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Biomedical subjects

A Nirenberg

Publications and source records attributed to A Nirenberg.

At least 37 records · Page 2Linked to original sources
PubMed1985

Neoadjuvant chemotherapy for osteogenic sarcoma: a five year follow-up (T-10) and preliminary report of new studies (T-12).

During the past 10 years, (November, 1973 through November, 1983) 208 patients with fully malignant primary osteogenic sarcoma of an extremity were treated with preoperative chemotherapy on 4 successive treatment protocols. Continuous improvements in the disease-free survival of patients were attributed to refinements in the chemotherapy regimens. These refinements were made after direct observation of the response of the primary tumor to chemotherapy. At a minimum follow-up time of over 38 months for 87 patients treated on the T-10 chemotherapy protocol, 67 (77%) have remained alive and continuously free of disease, and 71/87 (81.6%) are currently free of disease at a median follow-up time of 5 years. Overall complete response rate of the primary tumor to preoperative chemotherapy was 48%. Fifty-one patients were treated on a pilot protocol (T-12) from November, 1981, to November, 1983. The main difference was that after preoperative high dose methotrexate and combination bleomycin, cytoxan and dactinomycin therapy, patients having a good histologic response of the primary tumor (21/51 or 41%) had their chemotherapy stopped at 15 weeks and did not receive platinum or Adriamycin chemotherapy. 38/51 (75%) on T-12 remained continuously free of disease and 39/51 (76%) are currently alive and free of disease. There were 2 local recurrences on the T-10 protocol and 6 on the T-12 protocol. Excluding local recurrences 71/85 (84%), patients treated on T-10 are currently alive and free of disease and 38/45 (84%) patients treated on T-12 are alive and free of disease (at a median follow-up of 24 months for T-12). This preliminary study indicates that preoperative chemotherapy may be used to select a subset of patients (who respond well to preoperative high dose methotrexate) who can have therapy terminated early, sparing those patients the undesirable side effects and cost of additional therapy with platinum and Adriamycin.

Adult↗
PubMed1984

Primary osteogenic sarcoma of the femur: a model for the use of preoperative chemotherapy in high risk malignant tumors.

The value of adjuvant chemotherapy in primary osteogenic sarcoma (OSA) is still considered controversial by some. One reason may be that various reported series include patients with widely varying prognostic variables. To address this, the effect of chemotherapy on the continuous disease-free (CNED) survival was analyzed in 100 patients aged 21 yr or less with OSA of the femur. This classically poor prognostic group of patients represented 51% of all primary OSA seen at the Memorial Sloan-Kettering Cancer Center during the study interval. This study includes all patients aged 21 yr or less with fully malignant (Grade III-IV/IV) OSA of the femur and no metastases treated from November 1973 through November 1981. The first (T-4) protocol (31 patients) consisted of high dose methotrexate (HDMTX) with leucovorin rescue, cyclophosphamide (Cyc), and adriamycin. In the second (T-7) protocol (23 patients) the dose of HDMTX was increased to 12 g/m2 for prepubescent patients, and bleomycin, Cyc, and dactinomycin replaced Cyc. The current (T-10) protocol (46 patients) uses the same CT as T-7, but patients not having a complete response of the primary tumor to preoperative CT receive additional cisplatinum (120 mg/m2) with adriamycin (30 mg/m2/day for two consecutive days). In 31 patients treated with T-4 the CNED survival was 32% with a minimum follow up of over 7 yr. On T-7, 15/23 patients with femur primaries had a CNED survival of 65% with all of the surviving patients followed for more than 5 yr. The addition of cisplatinum in T-10 has resulted in CNED survival rate of 77% in 34/44 patients (excluding two patients that died CNED during and after treatment); the median follow-up patients who are alive CNED is 33 months, with a minimum of 2 yr follow up on the last patient entered.

Adolescent↗
PubMed1983

Chemotherapy of malignant fibrous histiocytoma of bone. A report of five cases.

Five patients with evaluable malignant fibrous histiocytoma (MFH) of bone (three with primary tumor and two with primary tumor and metastatic disease) were treated with preoperative chemotherapy including high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) as is used for patients with osteogenic sarcoma. All five patients demonstrated a clinical response to chemotherapy. Three of four patients who underwent surgery had complete responses and one patient had greater than 90% tumor necrosis as documented by histologic examination of the resected primary tumor. All four patients who underwent surgery following preoperative chemotherapy are surviving free of disease from one to six years from the start of treatment; chemotherapy was discontinued after six to 11 months in these patients. The median disease-free survival time is 31.5 months. This study demonstrates the effectiveness of chemotherapy in MFH of bone, and in particular the effectiveness of HDMTX with CFR which caused measurable responses in all patients while receiving this therapy as a single agent.

Adolescent↗
PubMed1983

Chemical pleuritis as the cause of acute chest pain following high-dose methotrexate treatment.

This report describes the clinical and roentgenographic features of a pleuritis seen following the administration of high-dose methotrexate (HDMTX). Among 210 patients who received 3130 courses of HDMTX from 1977 through 1980, the incidence of this clinical entity was 8.5% (n = 18). The sudden onset of chest pain occurred only after the third or fourth HDMTX treatment and usually lasted between three and five days; the pain was often quite severe and led to extensive clinical examination before recognition of the benign transient nature of this syndrome. Roentgenographic examination of the chest revealed thickening of the intralobar pleura, most prominent on the right side. Our observations support the hypothesis that this adverse drug reaction occurs more frequently than assumed, but is often ignored or misinterpreted.

Adolescent↗
PubMed1983

Primary osteogenic sarcoma: eight-year experience with adjuvant chemotherapy.

Since October 1973, 185 patients 21 years of age or younger with primary osteogenic sarcoma of an extremity were treated with adjuvant chemotherapy. Twenty-five of the first fifty-two patients (48%) have remained free of disease for a median of 7 years. In the next chemotherapy protocol most patients had chemotherapy prior to amputation or resection, during which time the dose of high-dose methotrexate was escalated in many patients to that needed to shrink the primary tumor. For a median of 4 years 43 of 54 patients (80%) have remained free of disease. In the current protocol, the response of the primary tumor to chemotherapy with high-dose methotrexate was used to select postoperative adjuvant chemotherapy for the patient. With the latter approach 73 of 79 patients (92%) have remained continuously free of disease for a median of 2 years. This experience demonstrates the value of chemotherapy in increasing the cure rate in osteogenic sarcoma and that the response to preoperative chemotherapy can help select postoperative chemotherapy to produce an even higher potential cure rate for osteogenic sarcoma.

Adolescent↗
PubMed1982

Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy.

Since June 1978, 57 patients with primary osteogenic sarcoma of an extremity were treated with high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR), Adriamycin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) given for 4-16 weeks prior to definitive surgery. Histologic examination of the resected primary tumor determined the effect of preoperative chemotherapy with many primary tumors showing greater than 90% tumor necrosis attributable to preoperative chemotherapy. All patients having this favorable effect of chemotherapy on the primary tumor were continued on the same chemotherapy regimen postoperatively (regimen B). However, in those patients not having a good effect of preoperative chemotherapy on the primary tumor, HDMTX with CFR was subsequently deleted from their postoperative chemotherapy and they were placed on a regimen containing cisplatinum at the dose of 120mg/M2 with mannitol diuresis combined with Adriamycin in addition to BCD (regimen A). In the current study, 35 of the 57 patients did not demonstrate a good effect of chemotherapy on the primary tumor and were assigned to regimen A postoperatively. Of these 35 patients, 32 (91%) have remained continuously free of recurrent or metastatic disease from 6-34 months following the start of therapy. Among the 22 remaining patients having a good histologic response and treated with regimen B postoperatively, there has been only one relapse in a patient who had a local recurrence in the area of an inadequately resected primary tumor three months after the cessation of chemotherapy. Thus, 53 of 57 patients (93%) are continuously with no evidence of recurrent or metastatic disease from 6-35 months (median, 20 months) from the start of treatment. This study demonstrates the value of thorough histologic examination in predicting survival in responding patients and in helping identify patients whose disease-free survival rate can be substantially increased if they are given alternative postoperative adjuvant chemotherapy after failing to have a good response to preoperative chemotherapy. This individualized chemotherapeutic strategy has yielded the highest disease-free survival rate reported to date for osteogenic sarcoma.

Antineoplastic Agents↗
PubMed1981

Ewing's sarcoma: ten-year experience with adjuvant chemotherapy.

Since May 1970, 67 consecutive patients with primary (nonmetastatic) Ewing's sarcoma were treated with adjuvant chemotherapy (CT) in addition to radiation therapy (RT) or surgery for the primary tumor. The first 19 patients were treated with four-drug sequential CT (T-2). The second protocol was a seven-drug induction combination CT (T-6) followed by T-2 maintenance CT; in both protocols CT was continued for 18 months. The current protocol (T-9) consists of combination CT given continuously for a period of 9 months. Of the entire group of 67 patients, 47 (70%) had axial and proximal lesions (pelvis, spine, rib, humerus, and femur) and 20 (30%) had distal lesions (forearm, leg, and foot); 53/67 (79%) are surviving free of disease 12--118 months (median 41 months) from the start of treatment. Fifteen of 23 (65%) patients with axial lesions, 19/24 (79%) patients with proximal lesions, and 19/20 (95%) patients with distal lesions are free of disease. Disease-free survivors include 28/39 (72%) male patients and 25/28 (89%) female patients. Thirty-four patients had RT, and 33 had surgery or surgery and RT, in addition to chemotherapy, for local treatment. The disease-free survival rate was 76% in the RT group and 82% in the surgery group; failure in the RT group was attributable to local recurrence in 7/34 (21%) patients. Recent experience with T-9 CT has demonstrated that CT given prior to RT or surgery can cause a great reduction in the size of the primary tumor while allowing the pathologically-eroded bone to heal prior to the initiation of RT; this also allows the high-risk patient with an axial primary (pelvis or spine) to tolerate the aggressive CT needed to prevent distant metastases. In addition to dramatically increasing survival in patients with Ewing's sarcoma, combination CT has helped achieve permanent local control. The superior survival rates for all sites of primary tumor are attributable to the early use of aggressive combination CT.

Antineoplastic Agents↗
PubMed1981

Osteogenic sarcoma: eight-percent, three-year, disease-free survival with combination chemotherapy (T-7).

Sixty-one patients were treated with combination chemotherapy (T-7) for biopsy-proved, fully malignant, osteogenic sarcoma (OS) of the extremity. Chemotherapy consisted of the combination of bleomycin, cyclophosphamide, and dactinomycin, followed in 2 weeks by vincristine and high-dose methotrexate (HDMTX) given in doses of 8 g/m2 for adolescents and 12 g/m2 for children 12 years old or younger with citrovorum factor rescue. The HDMTX was administered weekly for 4 weeks. One week following the 4 HDMTX treatments, adriamycin (ADR) was given at a dose of 90 mg/m2 for 2 days. Two weeks after the ADR, 2 additional doses of HDMTX were given before surgery. Thirty-eight of the 61 patients were referred before amputation and underwent preoperative chemotherapy for approximately 3 months. After surgery, chemotherapy was resumed. Of the 61 consecutive patients with primary OS entered in the T-7 protocol, 54 (88%) remained free of disease for more than 8 to over 35 months (median 18+ mo), with a projected 3-year disease-free survival in excess of 80%. Of the 38 receiving T-7 chemotherapy before surgery, 28 demonstrated a near complete or complete lack of viable tumor cells on examination of the resected primary tumors. All 28 are surviving free of disease. Nine of the 10 patients less than 12 years of age remain free of disease from over 12 to more than 35 months (median 24+ mo). A significant increase in disease-free survival in the younger patients could presumably be attributed to the use of 12 g HDMTX/m2 in that age group. The prognostic value of the effect of preoperative chemotherapy on the primary tumor is statistically highly significant. These data indicated that preoperative chemotherapy with the proper dose of HDMTX would be valuable in all patients with OS.

Antineoplastic Agents↗
PubMed1981

Prognostic factors in the response of primary osteogenic sarcoma to preoperative chemotherapy (high-dose methotrexate with citrovorum factor).

Forty-three patients, ranging in age from 7 to 30 years (median age, 17 yr), with primary osteogenic sarcoma (OS), confirmed by biopsies and with no evidence of metastatic disease at the time of diagnosis, received T-7 chemotherapy for an average of 4 months before surgery, including high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR) (median, 7 courses), and 1 course each of bleomycin, cyclophosphamide, and dactinomycin, and adriamycin. At the time of definitive surgery, the surgical specimen showed a good histologic response to chemotherapy (grade III or IV response) in 29 (67%) of 43 patients and a poor histologic response (grade I or II response) in 14 (33%) of 43 patients. Among those who responded well, no patient relapsed, as all received a complete course of preoperative and postoperative chemotherapy for more than 5 to over 28 months after the initiation of treatment (medium, 13 mo). Among those who responded poorly, 6 of 14 patients relapsed with pulmonary metastases (a thoracotomy was beneficial to 1), 4 of 6 patients are alive with disease, and 1 patient died of progressive disease. On retrospective analysis, we observed that good and poor responders did not differ in the distribution of sex, age, race, primary site of disease, or histologic subtype of OS. An elevated alkaline phosphatase level that returned to normal under preoperative chemotherapy indicated a good response. Neither the 24-, 48-, and 72-hour serum MTX levels nor the fluid intake and urinary output during 3 days that followed HDMTX with CFR correlated significantly with tumor response. Based on our studies with this form of therapy, we concluded that the response of OS to preoperative chemotherapy is of prognostic value.

Adolescent↗
PubMed1981

Combination chemotherapy (T-6) in the multidisciplinary treatment of Ewing's sarcoma.

Twenty-eight patients with primary Ewing's sarcoma (ES) and 10 with primary and metastatic ES were treated with intensive induction (T-6) and maintenance sequential chemotherapy (T-2). Local treatment for the primary tumor was surgery and/or radiation therapy (RT), and the choice depended on the patient's age and the location and size of the tumor. Patients with pulmonary metastases received bilateral pulmonary RT with 1,400 rad before T-2 maintenance chemotherapy. Most patients who were given T-65 induction chemotherapy before local therapy had healing of pathologically destroyed, tumor-bearing bones before the initiation of RT. None who had RT after T-6 chemotherapy developed pathologic fractures. Of the 28 with primary ES, 23 (82%) remained free of disease for more than 12 to over 46 months (median 22+ mo). Six of 10 with primary and metastatic disease are free of disease from more than 14 to over 34 months (median, 22+ mo). In addition to producing higher survival rates in the patients with poor prognoses, T-6 chemotherapy also improved the treatment of the primary tumor and achieved better function and, it is hoped, a lower local recurrence rate following RT. We found that the timing of T-6 chemotherapy and RT was crucial to obtaining a maximal response of the primary tumor and to maintaining patient tolerance for this aggressive treatment. The long rest required after patients were given 1,3-bis (2-chloroethyl)-1-nitrosourea makes its use in future protocols undesirable.

Adolescent↗
PubMed1979

Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery.

From 1973--1975, 31 patients with biopsied primary osteogenic sarcoma were treated with preoperative chemotherapy followed by surgical ablation of the primary tumor. Surgery was delayed in order to obtain a custom-fitted prosthetic bone implant in an attempt to avoid amputation. Preoperative chemotherapy included high dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and adriamycin (T-5 protocol) and was administered for 3 months preoperatively and continued with the inclusion of cyclophosphamide for approximately 5 months postoperatively. At a follow-up period of 30--52 months, 23 of 31 patients (75%) are surviving (21 of 23 with no evidence of disease). Histologic examination of primary tumor removed at surgery revealed varying degrees of tumor destruction (from very little effect to no evidence of viable tumor) attributable to the effect of chemotherapy. The 21 patients that are disease-free survivors had a more complete effect of preoperative chemotherapy on the primary tumor. Some patients achieving favorable effects upon the primary tumor did so only after the dose of HDMTX was escalated to greater than the starting dose of 8 g/m2. Preoperative chemotherapy for all patients with osteogenic sarcoma would seem to offer the following advantages: 1) Evaluation of the effect of HDMTX with CFR on the primary tumor with escalation of the dose of HDMTX until a clinical response is observed, thus defining the dose of HDMTX effective in that patient, to be continued postoperatively as adjuvant therapy; 2) The early use of systemic therapy to eradicate distant microfoci of disease that will eventually kill the patient if not adequately treated by effective chemotherapy; 3) Allow more time for postoperative healing without the need to start adjuvant chemotherapy immediately; and 4) Provide the surgeon time to plan resection surgery. To date, 20 additional patients with biopsy proven osteogenic sarcoma have been treated with more aggressive preoperative chemotherapy (T-7) for approximately 2 1/2 months prior to definitive surgery (resection or amputation). Doses of HDMTX were escalated where necessary and good clinical responses were obtained in 19 of 20 patients. In the majority of patients, no evidence of viable tumor was found on histologic examination of the surgically removed primary tumor. All 20 patients are surviving free of active disease at this brief follow-up period of 4--20 months.

Adolescent↗
PubMed1977

High-dose methotrexate with citrovorum factor rescue for the treatment of central nervous system tumors in children.

Eleven patients with brain tumors recurrent after surgery and radiation therapy were treated with high-dose methotrexate (MTX) (300-500 mg/kg) with citrovorum factor rescue (CFR). MTX was given as an iv infusion over 4 hours followed 2 hours later by oral CFR (10 mg every 6 hours X 12). MTX levels were measured in the serum, lumbar cerebrospinal fluid (CSF), and ventricular CSF at 0, 4, 12, 24, 48, and 72 hours from the start of the MTX infusion. MTX concentrations of greater than 10(-6) M were measured in the CSF over a period of 24 hours after the iv infusion. Peak CSF concentrations reached were greater than 10(-5) M. After the response to high-dose MTX with CFR was evaluated, vincristine (1.5 mg/m2) and a nitrosourea (methyl-CCNU or BCNU) were added to this treatment regimen. Two of four patients with recurrent pontine glioma and five of seven patients with recurrent medulloblastoma had favorable objective responses to treatment. It is suggested that high-dose MTX with CFR be cautiously considered for the primary treatment of intracranial neoplasms in children with the hope of increasing the cure rate for children with malignant brain tumors.

Brain Neoplasms↗