Joseph A. Libnoch

The Impact of Current Staging Procedures in Assessing Disease Extent of Prostatic Adenocarcinoma

We studied 454 patients with prostatic adenocarcinoma who were assigned a preliminary clinical stage on the basis of serum acid phosphatase, routine bone survey and physical examination. Subsequently, they were assigned a final clinical stage after radioisotopic bone scanning, lymphangiography and staging pelvic lymph node dissection. Only 53, 54, 57 and 26 per cent, respectively, of patients initially assigned the preliminary clinical stage of IB, II, III or IVA remained at that stage after the additional studies.

The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies

It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck. Two regimens of induction chemotherapy were studied in separate randomized, prospective trials over the last 6 years. Eighty‐three patients with advanced disease were entered into the first study (43/chemotherapy; 40/control), and 60 into the second (27/chemotherapy; 33/control). Patient randomization was stratified by stage (III/IV) and site (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses). The first study utilized bleomycin, Cytoxan,® methotrexate and 5‐fluorouracil in two cycles (one cycle if no tumor response), followed by standard treatment which consisted of combined irradiation and surgery or, in some instances, primary irradiation alone. The second study utilized cisplatin and 5‐fluorouracil in three cycles prior to standard treatment. An objective tumor response to chemotherapy was observed in 68% in the first study and 85% in the second. The patient survival in both studies @ 24 months in the first; @ 19 in the second) was better in the control than that in the experimental groups (43% to 31%; 69% to 46%). In the second study, the average length of delay of standard treatment was longer than in the first study (95 days vs. 66 days; P<.02). Results combining the P‐values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy. While toxicity to chemotherapy was not a factor in survival, the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups. Except for new drug regimens of exceptional promise, it is recommended that future studies be designed so that chemotherapy is given concurrent with, or following the completion of standard treatment.

What is the lowest effective biologic dose for prophylactic cranial irradiation

BETWEEN JANNUARY 1974 AND SEPTEMBER 1984, 327 CONSECUTIVE PATIENTS with small cell carcinoma of the lung (SCCL) free of clinical and brain scan (radionuclide or computed tomography) evidence of brain metastasis were treated at the Medical College of Wisconsin Affiliated Hospitals. All patients received single agent chemotherapy, consisting of cyclophosphamide or methotrexate (1974–1975), or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine with or without methotrexate and leukovorin (1976–1984). Between January 1974 and December 1974, 82 patients were treated with chemotherapy without prophylactic cranial irradiation (PCI). Between 1978 and 1984, all patients received PCI during the first week after diagnosis, simultaneous with their first cycle of chemotherapy. Chest irradiation was given to the complete responders to the chemotherapy. During the first 3% years of the study with PCI (January 1978-May 1981), 51 patients received 30 Gray (Gy) in 10 fractions in 2 weeks and five of them (10%) developed brain metastasis. Thereafter, 25 Gy in 10 fractions was consistently administered for PCI. Six of 194 patients (3%) developed brain metastasis. The cumulative (time corrected) probability of brain metastasis was approximately 10% at 1 year and was similar for patients who received 25 Gy and those who received 30 Gy. Although detailed neuropsychological testing has not been performed, clinically apparent late sequelae that might be attributed to PCI have not been seen. Nonetheless, the dose fractionation regimen of 25 Gy in 10 fractions with combination chemotherapy, cyclophosphamide, doxorubicin (or methotrexate), and vincristine is as effective in eliminating subclinical metastasis to the brain. It can be recommended for future trials until more data become available about late sequelae of treatment of SCCL and the patient characteristics and treatment factors that may contribute.

The role of consolidation irradiation in combined modality therapy of small cell carcinoma of the lung

Forty-four patients with small cell carcinoma of the lung (SCCL) were treated with a program of combined chemotherapy and radiation therapy. Prophylactic cranial irradiation was given concurrent with the first of six planned cycles of chemotherapy consisting of Cyclophosphamide, Adriamycin, Vincristine and high dose Methotrexate (CAV-M). All patients judged as complete responders (CR) received consolidative thoracic irradiation (CTI) to the locoregional primary lung involvement. The CR rate to chemotherapy alone was 84% for patients with limited disease (LD) and 44% for extensive disease. In comparison to a prior trial, which used similar chemotherapy, but with irradiation withheld until primary site relapse, the actuarial primary site relapse rate at 2 years was reduced by CTI from 92% to 18% (P less than .01). The median primary site remission duration has not yet been reached in the CTI group and was 34 weeks without CTI (P less than .01). CTI increased the 2 year actuarial survival from 6% to 66% (P less than .01) in the chemotherapy CR patients. Median survival has not yet been reached in the CTI group, but was 48 weeks without CTI (P less than .01). Leptomeningeal spinal cord relapse in patients with no prior central nervous system (CNS) involvement occurred in 16% of patients relapsing.

Local control of intrathoracic disease with chemotherapy and role of prophylactic cranial irradiation in small‐cell carcinoma of the lung

Between 1978 and 1979, 39 consecutive patients at the Medical College of Wisconsin were seen with small‐cell carcinoma of the lung; of these, 31 were treated with chemotherapy and prophylactic CNS irradiation (2500 rad/10 fractions) and were evaluable after 22 month median follow‐up. The intra‐thoracic primary was not irradiated unless there was no response to chemotherapy or subsequent recurrence. Of the 31 patients, 12 had limited disease (LD) and 19 had extensive disease (ED). Twenty, including all the patients with LD, had a complete response, eight had a partial response, and three were nonresponders. Of 24 patients with complete response at the primary site, 20 subsequently displayed local failure of the intrathoracic primary tumor, most developing disseminated extrathoracic disease simultaneously with or shortly after primary failure. The median survival time (MST) of the evaluable group was ten months with an actuarial one‐year survival of 39%. Patients with LD had a median remission duration of 13 months and a MST of 16 months. Three patients are still alive with no evidence of disease at 14,20, and 27 months. Of 26 patients receiving prophylactic cranial irradiation, all are free of CNS relapse. Chemotherapy alone appears insufficient to permanently control the bulky intrathoracic tumor, leading to the use of “consolidation” irradiation of moderate dose (3750 rad/15 fractions) to follow chemotherapy. Prophylactic CNS irradiation should be used routinely.

Total body irradiation vs. chemotherapy as a systemic adjuvant for small cell carcinoma of the lung

Abstract The success of total body irradiation (TBI) in producing “response rates” similar to those of chemotherapy for certain systemic lymphoreticular malignancies has generated interest in applying TBI as a means of controlling occult micrometastases in other relatively radiosensitive tumors such as small cell carcinoma of the lung. A pilot study was thus initiated to determine the efficacy of adjuvant TBI for small cell carcinoma of the lung confined to the thorax (limited disease). Following local irradiation of the primary tumor, patients were randomized to receive either TBI or combination chemotherapy. Despite excellent tolerance to TBI, 8/8 patients have been judged as failures to TBI and have developed evidence of metastases at from 2–12 months (average = 5 months). Some of the TBI failures were subsequently placed on chemotherapy with good response. The responses to TBI and chemotherapy are analyzed and compared to those reported in the current literature. The influence of treatment modality on site of failure is also discussed.

The role of thoracic and cranial irradiation for small cell carcinoma of the lung.

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.

Spinal cord metastasis in small cell carcinoma of the lung

Among 50 patients with small cell bronchogenic carcinoma who were placed on a protocol of combined chemotherapy and radiation therapy, seven patients developed recurrence in the spinal cord. Five cases terminated in paraplegia and death. One patient with pontine recurrence recovered with local radiation therapy. One patient, diagnosed early, responded to local radiation therapy and is ambulatory. Methods of diagnosis were myelogram, computerized axial tomography, cerebro spinal fluid, chemistry and cytologies. The poor prognosis and the difficulty of diagnosis suggest that we should evaluate prophylactic therapy of the entire cranio-spinal axis.

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung

Two chemotherapy trials using cyclophosphamide, doxorubicin hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first trial without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfate is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.

Continuous 5-Fluorouracil Infusion and Alpha Interferon in Advanced Cancers: A Report of Initial Treatment Results

Twenty-four patients with advanced metastatic cancer were treated with continuous intravenous 5-fluorouracil infusion 200-300 mg/m2/day and alpha interferon 3 million units subcutaneously 3 times per week. The average duration of treatment was 87 days (range 22-204 days). 5-fluorouracil could be infused 66% of the planned time on treatment, and patients received an average of 60% of the planned interferon injections. Objective tumor responses were seen in 6 of 17 previously untreated patients (35%). Twenty-two of the 24 patients (92%) experienced toxicity (greater than or equal to ECOG grade II) that required treatment interruption and subsequent dose reduction predominantly for the following reasons: mucositis (67%), hand-foot syndrome (21%), and leukopenia (25%). The incidence of treatment limiting toxicity is higher than previously observed with 5-fluorouracil infusion alone. This suggests true augmentation of 5-fluorouracil effect by interferon. 5-Fluorouracil infusion and alpha interferon is a potentially useful combination that needs further evaluation in future phase II and phase III trials.