 6 weeks for four doses. An update continues to show a significant survival advantage for the mitomycin-treated group. No statistical differences in survival were seen at 5 years, although 5-year survival for the chemotherapy patients was somewhat better than for the control group (P =. More recently, Nakajima and colleagues 194 have reported the results of another, larger trial performed in Japan. Five hundred seventy-nine patients with early-stage gastric cancer (T1 or T2 lesions) were stratified and randomized to receive postoperative chemotherapy or observation. Two hundred eighty-eight patients received treatment and 285 were followed expectantly. The authors of this study concluded that this regimen has no survival benefit in patients with serosa-negative, surgically resected gastric cancer. Although the initial report indicated an advantage to the mitomycin-containing arm, at the presentation itself no advantage was reported. Anthracycline-Containing Regimens the uses of several doxorubicin-containing combination chemotherapy adjuvant regimens have been reported (see Table 33. Twenty-six percent of patients in the control arm had N2 disease versus 18% in the treated group, but this difference was not statistically significant. With a median follow-up of 68 months, 56% of patients in the treated arm and 61% of those in the control arm had a recurrence in disease. A number of subgroup analyses were performed, the most positive of which was an effect for patients with T3 or T4 tumors who had positive lymph nodes (P =. Krook and colleagues 198 used a different doxorubicin-containing combination in the adjuvant setting. No differences were noted in overall survival between the two groups (median survival of observation group, 31 months; treatment group, 36 months). Two treatment-related deaths, both related to sepsis during leukopenia, were reported. Response evaluation after chemotherapy was possible in 25 patients: two complete responses, six partial responses. At an average of 36 months of follow-up, 25% of patients receiving adjuvant therapy were alive compared to 13% of those being followed expectantly. Although these results are encouraging, they are at odds with the study by Krook et al. Use of this regimen should still be considered experimental, and it requires a larger confirmatory trial. Cisplatin -Containing Regimens Although cisplatin-containing combinations have undergone extensive studies in patients with advanced metastatic disease, as discussed below (see Palliative Treatment of Gastric Cancer), currently no randomized trials are available in which patients with curative resections of gastric cancer were postoperatively and randomly assigned to receive or not receive a cisplatin-based regimen. In this analysis, the crude odds ratio for death for patients receiving adjuvant therapy was 0. These authors concluded that the survival benefit from these trials in patients undergoing curative resections was small. In these studies, surgery was followed by postoperative chemotherapy or by observation alone. In a later brief report by the same authors, two additional trials were added to this database that indicated a slight benefit to postoperative adjuvant therapy. They were a review of the literature, rather than a pooled analysis of individual patient data. Furthermore, the number of patients involved is relatively small in comparison to the metaanalysis in breast cancer, for example. Gastric cancer overviews to date suggest a modest benefit for older chemotherapeutic regimens. Almost all of these trials are seriously handicapped by their statistical design: With a small number of patients accrued, only very large differences could be expected to show a statistical benefit. Particularly as newer, potentially more effective chemotherapy regimens are developed, a high priority should be placed on designing trials that have adequate numbers of patients who are carefully staged so that the trials have appropriate power to allow an assessment of benefit. Autopsy series and second-look laparotomy series have reported that up to 50% of patients have clinically evident peritoneal carcinomatosis as a site (sometimes the only site) of failure. The pharmacokinetic rationale for intraperitoneal therapy has been well described. Drug concentrations within the peritoneal cavity are severalfold to one to two logs higher than concentrations that can be achieved after oral or intravenous treatment. Clinical support for the use of intraperitoneal chemotherapy also comes from other tumors. In ovarian cancer, a large randomized trial demonstrated a small but statistical and clinically significant survival advantage for women receiving a portion of their therapy intraperitoneally. Thus, as is the case for many abdominal malignancies, a strong rationale exists for maximizing the effectiveness of currently available antineoplastic agents by using intraperitoneal treatment as a portion of the adjuvant therapy. During the 1990s, an increasing number of reports have summarized data on the use of immediate postoperative intraperitoneal therapy for patients with gastric cancer. Interpretation of this data is hampered, however, by the retrospective nature of some of these trials. The technique most commonly used is to administer intraperitoneal treatment (with or without hyperthermia) at the end of resection of all gross disease. Intraperitoneal chemotherapy is delivered in the operating room or recovery room or, at the latest, within several days of resection. In the latter case, this involves placement of an intraperitoneal catheter with therapy started soon after operation and given for repeated courses. The theoretical advantage of immediate intraoperative treatment is better distribution, whereas the theoretical advantage of intraperitoneal therapy via an implanted catheter is the ability to give repeated courses. Both techniques also have been used with established peritoneal carcinomatosis, but it is even harder to draw conclusions regarding this patient population. In a second study, Murthy and coworkers 204 demonstrated in a mouse model that the frequency of tumor formation at sites of surgical trauma in the peritoneum ranged from 28% to 82%, depending on the type of incisions made in the peritoneal cavity, as opposed to a 33% rate of peritoneal tumors in nonoperated mice. Data from several animal models indicate that the risks of peritoneal implantation and intraabdominal tumor spread immediately after laparotomy are high. During the late 1980s and early 1990s, one of the most extensively used intraperitoneal agents in gastric cancer was mitomycin C. As is the case for all intraperitoneal therapy in gastric cancer, however, the small number patients involved hamper interpretation of this data. The initial promising study of Hajiwara and colleagues 308 indicated a marked improvement in survival for patients randomized to intraperitoneal therapy compared to those receiving no postoperative treatment. Mitomycin was adsorbed to a carbon-containing solution and infused immediately after the end of the operative procedure. In this study, 24 patients received treatment with mitomycin and 25 were observed after operation. A highly significant difference in favor of the intraperitoneally treated group was found (2-year survival, 68. Retrospective reviews using higher-dose mitomycin with or without activated charcoal raised concerns regarding toxicity, with some studies indicating a high risk of intraabdominal toxicity leading to an increase in perioperative mortality. To more definitively test the hypothesis that intraperitoneal mitomycin offered benefit, Rosen and colleagues 208 reported their results using a similar technique. Ninety-one patients were randomly assigned to resection followed by observation or resection followed by carbon-adsorbed mitomycin C, 50 mg, given intraperitoneally. The study was stopped prematurely when an interim analysis revealed a marked increase in postoperative complications (25% vs. No survival advantage was noted at the time of the interim analysis, and the trial was closed. Each drug was given daily for 4 days in a row for up to five cycles on a once a month basis. With a median follow-up of 24 months, 51% of patients remained alive and free of disease. An unusual side effect of sclerosing encapsulating peritonitis was noted in 15% of patients. The authors speculated that this resulted in hydrolysis of cisplatin to a reactive alkylating species. In a further update of this trial with a minimum follow-up of 42 months, 40% of patients remain alive and free of disease. As is the case in other mitomycin-containing trials, morbidity and mortality were higher in the experimental arm (postoperative mortality, 5. No statistical difference was noted in overall survival for the investigation arm (38. This study also allowed entrance of patients with documented peritoneal metastasis so that not all those treated were in the adjuvant setting. No difference was reported in survival for patients receiving or not receiving additional treatment. The authors concluded that intraperitoneal cisplatin as a single agent had no significant impact on recurrence. Steady-state concentrations of mitomycin C were approximately tenfold higher in the perfusate compared with serum. With the significant hyperthermia, a mild increase in hepatic transaminases was noted after treatment. In 12 of 31 patients who underwent a second-look operation, four had a complete response and one had a partial response to treatment. Prolonged survival was reported in the subgroup of patients with tumors that penetrated the serosa. In the two perfusion groups, survival was significantly better compared with the group receiving surgery alone. Future studies will probably require intergroup or international trials to accrue adequate numbers of patients in a timely fashion. Ochiai and colleagues 231 compared chemotherapy versus chemoimmunotherapy after resection. The chemotherapy group had 90 patients, and the chemotherapy immunotherapy group had 97 patients. A subgroup of 71 patients did not undergo a curative resection and were analyzed separately. In other trials, Korean investigators have studied the use of chemotherapy plus immunostimulants after potentially curative resection. A second group received chemotherapy alone, whereas the third arm was a control arm of observation after surgery. These authors reported a significant improvement in survival for chemotherapy plus immunotherapy versus chemotherapy alone (62% vs. In summary, data from Japanese and Korean investigators suggest that immunotherapy may improve outcome for patients undergoing potentially curative resection. The number of patients in any given trial is small, however, and the power of the observation therefore relatively weak. Large-scale confirmatory trials are necessary before accepting immunochemotherapy as a standard of care. The study, as is the case with other adjuvant trials, has only a small number of patients (41 in one arm and 46 in the other). In a second trial with a similar design using cimetidine, a similar lack of benefit was noted. Thus, to date, therapy using histamine-2 blockers has not shown benefit in preventing recurrence in patients with resected gastric tumors. This study allowed entrance of patients who had residual gross disease, and thus the study was not evaluating truly adjuvant chemotherapy. Tamoxifen had no effect on survival outcome; in fact, the control group did slightly better than the treated group. For patients with locally advanced gastric cancers, performing a potentially curative resection (R0) frequently is difficult; the risk of distant failure, even with resection, is high. Locally advanced localized gastric cancers usually are defined as those with potentially resectable T3 or T4 tumors without distant metastases. Because assessment of lymph node involvement is difficult with the preoperative staging techniques currently available, T2 lesions, particularly those with suspicious lymph nodes, also are frequently included in these studies. Almost all of these trials have involved the use of systemic chemotherapeutic regimens, which have demonstrated moderate response rates in patients with metastatic measurable gastric cancer. The overall accuracy of repeat endoscopy after induction chemotherapy has been poor. A decrease in F-18 fluorodeoxyglucose uptake has been proposed as an early marker for objective regression in patients receiving systemic chemotherapy for locally advanced or metastatic disease. Etoposide, doxorubicin, and cisplatin chemotherapy was given for three courses before operation followed by two planned postoperative courses. Eighty-five percent of patients underwent operation, and 77% had potentially curative resections. The most common site for recurrent disease was peritoneal carcinomatosis either found at surgery or developing subsequently. Although response to therapy can be difficult to interpret, 4% of patients had pathologic complete remissions. Response to chemotherapy as assessed clinically was thought to be an independent predictor of survival. Ninety-two percent of patients underwent laparotomy; 87% of patients had resection. Postoperative staging showed 14 patients with either stage 0 (one patient) or stage I disease. Kelsen and coworkers236 performed two trials involving preoperative chemotherapy followed by postoperative intraperitoneal treatment. Toxicity was tolerable, the major side effect was myelosuppression leading to hospitalization for neutropenic fever on at least one occasion in 60% of patients. The operability rate was 89%, and the resectability rate was 74% (61% curative, 20% palliative). With a median follow-up of 28 months, the median duration of survival for all patients was 15. Preoperative toxicity was tolerable, without any increase in operative morbidity or mortality. The R0 resection rate was 82%, and the estimated medial duration of survival was 22. Median duration of survival for all patients was 36 months, and at a median follow-up of 28 months, the median survival for the R0-resected patients had not been reached. The response rate to neoadjuvant therapy was 38%, and 18 patients (82%) underwent resection with curative intent. Fifty-three patients received preoperative chemotherapy, and 54 underwent immediate operation.

Twenty-three (29%) of 80 patients who received mitoxantrone plus prednisone medicine 4211 v discount oxytrol 2.5mg mastercard, as compared to 10 (12%) of 81 patients who received prednisone alone treatment xdr tb guidelines buy 2.5mg oxytrol otc, achieved this palliative response (P = symptoms high blood pressure purchase oxytrol 5 mg free shipping. In addition medicine guide trusted 2.5 mg oxytrol, the duration of the palliation was longer for those patients who received mitoxantrone plus prednisone (median duration medications 5 songs buy oxytrol 5mg without prescription, 43 weeks vs medicine world nashua nh cheap oxytrol 2.5mg without prescription. In another study symptoms neck pain discount oxytrol 2.5mg visa, hydrocortisone given as a split dose of 30 mg in the morning and 10 mg in the evening was compared to hydrocortisone plus mitoxantrone treatment zoster ophthalmicus purchase oxytrol 5 mg on line, 14 mg/m 2 given every 3 weeks. The primary end point for this study was an improvement in survival with mitoxantrone plus hydrocortisone as compared to hydrocortisone alone. Food and Drug Administration approval of mitoxantrone for the treatment of hormone-refractory prostate cancer. Estramustine-Based Chemotherapy Estramustine is a conjugate of estrogen mustard and estradiol. Originally synthesized to permit the selective delivery of an alkylating agent into an estrogen receptor­positive cancer cell, more recent studies have shown that estramustine possesses little alkylating activity and may work by inhibiting mitosis through binding microtubular proteins in the nuclear matrix. Estramustine preferentially enters cells that possess the estramustine-binding protein, a protein in high concentration in prostatic epithelial cells. Its activity is related in part to its estrogenic properties but, in addition, perhaps to its microtubular inhibitory properties. The value of adding estramustine to vinblastine was questioned in a randomized study in which 201 patients with hormone-refractory prostate cancer were randomized to either vinblastine alone, 4 mg/m 2/wk, or vinblastine plus estramustine, 600 mg/m 2/d. Patients who were treated with the combination had a longer progression-free survival (3. Interestingly, more frequent gastrointestinal toxicity but less frequent granulocytopenia was seen in the estramustine arm. Four trials have been conducted with this combination, enrolling a total of 205 patients. Interestingly, one small study of 23 patients with hormone-refractory prostate cancer examined the activity of taxol given as a 24-hour constant infusion at a dose of 135 to 170 mg/m 2. Picus and Schultz 681 demonstrated that docetaxel, when given alone, was active in prostate cancer. In this study, 16 of 35 patients (46%) responded to docetaxel (75 mg/m 2) given every 3 weeks. Because of the significant activity seen with estramustine plus docetaxel, a comparative study is now under way comparing docetaxel plus estramustine to mitoxantrone plus prednisone. Three-drug regimens have emerged, including estramustine, etoposide, and paclitaxel. Unfortunately, the incidence of deep venous thrombosis reported in this study was 25%. Second, what is the contribution of estramustine to these combinations and what is the optimal dosing of estramustine? What are the optimal doses and schedules of the taxanes, and what are the comparative values of three-drug versus two-drug combinations? Other Agents A number of other drugs are active in patients with hormone-refractory prostate cancer, including cyclophosphamide. Eighteen (60%) had significant improvement in symptoms, whereas 6 (20%) had objective responses. Doxorubicin has been used in the context of hormone-refractory prostate cancer as well. A popular regimen was the combination of 5-fluorouracil, doxorubicin, and mitomycin C. In one study, 39 patients were treated with weekly doxorubicin (20 mg/m2) and daily ketoconazole (1200 mg/d). This regimen has been used as an alternating regimen with estramustine and vinblastine. Osteoblastic metastases are seen most commonly, principally in the axial structures (pelvis, vertebral bodies) but also in the appendicular structures (long bones, ribs, etc. Other explanations include a similarity between the growth factor requirements that support prostate cancer cell growth and osteoblast growth. The extent of bone turnover of metastatic bone sites, as measured by a variety of parameters, is high. The value of bisphosphonates in reducing biochemical and clinical parameters of prostate cancer­mediated bone disease is uncertain. Several large, multiinstitutional, randomized trials have now been completed that should clarify these issues. Bisphosphonates have also been used in the context of preventing osteoporosis in patients undergoing androgen deprivation therapy. The value in this setting also remains uncertain, although randomized studies should answer this question. In a randomized study, strontium 89 was shown to be superior to placebo with respect to bone pain palliation. It is generally well tolerated, although progressive bone marrow suppression may occur with repeat dosing. Two trials have been completed that test the value of adding strontium 89 at the time of radiation therapy for symptomatic bone pain relief. In one study, 305 patients with symptomatic bone pain were randomized, after receiving radiation therapy, to receive strontium 89 or hemibody radiation. However, fewer patients developed new painful areas when strontium 89 was used (47% vs. In another trial, patients who had undergone palliative radiation therapy to a bone lesion were randomized to either strontium 89 therapy or no further therapy. Fewer patients had new painful lesions, and the interval before additional radiation therapy was needed was longer for those receiving strontium 89. The second general type of radiopharmaceutical in clinical use is a radioisotope coupled to a bisphosphonate. For these agents, homing to bone is based on the ability of bisphosphonate to adhere to the surface of bone. For several reasons, these growth factors and their tyrosine kinase receptors can be viewed as potential targets in prostate cancer. First, epidemiologic studies suggest that growth factor levels may be involved in either the development or progression of prostate cancer. Finally, there is evidence that targeting these pathways will be effective in cancer therapy. Specifically, an inhibitor of the Ab1 tyrosine kinase used for the treatment of chronic myelogenous leukemia has been shown to be effective. Furthermore, Herceptin, an antibody directed against Her-2/neu, is an effective therapeutic agent when coupled with chemotherapy in the treatment of breast cancer. Antibodies directed against the receptor (C225), as well as small-molecule inhibitors, have been developed and are in clinical trials. Akt, in turn, has the capability of activating several pathways that control proliferation and cell survival. Components of this pathway are, therefore, potentially critical targets in the treatment of prostate cancer. This has been demonstrated to be an effective modality for the treatment of promyelocytic leukemia. Phenylacetate and phenylbutyrate cause growth arrest and differentiation of prostate cancer cells in culture. Both agents have shown activity in early clinical trials in prostate cancer patients. The retinoids are compounds that bind to two classes of nuclear receptors, the retinoic acid receptors and the retinoid X receptors. In vitro, the activity of different retinoids is variable, ranging from growth inhibition to growth stimulation. The drug liarazole, which has a range of activities including inhibition of retinoid acid metabolism, has shown activity in prostate cancer. A fundamental step in this process is degradation of the extracellular matrix, which involves enzymes known as matrix metalloproteinase. One agent, Marimastat, a selective but non-specific matrix metalloprotease inhibitor, has been tested in patients with prostate cancer. One such regimen is a coupled antibody approach, in which antibodies are directed against tumor-specific antigens coupled to a toxin or radioisotope. Another approach is vaccination with antigens enriched on tumor cells, such as specific complex carbohydrate moieties. The loaded dendritic cells are infused into the patient in an effort to stimulate an immune response. One can also augment the production of specific cytokines that stimulate the immune system. One popular approach has been the use of granulocyte-megakaryocyte colony-stimulating factor administered exogenously or delivered in autologous or allogeneic prostate cancer cells. Clinical trials incorporating these different approaches are currently being conducted. This process appears to be important in the growth and progression of localized prostate cancer, as evidenced by a correlation between microvessel density and prognosis in this disease. Whether angiogenesis is important in the establishment of bone metastasis in prostate cancer is uncertain. The morphology of the prostatic capsule with particular regard to the posterosuperior region: an anatomical and clinical problem. The puboprostatic ligament and the male urethral suspensory mechanism: an anatomic study. The striated urethral sphincter: muscle fibre types and distribution in the prostatic capsule. In situ anatomical study of the male urethral sphincteric complex: relevance to continence preservation following major pelvic surgery. Prostate shape, external striated urethral sphincter and radical prostatectomy: the apical dissection. Anatomical variation of the superficial preprostatic veins with respect to radical retropubic prostatectomy. I mmunohistochemical and ultrastructural study of rhabdosphincter component of the prostatic capsule. Surgical anatomy of the somatic terminal innervation to the anal and urethral sphincters: role in anal and urethral surgery. The utility of basal cell-specific anti-cytokeratin antibody (34 beta E12) in the diagnosis of prostate cancer. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. Prostatic duct adenocarcinoma with endometrioid features: immunohistochemical and electron microscopic study. Mucinous adenocarcinoma of the prostate: histochemical and immunohistochemical studies. Prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. Basal cell hyperplasia, adenoid basal cell tumor, and adenoid cystic carcinoma of the prostate gland: an immunohistochemical study. A report of two cases and review of the literature on "adenoid cystic carcinoma" of the prostate. Squamous cell carcinoma of the prostate: report of 2 cases and review of the literature. Squamous cell carcinoma of the prostate: 2 cases of a rare malignancy and review of the literature. Effective treatment of metastatic squamous cell carcinoma of the prostate with Adriamycin. Transitional cell carcinoma of the prostate in patients undergoing radical cystoprostatectomy. Transitional cell carcinoma of the prostate: response to treatment with cisplatinum and cyclophosphamide. Small cell carcinoma of prostate associated with myasthenic (Eaton-Lambert) syndrome. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Prostatic intraepithelial neoplasia and well differentiated adenocarcinoma maintain an intact basement membrane. Prostate cancer on repeat biopsy in men with an initial biopsy of atypical adenomatous hyperplasia or high grade prostatic intraepithelial neoplasia. Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. Interpreting recent trends in prostate cancer incidence and mortality [editorial]. The nature of prostate cancer detected through prostate specific antigen based screening. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. The frequency of latent prostatic carcinoma in young males: the Japanese experience. Secular trend and age-period-cohort analysis of prostate cancer mortality in Taiwan. Removal of the financial barrier to health care: Does it impact on prostate cancer at presentation and survival? Black-white differences in the stage at presentation of prostate cancer in the District of Columbia. Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. Prostate cancer: demographic and behavioral correlates of stage at diagnosis among blacks and whites in North Carolina. Effect of age and race on the survival of men with prostate cancer in the metropolitan Detroit tricounty area, 1973 to 1987. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. A case-cohort study on prostate cancer risk in relation to family history of prostate cancer. A population-based study of clinical and pathological prognostic characteristics of men with familial and sporadic prostate cancer. Comparison of self-report data and medical records data: results from a case-control study on prostate cancer. Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Vasectomy and prostate cancer: a case-control study in a health maintenance organization. The association between vasectomy and prostate cancer: a systematic review of the literature. Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Actions of vitamin D 3, analogs on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D 3. Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer. Chemoprevention strategies for prostate cancer: the role of 5 alpha-reductase inhibitors. Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Mechanism of androgen receptor activation and possible implications for chemoprevention trials. Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. Attributable risk of breast, prostate, and lung cancer in Hawaii due to saturated fat. Certain aspects of molecular endocrinology that relate to the influence of dietary factors on the pathogenesis of prostate cancer. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Inhibition of prostate cancer neovascularization and growth by urokinase-plasminogen activator receptor blockade. Should Medicare provide reimbursement for prostate-specific antigen testing for early detection of prostate cancer?

Intractable pain is sometimes an indication for amputation medications prescribed for migraines purchase oxytrol 5 mg, but rhizotomy and chordotomy can accomplish the same goal while retaining the extremity medicine and health oxytrol 2.5 mg online. Recent interest has been demonstrated in a technique that uses radiographically guided percutaneous injection of polymethyl methacrylate into certain metastatic bony lesions symptoms jaw pain and headache generic oxytrol 2.5 mg with amex. The basic goal of this technique is to address mechanical symptoms by improving the mechanical stability symptoms yeast infection men effective 2.5mg oxytrol, particularly in compression treatment 2015 order oxytrol 5mg, of bones involved by lytic lesions medications with sulfa cheap oxytrol 5mg amex. In vertebroplasty symptoms 8 weeks pregnant purchase 2.5mg oxytrol free shipping, under radiographic guidance medications zocor generic oxytrol 2.5mg without prescription, liquid methyl methacrylate is injected directly into vertebral body lesions. One of the major complications of the injection technique is the extravasation of cement from within the contained bony space, with impingement on adjacent structures. This is particularly important in the spine, where spinal cord compression by cement can cause catastrophic neurologic compromise and requires immediate surgical decompression. Because of the complications associated with percutaneous injection of polymethyl methacrylate, it is important to coordinate the procedure to allow for emergent surgical backup to address acute extravasation issues. Treatment options consist of intralesional excision, wide excision, or excision plus a surgical adjuvant. Intralesional therapy occurs either at the time of biopsy or as a planned intervention. Once the biopsy confirms metastatic disease, a decision must be made as to whether to remove all gross disease, debulking the tumor, or to rely on external irradiation and systemic therapy for local control of the lesion. It is helpful if the members of the oncology team discuss the treatment options before beginning a course of therapy. Judgment, sensitivity, and skill are needed to integrate the biopsy process with overall tumor management and to prepare the patient and his or her family appropriately before surgery. Combining biopsy with tumor removal and bone stabilization best meets the goals of diagnosis, pain relief, and functional restoration. This is particularly important because biopsy further disrupts the already weakened bone. Intralesional curettage of tumor in and around the fracture site is the principal strategy in addressing metastatic lesions involving bone. Eliminating gross tumor achieves an immediate "partial response" that could take weeks to be achieved by other methods, improving local tumor control. The resultant defect can be filled much more effectively with methyl methacrylate cement, giving better long-term stability to the fractured bone. It is the most effective way to eliminate the biologic contribution to pain while correcting the structural deficiency. A long interval between primary tumor presentation and the development of a metastatic focus argues well for cancer resectability. Patients with a projected long survival, such as those with renal or thyroid cancers, are best suited to undergo extralesional excision of metastases. Even if systemic disease later develops, some clinicians contend that survival may be prolonged in surgically resected cases. Preoperative angiography and tumor embolization greatly reduce blood flow and intraoperative hemorrhage, particularly in vascular tumors such as thyroid and renal cell carcinoma. It is particularly suited for cancers that have failed to respond to systemic treatment or local radiation therapy and in which local tumor progression is expected. The addition of chemotherapeutic agents to the methyl methacrylate bone cement used in implant and fixation constructs is under investigation as a method of local delivery of antineoplastic drugs for enhanced local, and potentially systemic, disease control. Preliminary studies show promising results, but further clinical investigation is required before this method can be entered into the therapeutic armamentarium. It should be delivered to the entire surgical field and extend the length of any prosthesis or internal fixation device. Local tumor control helps to prevent destabilization of the implant construct by preventing local tumor progression from affecting the structural integrity of the bone in which the implant is fixed. Impending Fractures: Prophylactic Fixation There is no specific definition of an impending fracture, and the indications for operative treatment of impending fractures continue to be controversial. This controversy remains extant in part because of the evidence in the literature. Snell and Beals, 99 in their review of 19 pathologic femur fractures due to metastatic breast cancer, found that a lesion of 2. Parrish and Murray100 reported on their experience with 104 pathologic fractures due to metastatic disease and identified increasing pain, more than 33% cortical destruction, and lack of radiographic improvement after radiation therapy as indicators of impending fracture. Fidler, 101 in his retrospective study of 19 long bone fractures, showed that with 50% or more cortical involvement in a long bone, there is at least a 50% incidence of spontaneous fracture. Zickel and Mouradian, 102 in their retrospective review of 34 patients, found that size did not correlate with risk of fracture and that, instead, pure lysis on radiography, medial cortical involvement at the hip, and increasing pain were indicative of a high risk of fracture. Harrington, 103 in his review of the literature, summarized the positive predictors of pathologic fracture through a metastatic lesion as (1) a lesion of 2. This study involved 2673 breast cancer patients who had undergone skeletal surveys. They concluded that plain radiographic measurements are insufficient to identify high-risk lesions. This study, however, was limited to the single anteroposterior radiographic evaluation present in the skeletal survey. Mirels105 proposed a graduated scoring system that further refined the risk-factor criteria. Included are clinical and radiographic factors, which generate a composite score from 0 to 12 that correlates with fracture risk. Four factors-anatomic site, pain pattern, radiographic nature, and lesion size-were each evaluated on a 0 to 3 scale. The mean score for the nonfracture patients was 7, versus a mean score of 10 for the fracture patients; however, there was significant overlap between the two groups. The author concluded that lesions with scores of less than 7 could be irradiated, whereas those with a higher score should be managed with internal fixation followed by postoperative irradiation. Mirels 105 also made an important distinction between pain and "functional" pain, the latter being pain that worsens with weight bearing. Thus, functional pain reflects the structural insufficiency of bone and was found to be the most significant indicator of bone failure, enjoying an almost universal success in predicting fracture. Lesions measuring larger than twice the bone diameter were closely associated with functional pain. The scientific foundation for predicting fracture risk has been improved and summarized by Callaway and Healey. The spine, proximal femur, and pelvis cause the most problems and will be dealt with individually. The primary cancers responsible for spinal metastases are breast, lung, and prostate. Among reports regarding the prevalence of spine metastases, most emanate from referral centers. Remarkably, in 47% of the 131 patients with neurologic symptoms reported by Stark et al. In an autopsy study of 832 patients dying of metastatic cancer, 36% were found to have spinal metastases, and 26% of these patients had negative plain radiographs of the spine despite the gross evidence of tumor. It may be caused by intraosseous disease, motion segment instability, vertebral fracture, epidural compression, or nerve root impingement. Vascular insufficiency of the spine can also occur due to tumor or to associated spinal instability, surgery, radiation therapy, or embolization of the spinal arteries. These are harbingers of serious neurologic damage and are much less likely to return after any form of treatment. These authors recommended that an excisional operation be performed in patients with 9 or more points, whereas palliative surgery is indicated for the more seriously ill, those patients scoring fewer than 5 points. Influential factors are anatomic location of metastases, functional status, treatment, and primary tumor histology. Among the patients, 2 improved and 11 became paraplegic, whereas in 65, symptoms stabilized. There was a major difference in outcome based on the ability to restore ambulation. Ambulators had a 53-week survival in contrast to nonambulators, who survived less than 5 weeks. Radiation is the first line of treatment for most patients with spinal metastases and pain. Symptomatic control lasted for 6 months, with subsequent deterioration that necessitated another treatment. The authors concluded that nonoperative treatment is appropriate for most patients without neurologic signs, particularly if the expected survival is in the 6- to 12-month range. They found no benefit from this form of surgery and therefore favored nonoperative treatment. However, the series was small, was not stratified for tumor location, and preceded the application of modern spine instrumentation methods. Laminectomy alone rarely accomplishes these goals and may further destabilize the spine. The debate continues as to whether an anterior, posterior, or combined anterior-posterior approach is better. Proponents of anterior decompression contend that it is often preferable because it addresses the primary site of the disease. Vertebral body resection and cement and rod vertebral body reconstruction achieved excellent pain relief in 13 of 14 patients. Patients were stabilized anteriorly or posteriorly as required; pins and cement usually were inserted to replace the vertebral body. Seventy-eight percent regained ambulatory ability, and 85% experienced pain relief. Morbidity was the least in patients who were treated de novo and underwent subsequent radiation therapy. Deterioration in function or pain control occurred in 7 months for cervical lesions, in 11 months for lumbar lesions, and in 22 months for thoracic lesions. If survival was expected to exceed the durability of the anterior reconstruction, then staged, posterior stabilization was recommended. It is particularly suitable for patients with extensive epidural disease and those who have had a previous thoracotomy or thoracic irradiation or who have significant pulmonary disease, which is a relative contraindication for thoracotomy. Metastatic disease involving the spine with fracture and spinal cord compression at T9. A: T2 stir, fat-suppressed magnetic resonance imaging scan demonstrating multiple-level vertebral involvement with extension of tumor involving the T9 vertebral body into the spinal canal with cord impingement. B: Postoperative radiograph after decompression and stabilization using the single-stage posterolateral, transpedicular approach with anterior reconstruction with pins and cement and long posterior fusion with pedicle screw fixation. Segmental spine fixation, including pedicle fixation, has greatly improved the ability to stabilize the spine posteriorly. In most situations, survival is insufficient for bone healing to occur and is well within the limits of synthetic durability. This is in distinction to the case for curative resection of solitary metastases or primary tumors. This is the most oncologically sound procedure described to date, removing the posterior elements as a single segment and resecting the vertebral body as a single segment. Careful spine stabilization and meticulous technique have prevented neurologic damage. Among the 12 patients who were alive at 14-month review, no local recurrence was found. These results are in contrast to the high local recurrence rates (up to 49%) that have been reported by King et al. Current surgical indications agreed on by most authors are (1) cord compression with myelopathy, (2) bone impinging into the spinal canal and producing thecal compression, (3) spinal instability with unremitting mechanical pain, (4) fracture-dislocation of the spine, (5) radiculopathy with progressive or uncontrolled symptoms, (6) tumor growth unresponsive to radiation therapy, and (7) direct tumor extension from primary lesions, such as Pancoast tumor invading the vertebra. Embolization of spinal metastases from renal carcinoma has been recommended as the sole treatment for patients with late-stage disease. Preoperative tumor embolization is warranted in renal carcinoma and, possibly, in other hypervascular lytic tumors. The value of embolization in the treatment of other tumors has not been as well documented, but it is often useful in the treatment of metastases to difficult sites such as the acetabulum. Sixty-six percent of pathologic long bone fractures involve the femur, and 80% of these occur in the proximal portion. The femoral neck is the location for approximately 52% of these fractures, with the intertrochanteric region responsible for another 15% and the subtrochanteric region for the remaining 33%. Underlying mechanical weakness from even a treated metastasis leaves the bone unable to withstand the forces of normal activity. This is true even for patients in whom anticancer therapy and resuscitation are no longer indicated. As in other anatomic locations, the goal of treatment is to reduce pain and maintain function. Maintenance of function usually means preservation of walking ability but, in severely disabled patients, functional restoration means regaining transfer ability, which facilitates nursing care. General indications for surgery are a life expectancy of at least 1 month, a general physical condition adequate to tolerate surgery, a result from surgery that will expedite patient mobilization and facilitate general care, and bone adequate to support fixation or a prosthesis proximal or distal to the fracture. Generally, all fractures require supplemental radiation therapy to treat underlying tumor. Tumor can be seeded down the femoral canal during intramedullary reaming, insertion of an intramedullary device, or injection of cement down the canal. This newly contaminated region must be treated with radiation to avoid tumor proliferation and a new fracture distal to the implant. Surgical treatment is largely dependent on fracture location and anatomy, which is discussed earlier, in Fracture Treatment. Avulsion fractures of the iliac crest or anterior-inferior iliac spine are common and should be treated nonoperatively. However, mechanical insufficiency of the acetabulum can be managed only surgically. The general surgical indications for metastatic disease involving the acetabulum are (1) continued acute symptoms despite management with protected weight bearing, antineoplastic treatment, and analgesics; (2) unsatisfactory function and pain control 1 to 3 months after irradiation; (3) a pathologic fracture of the acetabulum; or (4) an impending fracture in the ipsilateral femur requiring surgery. Harrington and Rock 135,136 described four types of acetabular bone deficiency and their surgical management among 58 patients with pelvic metastases. Their classification system is based on the extent of bony involvement by tumor and reflects surgical treatment. Pain relief was effective for at least 6 months in 67% of patients and for more than 2 years in 43%. Harrington did, however, treat a generally favorable group of patients, with 30 of 58 (51%) surviving 2 years or more after surgery. Preoperative evaluation, including Judet radiographs, must be performed carefully, to define disease in the anterior and posterior acetabular columns. Pathologic anatomy is better described by a four-part system that assesses the anterior column, posterior column, acetabular dome, and medial wall as separate components. Bone in each region can then be graded as sufficient or insufficient, whereby sufficient bone provides adequate support for the acetabular component and insufficient bone does not. Thus, the classification system combines both anatomic and reconstructive considerations. Forty-two of 55 patients (76%) had an insufficient medial wall combined with either an insufficient column or dome, and 47 patients (85%) had an acetabular fracture. In all 55 patients, the reconstruction was reinforced with pins or cannulated screws incorporated into cement, using a modified Harrington technique. This allows for bypass of major acetabular defects with proximal fixation of the socket into the remaining iliac bone. Insertion of pins or screws can be performed in an antegrade fashion from the iliac crest, using a vector guide, or retrograde from the bone defect. A protrusio ring "revision" hip socket can be used to transfer load to the remaining intact cortical bone when medial wall defects are present (. Of the 41 out of the 55 patients (75%) in this series that were evaluable at 3 months, 34 (83%) experienced significant pain relief, 9 of 18 nonambulatory patients had regained walking ability, and 14 of 17 patients maintained their ability to ambulate in the community. Fourteen of 55 patients (25%) developed significant local disease progression, but only 5 patients (9%) experienced fixation failure. Of the 21 patients (38%) who had more than 1 year of follow-up, 14 (67%) continued to experience improved pain relief and 12 (57%) remained community or household ambulators. In this series, despite the fact that patients with significant acetabular metastasis had a short life expectancy, the positive effect on both pain relief and functional improvement validated the role of surgery in managing this group. Acetabular reconstruction using the outlined techniques showed a low incidence of fixation failure, supporting the biomechanical stability of the construct and providing sufficient durability in these patients. Reconstructions using the techniques outlined for metastatic cancer to the pelvis and acetabulum. B: Reconstruction of a large lesion involving the posterior column, medial wall, and acetabular dome using antegrade pins, a protrusio ring acetabular component, and cement. The protrusio ring acetabular component lateralizes the socket and helps to bypass the central defect. Finally, massive pelvic involvement can be treated by acetabular resection and reconstruction using a saddle prosthesis (Waldemar Link, Hamburg, Germany), as reported by Aboulafia et al. Such aggressive surgical approaches may help selected patients with intermediate-term life expectancies. When coupled with systemic measures to control bony metastases, local care with radiation therapy and/or judicious surgery can achieve the goals of pain relief and functional preservation in patients surviving with metastatic cancer that involves bone. Direct osteolysis induced by metastatic murine melanoma cells: role of matrix metalloproteinases. Utilization of polymerase chain reaction technology in the detection of solid tumors. Comparison of radionuclide bone scans and magnetic resonance imaging in detecting spinal metastases. Bone scintigraphy and multimodality imaging in bone neoplasia: strategies for imaging in the new health care climate. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure.

Pheochromocytomas can be excluded by measuring normal urinary levels of epinephrine medications jfk was on best oxytrol 5 mg, norepinephrine medicine with codeine order 2.5 mg oxytrol otc, vanillylmandelic acid medications may be administered in which of the following ways discount 2.5mg oxytrol mastercard, and metanephrines treatment centers in mn safe 5mg oxytrol. If an elevated level is detected medicine 8 discogs cheap 2.5 mg oxytrol with mastercard, pheochromocytoma localization studies should be done symptoms 4 weeks pregnant discount 2.5 mg oxytrol with visa. Abdominal computed tomography and magnetic resonance imaging are frequently helpful in localizing the pheochromocytoma treatment innovations order oxytrol 5mg overnight delivery, but additional more sensitive studies may be needed medicine clip art buy 5mg oxytrol with amex. Patients diagnosed by genetic testing have surgically curable C-cell hyperplasia or carcinoma confined to the thyroid gland. Some advocate only resecting abnormal adrenal glands confirmed by palpation, 102 while others recommend routinely resecting both adrenal glands. With imaging studies to localize the adrenal tumor, laparoscopic methods are now used to remove it. Radioactive iodine ablation, thyroid suppression, and radiation therapy have not been helpful. Because of the indolent nature of the tumor, most have chosen not to aggressively treat metastatic disease. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type I. Multiple endocrine neoplasia type I: general features and new insights into etiology. Circulating fibroblast growth factor-like substance in familial multiple endocrine neoplasia-type I. Circulating fibroblast growth factor like antibodies in two patients with multiple endocrine neoplasia type 1 and prolactinoma. Increased basic fibroblast growth factor in plasma from multiple endocrine neoplasia type 1: relation to pituitary tumor. Association of parathyroid tumors in multiple endocrine neoplasia type I with loss of alleles on chromosome 11. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology and behavior. Loss of heterozygosity of markers on chromosome 11 in tumors with patients with multiple endocrine neoplasia syndrome I. Zollinger-Ellison syndrome can be initial endocrine manifestation in patients with multiple endocrine neoplasia type 1. Expression of basic fibroblast growth factor in hyperplastic parathyroid glands from patients with multiple endocrine neoplasia type 1. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 1. Primary hyperparathyroidism in familial multiple endocrine neoplasia type I: long-term follow-up of serum calcium levels after parathyroidectomy. Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome, and multiple endocrine neoplasia type 1: a prospective study. Pancreatic lesions and hormonal profile in pancreatic tumors in multiple endocrine neoplasia type I. Gastrinomas in the duodenums of patients with multiple endocrine neoplasic type 1 and the Zollinger-Ellison syndrome. Unresolved surgical issues in the management of patients with Zollinger-Ellison syndrome. Zollinger-Ellison syndrome: clinical presentation, pathology, diagnosis and treatment. Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1. Management of islet cell tumors in patients with multiple endocrine neoplasia: a prospective study. Prospective study of the utility of somatastatin receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type I. Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Islet cell tumor metastasis in multiple endocrine neoplasia type I: correlation with primary tumor size. Benefit of resection of metastatic gastrinoma in multiple endocrine neoplasia type I. Surgical management of hyperinsulinism in the multiple endocrine neoplasia, type I syndrome. Role of endoscopic ultrasonography in the localization of insulinomas and gastrinomas. Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas. Prevalence of endocrine abnormalities in patients with the Zollinger-Ellison syndrome and their families. Pheochromocytoma, hyperparathyroidism and thyroid carcinoma occurring coincidentally. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Multiple endocrine neoplasia type 2b: the most aggressive form of medullary thyroid carcinoma. Presymptomatic screening for medullary thyroid carcionoma in patients with multiple endocrine neoplasia type 2A. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Medullary thyroid carcinoma: relationship of method of diagnosis to pathological staging. Early diagnosis of medullary carcinoma of the thyroid by means of calcitonin assay. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. Spectrum of pheochromocytoma in multiple endocrine neoplasia: a scintigraphic portrayal using 131-I-metaiodobenzylguanidine. Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms. Thyroid venous catheterization in the early diagnosis of familial medullary thyroid carcinoma. They are, however, ideal prototypes to demonstrate the important role of multidisciplinary management. It is clear that soft tissue sarcoma, diagnosed at an early stage, is eminently curable. When diagnosed at the time of extensive local or metastatic disease, soft tissue sarcoma is rarely curable. Analysis of population based data from Connecticut 2 suggests an increase in incidence in both men and women, greater for women. Data suggest that genetic mutations in pluripotent mesenchymal stem cells give rise to malignant clones that differentiate along pathways that resemble normal histogenesis. Genetic Predisposition to Soft Tissue Sarcoma the most common tumors in patients with neurofibromatosis are in the central nervous system. Relatives of such patients, whether with a family history or not, are also at risk of developing malignant tumors. However, their natural history of slow growth with accompanying invasion of contiguous structures increases the risk of subsequent mortality when managed inappropriately. The development of soft tissue and bone sarcoma as a result of exposure to radiation has been known since 1922. In a review of 160 patients, 18 the antecedent diseases for which the radiation was given were predominantly breast and cervical cancer and lymphoma. External radiation therapy was given to 99% of the patients, 14% of whom received additional treatment with temporary or permanent radioisotope implantation. No significant difference in survival was found between patients with bone tumors and those with soft tissue sarcomas. Survival was not affected by site, latency period, and the amount of radiation received initially, nor were there any differences for patients receiving chemotherapy for their sarcomas. The three factors in the Cox multivariate analysis that had a significant unfavorable association were presentation with metastatic disease (P =. Tumor grade was not significant in any analyses, but only 6% of the patients had low-grade tumors. Radiation-associated soft tissue sarcoma: antecedent disease for which radiation was given and histopathology of sarcomas that developed in 160 patients at Memorial Sloan-Kettering Cancer Center. In one study19 all 122,991 women with breast cancer in Sweden from 1958 to 1992 were followed, and 116 soft tissue sarcomas were found. For other sarcomas, there was a dose-response relationship with exposure to radiation therapy. Lymphedema has long been established as a factor in the development of lymphangiosarcoma. The most well-recognized association is with the postmastectomy, postirradiated lymphedematous arm, described by Stewart and Treves. Similar advanced sarcomas have been seen following filarial infection and chronic lymphedema. Lymphangiosarcoma can arise in filarial lymphedema and remain localized for relatively long periods of time. Often a minor episode of injury is the factor that draws attention to the presence of a mass, implying a causative association that is not real. Through the years there have been conflicting reports about the relationship between occupational exposure to phenoxyacetic acids found in some herbicides and chlorophenols (found in some wood preservatives) (Table 39. Case-Control Studies of Relationship between Exposure to Phenoxy Herbicides and Incidence of Soft Tissue Sarcoma Interestingly, it has been suggested 35 that such exposure may be tissue type specific. An increased incidence of soft tissue sarcomas was seen in a cohort of 1520 industrial workers exposed for more than 1 year to 2,3,7,8-tetrachlorodibenzo-p-dioxin, but other studies did not substantiate these findings. A population-based case-control study assessed the risk of soft tissue sarcomas in Vietnam veterans, including those potentially exposed to Agent Orange, which contains dioxin, and found no increased risk among any subset of veterans compared with control groups. Chemotherapy for pediatric malignancies has been associated with the subsequent development of osteogenic sarcomas 45; a relationship with the development of soft tissue sarcomas has not been demonstrated. These are usually associated with high-grade tumors, but are not consistent between tumors. For example, an analysis of 36 tumors, 46 pleomorphic soft tissue sarcomas were examined. Multiple complex karyotypes were identified and at least 24 recurrent abnormalities (defined by their presence in at least five cases) were detected. However, none of the selected rearrangements was specific for any one of a particular subgroup. It seems unlikely at the present time, therefore, that cytogenetic analysis can help differentiate the pleomorphic sarcomas. In these situations, these genetic abnormalities can be used as a diagnostic tool. Chromosomal Changes in Soft Tissue Sarcoma Multiple other studies of genetic abnormalities have been published. Distribution by site of soft tissue sarcomas in 3968 patients aged 16 or older admitted to Memorial Sloan-Kettering Cancer Center between July 1982 and July 1999. Histologic Classification of Soft Tissue Sarcoma Soft tissue tumors may be benign or malignant, and a variety of borderline lesions are also recognized. Unlike carcinomas, sarcomas do not demonstrate in situ changes, nor does it appear that sarcomas originate from benign soft tissue tumors. Although each of the sarcomas has distinguishing histologic characteristics, the different types of sarcoma have many common clinical and pathologic features. Lymph node metastases are uncommon, with the exception of selected cell types usually associated with childhood sarcoma (Table 39. The clinical behavior of most types of sarcoma also is similar, determined more by anatomic location, grade, and size, than by specific histologic pattern. The pathologic features that define grade include cellularity, differentiation, pleomorphism, necrosis, and number of mitoses. In adjuvant chemotherapy trials high grade was defined differently at different centers, making comparison of results between trials, and combining results of multiple trials, extremely hazardous. For example, tumors of 240 patients who participated in the Scandinavian Sarcoma Group adjuvant trial for high-grade extremity sarcoma were reviewed by a panel of reference pathologists. On review, 5% of the patients were considered ineligible because their tumors actually were low grade. Although the adjuvant regimen did not affect survival (see below, in Adjuvant Chemotherapy), a difference in survival was noted between patients with tumors of these two grades as assigned by the reference pathologists. Many pathologists consider mitotic activity and degree of necrosis to be the most important pathologic features. Mutation of p53, nuclear overexpression of p53, and a high Ki-67 proliferation index are associated with high grade and poor survival. However, note that Ewing sarcomas are considered high-grade, undifferentiated sarcomas. Accurate diagnosis requires an adequate and representative biopsy of the tumor, and the tissue must be well fixed and well stained. Antibodies for immunohistochemical staining are available commercially, and this technique is readily applicable to paraffin-embedded tissues. In addition, the pathologist should be prepared to process tissue from selected cases for electron microscopy, cytogenetic studies, or molecular analysis. This implies that certain diagnoses are considered by the clinician, that the diagnostic biopsy is obtained appropriately, and that the clinician and pathologist communicate before the biopsy is performed to ensure that the necessary steps are taken in handling the tissue. Cytogenetic analyses reveal clonal chromosome alterations in the majority of sarcomas. Fusion genes resulting from chromosomal rearrangements may be detected by reverse transcriptase polymerase chain reaction. This technique has been quite effective in diagnosing and distinguishing among the small cell sarcomas. Fluorescent in situ hybridization using probes to locate specific chromosomal abnormalities may become clinically useful, but is unavailable for routine diagnostic use at this time. Supernumerary ring chromosomes, seen in mesenchymal neoplasms of low or borderline malignancy, such as dermatofibrosarcoma protuberans, may be identified with this technique. As might be expected from a group of rare, diverse, but related tumors, there may be considerable disagreement among pathologists regarding the specific histologic diagnosis in individual cases. Some types of sarcoma occur with greater frequency in certain age groups or in specific locations, forming clinicopathologic syndromes that permit standardized treatment strategies. The distribution of common histologic types among different age groups is demonstrated in Figure 39. Predominant histology by site of soft tissue sarcomas in 3968 patients aged 16 or older admitted to Memorial Sloan-Kettering Cancer Center between July 1982 and July 1999. The most frequently encountered chest wall sarcomas are desmoids, liposarcomas, and myogenic sarcomas. Three major types of uterine sarcoma are recognized: (1) leiomyosarcomas, tumors of the myometrium; (2) mesodermal mixed tumors (malignant mixed MÑŒllerian tumors), composed of elements of carcinoma and sarcoma; and (3) endometrial stromal sarcoma, the least common, which arises from endometrial stroma and usually has an aggressive behavior. In addition, there are a variety of fibrous proliferations of infancy and childhood that resemble lesions in the adult, but are associated with a better prognosis. Features of lesions that may be mistaken for sarcoma are summarized in the following sections. Nodular Fasciitis Nodular fasciitis, also called pseudosarcomatous fasciitis, is a benign lesion usually seen in adults aged 20 to 40, although it has been reported in both older and younger patients. The upper extremity is the most common site, especially the volar aspect of the forearm. Nodular fasciitis generally arises in the subcutaneous fascia or the superficial portions of the deep fascia. Histologically, the lesions are nodular, nonencapsulated masses, consisting of plump, immature fibroblasts arranged in short, irregular bundles or fascicles. Because of their cellularity, rapid growth, and high mitotic activity these lesions may be mistaken for fibrosarcoma. Fibroma Fibroma is a general term that has been applied to a group of poorly defined benign lesions that arise in the skin or soft tissues. Fibroma of tendon sheath is a slowly growing dense fibrous nodule that is attached to the tendon sheath, found most frequently in the hands or feet. Elastofibroma Elastofibroma is a rare, slow-growing benign tumor that characteristically arises between the lower portion of the scapula and the chest wall of older individuals. Elastofibromas grow as ill-defined masses, often measuring 5 to 10 cm in diameter. Histologically, these lesions consist of swollen eosinophilic collagen and elastic fibers, and stain intensely for elastins. Superficial Fibromatoses Superficial fibromatoses arise from the fascia or aponeurosis and generally are small and slow growing. Desmoid Tumor the desmoid was originally described as a tumor of the abdominal wall in women who had recently been pregnant, but these rare, slow-growing fibrous tumors may arise at any site in the body. The desmoids have been classified by location as abdominal, extraabdominal, intraabdominal, and mesenteric. As is the case for other sarcomas, site affects management, but it is unclear whether the distinction by site is biologically significant. The term aggressive fibromatosis, often applied to these lesions, especially when they occur in the retroperitoneum, belies their potential for invasion and progressive growth.

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