Aggressive Combined Modality Research Articles

A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma.

This study investigated the feasibility of a novel approach to the treatment of malignant pleural mesothelioma by combining surgical resection with immediate postoperative intrapleural chemotherapy and subsequent systemic chemotherapy. Patients with biopsy-proven, resectable malignant pleural mesothelioma underwent pleurectomy/decortication immediately followed by intrapleural chemotherapy with cisplatin 100 mg/m2 and mitomycin 8 mg/m2. Systemic chemotherapy was started 3 to 5 weeks postoperatively and included cisplatin 50 mg/m2 on days 1, 8, 15, 22, 36, 43, 50, and 57, and mitomycin 8 mg/m2 on days 1 and 36. Patients were then monitored by serial chest and abdominal computed tomographic (CT) scans every 3 months until death or for a minimum of 18 months, whichever occurred first. Of 36 patients entered onto the study, 28 had pleurectomy/decortication and intrapleural chemotherapy. There was one postoperative death, and two episodes of grade 4 renal toxicity after intrapleural chemotherapy. The 23 patients who also had systemic chemotherapy received a median of 80% and 87% of the planned total cisplatin and mitomycin doses, respectively. No grade 3 or 4 toxicities were observed. The overall survival rate of the 27 patients who were originally candidates for systemic chemotherapy was 68% at 1 year and 40% at 2 years, with a median survival duration of 17 months. Locoregional disease was the most common form of relapse (16 of 20 patients). This short but aggressive combined modality regimen was generally well tolerated, but should not be used outside of a protocol setting because of the potential for serious toxicity. Overall survival was as good or better than with previously reported multimodality approaches, but other strategies are needed to improve local control.

Mediastinal yolk sac tumor: The Indiana University experience, 1976 to 1988

Mediastinal yolk sac tumor (endodermal sinus tumor) is an extremely rare extragonadal germ cell neoplasm that has been associated with a grave prognosis. Twenty-one male patients with mediastinal yolk sac tumor received treatment at Indiana University between 1976 and 1988. Fourteen were seen after initial diagnosis, and their disease was treated with cisplatin-based chemotherapy in association with complete surgical resection if possible. Five are currently alive and disease free (36%). Seven were referred for salvage chemotherapy after relapse of their disease. Despite aggressive chemotherapy, these patients all died; they had a median survival time of 6 months. Our experience suggests that an aggressive combined modality approach with cisplatin-based chemotherapy followed by surgical resection of residual disease is the optimal management of this tumor. New regimens need to be explored for relapse of the disease after initial chemotherapy.

Long-term Survival and Toxicity in Small Cell Lung Cancer: Expanded Southwest Oncology Group Experience

The Southwest Oncology Group formed a database of 2,501 patients consecutively enrolled in small cell lung cancer (SCLC) trials since 1976. This report summarizes an analysis of this database to determine predictors of 2- and 5-year survival in limited stage disease (LD) and 1- and 2-year survival in extensive stage disease (ED). In addition, we analyzed the frequency of late recurrences, toxicity, and quality of life issues in the long-term survivors. For consecutive studies, greater than or equal to 2-year survival in LD were 15 percent, 21 percent, 28 percent, and 43 percent; 5-year survivals were 5 percent, 9 percent, 8 percent, and 20 percent. In ED, greater than or equal to 1-year survivals were 27 percent, 23 percent, 21 percent, and 42 percent; greater than or equal to 2-year survivals were 6 percent, 5 percent, 3 percent, and 19 percent. Using the logistic regression multivariate model, independent favorable predictors of 5-year survival for patients accrued to our older LD trials were normal lactate dehydrogenase (LDH) values and good performance status. Therapy as employed in these trials was not an independent factor. However, if patients enrolled on more recent trials were included, 2-year predictors could be assessed. Therapy with concurrent chemoradiotherapy and female gender then became additional independent favorable predictors. In ED, a single metastatic site and a normal LHH value were favorable predictors of survival beyond 1 year. The retrospective review of 63 patients with LD who survived at least 5 years found 33 asymptomatic patients with no recurrent disease; 6 with recurrent SCLC, 3 of whom died; 7 who died of non-cancer-related causes or unknown causes; 3 who died of secondary primary lung cancer; and 14 alive with persistent central nervous system symptoms and signs, possibly due to prophylactic brain radiation as given in the first 3 trials. No increased incidence of this syndrome has yet been observed in subsequent trials. For ED patients, 25 of 51 survivors greater than or equal to 2 years subsequently died of recurrent SCLC. The majority of the long-term survivors with ED (35 of 51) had either a single metastatic site or metastases limited to opposite side of the chest or regional nodes. Our multivariate models support the conclusion that aggressive combined modality, concurrent induction therapy, along with favorable prognostic variables, independently contribute to the improved long-term survival we have observed in LD. Longer follow-up is required to confirm that this improvement has occurred with less late toxicity.

Delayed split whole abdominal irradiation in the combined modality treatment of ovarian cancer

Fifty-eight patients with ovarian malignancies have been treated using a delayed split whole abdominal irradiation tecnique (DSA) allowing the entire tumor volume to be irradiated with tumoricidal fractional doses without undue toxicity. The lower hemiabdomen was irradiated with 2 Gy per fraction to a total dose of 40 Gy. A 2–6 hour delay was used between the irradiation of each half of the abdomen to avoid excessive acute gastrointestinal toxicity. The upper hemiabdomen was irradiated with 1.5 Gy per fraction to a total dose of 30 Gy. The acute toxicity was acceptable, with 53 of 58 patients able to complete the prescribed course of treatment. Three patients (5%) experienced grade 3 or greater acute gastrointestinal toxicity. Fourteen of 60 patients (24%) required treatment breaks because of thrombocytopenia. Nadir platelet counts were lower in patients who had received previous chemotherapy than in previously untreated patients (80,000 vs 118,000; p = .02). However, only 4 out of 60 patients were unable to complete DSA because of prolonged thrombocytopenia. In addition to DSA, patients were also treated with intraperitoneal 32p (52 patients), intraperitoneal human ovarian antitumor serum (14 patients), and prior (14 patients) or subsequent (32 patients) chemotherapy. Granulocytopenia was more severe among patients who had received prior chemotherapy (mean nadir 900 vs 2200). Seven patients (11.5%) developed delayed bowel obstruction in the absence of recurrence. There was one death caused by hepatitis, presumably related to colloidal 32P and DSA. Twenty-five percent of Stage III optimally cytoreduced patients were disease-free at 5 years; these patients had a median survival of 45 months. DSA irradiation is an acceptable technique for delivering a high fractional dose of radiation to the entire peritoneal cavity. Shielding of the iliac crests spares bone marrow allowing DSA irradiation to be integrated into an aggressive combined modality treatment plan.

Pineal and CNS germ cell tumors: royal marsden hospital experience 1962–1987

A retrospective analysis has been made of all patients with pineal and CNS germ cell tumors who were treated at the Royal Marsden Hospital between 1962–1987. A total of 67 new cases were seen: 17 had initial histological verification of tumor type and the remainder were tested for radiosensitivity with a dose of 20 Gy following a shunting procedure. Patients with germ cell or radiosensitive tumors were treated with a uniform policy of whole neuraxis radiotherapy giving 50 Gy to the local tumor and 30 Gy to the remaining brain and spinal cord. Nonresponding lesions continued with local fields to a dose of 50 Gy. Patients were divided into three groups (a) germinoma and radiosensitive tumours, 34 cases; (b) malignant teratoma, 12 cases; (c) non-germ cell, 21 cases. Median follow-up is 83 months (range 2–246 months). Overall and cause specific actuarial 5/10 year survival were for group 1, 81.7%/69.4% and 86.5%/86.5%; group 2, 18.2%/18.2% and 18.2%/18.2%, and group 3, 64.3%/46.8% and 64.3%/52.6%, respectively. No patient in group 1 treated during the last 12 years has recurred. Univariate analysis of factors at presentation, showed that neurological performance status if(p (001) as well as tumor type if(p <001) correlated with outcome. Recurrence was confined to the primary site in only 1 of 4 patients in group 1 compared to 6 of 9 patients in group 2 and 9 of 10 patients in group 3. No isolated spinal recurrence occurred in group 1 patients. A total of eight patients have received platinum containing chemotherapy for recurrence (6 cases) or adjuvant therapy (4 cases). Germinomas appear to respond better than teratomas, all of which have recurred rapidly following initial partial response. Shunting and radiosensitivity testing remains the treatment of choice for tumors compatible with germinoma. Craniospinal irradiation is associated with low morbidity providing spinal growth is complete and is recommended in older patients as salvage following spinal recurrence is unsatisfactory. Aggressive combined modality approaches with surgery, radiotherapy and chemotherapy need to be investigated to improve results in CNS teratoma.

Supportive care for patients with small cell lung cancer

Weight loss is frequently seen in patients with small cell carcinoma of the lung even when the tumour is small and there is no mechanical interference with the gastrointestinal tract [ 11. The use of increasingly aggressive chemotherapy drug regimens and combined modality programs increase the probability of weight loss and debility. These intensive programs can also produce severe and sometimes protracted myelosuppression with risk of intercurrent infections. This review will focus on these two aspects of supportive care: nutritional support and prophylaxis against infection. The etiology of cancer-related weight loss is likely multifactorial. Increased energy requirements, anorexia secondary to tumour-induced changes in taste, insulin resistance and other metabolic abnormalities and anorexia induced by psychological reactions to the disease likely all play a role in patients with small cell lung cancer. The frequency of weight loss in lung cancer (approximately 40-501 of patients) and its known negative impact on survival, led to several studies of intravenous nutritional support These studies, which administered the intravenous nutrients at the beginning of antineoplastic therapy, were given in the hope that they might increase response to therapy, improve survival and ameliorate toxicity [2,3]. As a result of encouraging preliminary observations, the Division of Cancer Treatment, National Cancer Institute organized a number of randomized controlled clinical trials in tumour types known to be responsive to chemotherapy, including small cell lung cancer. In the study of patients with SCLC mported by Clamon [4], 119 evaluable patients were randomized to receive either 28 days of intravenous hyperalimentation (IVH) or an ad lib oral diet. The IVH consisted of an amino acid mixture, hypertonic glucose and a lipid emulsion and the amount of calories and protein delivered was calculated to maximize nutritional repletion. The median survival time for patients with limited disease treated on the study was 18 months and for those with extensive disease, it was 11 months. However, there were no differences in the response rate or survival between the nutritionally supported group and the control group. In particular, IVH did not sig

Phase I–II study of prophylactic hepatic irradiation with local irradiation and systemic chemotherapy for adenocarcinoma of the pancreas

Although the addition of 5-FU to radiation therapy for locally advanced adenocarcinoma of the pancreas improved short-term survival (GITSG), there were no differences in patterns of failure. Hepatic metastases were equally common in both groups. Therefore, a pilot study of prophylactic hepatic irradiation was developed. Between March 1983 and May 1985, 16 patients were entered in a Phase I/II study of prophylactic hepatic irradiation with local irradiation and systemic chemotherapy for adenocarcinoma of the pancreas at the Medical College of Wisconsin Affiliated Hospitals. Megavoltage radiation (1.8 Gy/fraction) was given to the pancreas with a minimal margin (2 cm) around the tumor, localized by surgical clips or CT scan with a total dose of 61.2 Gy over 7 weeks. Prophylactic hepatic irradiation was added to the fourth week of irradiation to a total dose of 23.4 Gy over 2 1 2 weeks. 5-Fluorouracil, 500 mg/M2/day was given at Day 1, 2, 3, 29, 30, and 31 of radiotherapy, then a weekly maintenance for I year. Fifteen patients were evaluable: One patient refused chemotherapy. The follow-up period was 14 to 50 months (median 26 months). The most common side effect was nausea. Maintenance 5-FU was discontinued in one patient because of GI bleeding. Three-quarters of the patients developed temporary elevations of hepatic enzymes. No severe or life-threatening complications were observed. One, 2-, 3-, and 4-year disease-free survivals are 66.7%, 46.7%, 20% and 13.3%, respectively. Patterns of failure revealed that only two patients had hepatic metastasis as the first site of failure, five patients died of abdominal carcinomatosis, and three patients failed in the pancreas. Two patients died without evidence of cancer. Two patients are alive and well beyond 4 years after the diagnosis. This study confirms that such aggressive combined modality treatment is well tolerated and suggests that the frequency of hepatic metastasis can be reduced.

Aggressive combined modality treatment of progressive sinonasal fungal infections in immunocompromised patients

Invasive fungal infections of the paranasal sinuses in immunocompromised hosts are often fatal despite therapeutic interventions. In an effort to achieve a better outcome in patients with these infections, aggressive management was combined with medical/surgical intervention. A series of 18 immunocompromised patients with invasive sinonasal fungal infections was retrospectively analyzed. Management consisted of a combined modality clinical approach, including aggressively sought early diagnosis; early amphotericin use; extensive surgical debridement; and liberal use of granulocyte transfusion support. Eight of 13 patients with eventual neutrophil recovery survived with control of all local and systemic signs of fungal infection. All patients with persisting neutropenia died of progressive infection. We conclude that meticulous surveillance of patients in high-risk groups for fungal infection should be maintained due to the apparent value of rapid intervention with a combination of surgical resection and medical management (antifungal chemotherapy and white blood cell transfusions). Infection control and survival are ultimately dependent on recovery of marrow function and circulating neutrophils.

Treatment Toxicities in Long-Term Survivors of Limited Small Cell Lung Cancer

A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients.

Inflammatory breast cancer: advances in therapy.

Inflammatory breast cancer is the most aggressive breast neoplasm and one of the most ominous solid tumors. Because of distinct clinical characteristics, diagnosis can usually be made on clinical grounds. Biopsy including the overlying skin may demonstrate dermal lymphatic invasion, although the absence of dermal lymphatic invasions should not deter aggressive therapy. Surgery or irradiation alone has little effect on the natural history of this disease since lymphatic invasion and distant metastases are often present at presentation. Inflammatory breast cancer should be considered a systemic disease. Accordingly, aggressive combined modality therapy including multi-drug chemotherapy, surgery, and irradiation have prolonged disease-free survival and overall survival.

Aggressive combined modality treatment of progressive sinonasal fungal infections in immunocompromised patients1

Aggressive combined modality treatment of progressive sinonasal fungal infections in immunocompromised patients1

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.

Advanced epithelial ovarian cancer: Toxicity of whole abdominal irradiation after operation, combination chemotherapy, and reoperation

Thirty-five patients with advanced ovarian cancer have received, as salvage therapy, irradiation consisting of 30 Gy to the entire abdominal contents with partial liver/kidney shielding and boosts to 42 and 51 Gy for the paraaortic/diaphragmatic and pelvic regions, respectively. These patients had received 6 to 25 cycles (median, 11 cycles) of prior combination chemotherapy (included cisplatin in 30), with “second-look” laparotomy performed in 33; 24 (68%) had three or more laparotomies. Acute gastrointestinal toxicity was generally mild. Significant hematologic toxicity (leukocytes <2000/mm 3; or platelets <100,000/mm 3) was seen in 19 (54%); platelet suppression occurred in 18 of these 19. Nine patients failed to complete the prescribed course of therapy; in seven, this was secondary to hematologic toxicity. Amount of prior chemotherapy and advanced age correlated with degree of hematologic toxicity. Five patients without evidence of disease (laparotomy confirmed) have developed treatment-related bowel obstruction. No other chronic toxicity of clinical significance has been observed. Seven patients have developed bowel obstruction associated with progressive neoplasm. Irradiation was well tolerated symptomatically, but hematologic toxicity associated with prior chemotherapy prevented its completion in 20% of patients. Clinical manifestations of radiation bowel toxicity have been moderate to date and should be interpreted in the context of the aggressive combined modality program.

Residual, recurrent, or unresectable gastrointestinal cancer. Role of radiation in single or combined modality treatment.

When conventional modalities of external beam irradiation and chemotherapy +/- resection are used in the treatment of locally advanced gastrointestinal malignancies, although useful palliation can be achieved in many patients, cure and long-term survival is infrequent. Aggressive combined modality approaches have recently encorporated irradiation boost techniques with intraoperative electrons or intraoperative or transcatheter brachytherapy. Both local control and long-term survival appear to be improved when compared with results achieved with conventional treatment. Randomized trials are needed to determine if the observed differences are real or due to differences in case selection.

Small size T4 breast cancer. Natural history and prognosis.

The clinical records of 66 patients with T4 (for skin infiltration or ulceration) breast cancer not larger than 5 cm treated with primary radiotherapy at the Istituto Nazionale Tumori of Milan from 1968 through 1977 were reviewed. The tumor measured no more than 3 cm in 19 patients and 3-5 cm in 47 patients. In the first group axillary involvement was lower (32% vs 55%) and mean age was older (68 years vs 58). Thirty-four patients were irradiated with orthovoltage and 32 with cobalt, at full doses. In 22 of 66 patients (33.3%) a Halsted radical mastectomy was carried out after completion of radiotherapy. No medical treatment was planned. The incidence of locoregional and distant metastases was the same in both groups of patients, but that of patients with smaller T4 (up to 3 cm) demonstrated a better prognosis in terms of absolute survival at 5 years (71.3% vs 34.7%). T4 breast cancer of 3-5 cm had very poor results quite similar to those of historical large series of T4 carcinomas of any size; therefore they should be treated by the same aggressive combined modality approach adopted for locally advanced breast cancer. On the contrary, small T4, up to 3 cm, in older women could be treated by tumorectomy followed by radiotherapy at full doses; systemic medical therapy (hormonal manipulation or chemotherapy) should be decided according to endocrine receptor investigation and general conditions.

Radiation and chemical injury in the bone marrow.

Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.

Radiation and Chemical Injury in the Bone Marrow

Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.

Nutritional effects of surgery, radiation therapy, and adjuvant chemotherapy for soft tissue sarcomas

To determine the nutritional effects of aggressive combined modality cancer therapy, 35 consecutive patients undergoing surgery, radiation therapy, and adjuvant chemotherapy for soft tissue sarcomas of the head, neck, and trunk were prospectively studied. Changes in body weight, total protein, albumin, total lymphocyte count, and creatinine/height ratio were studied. Significant weight loss occurred with surgery, radiation therapy, and doxorubicin/cyclophosphamide, but not methotrexate, chemotherapy. Total protein and albumin did not change significantly with any of the individual therapies. On long-term follow-up (mean 27 months), patients who survived free of sarcoma showed little nutritional morbidity. Patients with progressive sarcoma, however, showed decreases of 9% in body weight (NS), 11% in total protein (p less than 0.01), 17% in serum albumin (p less than 0.05), and 64% in total lymphocyte count (p less than 0.02). These data indicate that aggressive combined modality cancer therapy can have significant acute nutritional effects. Long-term nutritional morbidity, however, is minimal in patients without recurrent disease. In contrast, patients with recurrent disease show severe nutritional deficits which seem more a consequence of the progressive disease than of the aggressive therapy.