This Article Abstract Full Text (PDF) CME: Take the course for this article: Osteogenic Sarcoma Presenting with Lung Metastasis eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Staddon, A. P. Articles by Warhol, M. Search for Related Content PubMed PubMed Citation Articles by Staddon, A. P. Articles by Warhol, M.

Osteogenic Sarcoma Presenting with Lung Metastasis

The Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, Pennsylvania, USA

Correspondence: Arthur P. Staddon, M.D., The Joan Karnell Cancer Center, Pennsylvania Hospital, 230 West Washington Square, Philadelphia, Pennsylvania 19106, USA. Telephone: 215-829-6088; Fax: 215-829-6104; e-mail: staddona{at}pahosp.com

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
After completing this course, the reader will be able to:

1. Understand the multimodality treatments needed for the best outcome in patients with osteogenic sarcoma.
   
2. Understand the selection criteria for resecting pulmonary metastases.
   
3. Identify the appropriate work-up and follow-up of patients with osteogenic sarcoma.
   

	ABSTRACT

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to appropriate diagnosis, staging, and treatment. Multimodality treatment options using chemotherapy, orthopedic surgery and thoracic surgery are presented. Physical medicine and rehabilitation evaluation and treatment are included. Current research options are discussed.

Key Words. Osteogenic sarcoma • Treatment • Surgery • Chemotherapy

	KARNELL CANCER CENTER GRAND ROUNDS AT PENNSYLVANIA HOSPITAL, OCTOBER 16, 2000

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
Case Presentation
O.N. is a 23-year-old male, working in Americorps, who noted pain in his right knee in May 1999. He went to his physician, who felt this was a sprain, and was prescribed physical therapy. The pain transiently got better and then returned. At Thanksgiving in 1999 the pain became much worse, and he was seen by his family physician, who ordered a plain x-ray of the knee, magnetic resonance imaging (MRI) of the knee, and a bone scan, all of which were positive for a mass in the right proximal tibia. The patient was referred to an orthopedic oncologist on December 11, 1999, and a needle biopsy was performed on December 13, 1999. The pathology showed high-grade osteogenic sarcoma.

Past medical history is unremarkable. The patient has no allergies, was on no medications, and only had wisdom teeth surgery. The patient had finished college in May 1999 and started work for Americorps in Boston, Massachusetts in June 1999. He denied smoking or drinking. On exam, his height was 5 feet 10 inches, weight was 150 pounds, and he appeared to be in no apparent distress. His general physical exam was normal without rales, wheezes, murmurs, or gallops. Liver and spleen were not palpable. He had no abdominal masses. His abdomen was nontender. His right proximal tibia revealed a small mass medially. Laboratory exam was unremarkable, with a hemoglobin of 14.3 g/dl, white count of 9,300 cells/µl, and a platelet count of 179,000. Protime was 11.4 seconds with an internationalized normalized ratio of 1.02. Bilirubin was 0.5 mg/dl, with an alanine aminotransferase of 12 IU/l and an aspartate aminotransferase of 23 IU/l. Alkaline phosphatase was slightly elevated at 153 IU/l. Blood urea nitrogen was 9 mg/dl with a creatinine of 0.6 mg/dl.

Chest x-ray showed multiple small pulmonary nodules, the largest being 1.2 cm, and a computerized tomography (CT) scan of the chest confirmed multiple bilateral lung nodules. A multiple-gated acquisition scan showed an ejection fraction in the normal range at 56%. A double port was placed.

From December 15, 1999 to February 25, 2000, the patient received two cycles of chemotherapy with cisplatin 120 mg/m² and doxorubicin 75 mg/m² on day 1 and with high-dose methotrexate at 12 g/m² (with a maximum of 20 grams) on days 22 and 29. The cycle was repeated on day 35.

On February 25, 2000, he had a repeat CT scan of the chest and had an excellent partial response with only minimal disease remaining. Because of his response, he underwent a third cycle of the same chemotherapy beginning March 1, 2000.

On April 13, 2000, he had a limb-sparing resection done by Dr. Richard Lackman. The pathology showed greater than 80% necrosis. The margins were negative. He had a repeat CT scan of the chest 2 days after surgery, on April 15, 2000, which clearly showed only a single 2 mm nodule in the right middle lobe, although there was a faint suggestion of several other residual nodules.

Postoperatively, he had three further cycles of the same chemotherapy beginning May 5, 2000 and finishing on August 14, 2000. On August 18, 2000, he had a CT scan of the chest, which still showed a single 1-2 mm lesion on the right and the possibility of several other tiny nodules bilaterally. On August 29, 2000, he had a sternotomy performed by Dr. Joseph Shrager of the Thoracic Oncology Department, and nine lesions were removed, all with negative margins and all showing osteogenic sarcoma; however, the pathology showed moderate differentiation of his tumor.

	OSTEOGENIC SARCOMA TREATMENT (DR. RICHARD LACKMAN)

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
The treatment for a suspected osteosarcoma, as with the case of O.N., begins with an appropriate preoperative evaluation. This usually requires an x-ray and an MRI scan prior to biopsy. This combination of studies accurately assesses the extent of local disease in terms of both intraosseous and extraosseous extension. They also, in combination, delineate the less calcified from the more calcified areas so that the latter can be avoided if the calcification is dense enough to make biopsy technically difficult.

The biopsy itself may be either an open biopsy or some form of needle biopsy. A well-planned open biopsy is still the gold standard. This supplies adequate tissue for histologic, immunohistologic, and genetic testing; and via frozen section, guarantees the presence of diagnostic lesional material within the biopsy specimen. The basic tenets of open biopsy involve obtaining diagnostic material while not interfering with subsequent treatment. In order to assure that both requirements are fulfilled, an extremity open biopsy should be performed through a short longitudinal incision, which is placed in line with the planned subsequent resection incision. The exposure should minimize soft tissue contamination, especially in terms of major neurovascular structures or important functional or flap structures. In completing the biopsy, it is important to continue careful surgical technique through the closure so that the incision is closed in multiple layers to prevent weeping and promote rapid healing. This is especially important in light of the fact that most patients go on to immediate postbiopsy chemotherapy.

Needle biopsies are possible and have the advantage of requiring little or no anesthesia and no actual incision. The disadvantages of needle biopsy are in terms of the small amount of tissue obtained and the potential sampling error. Needle biopsies are certainly appropriate in locations that are surgically inaccessible, such as about the spine or the acetabulum.

Once the diagnosis of osteosarcoma is histologically confirmed, neoadjuvant chemotherapy should be initiated quickly. Also, at this time, the work-up can be completed and should include a technecium bone scan and a computed axial tomography scan of the chest. At the completion of neoadjuvant chemotherapy, the staging studies (MRI of the lesion and CT scan of the lungs) should be repeated to help assess response to treatment prior to resection. Many attempts to quantify the lesional response have been published, but no one study is consistently able to accurately predict the percent necrosis seen in the resected specimen. The indicators of a good histologic response include the appearance of coalescing and benign appearing ossification on x-ray, decreased lesional vascularity as seen on angiography, and decreased soft tissue mass and reduced edema as seen on MRI scanning [1].

In the case of O.N., his soft tissue mass did shrink, his pain disappeared, and the lesion healed in with identifiable ossification on x-ray. As such, he was scheduled for wide resection and reconstruction. Safe limb-sparing resection of osteosarcomas was not possible prior to the era of modern chemotherapy, as most of these lesions extend beyond the bone of origin and usually grow in close proximity to major neurovascular structures. The process of tumor necrosis and healing in is what has allowed surgeons to pursue limb-preserving resection in place of the amputations that had been the routine for this disease prior to the 1980s [2].

In performing a wide resection, it is common to make the bone cut 2-3 cm above the highest level of abnormality as seen on MRI scan. In terms of the surrounding soft tissues, it is advisable to put as much distance and as many tissue planes as possible between the tumor and the plane of dissection. Despite this, surgeons are typically limited to only several millimeters of wide margin normal tissue adjacent to neurovascular structures, such as the femoral artery. It is the chemotherapy effect and the resulting tumor necrosis that make this a safe practice. It is obviously also desirable to leave grossly intact the surrounding muscles about the resection so that adequate motor function remains to control the reconstructed joint. In terms of major bone resection, the primary possibilities for reconstruction include segmental replacement prostheses or cadaver bone transplants (allografts). While allografts function well in nonweight-bearing areas, such as the proximal humerus or distal radius, their complication rate in weight-bearing applications has been enormous [3]. In lower extremity situations, such as reconstruction of the proximal femur, distal femur, or proximal tibia, metallic segmental replacement prostheses have proven to be much more durable and have had far fewer complications [4]. Prostheses also allow for much shorter rehabilitation times than allografts, due to the need for ligament and bone healing following allograft reconstruction.

O.N. did undergo proximal tibial resection and reconstruction, with a proximal tibial replacement, rotating kinematic hinge prosthesis. Because of the need to reattach the patellar tendon to the prostheses, he was treated initially with a cylinder cast for 6 weeks, during which time he was full weight bearing. Following this, his cast was removed and he began rehabilitation of the joint.

	MICHAEL WARHOL, M.D.

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
The patient's initial biopsy revealed a pleomorphic tumor with numerous large bizarre cells. The large bizarre cells were greater than 50 times the size of a normal lymphocyte. They had very hyperchromatic and pleomorphic nuclei and there were numerous atypical mitoses (Fig. 1). With conventional light microscopy alone, the differential diagnosis would include sarcomas, carcinomas, and amelanotic melanoma. Immunohistochemistry was of little help in resolving the differential diagnosis in this case. The tumor cells were positive only for vimentin, all epithelial markers were negative, as were markers for neural and muscle tissue. These results are consistent with a sarcoma, but do not help subtype the tumor. Focally, the tumor appeared to elaborate eosinophilic material highly suggestive of osteoid (Fig. 2) [5]. Electron microscopy of these areas revealed collagen fibers enmeshed with crystalline material confirming the presence of osteoid (Fig. 3). The identification of osteoid established the lesion as a high-grade osteosarcoma [6].

View larger version (148K): [in this window] [in a new window]   Figure 1. A photomicrograph of the tibial biopsy (200x, hematoxylin and eosin). Present are extremely large, pleomorphic cells with very hyperchromatic nuclei and abundant eosinophilic cytoplasm. There are bizarre mitotic figures.

View larger version (161K): [in this window] [in a new window]   Figure 2. Amorphous eosinophilic material within the tumor (100x, hematoxylin and eosin). This material is histologically consistent with osteoid.

View larger version (154K): [in this window] [in a new window]   Figure 3. An electron micrograph confirming the presence of osteoid (50,000x, uranyl acetate and lead citrate).

View larger version (115K): [in this window] [in a new window]   Figure 4. A gross photograph of the fixed, transected tibia. The large irregular white area surrounded by the hemorrhagic zone represents necrotic tumor. The tumor can be seen to penetrate cortical bone and extend into surrounding soft tissues.

View larger version (159K): [in this window] [in a new window]   Figure 5. A photomicrograph showing extension of tumor into adjacent skeletal muscle (40x, hematoxylin and eosin). The tumor has the same pleomorphic appearance that it did on the original biopsy.

View larger version (154K): [in this window] [in a new window]   Figure 6. A photomicrograph of the central portion of the tumor (40x, hematoxylin and eosin). Present are small, necrotic bony trabeculae embedded in amorphous necrotic tissue.

View larger version (156K): [in this window] [in a new window]   Figure 7. A photomicrograph of the lung resection (100x, hematoxylin and eosin). The metastatic osteosarcoma consists predominantly of osteoid, which is the amorphous eosinophilic material seen throughout the lesion.

	JOSEPH B. SHRAGER, M.D.

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

The lung is the most common site of metastasis for virtually all malignancies, with the possible exception of malignancies that drain into the portal venous system, for which the liver is likely the most common site of metastasis. In the not so distant past, patients with pulmonary metastases from any malignancy were thought to have incurable disease. Beginning in 1939, however, with the first report of an operation for a pulmonary metastasis by Barney and Churchill [7], we began to see increasing numbers of reports of pulmonary metastectomies. In 1947, Alexander and Hait [8] reported the first series of pulmonary metastectomies for various histologies, and there were a number of 3-year survivors in this series. In 1965, Thomford and colleagues [9] reported a 31% 5-year survival with multiple unilateral metastases from primaries of various histology. Subsequently, larger series resulted in expanded indications for metastectomy and attempted to establish selection criteria.

Virtually all agree that pulmonary metastectomy should not be done for esophageal carcinoma, gastric carcinoma, pancreatic carcinoma, or prostate carcinoma. The reason for this is that these diseases, when they appear in the lung, by virtue of the biology of the particular tumor, are very highly likely to be present in at least microscopic foci in other organs as well. As for other selection criteria for pulmonary metastectomy from histologies other than sarcoma, there is no clear agreement, and the selection criteria differ for different histologies. There are several selection criteria on which all authors agree and apply to all histologies. These are that the primary lesion must be controlled, that there is no evidence of metastatic disease outside the lung, and that all metastases are resectable (there seems to be no benefit to debulking procedures). Prognostic indicators, which some, but not all, studies support, are that patients with fewer metastases likely have a better outcome, and that patients with a longer disease-free interval before the appearance of the pulmonary metastases likely have a better outcome.

As I stated above, osteosarcoma is the prototype tumor for pulmonary metastectomy. This is the case because greater than 70% of patients with osteosarcoma metastatic to the lung have the lung as the sole site of metastasis. Furthermore, we have very effective chemotherapy for osteosarcoma now, and this has led to a great success with the combination of chemotherapy and surgical treatment. The incidence of pulmonary metastases fell from 92% to 31% after the advent of combination chemotherapy between the early 1970s and early 1990s [10]. Over the same time period, the percentage of those with metastases who underwent pulmonary resection increased from 70% to 82%. Although one might make the argument that a higher percentage underwent operation because selection criteria were loosened, a close analysis of these data suggests that there were decreased numbers of metastases in the lungs after the advent of effective chemotherapy, and therefore, there was a greater likelihood of complete resectability in patients who were considered for surgery.

The results of pulmonary metastectomy for osteosarcoma across a number of nonrandomized studies show 5-year survival rates in the 40%-50% range [11]. Although a selection bias is certainly not ruled out by these nonrandomized studies, it is very difficult to argue that surgical resection has not had an impact on survivorship in this disease when historical controls had 0% survival. It is very unlikely that a randomized study will ever be carried out.

The selection criteria for osteosarcoma in particular include those listed above for metastases from other histologies. That is, the primary lesion must be controlled, there must be no evidence of metastatic disease outside the lung, and the disease must appear to be completely resectable. On this last issue, it should be mentioned that we have certainly become increasingly aggressive due to: A) the effectiveness of the chemotherapy, which is likely to be able to eliminate microscopic disease that cannot be removed surgically, and B) the decreasing morbidity of a surgical approach with modern surgical care. Furthermore, while most reports demonstrate lower survival when there are greater than three nodules containing tumor, there are still many long-term survivors with many more metastases than this.

There also appears to be a role for reoperation when patients have recurrent pulmonary metastases after an initial metastectomy, and it is not uncommon that this is required. In the National Cancer Institute series reported by Temeck and colleagues [12], 70 of 152 patients required more than one operative procedure for removal of metastases. There was still an approximately 50% long-term survival in patients who were felt to be completely resectable at this second operation. There are also many reports in the literature of successful third reoperations.

In terms of surgical technique, simple wedge resections are typically all that is required. Anatomic resections, including removal of entire segments or lobes, are performed only when necessary in order to completely remove the disease. It is rare for these lesions to metastasize to the lymph nodes in the way that epithelial tumors of the lung do, so routine lymphadenectomy is not required. Furthermore, the lesions tend to be quite "punched out," so that they can be removed completely and without risk of recurrence with only small surgical margins. The incisions that are usually preferred are thoracotomy or sternotomy. As seen in O.N.'s case, sternotomy is most useful for disease that is bilateral at the outset. In cases in which there is disease in the left lower lobe, particularly disease in the basilar segments of the left lower lobe, sternotomy is not optimal, as these lesions can be difficult to reach due to the location of the heart. Thoracotomy is usually employed when the disease is unilateral, and staged bilateral thoracotomy must often be used if there is bilateral disease that includes significant left lower lobe disease, or if the disease is centrally placed and it is thought that it might require a formal, anatomic resection.

We tend to use a completely muscle-sparing, vertical axillary thoracotomy when thoracotomy is indicated in these patients. This creates less functional compromise postoperatively since the chest wall muscles are not divided, and it provides excellent access to all locations in the chest. When the best possible exposure is necessary, we perform a modified posterolateral thoracotomy with division of the latissimus dorsi but complete sparing of the serratus anterior muscle. Sternotomy is actually a very well-tolerated operation, with typically less postoperative pain than a thoracotomy, and for this reason, we prefer to use it for bilateral disease rather than the staged bilateral thoracotomy if we feel that all visible disease will be removable through this incision. In this case, after his sternotomy, the patient required narcotic analgesics for only about 1 week. Another alternative to staged bilateral thoracotomy is a thoracosternotomy, which divides the lower sternum transversely and extends into the intercostal spaces bilaterally. I have not tended to use this incision frequently as patients seem to have a significant amount of postoperative pain with its use.

Video assisted thoracoscopy (VATS) is useful only in very selected circumstances when treating metastatic disease. Indications for VATS include situations where the diagnosis is in doubt, or when there is a solitary nodule on one side. It should be noted, however, that using VATS at all for this disease is controversial. McCormack and colleagues from Memorial Sloan-Kettering [13] reported a prospective trial where they performed first VATS, then follow-up thoracotomy routinely in 18 patients with metastases. Of note, only one of these patients had sarcoma as the histology of the primary tumor, but nevertheless, they found that additional malignant nodules beyond what was seen on the preoperative CT scan were found at thoracotomy in 56% of patients. Other than the fact that a vast majority of these patients were not sarcoma patients, other problems with the clinical applicability of this study include the fact that: A) older generation CT scans were employed and it is likely that the newer, spiral CT scans show a higher percentage of the nodules present, and B) it is not clear what the significance is of tiny lesions when effective chemotherapy is available. Carrying this report's argument to its logical conclusion would suggest that we should be doing sternotomy or bilateral thoracotomy on all patients, even if they have a single visible lesion on one side on CT scan, and this would seem to many to be unreasonable. Thus, we do use VATS occasionally for metastatic sarcoma patients, but not with great frequency.

To justify taking an aggressive surgical approach to patients with metastatic sarcoma, we must be able to do these procedures with low morbidity and mortality. The surgical mortality for metastectomy is less than 1%, and the morbidity is similar to any pulmonary resection. The most common morbidities are minor pulmonary complications such as atelectasis causing fever. Wound infections are highly unusual in the chest. Patients who have undergone combination chemotherapy are always at some risk for pulmonary toxicity, and this was a particular problem in patients who had received bleomycin. With the advent of other agents, pulmonary toxicity appears to be less common, but we continue to evaluate all patients with preoperative pulmonary function tests to be sure they can tolerate the anticipated resection, and we limit intraoperative inspired oxygen concentrations to avoid any free radical effect that this may have in conjunction with the chemotherapeutic agents.

In conclusion, osteosarcoma is the prototype malignancy in which patients benefit from pulmonary metastectomy. We take a very aggressive approach to resection in these young patients who tolerate such an aggressive approach well. Prolonged survivals are 40%-50% with the combination of modern chemotherapy and aggressive surgery.

	KEITH M. ROBINSON, M.D.

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
O.N. presented to the Rehabilitation Medicine Outpatient Clinic about 6 months after the total knee replacement. At that time, he continued to complain of a "grinding" type of right knee pain associated with decreases in strength. Additionally, he complained of lower back pain that was nonradiating and localized to the high paralumbar area. Functionally, he was ambulating in the community with an axillary crutch in the left upper extremity.

A more extensive history was taken as to the nature of his knee pain prior to his diagnosis with osteogenic sarcoma. He reported that approximately 6 months prior to the biopsy, he had knee pain that was localized to the inferior aspect of the patella. His primary care physicians referred him to physical therapy who treated him for "muscular imbalance" of his quadriceps mechanism. Most likely, he had a patellofemoral syndrome or chondromalacia patellae with abnormal patellar tracking associated with imbalance of the medial and lateral quadriceps, possibly associated with iliotibial band tightness. His pain did not improve with physical therapy. In considering the possible mechanisms of pain during the prediagnostic period, most likely there was inefficient quadriceps contraction because of the close proximity of the patellar tendon to the tumor at its attachment on the tibial crest. Additionally, he inevitably sustained some disuse atrophy.

At the time of the exam 6 months after surgery, his medial quadriceps mechanism was quite impressively atrophied in comparison with the lateral quadriceps mechanism. Furthermore, the right knee essentially was stable with the exception of a moderate degree of lateral laxity. There was no pain during patellar compression or patellar inhibition with a gentle quadriceps contraction. In addition to the atrophy observed at the medial quadriceps, there was atrophy of the hamstrings, the anterior tibialis, and the gastroc-soleus groups. The quadriceps strength was graded at 2/5, the hamstrings at 3⁺/5, the anterior tibialis at 4/5, and the gastroc-soleus group at 4/5. There were no obvious distal sensory deficits. He had a mildly positive Romberg. He demonstrated a one-quarter of an inch leg length increase on the right side. This was associated with a mild degree of right ankle pronation. Balance screening, including five unsupported sit-stand maneuvers in under 30 seconds, tandem standing for greater than 10 seconds, and tandem walking for greater than 10 feet, was unremarkable. His gait showed a compensatory hyperextension at the right knee in midstance. Examination of the pelvis and lower back revealed that the right hip flexor was in a good degree of spasm on palpation and was causing some pelvic asymmetry. Provocative maneuvers of the sacroiliac joints were unremarkable. He had pain on palpation over the L2 facet on the right. There were no root tension signs.

The presumptive diagnosis of the knee pain was continued patellofemoral syndrome associated with severely imbalanced medial and lateral quadriceps mechanisms [14]. His lower back pain was associated with lumbar facet malalignment and pelvic asymmetry. Diagnostically, the plan was to obtain lumbosacral spine films with flexion-extension views to rule out any spinal instability and to screen for metastatic lesions. We revised his physical therapy program. During this 6-month postoperative course, he had been doing physical therapy every other week. The major obstacle with participating in more frequent outpatient physical therapy as well as a consistent home-based exercise program, was ongoing fatigue related to chemotherapy interventions. His pain also seemed poorly controlled at the right knee. Thus, we recommended that more aggressive isometric strengthening of the medial quadriceps mechanism and the hamstrings be operationalized, and that this progress eventually to short arc, isotonic, close kinetic chain strengthening. It was recommended that he obtain a home functional electrical stimulation unit such that when he was too fatigued to perform his own exercise program, he could use this to induce isometric contractions, particularly of the medial quadriceps mechanism, as a passive mode of strengthening. Moreover, the use of functional electrical stimulation was recommended to "jump start" the medial quadriceps strengthening. It was additionally recommended that he learn to use superficial ice after his exercise program in an effort to control pain associated with exercise-induced inflammation. Water walking was also advised, as well as a pelvic rebalancing and stabilization program, and muscle energy techniques for realignment of the lumbar facets. Finally, a nutritional assessment was recommended to explore whether his protein intake was sufficient to support a strengthening program.

	MEDICAL ONCOLOGY (DR. ARTHUR P. STADDON)

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
Is there a need for chemotherapy in osteogenic sarcoma? This is widely accepted now, but it has not always been in the past. Because of this, the Osteogenic Multi-group Study was started [15]. This study compared surgery alone with surgery followed by postoperative chemotherapy. In the surgery alone arm, 15 of 19 patients relapsed. In the patients who received postoperative chemotherapy, only 8 of 48 relapsed. This was statistically significant with a p value of <0.001, and the study terminated early. From this time on, it has been accepted that chemotherapy should be a standard part of treatment for osteogenic sarcoma. The rationale is that patients have micrometastatic disease at presentation and, if treatment is only local-regional, these patients will develop metastatic disease. The metastatic spread is usually to the lung [16].

Approximately 10%-20% of patients present with gross metastatic disease at initial presentation. Standard chemotherapy in the year 2002 includes cisplatin 120 mg/m², with doxorubicin 75 mg/m² on day 1, followed by methotrexate at 12.5 g/m² (maximum dose = 20 grams) on days 22 and 29 of each cycle. Each cycle is repeated every 5 weeks for a total of six cycles. Chemotherapy can be given as an adjuvant following surgery or in a neoadjuvant manner, where the chemotherapy is given prior to surgery.

Neoadjuvant chemotherapy has a number of benefits. It allows us to start systemic therapy earlier and not have to wait for healing after surgical intervention. Clinical response can be evaluated by pain relief, size of tumor mass, and by imaging studies. Pathologic response to the initial chemotherapy can be evaluated, and if the response is poor, the chemotherapy can be changed to noncross-resistant drugs. Finally, neoadjuvant chemotherapy increases the possibility of limb-salvage surgery. A potential disadvantage of neoadjuvant chemotherapy is the possibility of progression of the disease while receiving chemotherapy.

Besides cisplatin, doxorubicin, and high-dose methotrexate, osteogenic sarcoma is sensitive to ifosfamide (Ifex). Ifosfamide response is dose dependent and schedule dependent. Objective response varies from 10%, using 6 g/m², to 25%, using 10 g/m², to an objective response of around 40%, treating with 14 g/m² [17]. Schedule is also important. The response rates are higher when the ifosfamide is given over multiple days and by short intravenous infusion, as opposed to continuous 24-hour infusion.

Ifosfamide toxicities include nephrotoxicity, urothelial toxicity, encephalopathy, myelosuppression, reproductive toxicity, and the theoretic possibility of an increase in second malignancies. Nephrotoxicity is most commonly tubular, with patients developing an acquired Fanconi's syndrome with renal loss of potassium, magnesium, and bicarbonate. These electrolytes and bicarbonate need to be replaced. By keeping the serum bicarbonate above 25 mmol/l, the incidences of acute and chronic renal failure and encephalopathy are decreased. Nephrotoxic renal failure does occur, although it is rare, and the renal insufficiency can be insidious in onset. It is usual to hold ifosfamide if the creatinine is above 2.0 mg/dl, unless it can be lowered by hydration. To avoid nephrotoxicity, angiotensin-converting enzyme inhibitors should be avoided, as should nonsteroidal anti-inflammatory agents.

Urothelial toxicity includes hemorrhagic cystitis, which can be avoided by using mesna, given on an equal molar concentration to ifosfamide, as well as giving a bolus dose 4 and 8 hours posttherapy. Mesna can also be given by continuous infusion. Encephalopathy is rare but can include delirium, coma, and on occasion, seizures. There are data in the literature suggesting that methylene blue may be an antidote, although the data supporting this are not strong.

All patients who receive high-dose ifosfamide will have myelosuppression with white counts dropping to a nadir between 0.1 and 0.5. All patients need to be supported with growth factors. The question of reproductive potential has arisen, although there are little data in the literature. The majority of patients treated at our center and under the direction of Dr. Richard Lackman have been able to give birth to children or to father children. A recent abstract reports three cases of premature menopause in young women treated with high-dose ifosfamide [18]. Ifosfamide is similar to cyclophosphamide, which is known to induce secondary malignancies, but as of yet, secondary malignancies with ifosfamide have not been reported.

There are data from France and elsewhere suggesting that VP-16 may be synergistic with ifosfamide in osteogenic sarcoma [19-21]. VP-16 alone has a very low response rate in phase II studies. The Dana Farber group is currently using high-dose ifosfamide at 3.5 g/m² daily for 5 days with 100 mg/m² of VP-16 daily for 5 days given every 3 weeks with intensive support and growth factors. This is being given on protocol to patients who present with metastatic disease to try to confirm the results of a phase II Pediatric Oncology Group trial [22]. The preliminary data have recently been published [23].

In this case, the patient was treated with standard chemotherapy and had an excellent clinical response with nearly complete resolution of multiple fairly large lung nodules. His pathologic response, although 80%, is not considered optimal. His lung nodules, which were 1-2 mm at the time of resection, after six cycles of standard chemotherapy did show some differentiation with more osteoid formation (Fig. 7).

Another agent for which there are some recent data is MTP-PE (muramyl tripeptite phosphatidyl ethanolamine). The National Intergroup Protocol used cisplatin, doxorubicin, and high-dose methotrexate with or without the drug MTP-PE. The two other arms were the four-chemotherapy-drug combination (cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide) with or without MTP-PE. MTP-PE is a biologic agent that increases the number of natural killer cells and, in the animal model, initially showed response rates in dogs with osteogenic sarcoma, especially those with low tumor burden. MTP-PE has been shown to prolong progression-free survival in relapsed osteogenic sarcoma [24]. The five-drug arm, using cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide with MTP-PE, was significantly better than the other arms [25]. The role of MTP-PE in osteogenic sarcoma is unclear.

In summary, this patient had an excellent response to standard chemotherapy with resolution of his pain and a marked decrease in the number and size of his lung nodules, but only had an 80% pathologic response after three cycles of neoadjuvant chemotherapy. After completing six cycles of chemotherapy, he had residual small metastatic lung nodules. These were resected and on pathology he had viable tumor, even though marked differentiation of the tumor was noted. At the time of this presentation, he was in complete remission and was asymptomatic.

What can we conclude from this case? First, there was an excellent clinical response. Second, there was only a moderate pathologic response to the primary tumor, although we did have differentiation seen in the lung nodules. Third, there were more residual lung lesions noted at the time of surgery than seen on spiral CT scan. Fourth, it is clear that patients such as this need to have a multidisciplinary approach with interventional radiology, orthopedic oncology, thoracic oncology, medical oncology, rehabilitation, as well as supportive care with social work and counseling being involved. Fifth, I believe that there is a need for further therapy. Even though, at the present time, the patient has a complete response with the combination of chemotherapy and surgery, there is a high probability of recurrence.

What are the options that could be used at this time? The first would be to consider high-dose ifosfamide with or without VP-16. The patient has had six cycles of high-dose cisplatin, and there are data to suggest that it is more difficult to get full doses of ifosfamide/VP-16 in when patients have had more than 360-400 mg/m² of cisplatin. I do believe that this is possible, and that it would be possible to treat with ifosfamide at 3.5 g/m² and VP-16 at 100 mg/m² on days 1-5 at 3-week intervals and get two or three cycles in safely. We have been doing this on an outpatient basis in our patients who have good support and who are reliable.

A second possibility is the use of MTP-PE either on a compassionate basis following the ifosfamide/VP-16 or given in conjunction with the ifosfamide/VP-16. In the prior national study, MTP-PE was given twice a week, 3 days apart, for 3 months, then once a week for the next 3 months, and then the patients were followed. Recently, ET-743 has been shown to have activity in soft tissue sarcoma and in some osteogenic sarcomas [26,27] and STI571 has shown activity in gastrointestinal stromal tumors [28,29]. These drugs are being further evaluated and may be possible treatments for refractory osteogenic sarcoma patients in the future.

There should be close follow-up and the National Clinical Pathway Development Group [30] suggests a CT scan of the chest alternating with a chest x-ray every 3 months for the first 2 years, as well as an MRI at the site of the primary at 6-month intervals. In patients who present with metastatic disease to the lung, I prefer to follow with spiral chest CTs at 3-month intervals, watching for early relapse, and surgically resecting patients who have a small number of lung nodules at relapse.

The patient, after discussing this at length with all of his consultants and his family, decided to proceed with high-dose ifosfamide and VP-16 given at 3-week intervals for two cycles, then, if available, to proceed with 6 months of therapy using MTP-PE, and then to be followed.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 
For secretarial and editorial assistance, we thank Marylou Osterman.

	REFERENCES

Top Learning Objectives Abstract Karnell Cancer Center Grand... Osteogenic Sarcoma Treatment... Michael Warhol, M.D. Joseph B. Shrager, M.D. Keith M. Robinson, M.D. Medical Oncology (Dr. Arthur... References

 

1. Kumpan W, Lechner G, Wittich GR et al. The angiographic response of osteosarcoma following pre-operative chemotherapy. Skeletal Radiol 1986;15:96–102.[CrossRef][Medline]
2. Weis LD. The success of limb-salvage surgery in the adolescent patient with osteosarcoma. Adolesc Med 1999;10:451-458, xii.
3. Hornicek FJ Jr, Mnaymneh W, Lackman RD et al. Limb salvage with osteoarticular allografts after resection of proximal tibia bone tumors. Clin Orthop 1998;352:179–186.
4. Freedman EL, Eckardt JJ. A modular endoprosthetic system for tumor and non-tumor reconstruction: preliminary experience. Orthopedics 1997;20:27–36.[Medline]
5. Ghadially FN. Ultrastructural Pathology of the Cell and Matrix. Boston: Butterworths, 1988:127-128.
6. Dahlin DC, Unni KK. Bone Tumors. Springfield: Charles C. Thomas, 1986:269-285.
7. Barney JD, Churchill ED. Adenocarcinoma of kidney with metastasis to lung cured by lobectomy. J Urol 1939;42:269–276.
8. Alexander J, Haight C. Pulmonary resection for solitary metastatic sarcomas and carcinomas. Surg Gynecol Obstet 1947;85:129–146.
9. Thomford NR, Woolner LB, Clagett OT. Surgical treatment of metastatic tumors in the lungs. J Thorac Cardiovasc Surg 1965;49:357–363.
10. Skinner KA, Eilber FR, Holmes EC et al. Surgical treatment and chemotherapy for pulmonary metastases from osteosarcoma. Arch Surg 1992;127:1065–1071.[Abstract]
11. Temeck BK, Wexler LH, Steinberg SM et al. Metastasectomy for sarcomatous pediatric histologies: results and prognostic factors. Ann Thorac Surg 1995;59:1385–1389.[Abstract/Free Full Text]
12. Temeck BK, Wexler LH, Steinberg SM et al. Reoperative pulmonary metastasectomy for sarcomatous pediatric histologies. Ann Thorac Surg 1998;66:908–913.[Abstract/Free Full Text]
13. McCormack PM, Bains MS, Begg CB et al. Role of video-assisted thoracic surgery in the treatment of pulmonary metastases: results of a prospective trial. Ann Thorac Surg 1996;62:213–217.[Abstract/Free Full Text]
14. Kelley SS (section editor), Erpelding JM, Kobs J et al. American Academy of Orthopaedic Surgeons: Essentials of Musculoskeletal Care. Rosemont, IL: The Academy, 1997:361-363.
15. Link MP, Goorin AM, Horowitz M et al. Adjuvant chemotherapy of high-grade osteosarcoma of the extremity: updated results of the Multi-Institutional Osteosarcoma Study. Clin Orthop 1991;270:8–14.
16. Malawer M, Link M, Donaldson S. Sarcoma of bone. In: DeVita VT, Hellman S, Rosenberg S, eds. Cancer Principles and Practice of Oncology, Sixth Edition. Philadelphia: Lippincott Williams and Wilkins, 2001:1891-1935.
17. Patel SR, Vadhan-Raj S, Papadopolous N et al. High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies–dose-response and schedule dependence. J Clin Oncol 1997;15:2378–2384.[Abstract/Free Full Text]
18. Palmert MR, Abu KA, Goorin AM. Premature ovarian failure after ifosfamide administration. Proc Am Soc Clin Oncol 2001;20:378a.
19. Yalcin S, Gullu I, Barista I et al. Treatment of advanced refractory sarcomas with ifosfamide and etoposide combination chemotherapy. Cancer Invest 1998;16:297–302.[Medline]
20. Goorin AM, Canter A, Link MP. A phase I trial of etoposide (VP) and escalating doses of ifosfamide (IFCS) plus G-CSF in recurrent pediatric sarcomas. Proc Am Soc Clin Oncol 1994;13:1458a.
21. Gentet JC, Brunat-Mentigny M, Demaille MC et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer 1997;33:232–237.
22. Geiser P, Ferguson W, Goorin AM et al. Successful phase II trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a Pediatric Oncology Group trial (POG). Proc Am Soc Clin Oncol 1998;17:535a.
23. Goorin AM, Harris MB, Bernstein M et al. Phase II/III trial of etoposide and high-dose ifosamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002;20:426–433.[Abstract/Free Full Text]
24. Kleinerman ES, Gano JB, Johnston DA et al. Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol 1995;18:93–99.[Medline]
25. Meyers P, Schwartz C, Bernstein M et al. Addition of ifosfamide and muramyl tripeptide to cisplatin, doxorubicin and high-dose methotrexate improves event-free survival (EFS) in localized osteosarcoma (OS). Proc Am Soc Clin Oncol 2001;20:367a.
26. LeCesne A, Blay J, Judson I et al. ET-743 is an active drug in adult soft-tissue sarcoma (STS): a STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 2001;20:353a.
27. Demetri GD, Manola J, Harmon D. Ecteinascidin-743 (ET-743) induces durable responses and promising 1-year survival rates in soft tissue sarcomas (STS): final results of phase II and pharmacokinetic studies in the USA. Proc Am Soc Clin Oncol 2001;20:352a.
28. Blanke CD, von Mehren M, Joensuu M et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI 571, in patients with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing C-KITT (CD117). Proc Am Soc Clin Oncol 2001;20:1a.
29. Van Oosteram AT, Judson I, Verweij J et al. STI 571, an active drug in metastatic gastric intestinal strand tumors (GIST), an EORTC phase I study. Proc Am Soc Clin Oncol 2001;20:1a.
30. O'Reilly RO, Link M, Fletcher B et al. NCCN pediatric osteosarcoma practice guidelines. The National Comprehensive Cancer Network. Oncology (Huntingt) 1996;10:1799–1812.[Medline]

This Article Abstract Full Text (PDF) CME: Take the course for this article: Osteogenic Sarcoma Presenting with Lung Metastasis eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Staddon, A. P. Articles by Warhol, M. Search for Related Content PubMed PubMed Citation Articles by Staddon, A. P. Articles by Warhol, M.