Effects Of Combined Modality Therapy Research Articles

The effects of combined modality therapy on stage II-III primary gastric signet ring cell carcinoma.

e16530 Background: To date, there is no well-defined standard of care for gastric signet ring cell carcinoma (GSRC). Clinical guidelines support that combined modality therapy (CMT) on localized gastric cancer, but this may not be appropriate for GSRC as it was generally found to be chemo-resistant. We conducted a population-based study to examine the effects of therapeutic strategies on survival outcomes by using the Surveillance, Epidemiology, and End Results (SEER) data. Methods: Analyses included primary GSRC patients with stage II-III who survived more than 6 months, and were diagnosed between 2006 and 2016 from SEER data.CMT were categorized as gastrectomy group, adjuvant CT group (gastrectomy with adjuvant chemotherapy), neoadjuvant RT group (gastrectomy with neoadjuvant radiotherapy combined adjuvant chemotherapy), and adjuvant CRT group (gastrectomy with chemoradiotherapy). Survival analyses were conducted by Kaplan-Meier method and multivariate Cox proportional hazards models, adjusted for age, gender, race, marital status, histology, AJCC stage, tumor location, and lymph nodes removed. Models were stratified by gender, AJCC stage, lymph nodes removed and tumor location. Results: Of the 1,717 cases of stage II-III primary GSRC, the mean age was 66.9 (SD: 11.0) years, over a half were male (52.8%), and the majority were white (66.0%). A total of 39.9% received adjuvant CRT. The five-year overall survival (OS) rate was 34.6% for this treatment, and 29.6% for adjuvant CT group, 25.4% for adjuvant CRT group, only 23.8% for the gastrectomy group. The median OS of patients treated with adjuvant CRT was significantly longer than that of the gastrectomy group (33 vs 24 months, aHR = 0.71, 95%CI = 0.60,0.84). Although the crude model showed a significant association between adjuvant CT and total survival (cHR = 0.81, 95%CI = 0.68,0.96), the effect measure turned null in the multivariable and sub-group analysis. Independent prognostic factors were adjuvant CRT, ≥60 years old, AJCC stage, and > 20 lymoh nodes removed. Conclusions: In this study, GSRC patients with stage II-III experienced improved overall survival after receiving adjuvant CRT, which provides several treatment implications. Future clinical trials considering adjuvant CRT will be needed to verify the conclusion derived from this study.

Clinical characteristics and prognosis analysis of 46 cases of newly diagnosed localized head and neck rhabdomyosarcoma

Objective: To analyze the clinical characteristics and prognosis of newly diagnosed localized head and neck rhabdomyosarcoma. Methods: Cases of newly diagnosed localized head and neck rhabdomyosarcoma between January 2006 and December 2016 were analyzed retrospectively. The clinical features of the patients were described. The Kaplan-Meier method was used to analyze the survival rate under different combined modality therapy and the survival rate with or without chemotherapy. The prognostic factors were analyzed by Cox model. Results: A total of 46 patients were included in this study. Among them, the median follow-up time was 77 months and the median relapse free survival time was 13 months. The relapse free survival time of 5 cases with inadequate local treatment and without combined chemotherapy was 5 months as control, and it was 7 months (P=0.110) in 11 cases with adequate local treatment without combined chemotherapy. Then in 7 cases with inadequate local treatment combined with chemotherapy and 23 cases with adequate local treatment combined with chemotherapy, it was 13 months (P=0.007) and 21 months (P<0.001), respectively. The median relapse-free survival time of chemotherapy patients was significantly longer than that of those without chemotherapy (21 vs 6 months, P=0.018). The effect of combined modality therapy was evaluated according to the adequacy of local treatment and whether to receive systemic chemotherapy, and the combined modality therapy degree was the independent prognostic factor in Cox's proportional hazards regression model (P=0.004). Conclusions: Rhabdomyosarcoma in head and neck is a highly malignant tumor with high relapse rate and easy metastasis. In patients with tolerable condition, systemic chemotherapy and adequate combined modality therapy are recommended to improve relapse-free survival.

Cytologically Proven Meningeal Carcinomatosis in Patients with Lung Cancer: Clinical Observation of 34 Cases

Meningeal carcinomatosis (MC) is a rare neurologic complication of lung cancer. Occasionally, it is the initial presentation of lung cancer. The clinical features of MC exclusively in lung cancer patients have not been well identified and characterized. The purpose of this report is to disclose the clinical features, laboratory findings, treatment and survival of patients with MC from lung cancer. We reviewed the medical records of 34 lung cancer patients with cytologically diagnosed MC at National Taiwan University Hospital from 1992 to 2002. Clinical symptoms and signs, cerebrospinal fluid parameters and lung cancer staging at the time of presentation were summarized. Previous treatment modalities for lung cancer, various treatments and response of MC, complications and survival times were also analyzed. Cerebrospinal fluid cytology revealed adenocarcinoma in 32 patients, and small cell carcinoma and squamous cell carcinoma in one each. MC occurred in approximately 0.7% of lung cancer patients. Nine patients had MC as the initial presentation of lung cancer. Symptom improvement was found in six patients who had whole brain irradiation for MC and one patient who had a ventriculoperitoneal shunt. Two of the patients with whole brain irradiation survived for longer than 1 year. Survival from cytologic diagnosis of MC ranged from 1 day to 82 weeks (median, 5.1 weeks). There was no difference in survival between patients treated by whole brain irradiation and other treatment modalities. The prognosis of MC from lung cancer is poor. A prospective study is needed to establish the effectiveness of combined modality therapy for patients with MC from lung cancer.

Ototoxicity after combined platinum and fractionated radiation in a novel guinea pig model

Purpose Cis-platinum and radiation in combination are current organ preservation treatment strategies for head and neck cancer. Their individual ototoxicity has been investigated, with recent demonstration of ototoxicity in clinical studies. Currently, no ototoxicity studies have been performed in animals receiving similar schedules of radiation or cis-platinum to those patients with head and neck cancer. Materials and Methods In the present study, an animal model was developed to investigate the effects of combined modality therapy on hearing. Albino guinea pigs were given equivalent protocol dosages of cis-platinum (3 parenteral courses), fractionated radiation (25 fractions over 5 weeks), or both. Click and tone burst auditory brainstem response (ABR) measurements were performed before and 6 weeks after the completion of treatment. Results Animals receiving radiation or cis-platinum and radiation experienced permanent significant ABR shifts at all frequencies, with 33% of the animals experiencing complete unilateral sensorineural hearing loss at 2 or more frequencies in the ear receiving the full radiation dose (7075 cGy over 25 fractions) ( P < .05, paired t test analysis). The animals receiving 3 doses of cis-platinum had no significant ABR threshold shifts at 6 weeks. These data suggest that cis-platinum and radiation cause greater ototoxicity than cis-platinum alone. These findings correlate closely with sensorineural hearing loss in combined modality patients at our institution and in recent studies. Conclusions We conclude that the current animal results parallel those seen clinically and serve as a model for ototoxicity from combined modality therapies in future protocols.

Pancreatic cancer: what the oncologist can offer for palliation.

Because pancreatic cancer has a poor survival rate and only 20% of patients present with potentially resectable disease, a key goal of therapy is to provide palliation. The poor medical condition of many patients interferes with their ability to tolerate traditional chemotherapy. Recently, however, a nucleoside analogue, gemcitabine, has been developed. This drug is more effective than 5-fluorouracil (5-FU), can be used in patients who fail to respond to 5-FU and has only modest toxicity. Combination therapies including gemcitabine and other agents are being tested. Local radiotherapy seems to provide pain relief, but gastrointestinal toxicity is significant. The effect of combined modality therapy (5-FU with radiotherapy) on survival is unclear, and it does not prevent local disease progression. Some novel biological agents, including angiogenesis inhibitors, matrix metalloproteinase inhibitors, antisense compounds, inhibitors of cell signalling such as epidermal growth factor and vascular endothelial growth factor, and inhibitors of oncogene activation, are undergoing phase II and III trials in patients with pancreatic cancer. Among the most promising are farnesyl protein transferase inhibitors, which modulate K-ras function. Such an approach is promising for the treatment of pancreatic cancer because this tumour frequently exhibits mutation of the ras gene.

Effectiveness of combining plasma exchange and continuous hemodiafiltration (combined modality therapy in a parallel circuit) in the treatment of patients with acute hepatic failure.

Plasma exchange has gained widespread acceptance as an effective mode of blood purification in patients suffering from acute hepatic failure. However, it is still undetermined whether a single use of plasma exchange is capable of removing inflammatory cytokines completely or of preventing the development of citrate toxicity inherent with fresh frozen plasma. To clarify these issues we developed combined plasma exchange and continuous hemodiafiltration (CHDF) modality in which CHDF is performed in an opposite direction to plasma exchange. This study was designed to assess the effectiveness of combined modality therapy. Fifteen patients with acute hepatic failure were treated with plasma exchange (plasma exchange group) or plasma exchange and CHDF (plasma exchange + CHDF group), and various biochemical parameters were determined before and after treatment. Although citrate levels increased significantly after treatment compared with pretreatment levels in both the plasma exchange group and the plasma exchange + CHDF group, the percentage of the increase in citrate levels was significantly higher in the plasma exchange group than in the plasma exchange + CHDF group. Bilirubin levels were significantly lower after treatment in both the plasma exchange and plasma exchange + CHDF groups. There were no significant differences in tumor necrosis factor-alpha levels before and after treatment in the plasma exchange group, but they were significantly lower after treatment in the plasma exchange + CHDF group. Interleukin-6 (IL-6) levels increased significantly after treatment in the plasma exchange group, but there were no significant differences in the IL-6 levels before and after treatment in the plasma exchange + CHDF group. Interleukin-8 levels increased significantly after treatment in the plasma exchange group while decreasing significantly after treatment in the plasma exchange + CHDF group. These results indicate that combining plasma exchange and CHDF in a parallel circuit is an effective modality for suppressing the elevation of blood citrate levels and for removing inflammatory cytokines. This finding may have important implications for the development of an effective treatment for patients with acute hepatic failure.

Primary central nervous system lymphoma 1991-1997: outcome and late adverse effects after combined modality treatment.

This retrospective single-center study assesses the feasibility, therapeutic outcome, and late side effects of combined modality therapy with intravenous methotrexate, whole brain radiotherapy (WBRT), and intravenous cytarabine in patients with primary central nervous system lymphoma (PCNSL). All 28 consecutive patients diagnosed with PCNSL between 1991 and 1997 were scheduled to receive combined modality therapy. Seven of 28 patients did not receive combined modality treatment: 6 patients had WBRT alone because of poor physical condition, and 1 patient died before receiving treatment. Of the remaining 21 patients, 5 received the complete regimen, and 16 received a modified regimen with reduced dose intensity. Fourteen of 21 patients (67%) treated with combined modality therapy had a complete response; 1 had a partial response. Median survival was 11 months in all 28 patients, 23 months in all patients with combined modality treatment, and 41 months in patients receiving the complete regimen. Of 15 examinable patients with a follow-up of 8 months or more, 10 developed severely symptomatic and 5 mildly symptomatic or asymptomatic diffuse white matter changes. Only a small subgroup of all patients with PCNSL appears to be eligible for receiving all parts of the combined modality regimen. Treatment in these patients leads to a marked prolongation of survival. The risk of late side effects is high even with modified, dose intensity-reduced versions of combined modality treatment.

Chemoradiation with or without intraoperative radiation therapy in patients with locally recurrent rectal carcinoma: prognostic factors and long term outcome.

Rectal carcinoma patients with local recurrence are reported to have a dismal prognosis. The purpose of this study was to evaluate the effect of combined modality therapy on clinical outcome and to determine the prognostic impact of a "presurgical" staging system. Between September 1989 and June 1997, 47 patients (with a median follow-up of 80 months) with locally recurrent, nonmetastatic rectal carcinoma were classified according to the extent of pelvic sidewall involvement as determined by pretreatment computed tomography (CT) scan. They received preoperative external beam radiation (45-47 grays [Gy] in 34 patients; 23.4 Gy in 13 preirradiated patients) plus concomitant 5-fluorouracil (1000 mg/m(2)/day as a 96-hour continuous infusion on Days 1-4 + 29-32) and mitomycin C (10 mg/m(2) as a bolus intravenously on Day 1 + 29). After 4-6 weeks, the patients were evaluated for surgical resection and intraoperative radiation therapy (IORT) procedure (10-15 Gy) or, in unresectable patients, a boost dose was planned by chemoradiation (23.4 Gy) or brachytherapy. Thereafter, adjuvant chemotherapy (5-fluorouracil and leucovorin for a total of six to nine courses) was prescribed. During chemoradiation, 2 patients (4.3%) developed Radiation Therapy Oncology Group Grade 3-4 acute toxicity. Twenty-five patients (53. 2%) had an objective response after chemoradiation. Twenty-one patients (45%) underwent radical surgical resection. The overall 5-year survival and local control rates were 22% and 32%, respectively. The classification system significantly predicted survival (P = 0.008). Radically resected patients had better local control and survival (P < 0.0001); in patients treated with IORT, the 5-year local control and survival rates were 79% and 41%, respectively. The data from the current study suggest that combined modality therapy was well tolerated and improved resectability, local control, and survival. The classification system appears to be a reliable tool with which to predict clinical outcome in patients with locally recurrent rectal carcinoma.

Concurrent chemoradiotherapy in head and neck cancer.

Historically, patients with unresectable head and neck cancer have been treated with definitive radiation therapy alone. In recent years, numerous trials have assessed the role of concurrent chemoradiation for these patients. Many of the larger, more recent trials are summarized here, with particular emphasis on the effect of combined therapy on survival and toxicity. Most of the trials have demonstrated modest benefit or a trend toward benefit in survival, progression-free survival, or local control in patients treated with concurrent chemoradiation. However, nearly every trial also showed increased toxicity with the more aggressive regimens. Two meta-analyses also show a small but significant improvement in survival and increased toxicity from a concurrent treatment approach. Therefore, patients should be well selected by their physicians to be able to tolerate the side effects of combined-modality therapy and must be well informed of the pros and cons of concurrent chemoradiation during the decision-making process.

Assessment of Cardiac and Pulmonary Function in Adult Patients with Hodgkin's Disease Treated with ABVD or MOPP/ABVD Plus Adjuvant Low-Dose Mediastinal Irradiation

We evaluated the long-term effects of combined modality therapy (CMT) with adria-mycin, bleomycin, vinblastine, dacurbazine (ABVD) or mechlorethamine, vincristine, prednisone, procarbazine (MOPP)/ABVD plus adjuvant low-dose (<30 Gy) involved-field radiation therapy (LDRT) on cardiac and pulmonary functions in adult patients with Hodgkin 's disease (HD). Adjuvant LDRT (mean dose, 2340 cGy) to the mediastinum was administered to 24 patients after chemotherapy with MOPP/ ABVD (n = 10) and ABVD (n = 14). The mean doses of doxorubicin and bleomycin were 233 mg/m2 and 92 IU/m2, respectively. Cardiac and pulmonary function tests were performed in all patients and, when available, were compared with pretreatment studies. After a median follow-up of 6.3 years, none of the patients had cardiac or pulmonary symptoms. A 4.7% overall decrease in left ventricular ejection fraction (LVEF) was observed (p = 0.03), but only one patient had a mildly decreased LVEF (47%). Diastolic function, LVEF, and left ventricular volume remained within the normal range in the other 23 patients. Mild pulmonary function study abnormalities occurred in 8 of 24 patients, 6 of whom were cigarette smokers. There were no significant changes in total lung capacity and forced vital capacity (FVC) values, but there was a 3% overall decrease in FEV1/FVC ratio (p = 0.05). In adult patients with HD, adjuvant LDRT after chemotherapy with ABVD or MOPP/ABVD did not result in a significant incidence of permanent pulmonary or cardiac toxicity after more than 6.3 years of median follow-up. Further studies are warranted to fully evaluate the impact of such therapy on cardiopulmonary function.

2161 Reduction of adverse effects of combined modality therapy with subtotal nodal irradiation in stage IIIA Hodgkin's disease

2161 Reduction of adverse effects of combined modality therapy with subtotal nodal irradiation in stage IIIA Hodgkin's disease

Effect of combined modality therapy on the surgical management of locally advanced rectal carcinoma.

The treatment of locally advanced rectal carcinoma is one of the more complicated problems in the management of colorectal carcinoma. More than any other site successful treatment requires a multimodality approach as surgery alone is frequently insufficient to completely eradicate all disease. This review focuses primarily on the management of patients who present without prior treatment and discusses the role of preoperative radiation therapy as well as intraoperative radiation therapy. Although much less gratifying, patients who present after failing previous therapy may also benefit from an aggressive multimodality approach.

Lymphocyte migration to tumors after hyperthermia and immunotherapy

We have previously shown that the combination of immunotherapy with interleukin 2 (IL-2) and local hyperthermia (LHT) abrogates the growth of murine subcutaneous tumors significantly more than either modality alone. This study was undertaken to investigate whether the beneficial effect of combined modality therapy could be attributed to increased trafficking of effector cells to the tumor. After inducing MCA-105 sarcomas in the hindlimbs of C57BL/6 mice, animals were given no therapy, LHT, IL-2, or IL-2+LHT followed by an iv injection of 51Cr-labeled syngeneic splenocytes or LAK cells. Select organs and the tumor-bearing extremity were counted in a gamma counter. IL-2 or LHT alone did not affect lymphocyte migration, while IL-2+LHT significantly decreased trafficking ( P < 0.001) to the tumor. LAK cells showed increased migration to the tumor site compared to splenocytes in all treatment groups ( P < 0.02). IL-2 caused increased migration of LAK cells but not splenocytes to the lung; this was not affected by LHT. LAK cell trafficking to the spleen was decreased by IL-2 and IL-2+LHT, while splenocyte migration was decreased in the LHT and combined treatment groups. LHT and IL-2 had no effect on trafficking of either effector cell type to liver or kidney. These results show that the beneficial effect of combined modality therapy may not be due to increased trafficking of lymphocytes to the tumor area. In addition, LAK cells traffic more to subcutaneous tumors than splenocytes, and this cannot be explained by the differential trafficking to other organs. The results of this study will be important in the planning of future experiments with combined adoptive immunotherapy and hyperthermia.

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients ( p < 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients ( p < 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85j%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recured with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality patient developed acute leukemia.

Effects of combined modality therapy of head and neck carcinoma on shoulder and head mobility.

One hundred twenty-six patients were evaluated prospectively for head and shoulder mobility following combined treatment of their advanced head and neck carcinoma. In the absence of a pectoral myocutaneous flap reconstruction, the sacrifice of the spinal accessory nerve does not appear to be deleterious to overall head and shoulder mobility with the exception of shoulder elevation. The addition of the pectoral myocutaneous flap reconstruction negated the shoulder elevation difference between the modified neck dissection and the classical neck dissection. The administration of postoperative radiation therapy appears to decrease the range of motion of both the head and the shoulder by up to 20%. We conclude that head and shoulder mobility following combined modality treatment for patients with head and neck carcinoma appears to be a multifaceted problem involving more than the presence or absence of the accessory nerve and psychosocial considerations. The multifaceted etiology of this problem should be taken into consideration when developing physical and occupational programs directed specifically at this problem.

The effect of combined modality therapy on local control and survival

The systemic component of combined modality therapeutic programs has influenced both the selection of the approach to local control and survival in a number of tumor types. The more effective systemic therapy is against metastatic cancer by itself, the greater the impact on local control and survival. This observation is consistent with the invariable inverse relationship between curability and tumor cell number. For some common cancers, local control is good, but survival remains poor because of the inability to deal effectively with micrometastases. Improved systemic treatment is likely to have an impact on survival may shift local control measures, in some cases, to radiation therapy or lesser surgery without radiation therapy. There remains a substantial number of tumor types where both local control and survival is poor. In these tumors, improvement in local control by itself is not likely to improve survival because of the presence of micrometastases, but such improvements must occur before we can have a true evaluation of the systemic treatment of micrometastases in these tumors. The recent understanding that the metastatic process is under genetic control and the cloning of metastases genes offers a substantial opportunity to control this process and influence both local control and survival.

Clinical staging, primary chemotherapy and involved field radiotherapy in childhood Hodgkin's disease

Sixty children with Hodgkin's disease were clinically staged and treated by MOPP primary chemotherapy followed by 40 Gy nodal radiation limited to involved fields. Overall 5-year survival is 93% while relapse-free survival is 86%. Four patients relapsed. These results confirm that laparotomy no longer has a place in routine staging when chemotherapy is given to all patients and that radiotherapy of localized disease (IA and IIA) can be limited to involved fields. On the basis of these results and data of other published series, the French Society of Clinical Oncology and Hopital Saint Louis initiated a new joint national study to minimize the late effects of combined modality therapy without jeopardizing the good survival. Outlines and preliminary results of this study are presented.

Solid tumor models for the assessment of different treatment modalities. XXI. Comparison of different radiation dose schedules alone or in combination with cyclophosphamide.

Total radiation (4500 rad) and cyclophosphamide doses (450 mg/kg or 2.7 g/m2) were held constant over a 24-day period in rat hepatoma 3924A using radiation schedules in which 1500 rad were given over a 1- to 2-day period in 1-8 fractions, repeated at 11-day intervals, with or without cyclophosphamide. Reducing the rad per fraction resulted in a reduced incidence of complete tumor response and tumor cures, and a reduction in the magnitude of skin response. Cure rates were 40, 10, 0, and 0%, respectively, for the 1500, 750, 500, and 250 rad per fraction groups without cyclophosphamide. When the 1500, 750, 500, 375, 250, and 188 rad per fraction groups were given 150 mg/kg cyclophosphamide day 1 after radiation, major increases occurred in tumor cures, with the cure rates being 80, 80, 80, 70, 60, and 50%, respectively. The addition of cyclophosphamide did not significantly alter skin reaction to radiation. The higher rad per fraction schedules were more effective in controlling metastatic dissemination when radiation was used alone. The addition of cyclophosphamide markedly reduced metastatic dissemination in both high and low-dose per fraction schedules. Optimal treatment levels were estimated from analysis of fitted response surfaces, and the quantitative interrelationship between normal tissue reaction, probability of tumor cure, and associated relative hazard to the host estimated from the results of these analytical methods. Hyperfractionated radiation dose schedules with dose/fraction in the clinical range combined with cyclophosphamide can significantly increase the therapeutic ratio and prevent metastatic dissemination compared with radiation alone as a result of the increased effectiveness of combined modality therapy on the tumor, without a concomitant increase in normal tissue reaction.

Combined therapy for metastatic extradural tumors of the spine

The effectiveness of combined modality therapy was studied in 29 patients with metastatic extradural spinal tumor who had had a previous diagnosis of malignancy. Dexamethasone was begun upon suspicion of the diagnosis in a dose of 40 mg daily. Following emergency myelography, in all patients without rapid progression, dexamethasone in combination with radiotherapy and chemotherapy, when appropriate, was instituted. If deterioration occurred, decompressive laminectomy was performed. Five ambulatory patients had neurological function preserved and the condition of seven nonambulatory patients was improved to ambulation at discharge with a combination of dexamethasone, radiation therapy, and chemotherapy. These were patients with prostatic carcinoma, Hodgkin's disease, or breast carcinoma. In five patients who failed medical therapy decompressive laminectomy was successful. In patients with metastatic bronchogenic carcinoma, nonsurgical therapy failed and all underwent surgical decompression with a favorable outcome in only two of 10 patients.

Therapeutic challenges to a rat brain tumor model (author's transl)

A rat brain tumor model was prepared by stereotactically implanting 4×104 cultured 9L tumor cells in the cerebral hemisphere. The tumor bearing rats exhibited weight loss after two weeks, developed neurological symptoms several days later and died 19-20 days post-implant. Tumor take was 100% and the lethal tumor weighed 279 mg. The tumors had a doubling time of 39.5 hours. Cell kinetic parameters determined by PLM curve analysis 14-16 days post-implant were: TC-19.3 hrs.; TG1-8.6 hrs.; TS-7.6 hrs.; TG2-2.9 hrs.; and TM-0.2 hrs. The growth fraction was 0.55 and the cell loss factor was 0.24. The effectiveness of combined modality therapy on this model was analyzed in terms of survival, tumor size and colony forming efficiency. BCNU administered on day 16 post-implant produced an ILS of 122% while treatment on day 10 produced an ILS of only 60%, which corresponded to a 3-3.5 log cell kill and 2-2.5 log cell kill, respectively. Microsurgical removal of tumors on days 13 and 16 post-implant produced an ILS of 28% (1 log cell kill) and 56% (2 log cell kill). Surgery performed more than 3 days before or after BCNU therapy was less effective than BCNU alone on day 16. An ILS of over 200% (< 7 log kill) was achieved when BCNU was given 1 hr. before or 1 hr. and 12 hrs. after surgery performed on day 16. BCNU was not effective when administered during the surgical procedure. Cell kinetic parameters of both perturbed and unperturbed tumor cell populations can be used to design even more effective combined modality therapy.