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Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas
The St. Jude children's research hospital experience
Article first published online: 15 MAR 2006
Copyright © 2006 American Cancer Society
Volume 106, Issue 8, pages 1846–1856, 15 April 2006
How to Cite
Navid, F., Santana, V. M., Billups, C. A., Merchant, T. E., Furman, W. L., Spunt, S. L., Cain, A. M., Rao, B. N., Hale, G. A. and Pappo, A. S. (2006), Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas. Cancer, 106: 1846–1856. doi: 10.1002/cncr.21810
- Issue published online: 4 APR 2006
- Article first published online: 15 MAR 2006
- Manuscript Accepted: 9 NOV 2005
- Manuscript Revised: 7 OCT 2005
- Manuscript Received: 11 JUL 2005
- American Lebanese Syrian Associated Charities
- United States Public Health Service Cancer Center. Grant Number: CA21765
- high-risk sarcoma;
- intensive chemotherapy;
Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period.
In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support.
Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% ± 11.2%.
The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity. Cancer 2006. © 2006 American Cancer Society.
Ewing sarcoma family of tumors (ESFT) and soft tissue sarcomas comprise ≈10% of childhood malignancies.1 Patients with localized disease have benefited from multimodal therapy (chemotherapy, surgery, and radiation therapy):2, 3 however, patients with disseminated or bulky disease continue to fare poorly.4–6 Although novel treatment approaches are needed for this group of patients, maximizing the dose intensity of currently available drugs remains an attractive therapeutic alternative.
Agents used to treat sarcomas show a steep, linear relation between plasma drug concentration and log tumor cell kill.7 In an experimental model of osteosarcoma, small changes in cyclophosphamide dosage significantly affected survival. Similar results were observed with other agents. Dose intensity has been associated with clinical outcome in a variety of solid malignancies, including neuroblastoma and Wilms tumor.8, 9
Chemotherapeutic agents are used routinely in combination to minimize drug resistance, and vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against sarcomas.2, 3, 10, 11 We hypothesized that intensive, concomitant administration of these agents (VACIE) within a defined period would reduce drug resistance and result in better tumor kill, thereby improving survival. This report describes the feasibility, toxicity, and response rate obtained by delivering these 5 agents in combination to patients with high-risk sarcoma. Because retrospective data suggest an improved outcome for patients with rhabdomyosarcoma (RMS) and ESFT who receive consolidation therapy after an early complete response (CR) to chemotherapy,12, 13 our patients received myeloablative chemotherapy and autologous stem cell/bone marrow support (ASCT) if they achieved a partial response (PR) or a CR to this regimen.
MATERIALS AND METHODS
Patients were eligible for this Phase II trial if they had a biopsy-proven diagnosis of metastatic RMS, ESFT that was metastatic or that measured > 8 cm in greatest dimension, desmoplastic small round cell tumor (DSRCT), metastatic nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), or nonmetastatic unresectable Grade 3 NRSTS. Other eligibility criteria included age younger than 25 years, weight > 11 kilograms, no prior chemotherapy or radiotherapy, normal cardiac function (shortening fraction [SF] > 28%), negative pregnancy test, and a negative human immunodeficiency virus test. Patients who had soft tissue sarcomas that resulted in base-of-skull erosion, cranial nerve palsy, or intracranial extension were excluded from the study.
The high-risk sarcoma 1 (HIRISA1) study opened in June 1996 and closed to enrollment in September 1997 after the first 11 patients failed to complete the required therapy in the specified time (29 weeks). A modified study, HIRISA2, opened in September 1997 and closed to accrual in July 2000 after enrolling 13 eligible patients. The main difference between the 2 studies was the delay in local control therapy in HIRISA2 (Week 16 instead of Week 9), and patients were required to complete 5 cycles of chemotherapy within 18 weeks. The eligibility criteria were identical, except that patients with NRSTS were not eligible for HIRISA2. Both studies were approved by the St. Jude Children's Research Hospital Institutional Review Board. Patients, parents, or guardians, as appropriate, provided written informed consent/permission in accordance with institutional and federal guidelines.
The treatment plans for HIRISA1 and HIRISA2 are detailed in Tables 1 and 2. Because of the various histologies, tumor sites, and/or organs involved, local control therapy (radiation and/or surgery) was individualized. The objective of surgery was complete tumor extirpation with minimal morbidity and loss of organ function; postoperative radiotherapy was given to patients with microscopic residual tumor. Definitive radiotherapy was used for tumors that were deemed unresectable after induction chemotherapy. Whenever feasible, sites of metastatic disease received site-specific, conventionally fractionated irradiation.
|Radiotherapy with or without surgery|
|Consolidation therapy (patients with CR or PR)|
|Radiotherapy with or without surgery|
|Consolidation therapy (patients with CR or PR)|
All cycles of chemotherapy were followed by filgrastim 5 μg/kg given subcutaneously daily for at least 7 days or until the patient achieved an absolute neutrophil count (ANC) >10,000/μL. If the patient had no morphologic evidence of bone marrow disease after 3 cycles of chemotherapy on HIRISA1 or after 2 cycles on HIRISA2, then leukapheresis or bone marrow harvest was performed. When leukapheresis was anticipated after a cycle of chemotherapy, the filgrastim dose was increased to 10 μg/kg per day.
On both HIRISA1 and HIRISA2, consolidation therapy was planned to begin at Week 25 for patients who achieved a PR or CR. These patients were eligible for myeloablative therapy with ASCT on an institutional protocol that was open at the time.
Dose Modification and Off-Study Criteria
Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Recovery from a cycle of chemotherapy was defined as an ANC > 300/μL and a platelet count > 50,000/μL on HIRISA1 and an ANC > 300/μL and a platelet count > 25,000/μL on HIRISA2. The definition of platelet recovery was changed on HIRISA2 to allow for further intensification of chemotherapy. The next cycle of chemotherapy was delayed for 1 week in the absence of recovery. Vincristine was suspended in patients who had of Grade 3 or 4 neurotoxicity and was restarted at a 50% dosage when major symptoms had resolved. Cyclophosphamide and ifosfamide were suspended if there was evidence of hemorrhagic cystitis and were restarted when < 50 red blood cells per high-power field were detected in the urine. Doxorubicin was suspended if echocardiography showed an SF < 28%. Patients were taken off study in the event of progressive disease (PD), 2 consecutive episodes of life-threatening toxicity (including sepsis, hypotension that required vasopressor support, and uncontrollable fungal infection), or the absence of hematologic recovery from all planned therapy in HIRISA1 by Week 29 or 5 cycles of VACIE by Week 18 in HIRISA2.
Tumor response was assessed at various times during treatment (Tables 1, 2). A CR was defined as the complete disappearance of all measurable disease on laboratory and diagnostic imaging studies and evidence of healing bone lesions by bone scan and/or plain radiographs. For patients with ESFT, a CR was defined as the complete disappearance of the soft tissue component. A PR was defined as a decrease > 50% in the product of the greatest 2 perpendicular dimensions of all lesions or of the soft tissue component of ESFT. PD was defined as an increase ≥ 25% in the product of the 2 greatest perpendicular dimensions of all lesions or the appearance of any new lesions. Stable disease (SD) was defined as no change in the size of any lesion or less than a PR without evidence of progression over a period of 4 weeks.
In HIRISA1, we tested the feasibility of administering intensified chemotherapy to children with high-risk sarcomas by estimating the proportion of patients who were able to complete treatment successfully within 29 weeks. Patients who did not have hematologic recovery from the last cycle of chemotherapy by week 29, who had PD prior to completion of therapy, or who were removed from study for any reason (toxicity, physician decision, death, parent decision, etc.) were considered as having failed the study. One interim analysis was planned after evaluation of the first 23 patients. If < 11 patients had successfully completed the treatment within 29 weeks, then the study would close. Otherwise, patient accrual would continue until 39 patients had been treated. If < 24 patients had successfully completed the treatment within 29 weeks, we would conclude with 90% confidence that the regimen was feasible for < 70% of patients. If ≥ 24 of 39 patients (62%) completed the treatment, then we would conclude with 90% confidence that the therapy was feasible for > 50% of patients.
The design parameters, planned sample size, and stopping rule for HIRISA2 was identical to that of HIRISA1, with the exception that feasibility was assessed by estimating the proportion of patients who were able to complete treatment successfully by Week 18 in HIRISA2 (after 5 cycles of VACIE and before local control therapy) rather than at Week 29, as in HIRISA1 (after all cycles of chemotherapy and local control therapy).
The probabilities of survival and of event-free survival (EFS) were estimated by using the method of Kaplan and Meier. The duration of survival was defined as the interval between study enrollment and death from any cause or last follow-up. The duration of EFS was defined as the interval between study enrollment and PD, recurrent disease, second malignancy, death, or last follow-up. Cox regression analysis was used to determine whether consolidation therapy with myeloablative chemotherapy and ASCT affected outcome and was considered a time-dependent covariate in the model.
The duration of local disease control was defined as the interval between study enrollment and local disease recurrence. Competing risks included distant recurrence or death prior to local recurrence. Patients who experienced simultaneous local and distant recurrence were considered to have local recurrence for the analysis of local failure. The cumulative incidence of local failure was estimated by using the methods of Kalbfleisch and Prentice.
Eleven patients were enrolled on HIRISA1, and 14 patients were enrolled on HIRISA2. One patient who was enrolled on HIRISA2 was found to be ineligible after a review of the diagnosis. The demographic and disease characteristics of the 24 eligible patients are shown in Table 3. Of the 11 patients with ESFT, 7 patients had metastatic disease. Of the 9 patients with metastatic RMS, 8 patients had alveolar histology. Four patients had DSRCT.
|Characteristic||No. of Patients (%)*|
|All Patients (N = 24)||HIRISA1 (N = 11)||HIRISA2 (N = 13)|
|Female||10 (42)||6 (55)||4 (31)|
|Male||14 (58)||5 (45)||9 (69)|
|Caucasian||14 (58)||5 (45)||9 (69)|
|African American||9 (38)||5 (45)||4 (31)|
|Hispanic||1 (4)||1 (9)||0 (0)|
|ESFT||11 (46)||5 (45)||6 (46)|
|RMS||9 (38)||5 (45)||4 (31)|
|DSRCT||4 (17)||1 (9)||3 (23)|
|Age at enrollment (years)|
The primary objective of the HIRISA1 protocol was to determine the feasibility of completing the planned chemotherapy and local control therapy within 29 weeks. Because the first 11 patients were unable to complete therapy within this time limit, the protocol was closed early. Five of those patients (Table 4) received all cycles of VACIE; however, 3 of the 5 (Patients 1, 2, and 8) did not complete therapy within the specified time, 1 (patient 6) was removed from the study after Week 12 because of noncompliance but received the remaining cycles at another institution, and 1 (Patient 7) was removed from the study after Week 15 because of delayed hematologic recovery but received the last cycle off-study. Of the 6 patients who did not receive all 6 VACIE cycles, 1 (Patient 4) died of toxicity after receiving Week 12 chemotherapy, 1 (Patient 11) left the study after Week 6 to pursue different therapy, 1 (Patient 5) was removed from the study after Week 2 because of presumed fungal disease, and 3 (Patients 3, 9, and 10) were removed from the study at Weeks 18, 11, and 11, respectively, because of delayed hematologic recovery.
|Patient||Histology||Age (Years)||Gender||Primary Site||Metastatic Sites||Surgery/Pathology||Total RT Dose (Gy)||Protocol Response||Consolidation ASCT (Regimen)||Outcome after Enrollment, Months||Recurrence Site|
|1||ARMS||7.3||Male||Paratesticular||LN, BM||Yes*||60.0 (renal hilum), 44.4 (inguinal/paraaortic LN)||CR||Yes (DICE)||NED, 92||—|
|2||ARMS||12.6||Male||Calf||Distant LN||No||45.6 (fibula and LN; popliteal to pelvic)||CR||Yes (DICE)||NED, 65||—|
|3||ARMS||16.2||Female||Perineum||LN, bone||Yes/no viable tumor†||60.6 (perineum/pelvis)||CR||No||LFU, 78||—|
|4||ARMS||14.8||Female||Foot||LN, BM, bone, breast, lung||No||17.3 (thorax), 43.7 (mediastinum)||PR||No||TD, 5||—|
|5||ARMS||17.8||Female||Mediastinum||LN, BM, bone, lung||No||37.4 (mediastinum)||NE||No||DOD, 16||Local and distant|
|6||ESFT||15.8||Male||Leg (> 8 cm)||None||Yes/viable tumor, positive margins||45.6 (leg; with 20-Gy IR-192 implant)||CR||No||LFU, 53||—|
|7||ESFT||17.4||Female||Pubis||Bone||No||45 (pelvis), 36 (iliac crest)||PR||Yes (DICE)||DOD, 27||Distant|
|8||ESFT||14.6||Male||Kidney||Bone, lung, BM||Yes/viable tumor||36 Gy (kidney), 36 Gy (to bone metastases before ASCT)||CR||Yes (DICE)||DOD, 28||Distant|
|9||ESFT||11.7||Female||Ilium||BM, bone||No||68.2 (pelvis)||PR||No||DOD, 10||Distant|
|10||ESFT||15.0||Male||Thorax (> 8 cm)||None||Yes/no viable tumor||36 (chest wall)||CR||No||DOD, 16||Local and distant|
|11||DSRCT||19.4||Female||Abdomen||Omentum, ovaries, peritoneum, LN, bone, liver||No||27 (whole abdomen), 25.5 (tibia)||PR||No||DOD, 51||Local and distant|
|12||ESFT||13.7||Female||Leg (>8 cm)||None||Yes/viable tumor, negative margins||36 (thigh)||CR||No||NED, 73||—|
|13||ESFT||14.9||Male||Chest wall (> 8 cm)||None||Yes/no viable tumor||None||CR||Yes (DICE)||NED, 73||—|
|14||ESFT||15.6||Male||Rib||Regional LN||Yes/no viable tumor||45 (mediastinum), 16.5 (hemithorax)||PR||No||NED, 80||—|
|15||ESFT||13.8||Male||Femur||Bone (multiple)||No||50 (ilium), 54 (femur; after Cycle 6)||PR||Yes (CYTOPO)||NED, 67||—|
|16||ESFT||16.5||Male||Rib||Lung||Yes/viable tumor||None||CR||Yes (CYTOPO)||NED, 57||—|
|17||ERMS||12.9||Male||Prostate||Lung, regional LN||No||60 (prostate: (after Cycle 6), 16.8 (lungs; after ASCT)||PR||Yes (CYTOPO)||NED, 63||—|
|18||ESFT||15.1||Female||Ilium||Lung, BM||Yes/no viable tumor||None||PR||Yes (CYTOPO)||LFU, 58||—|
|19||ARMS||1.6||Female||Pelvis||LN||Yes/viable tumor||10.8 (pelvis)||PR||No||TD, 8||—|
|20||ARMS||18.7||Male||Pelvis||LN, bone||No||None||PR||No||DOD, 9||Local and distant|
|21||ARMS||16.1||Female||Hand||Forearm, LN, lung, breast, skin||No||50.4 (hand), 41.4 (metastatic sites)||PR||No||DOD, 12||Distant|
|22||DSRCT||20.8||Male||Pelvis||Liver, spleen, omentum, peritoneum||Yes (partial resection)/viable tumor||60.0 (pelvis), 28.5 (abdomen; after ASCT)||PR||Yes (CYTOPO)||DOD, 21||Local|
|23||DSRCT||13.9||Male||Pelvis||Omentum, peritoneum||Yes (partial resection)/viable tumor||None||SD||No||DOD, 31||Local and distant|
|24||DSRCT||14.1||Male||Abdomen||Peritoneum, lung, LN||Yes/viable tumor||30.0 (whole abdomen), 45.0 (flank/umbilicus), 31.5 (inguinal LN) [all RT after Cycle 6]||CR||Yes (CYTOPO)||TD, 9||—|
Local control therapy in HIRISA1 began at Week 9. All 11 patients received radiation therapy at Week 9. In HIRISA2, to reduce the cumulative myelotoxicity of chemotherapy combined with radiation early in the course of therapy, local control therapy was delivered at Week 16 (after 5 cycles of VACIE), and feasibility was redefined in terms of hematologic recovery by Week 18. Seven of the 13 patients who were enrolled on HIRISA2 experienced hematologic recovery within this specified time. Four patients completed the 5 cycles but experienced delayed recovery. The median time to recovery among these 11 patients was 17 weeks (range, 14.7–22.8 weeks). Of the 2 patients who did not complete all 5 cycles; 1 (Patient 20) was removed from the study because of noncompliance after Week 6 chemotherapy, and 1 (Patient 14) was removed after 2 cycles because of delayed hematologic recovery and infectious complications (typhlitis, hypotension, and viral pneumonia). Although the stopping rule had not been met, the HIRISA2 protocol was closed early because of the availability of competing protocols.
Fifty-two of the 77 planned cycles of chemotherapy (68%) on HIRISA1 and 65 of the 78 planned cycles (83%) on HIRISA2 were administered (P = .026). Severe myelosuppression was the most common toxicity on both protocols (Table 5). The incidence of Grade 3 and 4 thrombocytopenia was similarly high on the 2 protocols. Despite low platelet counts, there were no episodes of life-threatening hemorrhage. Grade 4 neutropenia occurred after almost every cycle of VACIE on both protocols. Febrile neutropenia and bacteremia/sepsis were slightly less frequent on HIRISA2 than on HIRISA1. Other infectious complications included 5 episodes of herpes zoster, 7 episodes of Clostridium difficile colitis, 8 urinary tract infections, 5 pneumonias, 7 episodes of cellulitis/abscess, 2 episodes of otitis media, and 1 episode each of typhlitis, osteomyelitis, sinusitis, epididymitis, and otitis externa.
|Variable||HIRISA1||HIRISA2||VACIME*||VACIME and PBSC†|
|No. of patients||11||13||24||23|
|No. of courses received||52||65||170||170|
|Fever and neutropenia||94||85||81||85|
|Grade 3–4 mucositis||15||48||39||40|
|Grade 3–4 neutropenia||100||100||94||100|
|Grade 3–4 thrombocytopenia||88||95||90||93|
|No. of deaths from toxicity||1||2||1||1|
|Response and outcome|
|Complete response rate (%)||60||31||83||74|
|Median follow-up (range), years||5.9 (4.4–7.7)||5.5 (4.8–6.7)||4.3 (2.7–5.2)||3.8 (3.2–4.8)|
|EFS estimate (± SE), %||36.4 (± 14.5) (5 years)||53.8 (± 14.9) (5 years)||45 (± 10) (4 years)||30 (± 10) (3 years)|
Nonhematologic toxic effects were observed on both protocols. The most common were mucositis, malnutrition, hypotension, and neuropathy. The incidence of Grade 3 or 4 mucositis was greater on HIRISA2 (48%) than on HIRISA1 (15%). Eight of 11 patients on HIRISA1 and 10 of 13 patients on HIRISA2 required total parenteral nutrition during therapy. Four episodes of hypotension with no clear etiology were observed on HIRISA1, and 5 were observed on HIRISA2.
Delays in chemotherapy administration were frequent. However, when chemotherapy was administered, with the exception of vincristine, the other 4 chemotherapy agents were administered on average at > 90% of the intended dose (data not shown). Dose modification of an entire cycle of chemotherapy occurred in 6 patients (1 cycle each) and was due most frequently to an episode of severe infection or suspected septic shock associated with delayed hematologic recovery. The most frequently modified or omitted single chemotherapy agent was vincristine (17 doses in HIRISA1 and 32 doses in HIRISA2). Neuropathy (decreased gastrointestinal motility, weakness, ptosis, and/or pain) was the primary reason for vincristine dose reduction or omission. Doxorubicin dose was reduced or omitted for cardiotoxicity, elevated bilirubin, and severe mucositis/esophagitis (1 dose was modified in 1 patient for each toxicity). One patient on HIRISA2 required dose modification of ifosfamide because of altered mental status. Two patients (1 on each protocol) had 2 episodes each of hemorrhagic cystitis that resolved with continuous sodium mercaptoethanesulfonate and aggressive hydration. Fanconi syndrome was not observed. No second malignancies have been observed.
Three deaths were caused by toxicity. Patient 4 died of radiation pneumonitis at Week 14 of HIRISA1. The autopsy showed severe alveolar damage, evidence of earlier and recent myocardial infarction, and residual viable tumor. Patient 19 died of disseminated adenoviral infection while receiving the sixth cycle of VACIE (Week 16) and radiation therapy. She was being treated off-study because of the absence of hematologic recovery by Week 18. No tumor was identified at the time of autopsy. Patient 24 completed therapy on HIRISA2 and died of hepatic and renal failure as a complication of ASCT.
Response and Outcome
Tumor response was evaluated at multiple times during treatment on both HIRISA1 and HIRISA2. A common response evaluation for both protocols was at Week 8 after 3 cycles of VACIE. Twenty-one of the 22 evaluable patients had a response at that time (1 CR and 20 PRs). One patient had SD. Local therapy was instituted at this point to patients on HIRISA1, so that response to chemotherapy could not be assessed further. However, patients on HIRISA2 received 2 more cycles of chemotherapy prior to local therapy, and 10 of the 12 evaluable patients had further regression of their tumor but not enough to qualify for a CR. Overall, responses after the completion of all therapy (including surgery and/or radiotherapy) included 6 CRs (60%) and 4 PRs (40%) on HIRISA1 and 4 CRs (31%) and 8 PRs (61%) on HIRISA2.
Estimation of survival was not a primary objective of HIRISA1 or HIRISA2, because not all patients received the same therapies after completing these protocols; i.e., some patients received consolidation with high-dose chemotherapy with ASCT. Eleven of the 24 patients were alive at the time of analysis, with a median follow-up of 5.5 years (range, 4.4–7.7 years). The 5-year survival and 5-year EFS estimates of the 24 patients were both 45.8% ± 11.2%. The first adverse event was death in 3 patients and disease progression or recurrence in 10 patients at a median of 11.6 months (range, 7.9–42.4 months) after study enrollment. One patient had local treatment failure, 4 patients had distant failure, and 5 patients had combined local and distant failure. Three patients on each protocol failed locally (with or without distant failure). The cumulative incidence of local failure at 5 years was 25.0% ± 9.1%. If we excluded patients with DSRCT, in which local disease control is a significant problem, then the cumulative incidence of local failure at 5 years dropped to 15.0% ± 8.3%.
Patients with ESFT fared slightly better than patients with other tumors. Five-year EFS estimates were 63.6% ± 17.2% for patients with ESFT (n = 11 patients) and 30.8% ± 11.4% for patients with RMS or DSRCT (n = 13 patients). Nine of the 13 patients in this latter group had RMS, and 4 patients are alive without evidence of disease. None of the patients with DSRCT remained alive.
Seven of the 11 surviving patients underwent consolidation myeloablative chemotherapy with ASCT, whereas only 4 of the 13 patients who died had received this therapy. In this small number of patients, we explored whether transplantation had an effect on survival or EFS by using a Cox regression model that incorporated ASCT as a time-dependent covariate. According to this model, there was no evidence that transplantation had an effect on survival (P = .20) or EFS (P = .24).
The primary objective of HIRISA1 was to determine the feasibility of dose intensification achieved by administering 5 active agents concomitantly within a defined period to patients with high-risk sarcoma. Although 5 of 11 patients received all of the protocol therapy, no patients were able to complete therapy within the specified period, mainly because of myelosuppression. Therefore, this protocol was not feasible. Because it has been shown that radiotherapy early in the course of therapy has an impact on hematologic recovery,14, 15 a modified treatment plan (HIRISA2) in which local control therapy was delayed until Week 16 and at least 5 cycles of chemotherapy were given within 18 weeks proved to be more feasible. Delayed local control therapy in this small number of patients did not appear to result in a higher rate of local failure. Furthermore, the local failure rate in HIRISA2 was comparable to that reported for other therapy trials for patients with ESFT and RMS.2, 3, 16, 17
Despite its improved feasibility, HIRISA2 was associated with significant myelosuppression; only 7 of 13 patients (54%) were able to tolerate 5 cycles of chemotherapy within the specified time, and only 5 of those patients received all prescribed therapy. Furthermore, although the number of patients was small, we did not observe better outcomes in the 7 patients who completed the 5 VACIE chemotherapy cycles within 18 weeks. Three of those 7 patients were alive at the time of this report, compared with 4 of 6 patients who did not complete the treatment.
A similar approach to dose intensification for the treatment of pediatric sarcomas was reported by Felgenhauer et al.18 and Hawkins et al.19 In both of those studies, six 21-day cycles of the same 5-drug regimen (designated VACIME) were administered, and complete surgical resection was then attempted. Postoperatively, 2 more cycles of the same chemotherapy regimen without doxorubicin were administered; in most patients, radiation therapy was delivered last. In the latter study, peripheral blood stem cell support was used to maintain dose intensity, and the dosage of doxorubicin was decreased. The dose intensity of the HIRISA and VACIME protocols, calculated as the total dose of drug delivered per unit of body surface area per week, is summarized in Table 6. The planned dose intensity of vincristine and oxazaphosphorines (cyclophosphamide plus ifosfamide) was higher in the HIRISA protocols, whereas the dose intensity of doxorubicin and etoposide was higher in the VACIME trials. With the exception of the high incidence of bacteremia on the VACIME trials and the lower incidence of mucositis on HIRISA1, the toxicity of these protocols, including severe myelosuppression, was comparable (Table 4). The lower incidence of mucositis on HIRISA1 may be attributed to the relatively lower dose intensity of etoposide.
|Drug||HIRISA1 (24 Weeks)||HIRISA2 (19 Weeks)||VACIME (27 Weeks)*||VACIME and PBSC (27 Weeks)†|
The response rates and outcomes of the VACIME and HIRISA protocols are summarized in Table 5. Because these trials were designed to test feasibility in a small number of patients with different tumors, no firm conclusions can be made about response and outcome. Furthermore, a significant proportion of our patients went on to receive consolidation with high-dose chemotherapy and stem cell rescue. Although these limitations require caution in interpreting any observations, the rate of complete response after all therapy was completed on the VACIME trials appears to be higher than that observed on the HIRISA1/HIRISA2 trials and was similar to the rates reported for other studies.20, 21 The observed differences may be influenced by the response criteria, whether by imaging or by second-look surgery, established by the investigators. However, the estimated EFS was similar with VACIME and HIRISA1/HIRISA2. Overall, the EFS obtained with these dose-intensive regimens is somewhat higher than the EFS (<30%) obtained with conventional treatment for metastatic ESFT and metastatic RMS.3, 4, 22
The favorable EFS estimate we observed may be unrelated to the chemotherapy dose intensification. At the time this protocol was designed, patients with nonmetastatic ESFT that measured >8 cm in greatest dimension had a poor outcome and, thus, were included in the study. With the improvement of multimodal standard therapy, this group of patients now has an outcome approaching that of patients with smaller tumors.3, 22–24 Three of our 4 patients with nonmetastatic ESFT >8 cm in greatest dimension are long-term survivors. It is possible that these patients would have had the same outcome with less intensive therapy, along with patients who had isolated lung metastases of ESFT. Recent studies show that patients with isolated lung metastases have a better outcome than patients with metastases in bone marrow and bone.5, 25–27 In our study, 1 of the 4 surviving patients with metastatic ESFT had isolated lung disease.
Risk groups have been described for patients with metastatic RMS, but the prognostic factors that define these risk groups have not been consistent among reported studies. Primary site and age younger than 11 years were important prognostic factors in Intergroup Rhabdomyosarcoma Study I (IRSI) and IRSII.28 Two or fewer metastatic sites and embryonal histology were associated with better outcome in IRSIV4; whereas age, bone marrow involvement, and primary site did not affect survival. Data from the European Cooperative Group studies in the 1970s and middle 1980s showed that the number of metastatic sites, embryonal histology, and genitourinary primary sites other than bladder/prostate conferred a favorable outcome.29 In the more recent European studies of therapy for metastatic RMS (MMT4-89 and MMT4-91), primary tumors of the genitourinary tract (nonbladder/prostate), age from 1 to 9 years, and absence of bone or bone marrow involvement were associated with a favorable outcome in multivariate analysis.30 Histology was not an independent prognostic factor, although alveolar histology was associated closely with bone marrow involvement and unfavorable sites of disease. Four of 9 patients with RMS in our study group were alive without evidence of disease at the time of this report. We observed no specific favorable prognostic factor in the survivors in our study, but all survivors had ≤2 metastatic sites, including 1 patient with bone marrow involvement and 1 patient with bony metastasis.
Only four of our patients had DSRCT. Although patients with DSRCT, including 3 patients who were treated on the VACIME protocols, reportedly have benefited from dose-intensive chemotherapy,31–33 the outcome of our patients was poor: Three patients died of recurrent or PD, and 1 patient died of toxicity.
In summary, dose intensification of VACIE chemotherapy in patients with high-risk sarcoma appears to be feasible but is associated with significant myelosuppression, which can delay timely administration of therapy. Our experience suggests that delay of local control therapy facilitates the maintenance of dose intensity and does not appear to increase the risk of local treatment failure. Although there may be a subset of patients who benefit from chemotherapy dose intensification, our small trial could not define this subset. In addition, results from a number of recent trials also support the notion that intensification of alkylator-based therapies in sarcomas is associated with appreciable toxicity and apparently marginal benefit.15, 34, 35 Therefore, we cannot recommend dose-intensive treatment strategies for patients with high-risk sarcoma outside of a clinical trial setting. Our results also do not indicate whether high-dose chemotherapy with ASCT improved our patients' probability of survival. Therefore, we encourage the pursuit of novel therapeutic approaches for patients with high-risk sarcomas.
The authors thank the patients and their families who participated in these studies. They also thank Sharon Naron for her editorial assistance with this article.
- 34Comparison of dose intensified and standard dose chemotherapy for the treatment of non-metastatic Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone and soft tissue: a Pediatric Oncology Group-Children's Cancer Group Phase III trial. Med Pediatr Oncol. 2001; 37: 172., , , et al.
- 35Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Clin Cancer Res. 2004; 10: 6072–6079., , , et al.
- 36Cyclophosphamide and targeted dose topotecan with autologous hematopoietic stem cell rescue for solid tumors [abstract]. J Clin Oncol. 2004; 22(14S): 807s., , , et al.