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NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES |
From the Institute for Limb Preservation at Presbyterian/St. Luke’s Medical Center (RMW, JWC, BAJ, PMC, KF, SDP, SLS, CMK, ABC) and The Children’s Hospital (LO), Denver, Colorado.
Correspondence: Address correspondence and reprint requests to: Anne B. Camozzi, BA, The Institute for Limb Preservation at Presbyterian/St. Luke’s Medical Center, 1601 E. 19th Avenue, Suite 3250, Denver, CO 80210; Fax: 303-839-6399; E-mail: anne.camozzi@healthonecares.com.
ABSTRACT
Background: A protocol to treat osteosarcoma of the extremity was developed at two local institutions.
Methods: The study involved a dose-intensified neoadjuvant protocol
of intravenous doxorubicin and intra-arterial cisplatin administered
repetitively until maximum angiographic response was noted.
Definitive surgery was delayed until
90%
reduction in tumor neovascularity was documented. Prospective
assessment of serial arteriograms was highly accurate (94%) in
predicting histological response and assisted in surgical planning.
After resection, if patients were determined to be good responders (90%
tumor necrosis), they underwent a 4-month postoperative course with
the same agents. Poor responders (<90% necrosis) were treated
with alternative agents for 12 months from diagnosis. Forty-seven
assessable patients with primary, high-grade, nonmetastatic
osteosarcoma of the extremity were included in this analysis. The
median age was 15 years (range, 7–21 years).
Results: Patients underwent an average of four preoperative intra-arterial courses. Forty-three patients underwent limb-preservation procedures, and 41 had >90% tumor necrosis. With an average follow-up of 92 months (range, 20–178 months), 39 patients were continuously disease free, 3 died of disease, 1 died of other causes, and 4 have no evidence of disease 11 to 51 months after relapse (all pulmonary metastases). There were no local recurrences. Kaplan-Meier analysis demonstrated a 10-year overall survival of 92% and an event-free survival of 84%.
Conclusions: This study demonstrates excellent survival with a dose-intensified neoadjuvant protocol. Future endeavors should involve a multi-institutional randomized study comparing this approach with another multiagent intravenous neoadjuvant protocol.
Key Words: Osteosarcoma • Doxorubicin • Cisplatin • Tumor vascularity • Infusions • Intra-arterial
Although osteosarcoma is the most common primary bone malignancy seen in the childhood population, little progress has been made in the last 10 years regarding the survival of these patients with extremity disease.1–11 Untreated osteosarcoma claims the lives of >80% of patients with the disease. Improvements in survival first became evident with the use of adjuvant postoperative chemotherapy, increasing survival into the 40% to 50% range.8,9 Subsequent pilot studies with various multidrug regimens in the late 1980s boosted survival rates to 60% to 70%, suggesting the probable benefit of neoadjuvant chemotherapy.6,8,12–14 Since then, there have been no reports of significant improvement in the survival of young patients with primary nonmetastatic extremity osteosarcomas.
In the mid 1980s, a multispecialty group was formed to initiate a study in an attempt to improve the overall survival and control of pediatric osteosarcoma. Tumor response to preoperative chemotherapy was identified as the single most important factor in the overall prognosis in pediatric nonmetastatic osteosarcomas. Of the chemotherapeutic agents active in osteosarcoma, a repetitive administration of dose-intensified intravenous (IV) doxorubicin (DOX) and intra-arterial cisplatin (CDDP) was proposed to achieve an improved tumor response. Several centers had reported on the use of CDDP as a single intra-arterial agent or in combination with IV DOX to show improved survival in both adults and children.9,13–15
One of the challenges with preoperative chemotherapy has been the
attempt to accurately predict tumor necrosis before the surgical
procedure. Most protocols prescribed a standard dosage and number of
courses before local control. Because catheter placement before
intra-arterial CDDP infusion was already necessary, it was
hypothesized that subtle changes in the serial arteriograms of the
involved vascularity could be used to predict tumor necrosis. It
would then be possible to treat individual patients before surgery to
maximum response by tailoring each patient’s therapy with a guided
dose intensification. Tumor response, or reduced neovascularity,
could thus be assessed after each course of IV DOX and intra-arterial
CDDP. Once the decrease in neovascularity was maximized, local
control was instituted. Surgery was performed without further delay
if (1) tumor neovascularity appeared reduced by
90%
on arteriogram, (2) there was a leveling off of response, or (3)
there was an increase in neovascularity indicative of a poor
response. Tumor necrosis was confirmed once the resected specimen was
analyzed by pathology, and postoperative chemotherapy was planned
accordingly.
The purposes of this study were to (1) investigate and report the effects of maximizing the dosages of two osteosarcoma active chemotherapeutic agents, (2) evaluate the use of serial arteriograms to predict tumor response before surgery, (3) maximize the percentage of tumor necrosis by individualizing the number of preoperative chemotherapy cycles on the basis of the perceived decrease in neovascularity, and (4) improve survival and event-free survival in young patients with nonmetastatic osteosarcoma of an extremity.
MATERIALS AND METHODS
Eligibility requirements for this study included (1) histologically proven, previously untreated, high-grade osteosarcoma of an extremity; (2) no metastatic disease; (3) no prior cancers; (4) age <21 years; and (5) normal cardiac function. The protocol was approved by both institutional review boards, and informed consent was obtained before the initiation of treatment. All patients had initial biopsies, which confirmed high-grade osteogenic sarcoma. Other parameters used to establish the diagnosis of nonmetastatic primary osteosarcoma were radiographs and magnetic resonance imaging scans of the primary disease site, computed tomographic (CT) scan of the chest, and bone scan. Pretherapy baseline study requirements included echocardiogram, hemogram, and blood chemistries. A central venous access device was placed in each patient before treatment was initiated.
Between July 1987 and September 2000, 75 consecutive patients <21 years old were diagnosed with osteosarcoma at Children’s Hospital or at Presbyterian/St. Luke’s Medical Center in Denver, CO. Of these, 23 were not eligible for this study for the following reasons: 9 tumors were low grade, 8 patients had metastases at presentation, 4 primary tumors involved the pelvis or spine, and 2 patients had been treated for previous malignancies. Of these 52 eligible patients, 3 declined to participate: 1 patient with a small hypovascular tumor of the distal fibula declined intra-arterial treatment, a second patient relocated to another city after biopsy before receiving any therapy, and a third decided against intra-arterial CDDP because of a history of partial deafness. Forty-nine patients entered onto the IV DOX/intra-arterial CDDP protocol, but two of these patients were not assessable. The first patient successfully completed four preoperative cycles and was predicted to be a good responder, but the parents withdrew their child before surgery or further chemotherapy, opting instead for alternative treatment. It was learned that this patient died of disease. The second patient received two courses of intra-arterial therapy and then withdrew for psychosocial reasons. Forty-seven patients were thus assessable for toxicity, response, and survival.
The 47 patients who met the eligibility criteria and completed the protocol are listed in Table 1. There were 33 males and 14 females, with a median age of 15 years (range, 7 to 20 years). Sites of involvement included the femur (n = 30), tibia (n = 9), humerus (n = 5), fibula (n = 2), and ulna (n = 1), with the vast majority of lesions involving the knee joint (n = 38).
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10
cm in maximum dimension at diagnosis and 160 mg/m2 over 24
hours for tumor dimensions >10 cm. Intra-arterial catheterization for
administration of CDDP was performed under conscious IV sedation.
Anesthesia was used for very young patients. The femoral artery was
catheterized percutaneously in an angiographic suite under sterile
conditions by using fluoroscopic guidance. The tip of the catheter
was then positioned in the affected extremity to infuse all vessels
supplying the neoplasm administered in a heparinized solution with
volumetric and pulse infusion pumps (Cook Pulser Chemotherapy Pump;
Cook Inc., Bloomington, IN). The catheter was placed proximal to the
tumor and as far away from arterial side branches and skin
perforators as possible. The patient was restricted to bed rest with
hourly monitoring of limb and pulses. Infusions of CDDP were
accompanied by vigorous IV hydration, hypertonic saline diuresis, and
close monitoring of intake and output. Electrolytes were monitored
daily for 3 days.
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The percentage of tumor necrosis induced by chemotherapy was
confirmed after surgery by a thorough histological examination of the
tumor according to the method reported by Huvos et al.17
Representative sections were taken from all areas of the specimen
to assess the percentage of cell necrosis. Patients with few or
no viable tumor cells (90%
tumor necrosis) in all sections were deemed good responders. All
others were considered poor responders (<90% tumor necrosis).
Postoperative IV chemotherapy (PICT) was initiated within 2 to 3
weeks after surgery. PICT was chosen according to histological
response and modified for toxicity. Patients with
90%
tumor necrosis were to receive the same agents (CDDP and DOX), both
IV. Etoposide was substituted for DOX when the maximum dose of
DOX had been achieved, and ifosfamide or carboplatin was substituted
for CDDP for impending irreversible toxicity. Four postoperative
cycles every 4 weeks were given to good responders. Alternative
chemotherapy incorporating high-dose methotrexate, etoposide, and
ifosfamide was administered for patients who had <90% tumor necrosis.
Poor responders received chemotherapy for 1 year from diagnosis.
Myelosuppressive cycles of PICT were administered at 4-week
intervals, and GCSF was administered to absolute neutrophil count
recovery between these cycles later than March 1991.
At the time of evaluation for discontinuing chemotherapy, plain radiographs of the primary disease site, a chest CT scan, and a total body bone scan were obtained, along with appropriate laboratory studies. During the first year off treatment, complete blood counts and chemistries were obtained every 2 weeks until stable and then every 4 months. Chest x-rays were performed every 2 months and a chest CT scan at 6-month intervals unless indicated sooner by the chest x-ray. An echocardiogram and audiogram were performed at the completion of therapy. Initially, further studies were at the discretion of the treating oncologist. Beginning in 1993, audiograms were required 1 year after completion of chemotherapy. In addition, echocardiograms were to be performed 1 year after completion of chemotherapy and every 3 to 5 years thereafter.
After surgery, patients completed the Musculoskeletal Tumor Society Functional Evaluation System.18,19 This outcome system specifically evaluates the patient’s pain, emotional acceptance, and general functional level. The scores take into account the ability to lift, positioning and dexterity (upper extremity), and the need for supports, walking ability, and gait (lower extremity). It is believed that a patient-completed format gives the most accurate measurement of function and satisfaction and avoids clinician bias. Each of the six criteria is ranked 0 to 5 on a 100% scale, with the total score exhibited as a percentage of normal limb function.
Kaplan-Meier methodology was used to estimate the probability of survival calculated from the day on which preoperative chemotherapy was initiated to the first adverse event or until the date of the most recent follow-up. An adverse event was defined as recurrence of disease at any site or death from disease. A nonparametric survival method (Cox’s proportional hazards model) was used to investigate the effects of univariate or multivariate independent variables, such as tumor size or therapeutic response, on clinical outcomes.
RESULTS
Chemotherapy Toxicity
Patients received an average of four preoperative courses (range,
three to five). The preoperative protocol was modified in one patient
because of an abnormal echocardiogram after the first dose of DOX.
Etoposide was substituted for DOX in this patient. The echocardiogram
later returned to normal. Echocardiograms were performed 1 year after
completing therapy and every 3 to 5 years in the population of 21
patients treated since 1992. There were no grade 2, 3, or 4
cardiotoxicities detected (according to the standard National Cancer
Institute toxicity scale). There were five grade 1 echocardiographic
changes. Of the 47 patients, no patient has developed clinically
detectable cardiac toxicity.
Ototoxicity was objectively evaluated at the completion of chemotherapy and 1 year later in the same group of 21 patients. There was no grade 3 or 4 toxicity by audiogram. There were four grade 2 and fourteen grade 1 toxicities, and three remained normal throughout therapy and follow-up. One early patient (patient 5) required a hearing aid.
From 1987 to 1992, DOX was infused over 72 hours. Grade 3 or 4 mucositis followed most infusions. This frequently required hospitalization, IV narcotics, and hydration. IV nutritional support was required in most. In 1993, the protocol was changed to infuse DOX over 48 hours. Mucositis became a rare complication, with only 3 of 21 patients developing grade 3 or 4 mucositis thereafter.
Myelosuppression was common and cumulative. After GCSF became available in 1991, it was prescribed for neutropenia. Occurrences of febrile neutropenia and bacteremia were infrequent and manageable. There were no toxic deaths.
Five patients developed painful inflammation of the soft tissue in the area of the tumor bed after the 24-hour intra-arterial CDDP infusion. Four of these patients had superficial epidermal sloughing at the site of the inflammation, which went on to heal. The fifth patient required a skin graft. No patient experienced a subsequent episode. The surgical options, eventual function, and ability to perform a limb-salvage procedure were not compromised. There were no other arterial catheter–related untoward effects.
Therapeutic Response
All patients had clinical and angiographic evidence of response from
administration of preoperative chemotherapy, as demonstrated by an
initial reduction of pain and inflammation at the primary disease
site and a decrease in tumor neovascularity on a subsequent
arteriogram. Forty (85%) of 47 patients had a
90%
decrease in neovascularity as assessed on arteriogram. Seven patients
had an initial decrease in neovascularity, followed by a plateau
with a maximum response of <90%. No patient underwent surgery
because of progressive disease during preoperative chemotherapy.
Eighty-seven percent (41 of 47 patients) had
90%
necrosis on histological evaluation. The serial arteriograms were
highly predictive of tumor necrosis, demonstrating a sensitivity of
95% and a specificity of 83% for arteriographic prediction of
percentage necrosis. In only three cases did angiographic prediction
not correlate with the final pathology: one patient (patient 7) was
predicted to be a responder but was found to have only 80% tumor
necrosis on pathology. In two cases (patients 10 and 35), the
arteriographic response was interpreted to be <90%, but on histology,
the tumors were found to have
90%
necrosis.
Surgery
Forty-three patients (91%) underwent limb-preservation procedures.
Four patients had a primary amputation: two because of the location
of the tumor and involvement of the neurovascular bundle, one because
of preexisting fibrous dysplasia of the same bone, and one very young
patient.
The most common surgery for the 43 patients who underwent primary limb-preservation surgery was wide local resection with endoprosthetic replacement. Skeletally immature children estimated to have >4.0 cm of extremity growth received either a modular endoprosthesis (n = 25) or, later in the series, the "growing" prosthesis20 (n = 2) (Repiphysis; Wright Medical Technology, Arlington, TN). Nine patients underwent reconstruction with a massive allograft, five patients had an allograft prosthetic composite, and two patients had resection with soft tissue reconstruction only.
Three patients developed uncontrolled prosthetic infections after the cessation of postoperative chemotherapy, which necessitated subsequent amputation. At last follow-up, the average score for the limb-preservation group (n = 40) was 71% out of a possible 100%, compared with the patients with amputations (n = 7), who averaged 61%.
Survival
Eighty-three percent (39 of 47) of patients were continuously disease
free at an average of 7 years 8 months (92 months; range, 20–178
months). Seven patients developed lung metastasis, three of whom died
after progression of their disease. One patient died of causes
unrelated to cancer or therapy. Four of the seven who had metastasis
are currently alive with no evidence of disease
11,
17,
46,
and
51
months from the date of last relapse. The only site of metastasis was
the lung. There were no local recurrences. At 10 years, the
Kaplan-Meier estimate of overall survival was 92%, and event-free
survival was 84%. For good responders, survival and event-free
survival rates were 93% and 86.5%, respectively, compared with 80%
and 62.5% for poor responders. These results were not statistically
significant (P = .22 for survival and .13 for event-free
survival), most likely because of the small number of poor
responders. Survival and event-free survival also did not achieve
statistical significance when comparing tumor size >10 cm (n = 21)
versus
10
cm (n = 26; P = .47 for survival and P = .13 for
event-free survival). Survival data are listed in
Table 2.
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Improved survival of pediatric patients with osteosarcoma has been noted with the use of adjuvant chemotherapy and subsequently with neoadjuvant chemotherapy. Reported overall survival figures range from 40% to 70%, and event-free survival rates range from 50% to 70%.1–11,21,22 Despite reported outcomes of large-scale studies using multiagent preoperative regimens, there has been no significant improvement in these figures for the last 10 years. The purpose of this study was to investigate the use of dose-intensified repetitive DOX and intra-arterial CDDP. Tumor neovascularity (response) was monitored with serial arteriograms to individually maximize preoperative therapy. Survival of 92% at 10 years demonstrates improvement over other reported series.
Jaffe et al.23 described the angiographic, pathologic, and pharmacologic effects of intra-arterial CDDP in 1983. Tumor necrosis induced by CDDP as a single agent was reported in 1989.24 A series of studies using intra-arterial CDDP in the neoadjuvant setting in multiagent regimens followed.5,25–28 All of these published studies used a dose of 120 mg/m2 of intra-arterial CDDP over 72 hours, with the exception of the Cooperative (German-Austrian-Swiss) Osteosarcoma Study (COSS) 1986,5 which administered the CDDP over 1 hour. Pertinent data and findings of these studies are listed in Table 3.
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The most important risk factor in osteosarcoma is metastatic disease at diagnosis. Three of the above-mentioned studies included patients with metastatic disease. Because these patients uniformly do poorly, even in the face of good primary tumor response, their inclusion could decrease the likelihood of demonstrating the superiority of either regimen. In patients with nonmetastatic disease, the most important prognostic factor is the percentage of tumor necrosis after neoadjuvant chemotherapy. Bacci et al.25 reported that patients with a good response had a 62% event-free survival at 5 years versus 47% for poor responders (despite the inclusion of patients with metastatic disease at diagnosis).
Thus, an important issue is how to best achieve a good initial tumor response and to convert that response to ultimate cure. The concept of alternating drugs or drug combinations assumes that they are noncross-resistant and are equally effective. No such data exist that compare tumor response for methotrexate, ifosfamide, DOX, and CDDP singly or in various combinations. In our study, we used only IV DOX infused over 48 to 72 hours, followed by intra-arterial CDDP over 6 to 24 hours. The drugs were given repetitively every 3 weeks in a neoadjuvant setting. The dose of CDDP was increased by 33% (from 120 to 160 mg/m2) for patients with tumors >10 cm. The number of cycles given before surgery was then individualized on the basis of tumor response, evaluated by the decrease in tumor neovascularity on arteriogram. This method led to an 87% good response rate. Good responders continued the same drugs every 4 weeks for four cycles after surgery. Drugs were changed for cardiotoxicity or ototoxicity or when the maximum dose of DOX was reached (540 mg/m2 total dose).
The total dose of DOX is a major difference from previously reported studies using intra-arterial CDDP. In the Istituto Ortopedico Rizzoli (IOR-OS) 2 and 3 studies reported by Ferrari et al.,26 the total dose of DOX was decreased from 480 to 390 mg/m2, resulting in a decrease in event-free survival rates at 8 years from 63% to 54%. By giving response-based therapy and maximizing two agents, we achieved 92% survival and 84% event-free survival at 10 years. Poor responders received alternative therapy with high-dose methotrexate couplets alternating with ifosfamide and etoposide.
The dose and duration of the intra-arterial CDDP may be an important variable. In this study, the dose of CDDP was increased to 160 mg/m2 for patients with large tumors. In addition, the duration of the infusion was increased from 6 to 24 hours. These modifications differ from previously reported studies, which used 120 mg/m2 over 72 hours for all patients, regardless of tumor size. We found that survival and event-free survival related to tumor size were statistically insignificant. This suggests that dose and duration modifications for patients with large tumors may overcome the prognostic significance of the size of the tumor. This finding should be confirmed in a large multicenter trial.
There were only six poor responders. Two developed metastatic disease. One died of progressive osteosarcoma, and the other remains alive with no evidence of disease. This experience is insufficient to draw further conclusions regarding salvage treatment for poor responders on this protocol.
Despite the maximal use of CDDP and DOX, the therapy was tolerable. There were no toxic deaths and no episodes of congestive heart failure, and there was only one grade 3 or 4 ototoxicity. Mucositis was acceptable after decreasing the DOX infusion from 72 to 48 hours. In addition, the ability to perform limb-salvage procedures was not adversely affected by intra-arterial CDDP. Ninety-one percent of patients underwent limb-sparing procedures, with excellent functional outcomes. There have been no local recurrences. Despite close radiographical follow-up, there have been no relapses at any site beyond 48 months from diagnosis. This represents a dramatic departure from previous published reports.
Pathologic fractures are no longer reported to adversely influence the overall outcome of osteosarcoma.22,29,30 The activity levels of children and adolescents may contribute to the high incidence of pathologic fractures; however, the presence of a fracture at diagnosis did not affect the type of surgery performed in this study. Ten patients (21%) presented with a pathologic fracture in our group of 47. Nine of the these patients had limb-sparing surgery, and one patient underwent amputation because of tumor involvement of the neurovascular bundle.
The arteriograms were well tolerated. No unexpected complications were seen. There were 5 (2.7%) episodes of painful inflammation in 183 intra-arterial infusions. This compares favorably with previous reports of Bezwada et al.,31 Cheon et al., 32 and Tsuchiya et al.33 These inflammatory changes are due to infusion of CDDP into vessels supplying soft tissues—not from extravasation.
The decrease in neovascularity documented on serial arteriograms allowed for the accurate prediction of tumor necrosis (95% sensitivity and 83% specificity) found at the time of definitive tumor resection. This in turn led to successful response-based timing of surgery. No other modality has been shown to be predictive of tumor response.
In using a unique approach of individually adjusting for tumor size and tumor response to chemotherapy (the two most important determinants in the prognosis for nonmetastatic osteosarcoma),16,34,35 this protocol has been effective in increasing the life expectancy for young patients with primary nonmetastatic osteosarcoma of an extremity. Our results indicate that a similar individually modified, dose-intensified neoadjuvant protocol may yield significantly improved overall survival and event-free survival, as well as a reduced local recurrence rate. The intra-arterial route was associated with minimal morbidity and complications. The 10-year survival rate of 92% and the event-free survival of 84% is improved over other studies. Future endeavors should involve a multi-institutional randomized study comparing this approach with an IV multiagent neoadjuvant regimen.
Addendum
Since the time of this analysis (August 2001), there have been no further recurrences among the 43 surviving patients. Furthermore, an additional 10 patients have since completed the protocol without relapse.
Acknowledgments
The authors thank the referring physicians, oncologists, and house staff who participated in the care of these patients, and Deb Schissel, Anne Kurzner, and Zhaoxing Pan for help with data collection and analysis.
The acknowledgments are available online at www.annalssurgicaloncology.org.
Footnotes
A protocol to treat osteosarcoma used
dose-intensified neoadjuvant doxorubicin and intra-arterial cisplatin
administered repetitively until
90%
reduction in tumor neovascularity was noted on arteriograms.
Prospective angiographic assessment was highly accurate in predicting
histological response, and superior survival rates were attained.
Received for publication March 15, 2002. Accepted for publication January 21, 2003.
REFERENCES
This article has been cited by other articles:
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  J. W. Cullen, B. A. Jamroz, S. L. Stevens, W. Madsen, I. Hinshaw, R. M. Wilkins, P. Cullen, A. B. Camozzi, K. Fink, S. D. Peck, and C. M. Kelly The Value of Serial Arteriography in Osteosarcoma: Delivery of Chemotherapy, Determination of Therapy Duration, and Prediction of Necrosis J. Vasc. Interv. Radiol., August 1, 2005; 16(8): 1107 - 1119. [Abstract] [Full Text] [PDF]
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