Intensive Combined Modality Therapy Research Articles

Pretreatment evaluation of combined HIF-1alpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer.

Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle- and apoptosis-control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF-1-dependent. Our aim was to evaluate the expression of the HIF-1alpha, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF-1alpha expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF-1alpha-negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF-1alpha, p53 and p21 and proliferation and apoptosis. HIF-1alpha overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF-1alpha, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF-1alpha) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.

Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: A phase I report

Purpose To assess the benefits of aggressive chemoradiation therapy followed by surgery in resectable esophageal carcinoma. Method Twenty-nine patients with resectable carcinoma were treated with 60 Gy of radiation (2 Gy daily for 6 weeks) and concurrent chemotherapy consisting of continuous infusion of 5-fluorouracil (200-225 mg/m 2/d), paclitaxel (25, 40, 50, or 60 mg/m 2) weekly over 1 hour, and cisplatin (25 mg/m 2) weekly immediately following paclitaxel throughout radiation. Patients received either 4 cycles of postoperative paclitaxel 175 mg/m 2 over 3 hours and cisplatin 75 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 over 3 hours and cisplatin 75 mg/m 2 every 3 weeks prior to the initiation of chemoradiation. After induction therapy and restaging, esophagectomy was performed 4 to 6 weeks later. Results Twenty-seven patients were eligible for study (26 men, 23 with adenocarcinoma). Median age was 58 years (range 30-73). The maximum tolerated dose combination was paclitaxel 50 mg/m 2 over 1 hour weekly, cisplatin 25 mg/m 2 over 1 hour weekly, 5-fluorouracil 200 mg/m 2/d by continuous infusion throughout radiotherapy and radiation to 60 Gy. Twenty-two patients completed therapy and underwent surgical resection. Four patients had complete pathological responses and 18 had partial responses with no mortality. The commonest dose-limiting toxicity was mucositis and esophagitis (n = 7). Median follow-up of 27 patients was 150 weeks (range 7-303). At 2-year follow-up 16/27 (59%) were alive and 15/27 (56%) were free of disease. At 4-year follow-up 12/27 (44%) were alive and free of disease. Median follow-up of 22 patients undergoing esophagectomy was 205 weeks (range 26-303). At 4-year follow-up 10/22 (45%) were alive and free of disease. For the 18 patients treated at or above the maximum tolerated dose, median follow-up was 151 weeks (range 35-206) and at 3-year follow-up 9/18 (50%) were alive and free of disease. Conclusion Aggressive combined modality therapy of esophageal carcinoma was associated with excellent long-term survival in this phase I trial.

Combined modality therapy of early stage nonsmall cell lung cancer.

Therapy for locally advanced NSCLC has evolved into a multidisciplinary effort. Patients who are considered for this approach should undergo rigorous testing to accurately stage their disease. Patients with pleural effusions (with rare exception) are not candidates for intensive combined modality therapy. Appropriate patients for combined modality therapy should have a good performance status (generally Zubrod 0 or 1), adequate pulmonary function, absence of significant heart, lung, or other medical diseases, and be appropriate candidates for combination chemotherapy and thoracic surgery or thoracic radiotherapy. Several lessons can be learned from looking broadly at the phase II and phase III combined modality experience. The available data do not support the routine use of postoperative therapy in patients with completely resected disease. Treatment with chemotherapy before surgery or radiation has demonstrated survival benefit in patients with stage III disease. The French phase III trial of induction chemotherapy in patients with early stage disease found an 11-month improvement in overall survival (P = 0.15) and a significant increase in the risk of death for patients with stage I and II disease. The ongoing U.S. intergroup trial (SWOG 9900) and European trials will help to further define the role of chemotherapy in patients with clinical stage IB, II and IIIA NSCLC. Clinical trials should be conducted to compare preoperative chemoradiotherapy with preoperative chemotherapy. The recently completed intergroup 0139 trial (chemoradiation followed by surgery or not) should help to define whether surgery and radiation are required in the management of stage IIIA NSCLC. Finally, further improvement in survival with the use of "newer" cytotoxic agents seems unlikely as phase III trials in metastatic NSCLC have not demonstrated marked superiority over cispiatin-based regimens. Ongoing trials are assessing the incorporation of newer, biologic-based "targeted" therapies. Despite the dismal findings of trials of postoperative therapy, many patients continue to have surgery as their initial treatment followed by postoperative therapy. In contrast, trials with induction treatment seem to offer improved survival. It is time for a true multidisciplinary approach to the treatment of locally advanced NSCLC. Pulmonary physicians, thoracic surgeons, medical oncologists, and radiation oncologists should meet before the initiation of treatment to plan the most appropriate therapy for the individual patient.

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone.

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.

Concurrent chemoradiotherapy followed by surgery for advanced stage III non-small cell lung cancer (NSCLC): Katakami N. Matsumoto H. Tomioka H. Okazaki M. Hasegawa T. Sakamoto H. Pulmonary Unit, Kobe City General Hospital, Kobe. Jpn J Cancer Chemother 1995;22:531–537

Forty-two patients with stage IIIA (bronchoscopically T3 and/or bulky N2) and stage IIIB NSCLC were treated with concurrent chemoradiotherapy (CRT). Treatment consisted of CDDP, 20 mg/m2 and etoposide, 40 mg/m2 by continuous infusion (day 1-5) of weeks 1 and 5 simultaneously with chest radiotherapy (RT), 50 Gy, 2 Gy/Fx, 5 Fx/week. Surgery was attempted 3-5 weeks after RT in pts clinically downstaged. Between 10/90 and 12/92, 43 previously untreated pts were enrolled and 42 were eligible. Pts characteristics were: male/female = 37/5; mean age, 61 yrs (range, 31-74 yrs); stage IIIA/IIIB = 10/32; 15 adenocarcinoma, 24 squamous cell, 2 large cell, 1 unclassified; PS 0/1/2 = 11/24/7. Excluding 1 ineligible pts, 42 pts were evaluated for CRT response. The response rate was 81% (1 CR, 33 PR, 5 NC, 1 PD, 2 NE). Clinical downstaging was achieved in 20 pts (48%). Twenty-one pts (50%) received surgery and 19 of them were completely resected. In 7 resection specimens, no tumor was observed. Toxicity of CRT was well tolerable (Grade 4 leukopenia, 15%; Grade 2-3 esophagitis, 15%). We conclude that this intensive combined modality therapy is acceptable and appears to increase the response rate as well as resectability. Prospective randomized studies should be conducted for further evaluation of this treatment modality.

Intensive combined-modality therapy in small cell lung cancer: Thatcher N, Lorrigan P, Burt P, Stout R. Department of Medical Oncology, Christie Hospital, Wilmslow Rd, Manchester M20 9BX. Semin Oncol 1994;21:Suppl 6:9–22

Combination ifosfamide/carboplatin/etoposide (ICE) chemotherapy and ICE plus mid-cycle vincristine (VICE) are reviewed. Thoracic radiotherapy and prophylactic cranial irradiation given as single fractions in the majority of patients have been intercalated with VICE in the later studies. The patient populations have not been intensively staged with computed tomography, etc, but do have reasonable Karnofsky performance status ratings and biochemical screens. A policy of no dose reduction over six courses of VICE chemotherapy has been followed in three consecutive studies of 166 patients. The minimum length of follow-up is 26 months and the 2-year survival rate is > or = 30%. Hematopoietic growth factor support in an attempt to overcome the considerable myelosuppression with VICE therapy is currently being evaluated.

Dose intensive combined modality therapy for small cell lung cancer : Anthony D. Elias, M.D. Dana-Farber Cancer Institute, Boston, MA 02115

Dose intensive combined modality therapy for small cell lung cancer : Anthony D. Elias, M.D. Dana-Farber Cancer Institute, Boston, MA 02115

Primary cns lymphoma: Long-term results of an intensive combined modality therapy

Primary cns lymphoma: Long-term results of an intensive combined modality therapy

Massive Chest Wall Tumor Diagnosed as Askin Tumor: Successful Treatment by Intensive Combined Modality Therapy in an Adult

A 24-year-old woman was admitted due to dyspnea on exertion. A chest roentgenogram revealed a massive tumor originating from the right anterior chest wall when pleural effusion was drained. Diagnosis of Askin tumor was made based on light microscopic findings characterized by composing with small round cells, immunocytochemical findings suggestive of neuroectodermal origin, and cytogenetic analysis demonstrating the chromosomal translocation (11; 22). After intensive combined modality therapy, including chemotherapy, irradiation, and additional surgery, she was followed up as an outpatient and has remained disease-free for 16 months after initial diagnosis.

Chemotherapy and radiation therapy before transhiatal esophagectomy for esophageal carcinoma

Recent efforts to improve survival in patients with esophageal carcinoma have combined both systemic and local therapy. From October 1985 to October 1987, 43 patients with local-regional esophageal cancer (adenocarcinoma in 21, squamous cell in 22) were treated with cisplatin, vinblastine, and 5-fluorouracil chemotherapy concurrent with 4,500 cGy radiation therapy for 21 days before transhiatal esophagectomy 3 weeks later. Two patients died of chemotherapy/radiation therapy toxicity. Forty-one completed preoperative chemotherapy/radiation therapy. At operation, 2 patients had incurable metastatic disease; 39 underwent transhiatal esophagectomy. Eleven patients had no residual tumor in the resected specimen for a 27% (11 of 41) pathological complete response rate. Preoperative chemotherapy/radiation therapy resulted in no increased perioperative morbidity as compared with our historical controls. One patient died postoperatively of an unrecognized brain metastasis (2% operative morbidity). At a median follow-up of 27 months, 20 patients (47%) are alive and clinically disease-free and 21 have died, 19 from progression of their carcinoma. The median survival time for all 43 patients is 29 months (Kaplan-Meier estimate), and cumulative survival is 72% at 12 months, 60% at 24 months, and 46% at 36 months. All 11 patients with a complete response are alive at a median follow-up of 36 months, and all are disease-free. The 2-year survival of 60% of this group as compared with 32% in our earlier patients treated with transhiatal esophagectomy alone suggests that intensive combined modality therapy improves survival in these patients. A randomized prospective trial is now in progress.

Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: local control and patterns of failure.

Seventy-five patients (ages 4-35 years) with the following small round cell tumors and undifferentiated sarcoma were treated at the National Cancer Institute: Ewing's sarcoma (n = 32), peripheral neuroepithelioma (n = 14), rhabdomyosarcoma (n = 24), undifferentiated sarcoma (n = 5). Most patients had poor prognostic features including 36 (48%) with metastatic disease, and 42 (56%) with central (truncal) tumors (22 in the pelvis). Treatment included 5 cycles of intensive induction chemotherapy with vincristine, cyclophosphamide and adriamycin, plus aggressive local radiation therapy using simulation and computerized treatment planning for all patients. Thereafter, complete clinical responses were consolidated with intensive chemotherapy, total body irradiation and autologous bone marrow transplantation. There were three local only failures, 10 local plus distant failures, 36 distant only failures, 3 treatment-related deaths, and one intercurrent death. Overall actuarial survival and event-free survival at 4 years are 49 and 29%, respectively. Actuarial freedom from local progression was seen in 74% of patients at 4 years, quite remarkable considering the bulk and location of most of these tumors. Without aggressive surgery, many of these high risk patients had satisfactory outcomes, but better systemic treatments are still needed.

Treatment of sarcomas of the chest wall using intensive combined modality therapy

As part of two sequential protocols using intensive combined modality treatment in pediatric and adolescent sarcomas, 31 consecutive patients with primary chest wall tumors were treated between November 1977 and March 1986. This group included 13 patients with peripheral neuroepithelioma (Askin's tumor), 11 patients with Ewing's sarcoma, 3 patients with rhabdomyosarcoma, and 4 patients with undifferentiated sarcomas. Following complete work-up, 17 patients presented with localized disease and 14 patients presented with metastases. Patients received intensive combined modality treatment with combination chemotherapy (vincristine, cyclophosphamide, Adriamycin, ± actinomycin-D and DTIC) and high-dose conventionally fractionated radiation therapy to the primary (55–60 Gy) and non-pulmonary metastases (45–50 Gy). Radiation techniques used for the primary chest wall tumor varied with the clinical presentation. Patients achieving a complete response received either low-dose fractionated TBI (1.5 Gy/0.15 Gy fx/5 weeks) or high-dose TBI (8 Gy/4 Gy fx/2 days) and an intensive cycle of chemotherapy followed by autologous bone marrow transplantation. Twenty-five of 31 patients were judged to have a complete response (including 1 patient with complete resection). With minimum follow-up of 6 months and median follow-up of 36 months from completion of treatment, 14 patients remain disease-free with 2 additional patients alive in second remission after relapse. Patients with localized disease at presentation have improved disease-free survival and overall survival compared to patients with metastases at presentation. All 17 localized patients achieved a CR and 11 are NED compared to 8 of 14 metastatic patients achieving a CR and only 3 are NED. There have been 5 loco-regional recurrences with 3 “in-field” failures and 2 failures in the regional pleura. There were no treatment-related deaths and no clinically significant cases of pneumonitis. To date, 2 patients have significant treatment related morbidity, including 1 patient with scoliosis requiring surgery and 1 patient with acute leukemia developing 42 months after the start of therapy (presently in remission). We conclude that this intensive combined modality therapy results in a high CR rate and good local control with acceptable morbidity. Patients with metastatic disease at presentation remain a therapeutic challenge.

Preliminary results of treatment of Ewing's sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance.

Thirty-one previously untreated patients with Ewing's sarcoma were treated with an intensive chemotherapy program of vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cyclosphosphamide (VADRIAC) in combination with radiation therapy to the primary site (greater than 50 Gy) and bone metastases (45 to 50 Gy). An intensified regimen with one further cycle of chemotherapy (VADRIAC), total body irradiation (TBI), and autologous bone marrow transplantation was given to patients with primary tumors of the pelvis, humerus, femur, and chest wall without metastases and to all patients with metastases at diagnosis. Patients with primary tumors of the distal extremity and other sites without metastases at diagnosis were treated on a less intensive chemotherapy regimen of VADRIAC without the intensification. Therapy was completed within 6 to 7 months in all patients. Thirteen patients had metastatic disease at diagnosis; only two of these had the lung as the sole site of metastatic disease. Eighteen patients had no evidence of metastatic disease at diagnosis: ten of these patients had tumors that arose in central axis and proximal extremity sites, and eight had tumors that arose in distal extremity and other sites. Thirty of the 31 patients achieved a complete remission, although two patients underwent amputation: one before chemotherapy and radiation and one after chemotherapy and radiation because of persistent local disease. Seventeen remain in their first complete remission at a median time on study of 30 months and a median time after completion of therapy of 24 months. Fourteen patients have relapsed (13) or progressed (1): ten in metastatic sites and four in the primary site. One patient had persistent local disease after radiation requiring amputation. Nine of the 13 patients with metastatic disease at diagnosis have relapsed compared with five of the 18 patients without metastatic disease. For the entire group, the actuarial survival is 78% (65% to 87%) at 30 months, and the actuarial disease-free survival is 58% (46% to 69%) at 30 months.

Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy

Adolescent and young adult patients with pelvic sarcomas continue to have a poor prognosis with standard combination chemotherapy and local irradiation. In addition to a significant risk of local failure, these patients are at high risk for systemic relapse. Twenty-three consecutive patients with Ewing's sarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or malignant peripheral neuroepithelioma originating in the pelvis were treated with short, intensive combined modality therapy. This approach integrates 5 cycles of VADRIAC chemotherapy (Vincristine, Adriamycin, Cyclophosphamide) with high dose irradiation to the primary lesion (55–60 Gy) and sites of gross metastatic disease (45–50 Gy). Following achievement of a complete response, intensification therapy consisting of total body irradiation (TBI) (8.0 Gy), high dose VADRIAC chemotherapy, and autologous bone marow transplantation is given. All therapy is completed within 6–7 months. No maintenance chemotherapy is given; no surgery is intended. Of the twenty-three patients with pelvic sarcomas treated on this combined modality protocol, 22 achieved a complete remission. Local control was achieved and maintained in all twenty-three patients. With a median follow-up of 21 months since initiation of treatment, there have been nine relapses (all systemic). Seven relapses occurred among the thirteen patients who presented with overt metastatic disease and the other two relapses were among the ten patients with localized disease at presentation. All seven metastatic patients who relapsed have died, whereas both of the relapsed localized patients remain alive. Acute and late toxicities have been acceptable using this aggressive combined modality approach. Induction chemotherapy had a significant impact on reduction of the typically large (>10 cm diameter) soft tissue mass associated with these pelvic tumors, thus facilitating achievement of local control by high dose irradiation. Of 18 patients with measurable soft tissue tumor, all experienced a partial response (>50% reduction in size) following the initial two cycles of chemotherapy given prior to local irradiation. In conclusion, this short, intensive chemoradiotherapeutic regimen is highly effective in controlling the primary lesion (100% local control) and inducing a complete response in a high proportion (96%) of these high risk pediatric and young adult patients with pelvic sarcomas. The role of TBI as “systemic” adjuvant therapy to control micrometastatic disease is discussed as still under investigation.

Treatment of pediatric sarcomas of the chest wall using intensive combined modality therapy

Treatment of pediatric sarcomas of the chest wall using intensive combined modality therapy

Treatment of pelvic sarcomas with intensive combined modality therapy

Treatment of pelvic sarcomas with intensive combined modality therapy

A pilot study to determine clinical tolerability of intensive combined modality therapy for locally unresectable gastric cancer

Eighteen patients with unresectable carcinoma of the stomach whose known malignant disease was confined to structures immediately adjacent to the primary tumor and could be encompassed within a radiotherapy field were treated with an intensive sequential combined modality regimen. The regimen consisted of 5-FU plus adriamycin chemotherapy, followed by high dose megavoltage radiation therapy with 5-FU given as a radiation sensitizer, followed by maintenance chemotherapy with 5-FU plus adriamycin plus methyl CCNU (FAMe). Our primary objective was to determine patient tolerability. Severe and prolonged anorexia, nausea, and decreased performance status occurred during and after high dose radiotherapy given twice daily in 150–170 cGy (rad) fractions when given with 5-FU. Lengthening intervals between treatment segments, and the use of one daily dose of radiation therapy combined with 5-FU or two fractions daily without 5-FU seemed to decrease nutritional complications. Control of tumor at the primary site appeared to be achieved in most patients. Distant metastases represented the predominant mode of treatment failure with only two patients currently without progression of malignant disease. Our treatment regimen as initially conceived was too toxic for general use. Improved therapeutic results in locally unresectable gastric cancer will require the development of more effective therapy for occult distant metastases.