A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification.

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and methotrexate) and then to HMiVe (hexamethylmelamine, mitomycin C, vinblastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

Response of eccrine adenocarcinoma to tamoxifen.

One of two patients with systemic metastases from a poorly differentiated eccrine adenocarcinoma of the scalp was found to have a tumor positive for estradiol receptors. In the receptor positive patient, after tamoxifen therapy, the lymph node metastasis regressed completely and was associated with full relief of pain from osseous metastases for nearly 3 years. Subsequently, progressive painful osseous metastases in the spine, skull, pelvis, and femur were palliated for shorter periods with sequential systemic therapy with megestrol acetate and fluoxymesterone. Osseous metastases were also palliated with external radiation therapy. In contrast, despite external radiation therapy, brain metastases proved fatal. Tamoxifen was ineffective in the estradiol receptor negative patient. Based on this report, it may be valuable to determine the presence of estradiol receptor protein in eccrine carcinoma as a predictor of response to hormonal therapy.

Multimodality treatment of non-small cell lung cancer: response to cisplatin, VP-16, and 5-FU chemotherapy and to surgery and radiation therapy.

Twenty-one patients with unresectable non-small cell lung cancer (NSCLC), 11 with stage III M0, five with malignant pleural effusion, and five with a single resectable metastasis were treated with multimodality therapy. All received two to three cycles of preoperative chemotherapy with a new sequential combination of cisplatin (50 mg/m2 IV X 1) followed by 5-FU infusion (40 mg/m2/hr X 72) and etoposide (80 mg/m2/day X 3). Thirteen of 21 (62%) had a partial response, and three (14%) had a minor response to chemotherapy. Of the 19 who underwent surgical exploration, 17 were confirmed to have NSCLC. Ten patients with NSCLC and one with choriocarcinoma were rendered disease free by resection of the primary tumor and lymph nodes. Six received intra- and/or perioperative interstitial therapy with 125I and/or 192Ir. Another patient was treated with 32P. Postoperative external radiotherapy was administered in 15 patients, and adjuvant chemotherapy was administered in ten. This multimodality therapy was well tolerated, safe, and highly effective, resulting in excellent palliation even in patients with pleural effusion and metastasis. The most promising results were in unresectable stage III M0 with a partial response rate of 82% following neoadjuvant chemotherapy and a complete response rate of 73% after surgery. In this group, median survival has not yet been reached and will exceed 12 months.

Metabolic control and compartmentation in single living cells.

Microspectrofluorometry of cell coenzymes (NAD(P)H, flavins) in conjunction with sequential microinjections into the same cell of metabolites and modifiers, reveals aspects of the regulatory mechanisms of transient redox changes of mitochondrial and extramitochondrial nicotinamide adenine dinucleotides. The injection of ADP in the course of an NAD(P)H transient produced by glycolytic (e.g. glucose 6-phosphate, G6P) or mitochondrial (e.g. malate) substrate leads to sharp reoxidation (state III, Chance and Williams, 1955), followed by a spontaneous state III to IV transition, and an ultimate return to original redox steady state. The response to ADP alone is biphasic, i.e. a small oxidation-reduction transient followed by a larger reverse transient. Similarities between responses to injected ATP and ADP suggest possible intracellular interconversions. Sequential injections of glycolytic and Krebs cycle substrates into the same cell, produce a two-step NAD(P) response, possibly revealing the intracellular compartmentation of this coenzyme. A two-step NAD(P)H response to sequentially injected fructose 1,6-diphosphate and G6P indicates the dynamic or even structural compartmentation of glycolytic phosphate esters in separate intracellular pools. The intracellular regulation and compartmentation of bioenergetic pathways and cell-to-cell metabolic inhomogeneities provide the basis on which the quantitative biochemistry of the intact living cell may be reconciled with these in situ findings.

Leiomyosarcoma of prostate gland.

A case of leiomyosarcoma of the prostate is presented. The patient was successfully treated with transperineal radon seed implantation and external irradiation. The five-year, disease-free survival suggests that such patients can benefit from this therapeutic approach.

Radiotherapy for idiopathic inflammatory orbital pseudotumor. Indications and results.

Supervoltage radiotherapy was used in 21 orbits of 19 patients with idiopathic inflammatory orbital pseudotumor. Seventeen orbits (15 patients) were initially treated with systemic corticosteroids, but recurrence of orbital inflammation during dosage tapering was the most frequent indication for radiotherapy. Fifteen orbits (14 patients) responded favorably, as judged by reduced proptosis, decreased lid edema and conjunctival injection, improved ocular motility, and increased visual acuity. Six orbits (five patients) did not improve with radiotherapy. Patients who were successfully treated with radiotherapy have been free of recurrence for a mean follow-up period of 25.05 months; these patients have not required further corticosteroid treatment or additional radiotherapy. Low-dose (1,000 to 2,000 rad) supervoltage radiotherapy seems to have a definite role in the management of idiopathic orbital pseudotumor in the following instances: (1) when corticosteroids fail or systemic complications are unacceptable (2) when signs and symptoms recur during decreasing corticosteroid dosage, and (3) when systemic corticosteroids are medically contraindicated.

A controlled clinical trial testing two potentially non-cross-resistant chemotherapeutic regimens in small-cell carcinoma of the lung.

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Investigation of different combinations of estrogen therapy and radiation therapy on prostatic adenocarcinoma (R-3327).

The relative effectiveness of different combinations of estrogen therapy and radiation therapy against the R-3327 prostatic adenocarcinoma of the Copenhagen rat was studied. Because of similar actions of estrogens and radiation in the cell cycle, and possibly antagonistic effects reported in the clinical literature, we looked for an antagonism between these two therapeutic modalities. Radiation therapy consistently showed a greater tumor inhibitory effect than estrogen therapy alone at the dose tested. Combinations of radiation therapy with hormonal manipulation did not appear to show a greater inhibition of tumor growth than radiation therapy alone. There also did not appear to be an antagonistic effect between these two modalities in this system.

New metabolic parameters for the characterization of cells.

Microspectrofluorometric evaluation of coenzyme-linked transient changes in blue fluorescence, triggered by microinjections of metabolic intermediates, allows the definition of dynamic parameters in the characterization of cells. The observed fluorescence transients can be simulated by appropriate equations accounting for NAD(P) reduction-reoxidation, with NAD(P) as rate-limiting or not. From the above, the rate constants K1 and K2 of NAD(P) reduction and reoxidation can be determined. Other useful parameters in the metabolic evaluation of different cell lines, comprising normal and transformed fibroblasts, glia-glioma, melanoma lines, and a mouse embryo clone, can be derived from the relationship between injected dose of substrate and rise or decay rates of NAD(P) in equilibrium or formed from NAD(P)H transients. Reoxidation of NAD(P)H seems to be a useful target for such studies in view of possible impairment in malignant cells and X-irradiated cells. Cells followed by fluorometry are retrieved for subsequent ultrastructural and other analyses. Thus, the metabolic patterns associated with the operation of intracellular pathways or organelle interactions, and their aberrations can be recognized. On this basis eventually a classification of different cell lines according to structure-function should be feasible.

Randomized study of control of the primary tumor and survival using preoperative radiation, radiation alone, or surgery alone in head and neck carcinomas.

Fifty-five selected patients with previously untreated squamous cell carcinoma of the head and neck regions were studied in a randomized, prospective manner. The three treatment categories were primary radiation (Gp R), primary surgery (Gp S), and preoperative radiation of 4000 rads in four weeks (Gp R/S). The local control rates for the 44 evaluable patients with a two-year minimum followup were 24%, 39%, and 43% respectively. Further treatment attempts in patients failing initial therapy yielded local control rates of 35%, 39%, and 43% for Gp R, Gp S, and Gp R/S, respectively. None of the local control rates nor the corresponding survival curves were significantly different at P less than 0.10. However, the group sizes were sufficiently small that true differences might not have been detected. Postoperative complications were higher in the primary radiation failures subsequently operated upon compared to the primary surgery group (P = 0.07).

Randomized study of local control and survival following radical surgery or radiation therapy in oral and laryngeal carcinomas.

From 1971 to 1975, 100 patients with glottic, supraglottic, and oral cavity lesions were prospectively randomized between primary radiation treatment and primary surgery. Local control and survival were similar with either treatment for lesions of the oral cavity or supraglottic larynx. Comparison between radiation alone and surgery alone for T1 and T2 glottic laryngeal lesions showed local control rates of 76% and 100% (P=0.32); after secondary salvage attempts, local control rates were 82% and 100%, respectively (P= 0.52). Neither result approached statistical significance. Successful radiation for early glottic larynx lesions resulted in superior deglutition and equivalent voice function compared to successful primary treatment with conservation laryngectomy. For oral cavity lesions, swallowing was impaired in the same percentage of radiated and operated patients, but fewer primary radiation patients had articulation difficulties. Among the patients with supraglottic larynx lesions, aspiration was not a problem with either radiation or surgery, but successful radiation perhaps maintained a slightly better voice quality.

Anal carcinoma: basic concepts and management.

Surgery has been the mainstay in the management of anal carcinoma. However, anal carcinomas are reasonably sensitive to ionizing radiation. By appropriate combinations of external radiation beams and interstitial implantation techniques, curative therapy with preservation of anal continence can be rendered by radiation alone. Sufficient radiation dose to the draining lymph nodes, both intraabdominal and inguinal, along with intensified dose to the primary lesions, is required for high cure and low complication rates.

Adjuvant role of radiation in soft tissue sarcoma in adults.

Forty-seven patients with soft tissue sarcomas were analyzed retrospectively. Treatment was non-randomized between surgery alone, preoperative radiation of 5,000 rads/5 weeks, postoperative radiation of 6,000 rads/6 weeks following total gross tumor removal, and postoperative radiation (variable dosees) for residual gross or unresectable tumor. Preoperative radiation was not statistically better for local control or survival compared to postoperative radiation after local excision of gross tumor. Wide excision, higher postoperative radiation dosage, and/or enlarged radiation portals perhaps would improve results. Additional adjuvant therapies, such as chemotherapy or immunotherapy, needs to be investigated.