Cycles Of Multiagent Chemotherapy Research Articles

Phase III study of BEC2/BCG vaccination in limited disease small cell lung cancer (LD-SCLC) patients, following response to chemotherapy and thoracic irradiation (EORTC 08971, the SILVA study)

7020 Background: Attempts to maintain the response to initial therapy have been unsuccessful in SCLC. BEC2 is a murine IgG2b antibody that elicits antiidiotypic response to GD3, a glycosphingolipid overexpressed on membranes of SCLC and other tumors derived from the neural crest. In a pilot study (Grant et al. Clin Cancer Res 1999) long-term survivors were reported in SCLC patients vaccinated with BEC2/BCG. Methods: LD-SCLC patients in response after 4–6 cycles of multi-agent chemotherapy and thoracic irradiation were eligible. PCI was recommended in complete responders. Patients were randomized to observation or to 5 BEC2 (Merck KGaA and ImClone Systems Inc.) vaccinations (2.5 mg by 8 intradermal injections) with BCG, given on week 0, 2, 4, 6 and 10. A total of 376 deaths were required to detect a 40% increase in median survival in the V arm using a 2-sided α of 5% and a 90% power. The protocol was amended after 55% of inclusions to allow patients with a PPD positive test, when this was found to be safe (Klimek et al, ASCO 2000).Results: From April 1998 to October 2002 515 patients were randomized to observation (O, n=258) or vaccination (V, n=257). Arms were well balanced; 38% female, Karnofsky PS >80% in 94%, PPD positive in 11%, complete response to initial therapy in 49%, sequential chemotherapy-thoracic irradiation in 40%; 62% received PCI. The most frequent treatment related side effect was local reaction at the injection sites (95% of patients, grade 3 in 35%). Lethargy was observed in 37% (grade 3 in 3%). Six toxic deaths have been reported, 4 in the O arm (1 radiation pneumonitis and 3 pancytopenia) and 2 in the V arm (2 radiation pneumonitis). So far 71% of patients have progressed and 72% have died. There was no difference in survival (median 16.3 vs 14.3 months, p=0.3) or progression-free survival (median 6.6 vs 5.7 months, p=0.2) between O and V arms. Conclusions: Vaccination with BEC2/BCG does not provide any survival advantage in limited disease SCLC patients after a major response to induction chemo-radiation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc.

Advanced Endodermal Sinus Tumor With Contralateral Dermoid Tumor During Pregnancy: A Case Report and Literature Review

An endodermal sinus tumor (EST) of the ovary and a contralateral dermoid cyst occur rarely in pregnancy. Alternative treatment for reducing the long-term sequelae in both the mother and fetus should be considered during pregnancy. At 27 weeks of gestation, a patient was diagnosed with advanced EST, FIGO (International Federation of Gynecology and Obstetrics) stage IIIc, by magnetic resonance imaging and surgery. Following optimal debulking surgery, three cycles of multi-agent chemotherapy, consisting of 25 mg/m2 cisplatin and 100 mg/m2 etoposide on days 1 to 4, were instituted at 21-day intervals. Maternal serum !-fetoprotein and CA125 titers soon returned to normal pregnancy levels. A healthy male infant was delivered at 38 weeks of gestation by cesarean section, after which a second-look laparotomy was performed. The micropathologic findings were negative for malignancy, except that a dermoid tumor of the right ovary was confirmed. Consolidation treatment with two cycles of chemotherapy, consisting of 20 mg/m2 cisplatin and 100 mg/m2 etoposide on days 1 to 5 and a total of 30 mg/day of bleomycin on days 6 and 7, was administered at 28- day intervals. The patient had no evidence of disease for 16 months, and her infant son has shown adequate growth and normal development. For pregnant women with an EST of the ovary, the optimal treatment modalities might be initial optimal debulking surgery followed by alternative chemotherapy, and further standard chemotherapy after delivery.

A Case of Extraskeletal Ewing's Sarcoma Arising from Duodenum.

Extraskeletal Ewing's sarcomas (EES) are rare. Recently, Ewing's sarcoma of the bone, primitive neuroectodermal tumor (PNET), Askin tumor and EES have been included into the family of Ewing's tumors, due to the overlapping features relating to their clinico-pathological and cytogenetic appearance. We experienced a case of an EES arising from the duodenum in a 14-year-old girl who presented with hematemesis and epigastric discomfort. A duodenal biopsy specimen revealed the infiltration of small round cells and rich vasculatures, with immunohistochemical finding of MIC-2 (CD99) (+), vimentin (+), CD56 (NCAM) (+), LCA (-), T-cell (-), B-cell (-), CD43 (-) and CD68 (-). She was treated with several cycles of multiagent chemotherapy, and achieved an initial partial response, but rapid progression of tumor followed, so she was treated with surgical excision. This is the first case report of an EES arising from the duodenum in the literature.

Prognostic factors and survival in late adolescent and adult patients with small round cell tumors.

The primary objective of this study is to review the clinical characteristics of 25 patients in the adult and late adolescent age group, diagnosed and treated with small round cell tumors involving soft tissues (extraosseous Ewing sarcoma, rhabdo-myosarcoma, primitive neuroectodermal tumor, and undiffer-entiated small round cell tumors). Additionally, survival and prognostic factors influencing the outcome with multimodality treatment are evaluated. There were 19 males (76%) and 6 females (24%). The median age was 26 years (range: 15-56 years). In 9 patients (36%), the tumor was located at an extremity, whereas 16 patients (64%) had central localizations. Tumor size was larger than 10 cm in 7 patients (29.2%). Six patients (24%) had metastatic disease. Twelve patients (48%) received radiation and 16 patients (64%) underwent surgery. Among the resected tumors, 2 were resected with contaminated margins (12.5%), whereas 2 were radically resected and 12 (75%) were resected with wide margins. All patients were given a median of 4 cycles of multiagent chemotherapy (1-14 cycles). With preoperative chemotherapy, complete regression (CR) of the tumor was achieved in 6 patients (24%). In 4 patients (16%), a partial response was obtained. After the completion of multimodality treatment, 12 patients (48%) had a CR. Progression-free (PFS) and overall survival (OS) for the entire group was 25.0 +/- 10.8% at 1 year and 30.5 +/- 15.5% at 3 years, respectively. Nonmetastatic disease, wide and radical resection, and presence of CR to multimodality treatment were associated with a significantly longer PFS and OS by univariate analysis. By multivariate analysis, CR to multimodality treat-ment was the only independent predictive factor for a longer OS (p: 0.0036, relative risk [RR]: 23.6, 95% CI: 2.8; 198.7) and metastatic presentation was the only independent factor predic-tive for a shorter PFS (p: 0.017, RR. 15, 95% CI: 1.6; 141.2). Large-scale, multicenter studies are required for a better eval-uation of the nonpediatric age group with small round cell tumors.

MULTIMODAL THERAPY FOR STAGE IV ADULT WILMS TUMOR

A 34-year-old Native American, with no significant medical history, presented with a 2 to 3 month history of persistent right low back pain, 10 lb. weight loss, and acute nausea and vomiting during a 2-week period. Abdominal ultrasonography revealed a large, predominantly solid, heterogeneous mass near the lower pole of an enlarged right kidney. Computerized tomography (CT) revealed a 15 cm. mass arising from the superior pole of the right kidney, multiple lesions in the liver and both lungs, with significant pleural effusions (fig. 1, A). Positron emission tomography verified fluorodeoxyglucose uptake by these lesions in the liver and lungs, consistent with metastatic lesions. Additional staging included a bone scan, brain magnetic resonance imaging, testicular ultrasound, tumor markers and urinalysis, which were all normal. CT guided core biopsy of the renal mass was performed. Histopathological analysis revealed malignant small blue cells, consistent with Wilms tumor of a favorable histology (fig. 2). Pathological diagnosis was reviewed and independently confirmed by the director of the National Wilms’ Tumor Study pathology section. The patient was treated preoperatively according to a 48week pediatric high risk Wilms tumor protocol, which consisted of 5 cycles of multiagent chemotherapy (cyclophosphamide, etoposide, doxorubicin, vincristine and dactinomycin). Right radical nephrectomy was performed with the placement of a right hepatic artery perfusion catheter (Arrow pump*). Mediastinum and lungs were subjected to 2,000 cGy. radiation. A month after resection, systemic chemotherapy with vincristine, dactinomycin, cyclophosphamide and etoposide, and intrahepatic therapy (via the Arrow pump) with doxorubicin was resumed. Subsequently, the patient received 2 cycles of continuous intrahepatic infusion of doxorubicin, and a course of systemic 200 mg./m. 2 paclitaxel. Followup CT at 6 months after resection showed resolution of lung metastases, stable liver lesions and no residual disease in the renal bed (fig. 1, B). DISCUSSION

Adjuvant Chemotherapy in the Treatment of Localized Medulloblastoma in Children 791

Medulloblastoma (MB) is the most common malignant brain tumor of the posterior fossa in children. Surgical excision followed by neuraxis radiation has been the mainstay of therapy for children with localized posterior fossa(PF) MB. This treatment has resulted in a 60-65% long term disease free survival. In an effort to improve the outcome of children with this chemosensitive tumor, some institutions have incorporated adjuvant chemotherapy into the initial therapeutic regimen. Between 5/92 and 1/97, 12 children (mean age 10 years 3 months) presented consecutively with localized PF MB. Magnetic resonance imaging of the spine showed no evidence of metastatic disease. All patients underwent gross total surgical excision of the primary tumor followed by total neuraxis irradiation, and then treatment with 6 cycles of multiagent chemotherapy. The median radiation doses to the spinal axis, brain, and tumor were 3600 cGy, 4000 cGy and 5450 cGy, respectively. Following radiation therapy, all patients were treated with cycles of vincristine 2 mg/m2 IV, methylprednisolone 300 mg/m2 IV every six hours for three doses, cisplatin 90 mg/m2 IV, and cyclophosphamide 1200 mg/m2 IV. G-CSF was subsequently administered until neutrophil recovery. Chemotherapy cycles were administered every 3-4 weeks. Nine of twelve (75%) patients received 6 of 6 scheduled cycles of chemotherapy with 68 of 72 planned cycles administered overall. At a mean duration from diagnosis of 3 years, all patients remain disease-free. Hematopoietic toxicity predominated with grade III/IV neutropenia and thrombocytopenia following 66% and 32% respectively, of administered cycles of chemotherapy. Infectious complications included 13 episodes of fever and neutropenia (4 with positive blood cultures), 2 episodes of cellulitis and 2 episodes of herpes zoster. GI and renal toxicities were minimal with one episode each of pancreatitis, ileus and hepatic enzyme elevation; 2 episodes of transient reduction in creatinine clearance (25-49%); and 6 episodes of electrolyte imbalance. One patient developed severe unilateral hearing loss. Transfusion support with packed red blood cells and platelets was required following 40% and 10%, of administered cycles of chemotherapy respectively. Dose modification due to toxicity occurred following 42% of cycles of therapy, and 50% of patients required nutritional support. This regimen was well tolerated with the major toxicity being hematopoietic. While longer follow up is necessary, this regimen shows promise for improved clinical outcome in children with PF MB.

Comparison of combined modality (chemoradiotherapy) with chemotherapy alone in small cell lung carcinoma

Thirty-nine cases with small cell lung carcinoma (S.C.L.C.) who were treated with radiation therapy and/or chemotherapy were analyzed retrospectively. All patients had limited disease. Mean age of the cases was 58 years. Thirty-six patients were male (92%). The most commonly seen initial symptoms were cough (72%), pleural pain (44%), dyspnea (36%), hemoptysis (28%) and fatigue (28%). Diagnosis was made by sputum cytology in 16 cases (41%), by bronchoscopy in 12 cases (31%). Seventeen cases were treated with chemotherapy alone and nineteen with combined modality. Radiation therapy was administered either concomitantly with multi-agent chemotherapy (concurrent), or after multi-agent chemotherapy (post-chemotherapy), or in between the cycles of multi-agent chemotherapy. These patients also received one of the combinations of Vp16-P, CAV, Vp16-PCc, CVCc, AVBMVp16 or Vp16-P/CAV. Patients in chemotherapy alone group received Vp16-P or CAV combinations. In the chemotherapy alone group, seven patients had a complete response (CR, 41%) and six had partial response (PR, 35%). In the combined modality group, the CR rate was 63% and the PR rate 26% ( p=0.11). There was no correlation between the CR rate and total radiation dose or radiation dose per fraction ( p=0.33 and 0.28). No correlation was found between the multi-agent chemotherapy regimens and the CR rate ( p=0.25). Median survival in chemotherapy alone group was 7.5 months and 9.0 months in the combined modality treatment group. Overall complication rate in the chemotherapy alone group was 12% ( 2 17 ) while it was 32% ( 6 19 ) in the combined modality group (p=0.12). Distant metastasis rates were 29% and 21%, respectively. It is concluded that the addition of radiation therapy to multi-agent chemotherapy may be of some benefit in terms of complete response rates without any significant increase in complications but well-designed, prospective, randomized, controlled studies are needed to assess the role of radiation therapy in terms of local control and overall survival and optimal treatment schedules.

Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small-cell lung carcinoma: An update

Between 1974 and 1986, 576 patients (284 limited and 292 extensive stages) were treated at this institution. To keep multiagent chemotherapy (CT) at a uniform intensity, patients who received (a) combined modality approach of both multiagent chemotherapy and thoracic radiotherapy (RT) and (b) ≥3 cycles of multiagent chemotherapy (≥3 drugs), were chosen for this analysis. Out of 284 patients with limited Stage small-cell lung carcinoma, there were 154 such patients who met these strict criteria, and the treatment methods for the remaining 130 patients were as follows: (a) chemotherapy alone with radiotherapy reserved for local failure (47 pts); (b) radiotherapy alone (20 pts); (c) surgery ± adjuvant chemotherapy or radiotherapy (37 pts); (d) modified chemotherapy plus radiotherapy (26 pts). During the 12-year period, the therapeutic factors have evolved. Radiation-dose was increased from 30–40 Gy (time dose fractionation 49–66) in 1974–1977 to 44–52 Gy (time dose fractionation 73–86) in 1978–1986. The target volume for radiotherapy included the primary lesion with a 2-cm margin of normal lung and the mediastinum. Chemotherapy program also evolved from COP, CAV (1974–1977) to MACC, VCE-VCA, PCE-ACE (1978–1986). Fifty of 154 patients (32%) developed loco-regional recurrence (infield failure) and 98% ( 49 50 ) of these patients exhibited this by 2.5 years. Survival data of 154 patients were as follows: (a) Median survival time (MST) was 12 M; (b) actuarial survival rates at 2 and 5 years were 21% and 8%, respectively. Fifty percent of these patients died within 12 months (MST 12 M) and were not exposed to the full length of the risk period for loco-regional failure. To take into account the duration of exposure to the risk period, actuarial method was employed to measure the probability of loco-regional failure. Loco-regional failure rates at 2.5 years were 37%, 39%, 49%, 79%, and 84% for 50 Gy, 45 Gy, 40 Gy, 35 Gy, and 30 Gy, respectively. The difference between the recurrence rates of 37% and 79% by 50 Gy and 35 Gy was statistically significant, p < 0.05. Although the recurrence rates of 37% and 49% by 50 Gy and 40 Gy were not statistically different, there was a strong trend of a better control rate of loco-regional carcinoma by higher radiation doses. The time to recurrence seems also shorter with lower radiation-dose than that of higher radiation doses. Current radiotherapy schedules using 45 Gy to 50 Gy (time dose fractionation 75–82) are still associated with 37% to 39% of loco-regional failure rates at 3.0 years, and these data urge trials employing radiation-doses higher than 50 Gy or altered fractionation schedules to achieve the best possible rate of loco-regional control of small cell lung carcinoma.

Three-dimensional volumetric assessment of response to treatment: Stage I and II diffuse large cell lymphoma of the mediastinum

From 1981 to 1986, 12 patients with Stage I and II diffuse large cell lymphoma of the mediastinum were treated with 4 or more cycles of multiagent chemotherapy and for nine patients this was followed by mediastinal irradiation. The response to treatment was assessed by three-dimensional volumetric analysis utilizing thoracic CT scans. The initial mean tumor volume of the five patients relapsing was 540 ml in contrast to an initial mean tumor volume of 360 ml for the seven patients remaining in remission. Of the eight patients in whom mediastinal lymphoma volumes could be assessed 1–2 months after chemotherapy prior to mediastinal irradiation, the three patients who have relapsed had volumes of 292, 92, and 50 ml (mean volume 145 ml) in contrast to five patients who have remained in remission with residual volume abnormalities of 4–87 ml (mean volume 32 ml). Four patients in prolonged remission with CT scans taken one year after treatment have been noted to have mediastinal tumor volumes of 0–28 ml with a mean value of 10 ml. This volumetric technique to assess the extent of mediastinal large cell lymphoma from thoracic CT scans appears to be a useful method to quantitate the amount of disease at presentation as well as objectively monitor response to treament.

Stage IA to IIB mediastinal Hodgkin's disease: three-dimensional volumetric assessment of response to treatment.

From 1979 to 1986, the response to treatment of 53 patients with stage IA to IIB mediastinal Hodgkin's disease was evaluated by three-dimensional volumetric analysis using thoracic computed tomographic (CT) scans. The mean initial volume of mediastinal disease in 34 patients treated with mantle and para-aortic irradiation was 166 mL, whereas for 19 patients treated with two to six cycles of multiagent chemotherapy and mantle and para-aortic irradiation the mean initial volume was 446 mL. Preliminary data suggested that patients with mediastinal volumes of less than 200 mL had a lower mediastinal relapse rate (13%) than patients with volumes greater than 200 mL (32%). For 12 patients receiving six cycles of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), those with a greater than 85% reduction in volume 1 to 2 months after chemotherapy had a lower incidence of mediastinal relapse (zero of six, 0%) compared with patients having 85% or less reduction in volume (four of six, 67%). The primary value of this technique is that it provides a sensitive assessment of response to treatment and may aid in monitoring the effectiveness of a given treatment.

Results of treatment of stage IA and IIA Hodgkin's disease.

This study analyzed the 5 year actuarial survival and disease-free survival of 122 patients with Stage IA and IIA Hodgkin's disease, (108 patients laparotomy staged) treated with mantle and paraaortic irradiation from 1975 to 1981. Prognostic subgroups and patterns of treatment failure were investigated. The 5 year actuarial survival and disease-free survival was 91% and 75% respectively for the entire group. For Stage IA patients, the 5 year survival and disease-free survival was 92% and 86% respectively, whereas for those in Stage IIA the respective figures were 86% and 65%. Individuals with greater than four sites of involvement at initial presentation; extensive mediastinal adenopathy; hilar or extramediastinal extension to lung, pleura or pericardium, had a poorer 5 year actuarial disease-free survival (43%-60%) than those without these factors (70%-85%). Of the 122 patients, there were 26 relapses: nine infield failures; two concurrent infield and systemic failures; nine marginal recurrences, and three relapses occurring systemically and three in nodal groups not irradiated. Following relapse, 17 patients were salvaged with chemotherapy. Two patients are alive with disease and seven patients died of Hodgkin's disease. Patients with less extensive mediastinal adenopathy and supradiaphragmatic nonmediastinal presentations can be satisfactorily treated with mantle and paraaortic irradiation, whereas patients with extensive mediastinal adenopathy receive six cycles of multiagent chemotherapy before irradiation.

Results of treatment of stage 3A Hodgkin's disease

From 1975 to 1981, 38 patients with Stage 3A Hodgkin's disease (35 patients pathologically staged) underwent mantle and para-aortic irradiation, and in 36 patients this was preceded or followed by at least six cycles of multiagent chemotherapy. Both the 5-year actuarial survival and disease-free survival for all 38 patients were 83%. There have been six treatment failures: two patients have relapsed within irradiated nodal groups, one patient in apical pericardial lymph nodes as a marginal recurrence, one patient concurrently infield and in unirradiated nodal groups, and two patients systemically (concurrently in unirradiated nodal groups). Of these six relapses, three patients have died of Hodgkin's disease, one patient has been salvaged, and two patients currently are under treatment for salvage. One patient has developed acute nonlymphocytic leukemia and died of this disease. Extensive disease, as estimated by the number of sites of involvement at presentation, degree of splenic involvement, extent of intra-abdominal disease or mediastinal involvement, did not reveal statistically significant prognostic subgroups for relapse. It is currently recommended that patients with Stage 3A Hodgkin's disease receive six cycles of multiagent chemotherapy and mantle and para-aortic irradiation.