פרופסור עפר מרימסקי

סרקומה של עצם Bone Sarcoma, Osteogenic Sarcoma, Osteosarcoma      

 

סרקומה הינה שאת ממאירה ממקור הרקמות המהוות את מערכת השלד והתנועה, העצבים ההיקפיים, כלי הדם, השומן או דפנות האיברים השונים. סרקומה של עצם (ס"ע) נוצרות בדרך כלל מרקמת העצם, ובמיקרים נדירים יכולה להתפתח גם ברקמות אחרות של מערכת התנועה (ס"ע חוץ-שילדיות). סרקומת השלד הינה גידול נדיר ומהווה כ- 0.2% מכלל השאתות הממאירות. השאתות השכיחות ביותר מבין סרקומות השלד הן סרקומה ע"ש יואינג ו-אוסטאוסרקומה (ס"ע). הסיבה להתפתחות ס"ע אינה ברורה. ובמקרים אחדים ניתן לקשור אותה למחלות רקע כמו רטינובלסטומה, מחלת פג'ט, אולייר, וטיפול קרינתי קודם.  הממצא הקליני השכיח הוא כאב קל עד בינוני. בתחילה הכאב אינו קבוע ובהמשך מתחזק ומופיע ברוב שעות היממה. בדרך כלל ניתן לחוש בגוש נוקשה שאינו נייד, ההולך וגדל,  ומלווה תפיחות הרקמות הרכות סביבו, ולעיתים חום ואודם מקומיים. לעיתים ממקדת חבלה אקראית לאזור את תשומת ליבו של החולה לכאב חריג ביחס לעוצמת החבלה. פרק הזמן הממוצע החולף בין תחילת ההסתמנות לבין קביעת האבחנה הוא 3-6 חודשים. המהלך הקליני של ס"ע בלתי מטופלת הוא הופעת גרורות ראתיות וגרמיות ומוות תוך 18-24 חודשים. בכל מקרה בו נחשד קיומה של ס"ע יש לפנות לצוות-מומחה לטיפול בסרקומה, הפועל ביחידה משולבת של אורטופדיה-אונקולוגית. הצוות כולל אונקולוג מומחה בסרקומה, אורטופד מנתח מומחה בגידולים של מערכת השלד, פתולוג, רדיולוג, מרדים מומחה בטיפול בכאב, פיזיותרפיסט(ית) ואחות. השלב הראשון בקביעת האבחנה הוא נטילת דוגמת-רקמה מהגוש (ביופסיה), ובדיקתה על ידי פתולוג מומחה. בשלב השני מבוצעות בדיקות הדמייה לקביעת שלב המחלה. לאחר מכן מתכנס הצוות המורחב לקביעת הגישה הטיפולית האינדיבידואלית. על פי רוב ניתנת כימותרפיה טרום-ניתוחית שמטרתה להביא למות הגידול הסרטני ולחיסול הפיזור המיקרוסקופי באזור צמיחתו ואיברים מרוחקים. הטיפול כולל תרופות שונות, ומלווה טיפול תומך מודרני המאפשר לחולה להתמודד היטב עם תופעות הלוואי. לאחר מכן מבוצע ניתוח משמר-גפה. לאחר קבלת התשובה הפתולוגית, מותאם טיפול כימי אחר-ניתוחי שנועד להמשיך ולחסל מוקדי פיזור סמויים באיברים מרוחקים. עם תום הטיפול מתחילה תקופת השיקום והמעקב הכוללת פיזיותרפיה, התעמלות, חזרה לשיגרה במקביל לבצוע בדיקה גופנית, בדיקות הדמייה ובדיקות דם לעיתים מזומנות. סיכויי ההחלמה טובים. מחלה גרורתית המופיעה לאחר מכן מטופלת בכימותרפיה ולעיתים בניתוח להסרת מוקדי מחלה שאריתיים. במקרה כזה סיכויי ההחלמה תלויים באפשרות להביא את החולה למצב של "חופשי ממחלה". 

 

בדיקות הדמיה ובדיקות דם לעיתים מזומנות. סיכויי ההחלמה טובים. מחלה גרורתית המופיעה לאחר מכן מטופלת בכימותרפיה ולעיתים בניתוח להסרת מוקדי מחלה שאריתיים. במקרה כזה סיכויי ההחלמה תלויים באפשרות להביא את החולה למצב של "חופשי ממחלה". 

 

Osteosarcoma Overview

Prof. Ofer Merimsky, MD 

Head of Unit Of Soft Tissue And Bone Oncology, Division Of Oncology,

Tel-Aviv Sourasky Medical Center, Affiliated With Sackler School Of Medicine, Tel-Aviv University, Israel.

Osteosarcoma: Background

Osteosarcoma occurs predominantly in children, adolescents and young adults. It is the most common primary malignant bone tumor (excluding myeloma), comprising 20% of all primary skeletal malignancies. Peak incidence (60% of cases) is during the second decade of life. It accounts for approximately 5% of the cancers in childhood. Chondrosarcoma is approximately half as common as osteosarcoma and accounts for 10% to 20% of the primary malignant bone tumors. Patients’ ages range from 7 to 73 years, but most tumors are diagnosed in patients between 30 and 60 years of age. Malignant fibrous histiocytoma of bone represents 2% to 6% of primary malignant bone tumors, and occurs between the ages of 30 and 70 years old [1].

 

Approximately 50% to 60% of osteosarcomas are located in the distal femur or proximal tibia, while the third most common site is the proximal humerus. In 75% of patients, the disease occurs in the metaphysis of long bones. In children and adolescents, 80% of these tumors arise from the bones around the knee, whereas in patients above 25 years of age, 40% of lesions are located in flat bones. Chondrosarcoma most commonly involves the femur and the pelvis, with a notable  preference for the secondary ossification centers. Primary fibrosarcomas and  malignant fibrous histiocytomas arise most commonly in long bones, usually the shafts of the femur or tibia [1]. Other primary malignant bone tumors also exist (myeloma) but this chapter will concentrate only on osteosarcomas as a model.  

 

The natural history of localized and resectable osteosarcoma of the extremity is dismal without adjuvant therapy. Literature data suggest that more than half of these patients develop metastases within 6 months of diagnosis, and overall, more than 80% develop local or distant recurrence within 2 years of diagnosis [2,3]. The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized resectable primary tumors treated only with surgery (amputation or limb sparing) can be expected to survive free of relapse [2,4].

Patients with localized disease have a much better prognosis than those with overt metastatic spread at diagnosis. The site of the primary tumor is a significant prognostic factor in localized disease: tumors of the axial skeleton have the greatest risk of progression and death versus limb tumors. Resectability, determined by the anatomical location and size of the tumor, is the most important prognostic feature since this neoplasm is relatively radio-resistant. Patients with osteosarcoma of craniofacial and other flat bones have good survival with complete removal of the involved bone, and may even have an improved outcome when treated by chemotherapy [5-7] . Patients with osteosarcoma as a second malignant neoplasm (not radiation-induced osteosarcoma) share the same prognosis as newly diagnosed patients if they are treated aggressively with surgery and combination chemotherapy [8]. The only feature that consistently predicts outcome is the histologic response to preoperative chemotherapy. Patients with greater than 95% necrosis in the tumor mass after induction chemotherapy, have a better prognosis than those with lesser amounts of necrosis [9,10,11].

Metastatic or unresectable osteosarcoma at diagnosis, although advanced and forecasting a grim prognosis, should not be regarded as a lost case. In the past, the progression-free survival rate for patients with metastatic or unresectable osteosarcoma was less than 20%. Later studies showed a better than 40% survival rate for patients with only pulmonary metastatic disease [1,12] . Prognosis for these patients appears to be more favorable with unilateral rather than bilateral pulmonary metastases, and for patients with fewer nodules as compared to those with many nodules. Patients with bony metastases have a poor prognosis. Aggressive treatment, including surgical removal of primary and/or metastatic disease at the time of diagnosis or after intensive polychemotherapy, is necessary [12].

Treatment options are indeed limited to either preoperative chemotherapy followed by surgical ablation of the local tumor and resection of metastatic disease, or surgical ablation of the local tumor and metastases, where possible, followed by combination chemotherapy. In any case the chemotherapeutic regimens are based on high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.

 

Definition Of Advanced Osteosarcoma

Advanced bone sarcoma has two distinct clinical forms: it may be either locally advanced or metastatic in various organs.

Locally advanced bone sarcoma usually involves all the compartments of the limb, or involves a major adjacent structure such as the neurovascular bundle,  or organs like the chest wall or vertebra. The disease is not amenable to limited locoregional intervention such as simple limb sparing surgery or isolated limb perfusion with chemotherapy, but necessitates a life-threatening or highly mutilating surgical procedure.

Local recurrence of osteosarcoma represents failure of primary surgery with or without chemotherapy. The tumor tends to be chemo-resistant and requires salvage amputation unless other sites are involved by metastatic disease.

Such tumors tend to be very symptomatic and impair the patient’s quality of life, especially when their location involves a proximal limb, a major joint or the spine. The symptoms might include intractable pain, sepsis, tumor fungation, hemorrhage, vascular thrombosis, pathological fractures, tumor and previous radiation-induced necrosis, or severe functional impairment.

Diffuse metastatic osteosarcoma is usually regarded as an incurable condition that requires palliation. Metastatic disease may be the first presentation of osteosarcoma or more often a late evolutionary phase of a formerly localized tumor, that had failed to respond to induction chemotherapy, limb sparing surgery and adjuvant chemotherapy. Several target organs for metastatic spread that are common include the lung, bone, liver, and brain. In such cases with diffuse spread  the disease is usually incurable by further chemotherapy or surgery. Exceptions are solitary metastatic lesions in certain organs that can be completely resected (eg pulmonary metastasis).

 

Treatment Options For Advanced Or Recurrent Osteosarcoma

Palliative chemotherapy

Advanced bone sarcoma is usually fatal and treatment options are rather limited. Close to one half of patients succumb to it. Median survival from the time metastases are detected is relatively short, although 20% to 25% of patients with metastatic sarcoma are alive 2 years after diagnosis [1].

Patients with metastatic sarcoma often are asymptomatic at the time that a radiograph or CT reveals metastases, and may remain free of symptoms for long periods of time. Thus, alleviation of symptoms is not an immediate concern in many patients, although disease progression is eventually inevitable [1].

Numerous drug combinations have been assessed in treated and untreated metastatic disease. The most effective of these have contained cisplatin, doxorubicin, and high-dose methotrexate plus leucovorin either as a two- or three-drug regimen. Response rates of the order of 25-35% have been obtained, although often based on rather small numbers. The most important studies on palliative chemotherapy in metastatic osteosarcoma include cyclophosphamide + doxorubicin + dacarbazine (29 patients, response rate 24%, [13]), cisplatin + vincristine + high-dose methotrexate (29 patients, response rate 28% [14]),

dacarbazine + doxorubicin (20 patients, response rate 35%, [15]), Dacarbazine + doxorubicin (19 patients, response rate 26%, [16]), and cyclophosphamide + doxorubicin + actinomycin D (20 patients, response rate 25%, [13]).

The valid oncological problem starts after failure of these agents to affect the disease course. The patients, especially the younger ones, may still have considerable life expectancy and good performance status, and are eager to be treated, but the caring oncologist may have nothing to offer.

Our protocol of combination chemotherapy for neoadjuvant and adjuvant chemotherapy for osteosarcoma is based on alternation of doxorubicin/cisplatin/ifosfamide with doxorubicin/ ifosfamide given in 3 week intervals before and after surgery. In case of suboptimal response to preoperative treatment courses, as histologically assessed, the adjuvant treatment includes etoposide plus ifosfamide.

Salvage or palliative chemotherapy for recurrent or metastatic disease has limited options. As a rule it may be possible to prescribe the same agents that have been used for induction and postoperative therapy, namely doxorubicin, cisplatin and ifosfamide provided that the left ventricular ejection fraction and renal function are preserved. The recent introduction of dexrazoxane (cardioxane) as a cardioprotector agent enables the administration of doxorubicin in total doses higher than 400-450 mg/m2 as long as the cardiac function is normal.

High dose methotrexate (8-10 gm/m2) and folinic acid rescue is our first priority for metastatic osteosarcoma, provided that the renal and the bone marrow reserves are adequate, and that there is no cardiac contraindication for massive hydration. Methotrexate is not well tolerated by adults due to renal toxicity, delayed clearance of the drug from the body, neurological toxicity, and the need for relatively prolonged hospitalization (5-7 days for each MTX course).

Ifosfamide may be given as a single agent or in combination with etoposide, together with mesna uroprotection. While given as a monotherapy, the dose of ifosfamide ranges between 9-12 gm/m2 administered by continuous intravenous infusion at a rate of 1.8-3 gm/m2/day . In combination with etoposide (100 mg/m2/d for 3-5 days) the dose of ifosfamide is 1.8 gm/m2/day given for 5 days. The response rate is low and of short duration. It should be noted that high dose ifosfamide therapy may be nephrotoxic [17].

Harris et al [18] treated young patients with recurrent osteosarcoma with ifosfamide. The response rate to ifosfamide was compared in two groups of patients younger than 30 years of age: Those with previously untreated osteosarcoma with metastases at diagnosis and/or unresectable primary tumors (group 1) and those patients with recurrent osteosarcoma following adjuvant chemotherapy who were not previously exposed to ifosfamide (group 2). Evaluation of response was conducted 3 weeks after two courses of ifosfamide (2400 mg/m2 x 5 days) were administered 3 weeks apart. Nine out of 33 (27%) evaluable patients in group 1 responded (1 complete and 8 partial responses) to ifosfamide. Among 30 evaluable patients in group 2, only 3 (10%) responded (1 complete and 2 partial responses; P = .04) Both groups of patients received equal doses of ifosfamide and experienced comparable toxicities. Results from this study suggest that the activity of new agents will be underestimated if tested in a population of heavily pretreated patients with recurrent disease. When possible, new chemotherapeutic agents should be tested in patients with a poor prognosis who have not been exposed to chemotherapy.

It is ethical to enroll the patients with metastatic osteosarcoma into trials with experimental agents or combinations. One example is the application of modulators of multi-drug resistance protein or gene. Brach Del Prever et al [19] reported an important observation in a young boy with metastatic osteosarcoma who was treated by cyclosporine and verapamil in addition to adriamycin and etoposide in order to overcome multi-drug resistance (MDR). Five treatment courses were provided. ECG monitoring during verapamil infusion did not show any cause for trouble; myelotoxicity was mild, with no need of transfusions. A lung CT scan at the end of therapy demonstrated an important decrease of the subpleural metastasis and the vanishing of lung nodules. A surgical intervention was provided together with 2 postoperative chemotherapy treatments. Twenty-six months later no sign of the disease was observed. Association of verapamil and cyclosporine with chemotherapy allowed a good clinical response with a very low toxicity, in a critical situation in which chemotherapy alone did not seem to offer any real possibility.

There is a need for active and minimally-toxic agents that can be given as second line treatment in patients with bone sarcomas. Palliation of symptomatic disease in a heavily pre-treated patients with low organ-reserves may serve as an end-point for phase II studies exploring the role of new chemotherapeutic agents.

We have treated a series of patients with advanced and doxorubicin-resistant osteosarcoma by gemcitabine.

 

Gemcitabine In Advanced Bone Sarcoma Resistant To Doxorubicin-Based Chemotherapy

Gemcitabine hydrochloride, 2’, 2’-difluorodeoxycytidine hydrochloride (Gemzar, Eli Lilly USA) is a pyrimidine nucleoside analog used as a chemotherapeutic antimetabolite. Although gemcitabine is similar in structure to cytosine arabinoside, it exhibits different characteristics and pharmacology which enhance its usefulness in the treatment of patients with solid tumors. Gemcitabine inhibits DNA replication by inhibiting DNA synthesis and by blocking repair mechanisms through masked chain termination. Additionally, gemcitabine exerts several other actions that self-potentiate its cytotoxic activity. Gemcitabine is usually well tolerated by the patients and its common associated side effects are not severe, and include low grade myelotoxicity, flu-like syndrome, fever, rash, swelling of the legs, nausea and vomiting. Gemcitabine has demonstrated significant clinical activity and clinical benefit response in a variety of tumors including non-small cell lung cancer, pancreatic carcinoma, breast, bladder and ovarian cancers  [20-23].

Available data on the use of gemcitabine in soft tissue or bone sarcomas is very scarce. Gemcitabine was found to be active on xenograft of STS growing in nude mice [24,25] . Palliative effects of gemcitabine in a patient with osteosarcoma who is resistant to standard chemotherapy [26] were recently mentioned by our team. We have recently reported our experience with gemcitabine in patients with a variety of sarcomas [27], of whom 7 had primary bone sarcomas, who have failed to respond to doxorubicin (adriamycin) and ifosfamide based chemotherapy.

The information given to patients before participation in such a study, especially when no more standard therapy exists for young patients with strong will power to live, should be given “controlled hope” but without illusions for cure. The patients were told that gemcitabine was highly experimental in sarcoma, that there was no literature on the topic, that worldwide experience with the drug was achieved in other diseases, and that the expected toxicity was relatively mild.

Treatment consisted of induction by gemcitabine 1000 mg/m2/w for 7 consecutive weeks, followed by one week recess. Response to the induction course was assessed by interview (for clinical benefit response and quality of life) and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m2/w for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Evaluation of response, toxicity and quality of life, was performed every 3 months by interview, physical examination, and ancillary tests, according to the WHO criteria. Progression was determined by  deterioration in clinical symptoms, appearance of new lesions or enlargement of a lesion by at least 25% of its pre-treatment size. Treatment was to be stopped in case of life threatening toxicity, progression of the disease, or upon patient’s refusal to continue.

Seven patients had advanced or metastatic extremity bone sarcoma, at age range of 15 to 43 years. All the patients were heavily pre-treated by various agents according to their disease, such as adriamycin, ifosfamide, high-dose ifosfamide, methotrexate, and etoposide. The involved sites were mainly the local tumor bed and lung.

The true objective response rate of osteosarcoma to gemcitabine was 0%. However, disease stabilization was observed in 5 out of 7 patients after having failed in previous treatments. Time to progression varied from 13 to 96 weeks. It should be noted that disease stabilization was accompanied by clinical benefit response, (improvement of performance status, alleviation of respiratory symptoms, alleviation of pain and reduction in narcotics consumption) and was observed only in those who also achieved a progression-free state.

All the patients who failed to respond to gemcitabine did not have any clinical benefit response. The treatment was well tolerated by the patients. Hematological toxicity was the main concern in our patients, of whom the vast majority were heavily pre-treated. Other toxic effects included weakness, rash, ascites (with no malignant cells in repeated taps), limb edema (deep vein thrombosis was excluded by Doppler-Ultrasound study), and low grade fever.

Our results pointed to important efficacy and a possible role for salvage of gemcitabine treatment in heavily pretreated patients with progressive bone sarcomas. Gemcitabine was found to be effective in achieving stabilization of osteosarcoma refractory to standard-chemotherapy consisting mainly of adriamycin, high-dose methotrexate, cisplatin and ifosfamide. Although disease stabilization is generally accepted as failure of chemotherapy, in this series of cases it should be regarded as success due to noteworthy disease control, clinical benefit response, low toxicity profile, especially in view of failure of accepted drugs.

It is interesting to note that gemcitabine has shown activity in soft tissue sarcoma [27,28,29]. In a recent study reported by our group [27] we have documented one partial response (leiomyosarcoma) and one minimal response (angiosarcoma) , yielding an true objective response rate of 5.5%. Another 6 patients achieved stabilization of disease, yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Postponing an inevitable death with a relatively non-toxic treatment, is an important issue especially in cases of young patients.

It is clear that no treatment recommendations can be made on the basis of such small series. However, it may be justified and warranted to investigate the activity of gemcitabine in a larger group of patients with sarcomas, particularly in osteosarcoma and leiomyosarcoma, even as a first line treatment for recurrent or metastatic disease.

 

Radiation Therapy

Radiation therapy has not played a relevant role in the management of  osteosarcoma because of the natural history of the disease, and because large doses of radiation (>70 Gy) are required to affect this tumor. However, it has been used as a palliative modality.

 

Palliative Major Amputation Of An Involved Limb By Advanced Bone Sarcoma

Major amputation was considered a procedure of choice for treating patients with bone and soft-tissue sarcomas of the limbs [30]. Limb sparing surgery [31], preceded and followed by effective chemotherapy with or without radiation therapy, has replaced amputation surgery [30] in most cases. Hemipelvectomy, forequarter amputation and hip, knee or shoulder disarticulation have become relatively rare procedures in the primary treatment of extremity sarcomas. The local control achieved by limb sparing surgery is similar to amputation surgery [31]. Local recurrence or persistent chemo- and radio-refractory disease constitute a major problem, both in the absence or presence of systemic metastases, whether symptomatic or not. Local symptoms such as agonizing pain that is only partially alleviated by narcotics, disease or treatment-related fractures, persistent ulceration and localized antibiotic-refractory infection, bleeding, tumor fungation, inability to walk and to enjoy daily activities, further aggravate the problem and impair the patient’s quality of life. In this clinical set-up palliative amputation of the limb should be considered. Paradoxically, the limited and relatively tolerable limb sparing surgery is performed on patients with high performance status attempting to achieve cure. On the same time, extended hemipelvectomy and the other major amputations that might be associated with a higher rate of morbidity and mortality, are performed on debilitated, ill patients with low performance status just to preserve their quality of life during their last months !

We have reported the results of our experience with major amputation carried out for palliation in 21 patients with cancer, of whom 12 had primary bone or cartilage malignancy [32].

The primary tumor was located in the upper limb in 2 patients and in the lower limb and pelvic girdle in 10 cases. The histological type of the primary disease was osteosarcoma in 6 patients, chondrosarcoma in 4 cases, malignant fibrous histiocytoma (MFH) of bone in 2 cases.

The treatments that had been given in order to control the disease and related manifestations included: Surgical attempts to resect the tumors and covering the exposed area with skin and/or muscle flaps. Isolated perfusion with tumor necrosis-a was tried in one case. Tumor regrowth, especially when accompanied by severe symptoms raised the option of amputation.

Chemotherapy, consisting of all the effective drugs (adriamycin, cyclophosphamide, ifosfamide, dacarbazine, vincristine, etoposide and cisplatin) alone or in combinations, given until the documentation of progression. A locally progressive disease, even in the presence of systemic metastases, provided that it was at least stable (or responded to chemotherapy) suggested amputation.

Pain control was carried out by using high doses of morphine (oral: morphine controlled release tablets: MCR, or parenteral) alone or in combination with other drugs (steroids, non-steroidal anti-inflammatory agents). Epidural analgesia was tried in patients with lower limb or pelvic tumors, but was not used continuously because of patient’s refusal to have an indwelling epidural catheter. Pain was assessed by the patients by using a pain scale from 1 (trivial pain) to 10 (“the worst pain in life”). The maximal dose of narcotics was defined as the dose that is no longer compatible with wakefulness and consciousness, or causes other intolerable side effects. It should be emphasized that major amputation was considered only after having clear-cut proof for failure of all the relevant treatment modalities.

The disease was loco-regional in 1 patient, both loco-regional and metastatic in 11 cases, and loco-regional complicated by a pathological fracture in 3 cases. The most frequent site of metastases was the lung, accounting for 11 cases. The local manifestations of the disease included severe pain and limb disability in all the cases, and fungating tumor (i.e.: open wound with tissue necrosis, purulent discharge) in 4 patients.

The performance status, according to Karnofsky’s scale (KPS), is disease-related, but not treatment-related. The KPS is influenced by the disease in all the involved sites, and its value (percentage) summarizes the overall functional capacity of the patient. If a cancer patient following major amputation had no signs or symptoms of disease, and was able to enjoy the same activities as another patient who had undergone an amputation for another reason (e.g. traumatic), his KPS was defined as 100%. The pre-operative KPS in our series ranged from 30% to 70% (median 40%). The postoperative KPS assessment was performed in the 3rd week postoperatively in cases of amputation, and in the 6th week postoperatively in cases of hemipelvectomy and FQA. Further KPS assessment was carried out during follow-up visits until demise. Quality of life was assessed before and after the procedure by a quality of life questionnaire (QLQ) [32]. The first questionnaire was completed by the patients 1 week prior to the operation. The second one was completed within 2 to 4 weeks following the procedure.

The surgical procedures were carried out after receiving  a thorough explanation by the surgeon, an interview by the chief-nurse of the Unit and later by a social worker, and after signing an informed consent. The procedures included hip disarticulation, knee disarticulation or below-knee amputation, forequarter amputation (FQA), and hemipelvectomy (simple or extended). Hemipelvectomy included complete removal of the lower limb, the innominate bone from the symphysis pubis to the sacro-iliac joint and the corresponding buttock [33]. Extended hemipelvectomy also includes in addition to simple hemipelvectomy, parts of the sacrum, the contra-lateral pelvic ring and adjacent organs that are infiltrated by the tumor [30,33,34].

 

Major amputations were performed in 12 patients with low performance status for palliation of agonizing pain, limb disability and fungating tumor. The length of hospitalization was 5 to 7 days in cases of upper limb amputation, 10 to 14 days in cases of lower limb amputation or simple hemipelvectomy, and 3 to 6 weeks in cases of extended hemipelvectomy. Local control of the disease and the disease-related pain were observed in all 12 patients. Phantom sensation and mild phantom pain were reported by all the patients. However, severe and long-lasting phantom pain necessitating repeated administration of narcotics, were not noted in any of the cases.

Mobility was assessed in 10 patients who had undergone a lower limb procedure. Two enjoyed the use of a prosthesis, six used a wheel-chair, and two used crutches. One patient succeeded in resuming to swim following forequarter amputation. An exceptional case was a Bedouin who lived in a tent in the desert of southern Israel. This man was bed-ridden because of a right distal femur tumor, and returned to his natural habitat following surgery. He was able to walk with the help of crutches or to get around with the aid of a wheelchair.

The KPS improved in 12/12 patients. Later, during the follow-up, the KPS dropped in the 12 patients due to disease progression in other sites. The KPS values following the amputation are listed in table 2.

Each QOL parameter was scaled from 1 (no intervention, e.g. no need of help in dressing), to 4 (maximal degree, e.g. suffering severe pain), via 2 (minor) and 3 (moderate). The quality of life was assessed in all the patients according to the questionnaires. The ability to perform activities requiring physical effort (i.e. carrying a bag, walking a distance), or to carry-on daily activities (i.e. eating, dressing, etc.) was moderately or greatly improved in the majority of the patients. Pain was reported to be alleviated in all the assessable cases. The physical well-being of the patients, reflected by weakness, tiredness, or the need for bed-rest was improved in approximately half of the patients. Emotional problems (i.e. stress, nervousness, depression) were improved in half of the patients. Sexual and social life were improved in most of the patients who answered the relevant questions. Overall, the quality of life was reported to be at least moderately improved by 2/3 of the patients. Negative effects (e.g. severe phantom pain) were not reported by the patients, probably due to the fact that disease-related invalidity was much more prominent than the procedure-associated invalidity.

The quality of life questionnaires were analyzed according to each of the parameters. The duration of the clinical benefit related to the amputation lasted till the patients’ death, while the KPS dropped due to disease in other sites.

Survival was not an endpoint of the study, but was calculated in order to have a control on the pre-operative estimated life duration. In other words, that we did not operate on terminally ill patients who had a life expectancy of only 2-3 weeks. The median survival of the patients following the procedure was 9 months, ranging from 3 to more than 85 months (the patient is still alive). The survival is presented in table 2. The status of the patients and their diseases are detailed in table 2. Lung metastases were the dominant cause of the death in our patients.

Major amputation carried out on severely ill, debilitated and invalid patients, accompanied with possible morbidity and mortality, without any obvious improvement of life expectancy, causes a major clinical and ethical dilemma. Should we urge the patient towards the risks of a major surgery, just for controlling pain and other local problems, without any chance of an overall control of the disease? Is there a place for “heroic” palliative procedures in cancer patients with a relatively short life expectancy? Do we have the right to perform a mutilating major amputation, that will probably change the self body- image of the patient, who already has clinical, social, psychological and emotional problems due to his uncontrolled malignancy? Or should we be conservative, and continue to try to control the pain and other symptoms by an intravenous drip of narcotics, even at the cost of impairment of mental functions, loss of consciousness, coma and death?

Our data points to the fact that palliative amputation is feasible, associated with acceptable mortality, and is worth-performing in low-performance status cancer patients with locally advanced disease. Local symptoms and signs were controlled, and quality of life was restored.

Amputation as a palliative procedure in patients with metastatic carcinoma, melanoma, or sarcoma has already been suggested in the literature [30,35,36]. Several clinical situations were raised by Malawer et al. as indications for palliative major amputations: involvement of a proximal limb or a major joint, accompanied by intractable pain, sepsis, tumor fungation, hemorrhage, vascular thrombosis, pathological fractures, radiation-induced necrosis, or a limb with severe functional impairment [35,36]. Pain alone, according to Malawer et al. [35], is not an indication for major palliative amputation, and should be accompanied by a local complication such as fracture, hemorrhage, and / or tumor fungation. In our opinion, pain alone does constitute an indication for palliative major amputation, especially if it is accompanied by pain-related limb dysfunction or low performance status due to the inability to use the limb because of agonizing pain. Palliative major amputation may be carried out in the presence of metastatic disease provided it is stable and does not seem to endanger the patient’s life in the near future, or in the presence of locally advanced disease without evidence of metastases. In any case, the low performance status is not a contra-indication for such a procedure, since it is influenced by the presence of a painful and actually useless limb.

Major amputation surgery might be associated with an operative mortality rate of 1 to 7% [30,,36,37,38,39]. The peri-operative morbidity is not negligible, and includes blood loss, hematoma, flap necrosis and wound infection [36,37,39]. In our series, only one out of 21 patients succumbed to immediate post-operative complications (cardiogenic shock in case number 10). In the remaining 20 cases, the complications (data not shown) were temporary and tolerable, and did not interfere with patients’ quality of life.

Phantom pain is reported in association with major amputation in cases of severe trauma, vascular disorders and malignancy. In our experience, 9 out of 19 patients who had undergone major amputation for cure of limb sarcomas (data not shown), noted severe phantom pain, while none of the 21 patients who had undergone similar type of procedures for palliation, reported severe phantom pain. The reason for the lack of severe phantom pain in our patients who had undergone palliative amputation, and who would normally require narcotics for pain control, is not clear. The fact that palliative major amputation was not associated with severe phantom pain contributed to the success of the procedure, and to the marked improvement of the patients’ quality of life.

The success of palliative major amputation can be assessed by the amelioration of the performance status, the local control of the symptoms and signs of the disease, the extent of rehabilitation of the patient, i.e. the use of wheel chair versus limb prosthesis, and the lack of complications.

The quality of life and the KPS of patients with advanced cancer are usually viewed in the context of the actual situation, as well as the remaining life until terminal care and death. In our series the quality of life was greatly affected by the local uncontrolled disease. The KPS is usually influenced by the local disease and the disease in other sites. The benefit of the local major amputation in terms of KPS might be masked by the deterioration of the clinical status due to other sites of metastases (e.g. the lungs). For this reason we evaluated the KPS following the procedure, within a period of time expected to be long enough for healing of the surgical wounds, resolving of immediate post-surgical complications, and for detection of changes in the KPS, while having no notable changes of the disease elsewhere. However in order to compensate for a possible bias (since the KPS represents an overall estimation of the functional capacity, and is not specifically related to the local problem), we added the quality of life questionnaires, in which each type of parameter was independently investigated before and following the amputation, as well as during the follow-up.

Since the group of patients was heterogeneous in ages and in location of masses, and patients with upper limb amputation were listed together patients who had undergone lower limb procedures, some of the QOL questions were irrelevant. The rationale for grouping the patients together and not according to the type of amputation was:

a) A relatively low number of cases. In larger series subgrouping may be possible.

b) The need to evaluate the QOL aspects of such a major intervention and the local success of the procedure. In our opinion, assessment of the QOL resulting from improved local control of an invalidating disease does not require subgrouping of the cases according to the affected organs. However, since certain parameters are specific to the upper or lower limb, the patients had the option of answering “NR” (not relevant).

In our series, the surgical procedure was considered “successful” in all but one case. In all the evaluable patients, pain relief was noticeable, and the need for narcotics was minimized. A high proportion of our patients restored their mobility by using a prosthesis or crutches, although their initial performance status was relatively low.

Improved survival is not an endpoint of this treatment, as suggested by others [35], and is probably not affected by the procedure as far as it is not complicated by early death. It can, however, be claimed that since the patient is not bed-ridden any more, and the fungating tumor and open wound are no longer present, the risk for major infection, sepsis and death is reduced, and the possibility of survival is improved. In our series, a median survival of 9 months supports our estimation of the patient’s life expectancy prior to the amputation. The patients were indeed at advanced stages of their disease, but no one was terminally-ill.

The approach was profitable for the vast majority of the patients (20/21 evaluable patients). Each patient was evaluated independently according to the list of parameters and according to the KPS. It is difficult to decide which cases mostly benefited from the surgery. Each of the cases was referred to palliative major amputation only after it was clear that no other modalities for alleviation of symptoms existed, and the life expectancy was long enough to allow the patient to enjoy the results of the procedure. A case with an upper limb mass was clinically different from a case with lower limb disease. However, what they had in common was the self-appreciation of the QOL in each individual patient, which was low and markedly impaired. The baseline for the assessment of the procedure success was the improvement of the QOL irrespective of the site of the tumor. It should be mentioned that a large (>10 cm in diameter), painful mass in the axilla, that required hundreds of milligrams of morphine a-day, could influence the walking ability of the patient. The patient was too drowsy to walk, and had to hold the ipsilateral arm by the contra-lateral one in order to prevent any movement of the painful arm. Following the FQA, the patient was able to walk more freely.

The indications for palliative major amputation should therefore be as follows:

• Symptomatic local disease, as already described.

• Locally progressive disease not amenable to surgery

• Resistance to chemotherapy, following administration of all the relevant drugs.

• Resistance to radiation therapy, after completion of the maximal external beam     radiation dose and failure of Brachytherapy (whenever possible).

• Markedly impaired quality of life and KPS

• Patient’s will / agreement

In conclusion, limb dysfunction due to agonizing pain and fungating tumor, associated with infection, necrosis, discharge and bleeding, resulting from uncontrolled malignancy localized in a limb, can be safely and completely eradicated by major amputation. The fact that the disease is very advanced, and is usually beyond any specific oncological treatment, coupled by the fact that the patient’s performance status is rather low and his prognosis and life expectancy are grim, do not exclude a major surgical attempt in order to restore the patient’s quality of life.

 

Pulmonary Metastasectomy

The pattern of relapse of osteosarcoma was investigated by Huth et al [40] in 255 patients with high grade osteosarcoma of the extremity. One hundred and seven patients developed metastatic disease: 77 had isolated pulmonary metastases, 17 had simultaneous metastases to lung and elsewhere, and 13 had metastases in other sites. Of the 77 patients with metastases confined of the lung, 51 (66%) underwent thoracotomy for resection of the metastases, and 13 (17%) are long-term disease-free survivors. Patients with simultaneous metastases to lung and other sites, and patients with metastases to sites other than lung, have a poor prognosis with only one long-term disease-free survivor in these groups.

The evolution of the natural history of osteosarcoma was investigated by Bacci et al [41] on 193 patients with high-grade, non-metastatic osteosarcoma. All patients had the primary lesion in the extremities and were treated with surgery alone )30 cases( or surgery plus adjuvant chemotherapy (163 cases(. One hundred and fourteen patients, of which 27 were treated with surgery alone and 87 treated with adjuvant chemotherapy, developed metastatic disease. No differences were found concerning the sites of the first relapse which, for approximately 90% of cases, were the lungs in both groups. However, in the group of patients treated with adjuvant chemotherapy the development of metastatic disease, as compared to non-adjuvant patients, was delayed with time (13 vs 8 months) and the number of metastatic nodules in the lung at first relapse was reduced. This alteration in metastatic pattern due to adjuvant chemotherapy is important because it allows surgical resection of pulmonary metastases in a larger number of patients (51% vs 29%(.

In a study on osteosarcoma of the extremities with synchronous pulmonary metastases, patients were treated with preoperative chemotherapy, and underwent resection of the primary bone tumor and the metastatic lesions, followed by further chemotherapy. Simultaneous resection was feasible in 65% of the patients. Survival advantage was evident for those who remained disease free after treatment. However the relapse rate was high (90%) and the prognosis was  very poor [10].

 

A retrospective study of long term outcome after the development of metastases from osteosarcoma was performed by Saeter et al [42], with emphasis on the impact of different treatment strategies and the identification of prognostic factors. A population-based series of 60 patients relapsing with distant metastases  from high grade, extremity-localized osteosarcoma was treated. Six patients relapsed after surgery alone, 28 patients relapsed after primary chemotherapy of low potency, and 26 patients after modern, intensive chemotherapy. Lung metastases were present in 88% of the patients, 52% had bilateral lesions, and the median number of lesions was three (range, 1-25 lesions). Forty-seven percent of patients had complete surgical excision of all identifiable metastatic nodules and 54% of these had additional second line chemotherapy defined as adequate. Adequate chemotherapy included further dose escalation of methotrexate in approximately half of the patients, usually from 8 to 12 g. The rest were exposed to agents such as cisplatin, etoposide, and ifosfamide. Of the operated patients, 43% had additional thoracotomies after subsequent relapses. The projected 5-year survival rate from the first metastatic event was 24% for all patients and 50% for patients who underwent complete metastasectomy. In a multivariate analysis, the factors with independent predictive value for improved overall survival were the presence of a solitary metastasis, the accomplishment of complete metastasectomy, and the administration of adequate salvage chemotherapy. It was concluded that complete metastasectomy was mandatory for long term survival of patients with metastatic osteosarcoma, and repeated lung resections were necessary in nearly half the patients. Second line chemotherapy and following primary treatment with modern intensive chemotherapy protocols may prolong survival further.

Recurrence of osteosarcoma is most common in the lung. Patients with recurrent osteosarcoma confined to the lungs should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy [43,44,45].

The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 3-5 year survival rate of 20%-40% following complete resection of metastatic pulmonary tumors [46]. The 5-year survival rate following pulmonary metastatic resection is 23%-31%. Factors that suggest a better outcome include four or fewer pulmonary nodules, unilateral pulmonary metastases, or longer intervals between primary tumor resection and metastases [47]. The prognosis is poor for patients with bony metastases who have recurrent or progressive metastatic osteosarcoma that is unresectable. The post-relapse outcome of patients who have a local recurrence is worse than those patients who relapse with metastases alone [48]. In a study of 540 patients with localized disease at the time of diagnosis, only one out of 31 patients who had locally recurrent disease was disease-free 15 months after the last treatment, whereas the disease-free survival was 25% for those who only had metastases [48]. The selection of further treatment depends on many factors, including the site of recurrence, the patient's previous primary treatment, and individual patient considerations. Ifosfamide with mesna uroprotection, alone or in combination with etoposide, has shown activity in up to one third of patients with recurrent osteosarcoma who have not previously received this drug [49,50]. Clinical trials (phase I and II) are appropriate and should be considered.

 

Isolated limb perfusion (ILP)

The novel technique of isolated limb perfusion with tumor necrosis alpha (TNFa) plus melphalan is now accepted for limb salvage in patients with advanced primary or recurrent soft tissue sarcomas [51]. Most of the published series deal with the results in soft tissue sarcomas, and only one series has been reported on the effect of ILP with TNFa in osteosarcoma. This approach is appealing as an alternative for amputation surgery especially for recurrent symptomatic bone sarcoma that is unaccompanied by systemic spread.

Isolated limb perfusion (ILP) with recombinant tumour necrosis factor-alpha (rTNF-alpha) and melphalan has recently been reported to induce major tumour responses in bone sarcomas [52]. Bickels et al. investigated whether TNF-based ILP could allow limb-sparing surgery in 13 patients with primary, recurrent or metastatic bone sarcoma to the lower extremity. Three patients met the criteria for an amputation and had failed or refused chemotherapy. Following ILP, none of the patients had severe local toxicity and only one patient experienced significant systemic side-effects. LSS was subsequently performed in nine of the 13 patients. LSS was feasible in an additional three patients but  was not performed because of the emergence of diffused metastatic disease. It was concluded that ILP with rTNF-alpha and melphalan could allow limb salvage in patients with locally advanced bone sarcomas who had failed standard treatment options. Its potential role in the treatment of unresectable bone sarcomas of the extremities merits further evaluation.

 

Brain metastases of osteosarcoma

Cerebral metastases of osteosarcomas are rare, but this may be changing with prolonged patient survival in the modern chemotherapy era. It is conceivable that pulmonary involvement by the tumor precedes the development of brain metastases. The frequency of brain metastases was 13% of those with lung metastases [53]. The clinical manifestations of brain metastases may be striking: massive hemorrhage and  status epilepticus. Metastases may be  single or multiple, and some may show osteoblastic pattern. The cases published up to now have manifested only a short relapse-free period of survival . The suggested treatment is craniotomy.

Brain metastases of osteosarcoma can arise long after resection of the primary tumor.  Intraparenchymal cerebral metastasis was diagnosed 76 months after amputation of the left leg because of a chondroblastic type osteosarcoma. The patient underwent craniotomy and remained disease free for more than a year after complete removal of lesion [54]. In a second series surgical intervention was feasible in 40% of cases and resulted in dramatic, though transient, clinical improvement [53]. However brain metastases of osteosarcoma are not always solitary, but may be a part of a diffuse disease.  A case of osteosarcoma was presented with a large intracranial "stone"  which was a subdural convexity metastasis. Smaller epidural metastases over other areas were noted by brain CT scan. Systemic workup showed lesions of bones, mediastinum, pleura, perirenal space, and adrenal gland. This condition might result from either early metastases or multifocal osteosarcomas. Craniotomy palliated the brain symptoms although for a short period [55].

 

Conclusions

There are many ways to handle an incurable advanced or metastatic bone sarcoma: amputation surgery, by limb sparing procedures, with conventional or experimental  chemotherapy, resection of metastases in specific sites, and also by good supportive care. As long as there is anything to offer to the patients, there is some hope for them for improvement of their condition. It is the hope that keeps them alive.