Bone cancer

Pain is the principal symptom of bone metastases. It is composed of a biologic and a mechanical aspect. The biologic component reflects the rate of tumor growth and biologic characteristics of the tumor. The increased blood flow and cytokines are important causes of bone pain and contribute to bone lysis. Finally, nerves within bone have recently been described; these transmit many neuropeptides such as substance P and calcitonin gene-related protein, which are involved in both pain modulation and bone metabolism.

Bone loss reduces bone strength and stiffness, increases strain, and leads to activity-related symptoms: so-called “mechanical bone pain.” Pain from mechanical insufficiency often increases after a treatment reduces turgor within the tumor. Bone collapse and even dislocation can then occur. This is seen most often in “successful” treatment of spinal lesions. Late sequelae such as osteonecrosis and fatigue fracture are other manifestations of mechanical insufficiency.

The initial pain pattern of a metastasis mimics that of primary bone tumors and osteonecrosis. The symptoms are intermittent but may be sharp and severe. Pain tends to be worst at night and maybe partially relieved by activity. As the lesions progresses, symptoms become more constant and take on more of a mechanical character.
General systemic issues are of concern in patients with skeletal metastases. Bed rest or reduced activity is frequently recommended for the bone pain of skeletal metastases. This produces general disuse and weakness. Manifestations commonly include atelectasis and thromboembolic disease. Careful screening for these conditions is imperative. Doppler ultrasound tests are convenient and sensitive to identify deep vein thrombosis. Loss of ambulatory ability is a poor prognostic factor in metastatic disease, particularly spine disease. Performance status should be specifically quantified as part of the preoperative evaluation.
DIAGNOSIS

Plain radiography remains the most specific test to diagnose bone diseases. Scintigraphy is extremely sensitive and practical because it can screen the entire body at one time. Certainly, any abnormality found on bone scan should be assessed with plain radiographs. Only when the diagnosis cannot be discerned from clinical information and these baseline tests should magnetic resonance imaging (MRI) be obtained.

Solitary bone lesions warrant a biopsy before treatment. Primary bone sarcomas occur in the population particularly under consideration. Lytic phases of dedifferentiated chondrosarcoma and Paget’s sarcoma can also produce pathologic fractures. These must not be confused with the pathologic fractures of metastatic disease. A firm diagnosis must be obtained before internally fixing such a fracture.

CT-guided needle biopsy is usually satisfactory when the lesion is osteolytic (diagnostic accuracy, 80%). When the lesion is osteoblastic or there is a thick overlying cortical rim, it is extremely difficult to insert a needle and obtain an adequate tissue sample. Such cases necessitate open surgical biopsy. Whether the biopsy is performed by closed or open technique, fracture risk is worsened by the new hole in the bone cortex. Weight bearing must be protected until bone healing occurs. Experimentally, this requires at least 6 weeks. Adequate tissue is necessary to perform special studies if required. For example, recently, the spectrum of Ki-1 lymphomas has been noted and these tumors frequently mimic metastatic carcinomas. Sufficient tissue for immunohistochemical studies should always be obtained.

Future directions.

Although uncontrolled studies and anecdotal reports of high-dose chemotherapy with marrow reconstitution appear promising, the highly selected nature of the patients and the expense of the procedures mandate that randomized, comparative trials demonstrate the superiority of this approach over standard therapy before it can be considered a valid part of the therapeutic armamentarium. Such a study is underway with very poor accrual.

Intraperitoneal administration of drug, although under study for over a decade, still has no defined role in management. In the salvage setting, it appears to have no advantage over intravenous therapy. In the setting of first-line treatment, two large randomized trials in patients with small-volume disease show small advantages but have major design problems. The final determination of the role, if any, for intraperitoneal therapy awaits the completion of the current trial comparing intravenous paclitaxel-platinum to intraperitoneal paclitaxel-platinum. If a role for intraperitoneal therapy exists, data show that it will be in only those patients with extremely small-volume disease or perhaps no residual disease; hence, its role will be a very narrow one.
Breast cancer
In conclusion, the future holds the promise of continuing advances in the management of patients with celomic epithelial carcinoma of the ovary. Although the explosion of knowledge of the basic nature of the disease holds the greatest potential for improvement, the identification of an effective screening technique, the clarification of the role of surgery in advanced disease, and the introduction of exciting new agents such as Taxol offer the promise of better treatment in the immediate future. The great promise of dose-intense regimens, still worthy of further investigation, suffers from a growing body of evidence that no advantage is obtained at least over the clinically achievable range of doses unsupported by marrow reconstitution.

FUTURE DIRECTIONS. Fallopian Tube Cancer

Third, although the efficacy of initial surgical cytoreduction in patients with stage III disease has been accepted on the basis of retrospective analyses, prospective trials are needed to address several important questions. One such study suggests an advantage for interval surgical cytoreduction at the midpoint of a series of chemotherapy courses. Prospective randomized trials of initial or secondary surgical cytoreduction have not been completed. Investigations of the relative merits of each of these approaches versus no surgery are needed, as well as trials evaluating which of these points in the therapy represents the optimal time to introduce surgical resection into the management of advanced disease. Such studies are difficult to conduct because of the widespread acceptance of the role of surgical cytoreduction in ovarian carcinoma. A confirmatory trial of interval cytoreduction is nearing completion, but further study is needed.

Fourth, efforts continue to investigate the role of new agents in the management of ovarian carcinoma. Current interest continues to center on further delineation of the role of paclitaxel. The plethora of new agents with activity in patients who are clinically resistant to the platinum compounds and paclitaxel, however, opens the possibility for the addition of clinically non-cross-resistant drugs to front-line paclitaxel-platinum therapy. Defining the role of these new agents is of paramount importance.

Finally, dose intensity continues to command significant interest. Three basic ways to enhance the dose intensity have been proffered: escalation of dose within the range that can be achieved without marrow reconstitution, high-dose chemotherapy with support of autologous bone marrow transplant or peripheral stem cell transfusion, and, in the case of ovarian carcinoma, intraperitoneal administration of drug. Eight randomized trials of dose escalation over a standard range of doses have been completed. Six show no advantage to a doubling of dose intensity, and the other two have major design problems. Further exploration of this approach seems unwarranted.

New Treatments for Fallopian Tube Cancer

FUTURE DIRECTIONS

The development of additional information about the nature and management of germ cell cancers and rarer malignant tumors of the ovary as well as fallopian tube cancer will continue to be restricted by the low frequency of these lesions. With regard to celomic epithelial carcinomas of the ovary, however, progress should continue to be rapid. Current and future investigational efforts focus on several distinct areas: biology of ovarian carcinoma, screening and early detection, the proper role of surgery, new agents and their role in systemic therapy, and the value of approaches to achieve greater dose intensity.
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First, with regard to the biology of ovarian carcinoma, specific studies are seeking (1) to characterize factors associated with ovarian carcinoma and its outcome such as specific genetic defects associated with hereditary ovarian carcinoma, various oncogenes, and DNA ploidy; (2) to identify features predictive of the likelihood of developing ovarian carcinoma; and (3) to ascertain the biologic reasons for the observation that more aggressive disease is associated with older patients. As these and other investigations expand the understanding of the basic nature of ovarian carcinoma, the development of better and more specific methods for early detection and treatment of the disease should be possible. Where this line of work will ultimately lead is speculative but exciting.

Second, the evolution of effective techniques for screening for and early detection of ovarian carcinoma has a high priority in ovarian carcinoma, the only one of the major gynecologic cancer for which early detection is not the rule. Most interest centers on the potential for transvaginal sonography, especially when enhanced by color flow Doppler, to permit earlier detection of disease. Studies are currently directed at improving the specificity of the technique and at demonstrating an impact on the morbidity and mortality of the disease. Ultimately, confirmation of the value of the procedure will depend on a large screening trial of high-risk women (one or more first-order relatives), a study now planned but as yet unfunded.

THERAPEUTIC DECISIONS IN FALLOPIAN TUBE CARCINOMAS

Firm recommendations on the management of fallopian tube carcinomas are difficult because of the lack of extensive clinical studies. Using the best evidence available, there are four basic groups of patients.

Intramucosal Lesions Only

For patients with intramucosal lesions only, cure is excellent with surgical resection. Patients should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed closely with no further therapy.

Mucosal Wall Invasion

For patients with mucosal wall invasion, the recurrence rate approximates 50 percent. These patients are candidates for adjuvant therapy, but there are no data to support the use of such treatment. If adjuvant therapy is to be used, choices similar to those for high-risk ovarian carcinoma seem reasonable. If radiation therapy is to be used, it would seem appropriate to treat the entire abdominal cavity. A preferable approach would be the use of platinum-based chemotherapy on the assumption that this disease responds similarly to celomic epithelial carcinoma.

Penetration of the Serosa

For patients with penetration of the serosa but no gross spread, recurrence rate exceeds 75 percent. An even stronger case for the use of adjuvant therapy can be made. The choices are similar to those noted above.

For patients with obvious spread of disease to locoregional and distant sites, platinum-based chemotherapy is a reasonable choice. The overall strategy should be similar to that used for patients with advanced or recurrent celomic epithelial carcinoma of the ovary.

Fallopian Tube Cancer

The fallopian tube is the least common site of origin in the female genital tract for cancer. The most common histologic type of cancer, accounting for 90 percent of all malignancies of the tube, is papillary serous adenocarcinoma, but even this type is rare, with only 300 cases reported annually in the United States. The pattern of spread is similar to that seen with celomic epithelial lesions of the ovary, with dissemination throughout the peritoneal cavity perhaps the most important route of spread; hence, it is often difficult to distinguish between ovarian and fallopian tube primary tumors. Criteria have been set for lesions designated to be of fallopian tube origin: the main tumor arises from the endosalpinx and is in the tube, the histologic pattern shows a papillary pattern, a transition zone between benign and malignant epithelium must be demonstrable if the wall is involved, and the ovaries and endometrium must be either normal or less involved than the tube.

As a reflection of the propensity of tubal cancer to spread by intraperitoneal dissemination, 5-year survival rates correlate well with the degree to which the primary lesion penetrates the wall of the tube: 91 percent for intramucosal lesions, 53 percent for those with mucosal wall invasion, and 25 percent or less for lesions that penetrate the tubal serosa. The actual staging system employed, however, is a modification of the FIGO staging system for ovarian cancer.

In contradistinction to ovarian cancer, fallopian tube cancers tend to present at an earlier stage of development, with roughly 33 percent as stage I, 33 percent as stage II, and 33 percent as more advanced disease. The mainstay of therapy for patients with limited disease is surgical resection. Whether postoperative radiation therapy is of value as an adjuvant treatment in patients whose tumors have been completely resected is unclear in the absence of a randomized trial. If radiation therapy does have a role, it would seem to be in patients who have no gross disease.

Studies of chemotherapy in fallopian tube carcinoma are anecdotal. Agents noted to produce responses are the same noted to be active in celomic epithelial carcinoma of the ovary. It would seem reasonable to base the choice of systemic therapy in advanced or recurrent disease on extrapolation from data in ovarian carcinoma.

Esophageal Cancer. Part 6

Costs remain a significant problem. Those of you who are golfers who put titanium in your woods to hit the ball farther know that’s a very expensive metal. So some of these stents using nitinol and other compounds, the cost is still very high and that’s a major concern when we look at cost effectiveness. Our group last spring presented some information. This was a randomized study, a small number of patients, but we tried to really get to this issue of cost and cost effectiveness. Comparing patients who only received laser photoablation therapy to stent placement. Again, this was the Schneider Wallstent that was used. Again, a small number of patients but effectiveness was about the same, but the patients in the stent group had fewer initial treatment sessions, fewer need for re-interventional sessions, and total endoscopic sessions overall were much less than the patients in the laser group. If you look at the cost – although the stent itself was $1,700 or so – overall the cost to the patient in their remaining lifetime was much higher for those patients who received laser therapy than for stent therapy. So our conclusions were that it’s a more cost-effective form of therapy for patiens for palliative care.

One point to keep in mind, those patients who have a tracheoesophageal fistula, as seen here – a little small slit, or a much more significant opening here, we can almost see the lung parenchyma – what can you do? There are three stents on the market, the Wallstent, the Z stent and the Ultraflex which are covered and again the covering is designed to kind of fit against the esophageal wall and provide a barrier for secretions and other things. Actually the Ultraflex, as shown here, because it is so flexible it can nicely conform to the esophageal wall. It works well for tracheoesophageal fistulas, just to kind of serve as a good barrier.
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In summary, it’s important to keep in mind the characteristics of the tumor; is it exophytic? Is extrinsic compression present? What are your goals of palliative therapy? Is the patient going to undergo adjuvant therapy? If that’s the case, we usually don’t recommend placement of an expandable metal stent as hopefully with shrinkage of the tumor you wouldn’t want the stent to just to simply fall into the stomach. The expandable stents have certainly gained a strong hold in the 1990’s. Generally they are thought to be very safe. They are technically much easier to put in place, rather than the rigid devices. Their effect is immediate, and generally minimal follow-up is necessary for most patients. The main drawback is their cost, but as I mention, I think cost-effectiveness still weighs towards the stents. The ideal situation, what’s in the best interest of your patients, will certainly … if the endoscopist is comfortable and can offer the patient a complete spectrum of palliative techniques.
Esophageal Cancer

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