High Tumor Response Research Articles

Invited Review: For the clinical application of thermochemotherapy given at mild temperatures

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43oC. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0oC. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.

Toxicity and antitumor activity of interferon gamma alone and in combinations with TNFalpha and melphalan in isolated limb perfusion in the BN175 sarcoma tumor model in rats.

Isolated limb perfusion (ILP) with TNFalpha, melphalan (M), and IFNgamma results in high tumor response rates in patients with soft tissue sarcomas, melanomas and other tumors. IFNgamma can act synergistically in combination with TNFalpha but in clinical studies this has not been fully investigated. In the BN175 rat sarcoma limb perfusion model we investigated the role of IFNgamma. There were 8 different treatment groups: (I) sham ILP (n=9); (II) IFNgamma alone (n=10); (III) TNFalpha 50 microg (n=9); (IV) TNFalpha + IFNgamma (n=6); (V) melphalan (M) 40 microg (n=11); (VI) M + IFNgamma (n=6); (VII) TNFalpha + M (n=27); (VIII) TNFalpha + M + IFNgamma (n=9). Tumor response and hindlimb function were analyzed. In group I-VI no tumor regressions were observed at 5 days after ILP. ILP with TNFalpha + M had highly effective response rate (RR) of 73%; complete response (CR) rate 55%), very similar to RR in patients. Addition of IFNgamma increased the RR by 16% to 89% and the CR rate by 23% to 78%. This difference was not statistically significant. When IFNgamma was added to TNFalpha or TNFalpha + M it increased limb toxicity significantly (p<0.05 and p<0.005). Since such regional toxicity has not been observed in patients while similar increases in tumor response rates have been reported with IFNgamma it is of importance to define the role of IFNgamma in the clinical setting.

Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors

Patients with advanced metastatic carcinoid tumors who have disease progression despite conventional therapy are left with few therapeutic options. Hepatic artery chemoembolization (HACE) may play a role in palliating these patients' symptoms. Fifteen patients with biopsy-proven advanced bilobar hepatic carcinoid metastases who demonstrated progression of symptoms and/or tumor size despite treatment with somatostatin analogues were treated with intra-arterial chemotherapy and HACE to determine efficacy and safety. Five days of intra-arterial 5-fluorouracil (1 g/m2) were followed by HACE with adriamycin (60 mg), cisplatin (100 mg), mitomycin C (30 mg), and polyvinyl alcohol (Ivalon); 200 micron to 710 micron). Patients were continued on octreotide at the same dose (150 to 2000 microg subcutaneous q 8 hours) before, during, and after the procedure. Efficacy of treatment was assessed by comparing pretreatment and 3-month clinical, laboratory, radiographic, and quality of life parameters. Symptoms were improved in 8 of 12 patients who had diarrhea, 7 of 12 who had flushing, 9 of 12 who had abdominal pain, and in 4 of 7 who had malaise. Elevated tumor markers decreased in all patients. Biochemical markers (mean +/- SE) at 3 months decreased by 60% +/- 6% for 5-HIAA, 75% +/- 10% for chromogranin A and 50% +/- 7% for neuron-specific enolase. Tomographic assessment revealed tumor liquefaction in 10 of 13 patients. The Karnofsky performance status improved from a mean of 66 +/- 2 to 84 +/- 2 (P <0.001). Median follow-up was 16 months, with 13 deaths occurring from 1 week to 71 months after treatment. Hepatic artery chemoembolization improves symptoms of carcinoid syndrome, has a high tumor response rate, and improves short-term quality of life in this group of patients with advanced hepatic carcinoid disease.

Preoperative cisplatin and accelerated hyperfractionated radiation induces high tumor response and control rates in patients with advanced head and neck cancer

Preoperative cisplatin and accelerated hyperfractionated radiation induces high tumor response and control rates in patients with advanced head and neck cancer

The efficacy of doxorubicin microspheres for hepatic micrometastases in a rat tumour model.

The use of sustained-release microspheres is of potential benefit as an adjuvant treatment for patients with occult hepatic micrometastases. This study investigates the response of a model of implantable adenocarcinoma micrometastases in the livers of DA rats following the intraportal injection of doxorubicin-incorporated ion-exchange microspheres compared to free drug bolus administration. A point-counting technique was used to determine the percentage of liver consisting of tumour 13 days after treatment. This was used as an indicator of tumour response, as was the derived tumour mass. There was a significantly higher tumour response in animals treated with the microspheres compared to animals treated with free drug delivered at the same concentration. This effect, however, was shown to decrease with a delay in the time of treatment. The tumour response of the sustained-release microspheres was achieved in the absence of any detectable local or systemic toxicity. This study demonstrates the potential of sustained-release microspheres in the treatment of patients with hepatic micrometastases.

Preoperative cisplatin and accelerated hyperfractionated radiation induces high tumor response and control rates in patients with advanced head and neck cancer

Preoperative therapy with concurrent cisplatin infusion and accelerated hyperfractionated radiation has the potential to eradicate pools of resistant cells with high-growth fraction that accumulate during standard radiation therapy. Based on preliminary data showing a high complete response rate (necessary for organ preservation) in patients with advanced squamous cell cancer of the head and neck (stages III and IV), we conducted a multi-institutional study using accelerated hyperfractionated radiation to maximize local and regional tumor control without adding toxicity. Preoperative radiation was given in 1.8 Gy fractions for 2 weeks followed by 1.2 Gy BID hyperfractionation to 46.7 Gy. Continuous infusion of cisplatin 20 mg/m2 was given on days 1 through 4 and 22 through 25. Patients were initially assessed with panendoscopy and were subsequently reassessed with biopsy of primary site (+/- nodes). Patients with negative primary site biopsy received additional hyperfractionated radiation to 76 Gy with simultaneous carboplatin 25 mg/m2 BID for 12 consecutive days. Patients with residual disease after 47 Gy had resection of primary site and node dissection. Of 69 patients treated, 56 were T3 and T4, and 46 were N1, N2, and N3; 17 patients (25%) were stage III and 50 (72%) were stage IV; in 2 patients (3%) the stage was unknown. Treatment was well tolerated with no grade IV toxicities, but there were 13 patients with grade III toxicities (mucositis, dysphagia, or hematological toxicity). Biopsy specimens were taken from 84% of the patients, and 81% of the primary sites showed pathologic complete response and 49% of the lymph nodes showed a pathologic complete response. Thirty-four patients underwent curative surgery. Eleven required resection of the primary and 23 required neck dissection only. At 2 years (median followup 12 months), 44 of 69 patients (64%) have no evidence of disease, 9 are dead of disease, 9 are dead of other causes, and 6 are alive with disease. Surgical toxicities were minimal and primarily limited to fibrosis in 12 patients, edema in 8 patients, tracheoesophageal fistula in 1 patient, and delayed wound healing in 1 patient. Late toxicities included xerostomia in 22 patients, dysphagia in 17, and speech impairment in 9. Preoperative concurrent radiotherapy and chemotherapy provides a high level of organ preservation and local and regional control because of the high complete response rate at the primary site. A planned neck dissection with minimal morbidity ensures local/regional control, as well as providing definitive staging information. A randomized evaluation is suggested for this program.

Endoscopic Nd:YAG treatment of superficial gastric carcinoma: Experience in 18 western inoperable patients

Endoscopic treatment of superficial gastric cancer has been reported to be effective by many Japanese teams. In this study, the Nd:YAG laser was used to treat superficial gastric carcinoma in inoperable Caucasian patients with the aim of obtaining a complete response, i.e., disappearance of the lesion endoscopically and biopsy specimens negative for cancer. Eighteen patients unsuitable for surgery with various endoscopic patterns of superficial gastric cancer were treated with the Nd:YAG laser. The endoscopic pattern was type I in 4 patients, type II in 10 (5 type IIa, 1 type IIb, 2 type IIc, 2 mixed IIa + IIc), and type III in 4. Staging by echoendoscopy was performed in 11 patients (T1N0). Nd:YAG laser destruction of the gastric tumor was performed in all cases, with a mean of 4.4 laser sessions per patient. Tumor response was assessed by endoscopy and biopsy. Follow-up averaged 33 ± 23 (SD) months. Five patients died of diseases unrelated to gastric cancer. An initial complete response was obtained in 16 (89%) patients after a mean of 1.7 laser sessions; histologic evidence of cancer persisted in 2 patients during the entire follow-up period. Among patients with an initial complete response, recurrence was observed in 2. One of them was successfully re-treated. At the end of the follow-up period, 14 (77.7%) of the 18 patients had a complete tumoral response; only 4 patients had histologic evidence of cancer. In 3 of these 4 patients, pretherapeutic echoendoscopic staging had not been performed. Among the 14 patients exhibiting a complete response, 3 had negative biopsy results more than 5 years after diagnosis. No complications occurred. In gastric cancer classified as T1N0 on the basis of pretherapeutic echoendoscopy, a high tumor response rate and even 5-year disease-free survival can be obtained with endoscopic Nd:YAG laser treatment. Endoscopic laser destruction thus appears to be a valuable therapeutic alternative to surgery in inoperable patients with superficial gastric cancer. (Gastrointest Endosc 1995;42:340-5.)

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Defining the role of radiosurgery in the management of brain metastases

The role of stereotactic radiosurgery in the management of recurrent and newly diagnosed brain metastases was evaluated prospectively. From December 1988 to March 1991, 58 lesions in 40 patients were treated with accelerator-based stereotactic radiosurgery. All patients were followed for a minimum of 6 months or to death. The primary purpose was to determine the impact of radiosurgery on local control and its subsequent effects on quality of life. An overall tumor control rate of 82% with a complete response rate of 43% were achieved. As anticipated, the response rate for smaller tumors was substantially better than that for larger tumors (78% for lesions < 2 cm 3; 50% for lesions ≥ 10 cm 3). Although the overall in-field progression rate was 18.5%, only 1 23 (4%) complete responders subsequently recurred. The in-field failure rate is highly comparable with recently published surgical data. Progression outside the brain was noted in two-thirds of patients. One quarter of the deaths were neurologic. The median survival for this minimally selected patient population was 6.5 months. Stereotactic radiosurgery was also associated with improved quality of life as measured by Karnofsky score, neurologic function, and steroid dependence. Long-term steroid dependence was encountered in only four patients. We conclude that stereotactic radiosurgery can be used effectively in patients with brain metastases. In this series, a high tumor response rate was achieved which was associated with improved quality of life.

The clinical biology of hormone-responsive breast cancer

The notion of breast cancer as a systemic disease is a relatively new one. Originally born out of disenchantment with the long-term results of aggressive local therapy on disease outcome (60), this view has gained further support from recent clinical and laboratory observations: (a) breast cancer seems likely to be incurable in the biological (if not the actuarial) sense, commonly recurring after disease-free intervals exceeding two decades (22); (b) primary tumours are often multicentric in origin (177) and can be detected as such in up to 40% of patients following excision of macroscopically localized disease (76); (c) skin fibroblasts from patients with breast cancer display abnormal growth properties even prior to diagnosis (9); and (d) peripheral blood lymphocytes of affected patients exhibit defective DNA repair (110). Findings such as these have led to renewed interest in both the biology (189) and the systemic therapy (190) of breast cancer. One expression of this interest has been an abundance of clinical trials. Such trials have contributed significantly to our understanding of breast cancer biology (13) but, unfortunately, major advances in clinical progress have been less forthcoming. In the case of cytotoxic chemotherapy, initial enthusiasm generated by high tumour response rates has been tempered by negative reports of survival benefit (164) and serious doubts regarding palliative efficacy ( 102). This therapeutic cul-de-sac hints at the limitations of a purely empirical approach to this malignancy and suggests that the development of more effective systemic chemotherapy may depend upon combining insights gained from both basic and clinical research. This cooling of enthusiasm for aggressive cytotoxic management of breast cancer contrasts with the evergreen popularity of hormone therapy. Hormonally induced regression of breast cancer remains one of the most gratifying experiences in clinical oncology, while the minimal morbidity and relative cheapness of hormone therapy have ensured its continuing favour as a subject for clinical research. Moreover, well-characterised laboratory models of hormone-responsive human breast cancer now exist, permitting analysis of hormone action at the level of cellular and molecular biology. Since many of the developments which have revolutionized our ideas about breast cancer have arisen from the study of this fascinating entity, it seems timely to review the way in which clinical and

Pathohistologische Serienschnittuntersuchungen bei Patienten mit kompletter Tumorremission nach durchgeführter zytostatischer Induktionstherapie

Initial combination drug regimen containing cis-platin in patients with head and neck cancer produced a high percentage of clinical response. Despite numerous trials showing high tumor response rates, a survival advantage resulting from the use of chemotherapy has yet not been demonstrated conclusively. This trial was initiated to study the cytotoxic effect of chemotherapeutic agents on squamous cell carcinomas. 31 patients with oropharyngeal carcinomas received prior to surgical resection a polychemotherapy consisting of cis-platin and bleomycin. After surgical tumor resection the histopathologic examination based on the serial sections of the tumor tissues and neck dissection blocks showed no case of complete tumor response. Even in 9 patients with complete clinical tumor response the histopathological investigation revealed tumor cells.

Supraophthalmic carotid infusion for recurrent glioma: rationale, technique, and preliminary results for cisplatin and BCNU.

The chemotherapeutic agents 1-3 bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum II (cisplatin) have both shown activity against malignant glioma, especially when given by arterial infusion. The combination of these agents given by this method is logical because their individual major toxicities are directed at different organ systems, and because of their differences in restriction by the blood-brain barrier. Both agents are toxic to the eye, and infusion of both agents simultaneously into the internal carotid artery would deliver doses of the drug to the eye which should be associated with an unacceptable level of ocular toxicity. We have developed a technique utilizing a flexible flow-directed catheter with a tip which is manipulated by hydraulic forces for delivery of the drug into the intracranial carotid artery above the origin of the ophthalmic artery, thus sparing the eye from the high concentration of drug during the first pass through the arterial circulation. In 13 patients with recurrent malignant glioma treated by arterial infusion of both agents (cisplatin 150-200 mg, BCNU 300 mg fixed dose), we have had no damage to the ipsilateral eye. Preliminary results of treatment appear to be good, with definite tumor regression following arterial infusion in 10 of 12 radiographically evaluable cases. Median survival to date is 11 months with 3 patients still surviving. The longest survival is 24 months. The supraophthalmic infusion technique protects the eye and the combination of drugs given by arterial infusion produces a high tumor response rate.

Predictive factors for tumor response to preoperative chemotherapy in patients with head and neck squamous carcinoma. The Head and Neck Contracts Program.

The high tumor response rates associated with intensive chemotherapy in previously untreated patients with advanced head and neck squamous cell carcinoma (HNSCC) led to the initiation of a multi-institutional National Cancer Institute trial. This trial used preoperative chemotherapy in patients with resectable Stage III and IV squamous cell carcinoma of the oral cavity or larynx/hypopharynx. Response rates, toxicity, and a variety of patient and tumor characteristics were analyzed to determine which factors might be useful in predicting tumor response to preoperative chemotherapy. Two hundred eighty-two patients received one course of preoperative cisplatin and bleomycin chemotherapy and were evaluable. There were 22 complete responses (CR) and 114 partial responses (PR) at the primary site (48% response rate). Of 197 patients with clinically positive regional adenopathy, 29 CRs and 73 PRs were observed (52%). Toxicity associated with the chemotherapy regimen was minimal. Primary tumor and regional node responses to chemotherapy were strongly correlated. No significant differences were found in primary or nodal response rates with respect to differing tumor site, stage, histologic differentiation, patient performance status, nutritional status, leukocyte count, hemoglobin level, age, sex, or alcohol use. Primary tumor response, however, was significantly related to T classification (P = 0.048). Nodal response was strongly associated with N classification and nodal size (P = 0.02 and P = 0.075, respectively). These findings suggest that, of the patient and tumor characteristics analyzed, none were more useful in predicting tumor response than clinical tumor staging parameters.

The integration of chemotherapy into the management of locally advanced cervical cancer: A pilot study

Chemotherapy has been traditionally reserved as a last-line treatment for cervical cancer patients and in this setting long-term remissions are unusual. Platinum-based combination chemotherapy has been associated with high tumor response rates in patients with advanced and metastatic cervical tumors and past experience encouraged evaluation of chemotherapy as a first-line treatment in patients with locally advanced tumors where there is a high likelihood of relapse with local treatment. Thirty patients were treated initially with three courses of cis-platinum, vinblastine, and bleomycin with an overall response rate of 67%, and then had either radiotherapy or surgical resection. The initial results have been encouraging and the integration of chemotherapy into the management of locally advanced cervical cancer warrants further investigation.

Patterns of failure in small cell lung cancer: implications for therapy.

In recent years the management of patients with small cell lung carcinoma (SCLC) has undergone pronounced changes. Prior to 1970 surgery and radiotherapy constituted the most commonly applied forms of management. However, neither of these purely localised therapeutic modalities is capable of providing effective long-term disease control in the majority of patients (Broder et al. 1977; Bunn et al. 1977; Weiss 1978). Appreciation of the frequency and extent of metastatic disease (Bird et al. 1968; Eagan et al. 1973; Hansen and Muggia 1972) coupled with the sensitivity of SCLC to a variety of chemotherapeutic agents (Greco et al. 1978; Hansen 1982; Livingston et al. 1978) has led to the present emphasis upon the central role of systemic chemotherapy in patient management. Chemotherapy either alone or together with radiotherapy in combined modality schedules has resulted in high tumour response rates and a 4–5 fold prolongation of median survival (Hansen 1982). However, only 5%–10% of patients will achieve long-term disease remission. The majority of patients will relapse and die of their disease.KeywordsSmall Cell Lung CancerSmall Cell CarcinomaSmall Cell Lung CarcinomaBronchogenic CarcinomaCentral Nervous System MetastasisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

SOME LABORATORY AND EPIDEMIOLOGICAL ASPECTS OF AIR POLLUTION CARCINOGENESIS.

Chemical, analytical and biological studies were completed on the organic matter of large air pollution samples from Detroit. The high tumor response observed on mouse skin when the organic matter was applied in 12.5 per cent concentration can be partially explained by the presence of poly nuclear aromatic hydrocarbons (PAH) as tumor initiators and certain acidic components as tumor promotors. Certain polaric neutral components of still unknown nature are indicated also to act as tumor promotors. The concentrations of PAH in various locations in Detroit and New York during different seasonal, meteorologic and traffic conditions are compared. The relative importance of carcinogenic air pollutants in man’s environment is discussed in line with epidemiological evidence.