Advanced Malignant Disease Research Articles

Mini-dose weekly adriamycin therapy for patients with advanced malignant disease at increased risk for adriamycin toxicity

In an effort to administer adriamycin safely to patients with advanced progressive malignant disease and an increased risk for adriamycin toxicity, a weekly schedule of 10-20 mg of intravenous adriamycin was used for 38 patients. All patients had been previously treated with chemotherapy and/or radiation therapy. These patients also had advanced age (8), liver disease (8), previous radiation to the myocardium (18), prior bone marrow depression (21), concurrent bone marrow depression (9) and/or were intolerant to usual adriamycin dosages (2). Five patients had an objective remission and eight had disease stabilization. Toxicity was not eliminated; 39% had leukopenia (WBC <3,500); four had alopecia; nausea and vomiting forced one to stop therapy; extravasation occurred in three; vaginitis occurred in one; one had diarrhea; and one had an arrhythmia. One patient died a septic death during a leukopenic phase. Adriamycin can be given to poor-risk patients on a weekly basis using mini-doses, but severe toxicity cannot be avoided at these dosages.

Doxorubicin and hyperpigmentation.

Sixty‐four patients with advanced malignant disease underwent treatment with Doxorubicin alone or in combination with other drugs. Twenty‐one percent developed hyperpigmentation. Four patients were noted to have total body pigmentation, a side effect which has not been recorded before.

Plasma concentrations of carminomycin and carminomycinol in man, measured by high pressure liquid chromatography

In 9 patients with advanced malignant disease who received carminomycin (CMM) in an i.v. bolus injection (dose 18 mg/ m 2), curves of plasma concentrations of CMM and carminomycinol (CMMOH), a metabolite, versus time were constructed. For determination of plasma concentrations, high pressure liquid chromatography was used. For CMM and CMMOH the median areas under the curves (AUC's) were 31 (range 4–57) × 10 −8 mol/l/hr (measured over 24 hr) and 100 (range 30–158) × 10 −8 mol/l/hr (measured over 48 hr) respectively. From the data an accumulation of CMMOH in patients receiving treatments separated by brief intervals can be predicted (half-life time of plasma disappearance for CMMOH was 2 days). Clinical toxicity was lowest in those 3 patients showing the lowest AUC for both CMM and CMMOH.

Plasmapheresis in patients with advanced malignant disease: a pilot study.

Plasmapheresis has been performed in 16 patients with advanced malignant disease (12 malignant melanoma, 2 breast cancer, 2 colon cancer). Up to 3,000 ml of plasma (range 1,650-3,000 ml) have been replaced by one single plasma exchange. Side effects observed in about 50% of the patients were mainly nausea and chills. Serum proteins including acute phase reactants were monitored before and 2, 4, and 7 days after plasma exchange. A transient change of these proteins was observed in the first days, but, later on, pretreatment values were always retained. Peripheral blood lymphocyte blastogenic response to mitogens was increased in 5 out of 9 patients 7 days after plasma exchange. In 7 out of 9 patients pretreatment serum was found inhibitory to autologous lymphocyte reactivity to mitogens. Furthermore, plasmapheresis was found to decrease significantly the blocking effect of patients' sera on normal donor lymphocyte reactivity. Plasmapheresis was found tolerable in all patients treated, but without any clinical efficacy. Further studies are warranted to establish the therapeutic value of plasma exchange in patients with advanced malignancies.

Chemiluminescence in peripheral blood mononuclear cells of solid tumor cancer patients

Levels of chemiluminescence were measured in peripheral blood mononuclear cells (PBMC) from normal subjects and from solid tumor cancer patients. Patients with advanced malignant disease were found to have significantly elevated baseline chemiluminescence activity in their ‘resting PBMC’ as compared to normal subjects or to cancer patients with, at most, minimum residual disease. Patients with either advanced disease or minimum residual disease, however, were found to exhibit significantly elevated activation of chemiluminescence by treatment of cells with phorbol myristic acetate (PMA). Treatment of surgically resected stage I lung cancer patients with Freund's complete adjuvant alone or emulsified with extracted lung cancer antigens was found to elevate chemiluminescence levels in patient PBMC. Serum from those vaccinated patients was found to elevate chemiluminescence levels of resting PBMC from normal subjects. That serum activity did net correlate with levels of immune complexes measurable in the Clq or Raji cell assay.

An experimentally designed high dose simultaneous combination of a diaminopyrimidine and folinic acid for the treatment of human malignancies

Eighty patients with previously treated advanced malignant disease were treated with 2,4-diamino- 5-( 3′,4′-dichlorophenyl)- 6-methyl pyrimidine (DDMP) and folinic acid. Both compounds were given together every 7 days. The dose of DDMP ranged from 1 to 10 mg/kg. The average weekly dose of folinic acid was 2.1 mg/kg. Of 75 assessable patients, 14 responded with a 50% reduction in tumour size, 7 showed partial regressions with a 20–50% reduction, 6 showed disease arrest and 48 failed to respond. No responses seen from DDMP doses less than 3 mg/kg/wk administered for less than 3 weeks. Toxicity to bone marrow and other tissues was far less than in other published studies using different scheduling of these two compounds. The safety of this protocol, together with the encouraging preliminary results justify further trials especially for tumours in sites in which DDMP reaches high concentrations, e.g., kidney, brain, skin and pancreas, where current drug treatment is relatively ineffective.

Multiple daily fractions in radiotherapy

Summary Conventional fractionation in radiotherapy may not be the most optimal with respect to the cellular kinetics and radiosensitivity of the proliferating tumour cells. Some biological experiments suggest that if the interval between treatments is reduced to 3 to 8 h and irradiation given 2 to 3 times/day then the therapeutic ratio can be improved because o (a) repair will be completed in normal well oxygenated cells but not in hypoxic cells of tumour which will suffer greater damage from subsequent doses of radiation, (b) repopulation of tumour cells between fractions of radiation can be minimized, (c) redistribution of cells into more sensitive phase of division cycle can occur, (d) reoxygenation may be completed. The interpretation of some of the experiments is controversial and there is an ever existing problem as to how well will in vitro findings apply in vivo. Yet, there is a suggestion that small doses per fraction (about 100 rad) can exploit minor differences in radiation response between normal cells and tumour cells and decrease or eliminate the problem of relative resistance of hypoxic tumour cells. If therapy is given 2 or 3 times/day, a full or almost full usual daily dose (150–300 rad) can be given in each session, thus doubling or tripling the usual daily dose and in this way the overall treatment time will be substantially reduced (1–3 weeks). It is proposed to call this method “hyperfractionation”. Another approach is to use smaller doses per fraction (50–150 rad), 2 to 4 times/day, which together would amount to or exceed somewhat the usual daily dose of conventional radiotherapy. The term “superfractionation” is proposed by the reviewer (Table 1). There is some experimental and theoretical evidence that this second approach could be more advantageous. Clinical studies reporting on the treatment of 713 patients were published by 14 groups of clinical investigators and these suggest that both methods using multiple daily fractions are feasible. In no case was this new fractionation found to be inferior to conventional treatment. The treatment results are at least as good and usually better than conventional radiotherapy in the treatment of Burkitt's lymphomas, skin carcinomas, anaplastic carcinoma of the thryoid, carcinoma of the head and neck, bladder, cervix and inflammatory carcinoma of the breast (Table 2). The use of multiple daily fractions was found to be safe in a wide range of dose and time factors with the regimes characterized by Cumulative Radiation Effect (CRE) up to 1900 reu. Acute reactions were usually the same or less severe than with similar conventional therapy. In situations where more severe reactions were observed, the regime was slightly modified and reactions became acceptable (Table 3). Late complications were not frequent and usually could be related to higher dose/shorter time regimes than that used in other patients but more observations are needed concerning the effect of multiple daily fractions on tissues such as the spinal cord and lung (Table 4). Only 3 of the clinical studies, discussed in this review, were randomized, with a control group treated by conventional fractionation. In other studies authors used historical control groups, sometimes not well defined. Some authors indicating superiority of multiple daily fraction therapy refer only to their general past experience to support their conclusion. The follow-up period of many studies was short and further limited by deaths from distant metastases, because most patients had very advanced malignant disease. Future studies also need to incorporate the state of art treatment planning and pay full attention to the best selection of treatment volumes, beam energy and adjuvant chemotherapy if the advantage of any particular fractionation is to be convincingly demonstrated. CRE formalism, applied to regimes with three daily fractions, underestimates the effect on skin by 5 to 10% but after such correction it could have good predictive value. Mathematical modelling can be also a useful tool for design of more effective unconventional fractionation regimes. There is need of further experimental work to evaluate the effect of various fractionation regimes on both the tumour and the normal tissues and to estimate the therapeutic ratio. In some clinical situations (e.g. very advanced cancer of the head and neck) locoregional control with conventional radiotherapy is so poor and accumulated experience with multiple daily doses so promising, that the superfractionation may fast become the treatment of choice. In several other malignant diseases, prospective controlled clinical trials comparing the best conventional fractionation with multiple daily fractionation, are urgently required.

Cancer and stress: counselling the cancer patient.

In addition to the commonly accepted aetiological agents of cancer, such as chemical carcinogens, oncogenic viruses, hereditary factors, irradiation, and chronic trauma, multiple psychological factors are also important. Among these are psychological depression, impaired emotional outlets, and perceived lack of closeness to parents. The effect of addressing these factors in addition to standard medical factors in addition to standard medical management is an important question to be answered. A pilot study is in progress, in which patients with medically advanced malignant disease are being counselled in addition to receiving appropriate medical treatment. Standard mental health processes of counselling are employed in a combination of individual and group counselling sessions. From 1974 through 1978, a total of 193 patients with medically advanced malignant disease have received counselling in addition to their medical treatment. The three most frequent diagnoses are breast cancer (71), bowel cancer (28), and lung cancer (24). These are also the three most common diagnoses in the United States. In this study we have observed median survival times of 38.5 months in advanced breast cancer, 22.5 months in advanced bowel cancer, and 14.5 months in advanced lung cancer. These survival times are considerably longer than expected median survival times reported in the literature. Our primary concern in using this approach was that the counselling be helpful and not detrimental to the duration of life, quality of life, and quality of death of the individual. Preliminary results indicate that counselling can be helpful and can also be detrimental, depending upon the dynamics of the relationships among the counsellor, the patients, the medical team and the family. This is a preliminary study, and many major questions remain unanswered.

Concentrations of N-(Phosphonacetyl)- l-aspartate (PALA) in plasma and tears in man

Plasma concentrations of N-(phosphonacetyl)- l-aspartate (PALA) have been determined in 23 patients with advanced malignant disease during phase I/II clinical trial. Drug levels were determined by high pressure liquid chromatography. In 11 patients, who received PALA in a 1-hr infusion (doses ranging from 1 to 4 g/sq m), curves of plasma concentration vs time were constructed. The average absolute and relative total body clearances were 95 ± 24 ml/min and 1.43 ± 13 ( ± S.E.)ml/min, kg, respectively. Values of 27 ml/min and 0.52 ml/min, kg were measured in a patient with renal dysfunction. The apparent distribution volume was 0.291/kg, with an exception of 0.541 1/kg for a patient with a considerable amount of ascites fluid. The mean residence time was 3.2 ± 0.4 hr. Plasma peak levels and 24-hr concentrations of PALA were measured for 3-hr PALA infusion. Peak concentrations were lower and 24-hr concentrations were the same when compared with 1-hr infusion (4.9 x 10 −4 M compared to 9 × 10 −4 M and 2.3 × 10 −6 M compared to 2.45 × 10 −6 M, corrected for a dose of 2.5 g/sq m). In 7 patients PALA was measured in tears, due to the occasional occurrence of conjunctivitis during PALA treatment. A rapid increase in drug concentration to 10 −4 M-6 × 10 −4 M was measured within 2 hr from the start of 1-hr infusion in 7 patients with an average concentration ratio between plasma and tears of 3.7.

Local immunotherapy of stomach and intestinal carcinoma by Propionibacterium granulosum.

The effect of cell suspension of Propionibacterium granulosum strain KP-45 injected intratumorally was estimated in patients with advanced malignant neoplastic disease of the upper and lower part of the digestive tract. These patients received no other anticancer treatment, and results of therapy with P. granulosum were compared with a control group of nontreated patients. In the course of immunotherapy, general clinical state, dynamics of tumor growth as judged by endoscopy and morphologic, biochemical and immunologic parameters of the peripheral blood, were evaluated. Treatment with KP-45 preparation usually resulted in partial regression of tumor growth, accompanied by improvement of the clinical state of these patients, as well as reappearance of normal values of blood picture and biochemical parameters. Enhancement of cellular immune response, evaluated by increased number of peripheral blood T lymphocytes and increased skin reactivity to PHA and PPD, was observed. No serious side effects or complications of local immunotherapy were noted. No patients who had immunotherapy suffered from bacterial infection; this was not the case in the control group.

Intravenous hyperalimentation. An adjunct to treatment of malignant disease of upper gastrointestinal tract.

A prospective search for factors that would anticipate successful nutritional repletion was undertaken in patients with advanced malignant diseases of the upper gastrointestinal tract. After two weeks of intravenous hyperalimentation, increasing serum transferrin levels, total lymphocyte counts, and, to a lesser extent, arm muscle circumferences predicted an improved quality of survival, whereas declines in these factors were seen in patients who died. Skin tests, T-lymphocyte counts, albumin levels, and other anthropomorphic measurements were not predictive. The single most useful test was the serum transferrin: in only one patient did it not reflect the eventual outcome of therapy.

The Management of Intractable Pain in Patients with Advanced Malignant Disease

Abstract The Brompton mixture is a highly effective, flexible, safe and convenient means to control chronic pain of malignant disease. The mixture is a solution containing morphine, the dose of narcotic varying with the need for analgesia, and is given regularly, usually every 4 hours, with a phenothiazine. The main aims oftherapy are prevention of pain rather than treatment, an unclouded sensorium and a normal effect. Terminally illcancer patients were given the Brompton mixture and a phenothiazine in an attempt to control their pain. The mixture was administered to patients in 3 hospital environments: 1) a palliative care unit, 2) general wards and 3) private rooms. Pain was measured in 92 patients with the McGill-Melzack pain questionnaire. The Brompton mixturecontrolled pain in 90 per cent of patients in the palliative care unit and in 75 to 80 per cent of patients in the wards or private rooms. The differences in pain scores between patients in the palliative care unit and the other groups were significant. The mixture produced substantial decreases in the 3 major dimensions of pain: 1) sensory, 2) affective and 3) evaluative. Comparison of these results with data obtained in an outpatient pain clinic showed that the Brompton mixture was strikingly more effective than the traditional methods of managing cancer pain.

Reversal of Protein-Energy Malnutrition in Children During Treatment of Advanced Neoplastic Disease

The effectiveness of enteral and parenteral feeding in supporting a satisfactory nutritional status and/or reversing protein-energy malnutrition was evaluated in 28 children, ages 1-19 (14 female) with advanced malignant disease (21 solid tumors, 7 leukemia-lymphoma). At the onset of treatment, 21 patients received intensive nutritional counseling (INC) and oral supplementation while seven received total parenteral nutrition (TPN). Sixteen of 21 patients who received INC had a decreased intake (x 48 +/- 24%) Recommended Dietary Allowances (RDA) for kilocalories and dramatic weight loss (x 16.4 +/- 12.4%). A total of 18 patients received TPN for a mean of 24 days (7-60); kcal averaged 90 +/- 26% RDA during weight gain. At onset of TPN, the mean serum albumin, transferrin and total lymphocyte counts were 3.06 +/- 0.38 g/dl, 175 +/- 62 mg/dl, and 1102 +/- 966/mm3 respectively, 15/18 children had subnormal anthropometric measurements and 17/18 patients were anergic to recall skin test antigens. TPN for less than 9-14 days neither repleted weight, skinfold reserves, nor serum albumin concentrations (greater than 3.2 g/dl) although an early increase (p less than .02) in transferrin concentration was observed. However, TPN for 28 days supported weight gain (3.27 kg, 16 +/- 6%), increased serum albumin (0.62 +/- 0.43 g/dl, p less than .001) and transferrin (62 +/- 42, p less than .002) to normal concentrations and reversed anergy in 7/11 patients retested. This study documents the severity of protein energy malnutrition which accompanies intense treatment of children with cancer and the nutritional and immunological benefits of a 28 day course of TPN.

Cancer chemotherapy in advanced malignant disease. A cost benefit analysis.

A cost benefit analysis of chemotherapy in unselected patients with advanced malignant disease originating in a defined population (250 000 inhabitants) demonstrated that the use of this therapy as the main treatment in hospitalised patients increased from a few per cent during 1973 to 60 per cent during 1977, corresponding to an increase in the cost of drugs from 10 000 to 200 000 dollars. At the same time the capacity for hospital care of patients with advanced malignancies increased from 317 to 488 patients without any enlargement of other resources. As more than 90 per cent of the medical budget consists of expenditures for salaries and localities, a cheaper medical care was obtained, but, above all, the survival rate and the quality of life for many patients was improved.

The Management of Intractable Pain in Patients with Advanced Malignant Disease

AbstractThe Brompton mixture is a highly effective, flexible, safe and convenient means to control chronic pain of malignant disease. The mixture is a solution containing morphine, the dose of narcotic varying with the need for analgesia, and is given regularly, usually every 4 hours, with a phenothiazine. The main aims oftherapy are prevention of pain rather than treatment, an unclouded sensorium and a normal effect. Terminally illcancer patients were given the Brompton mixture and a phenothiazine in an attempt to control their pain. The mixture was administered to patients in 3 hospital environments: 1) a palliative care unit, 2) general wards and 3) private rooms. Pain was measured in 92 patients with the McGill-Melzack pain questionnaire. The Brompton mixturecontrolled pain in 90 per cent of patients in the palliative care unit and in 75 to 80 per cent of patients in the wards or private rooms. The differences in pain scores between patients in the palliative care unit and the other groups were significant. The mixture produced substantial decreases in the 3 major dimensions of pain: 1) sensory, 2) affective and 3) evaluative. Comparison of these results with data obtained in an outpatient pain clinic showed that the Brompton mixture was strikingly more effective than the traditional methods of managing cancer pain.

Tumor invasion of the upper inferior vena cava: The use of profound hypothermia and circulation arrest as a surgical adjunct

Two children presented with abdominal tumors invading the upper inferior vena cava. To facilitate removal of the tumors, cardiopulmonary bypass with profound hypothermia and circulation arrest were utilized. This technique simplifies tumor excision and is worthwhile even in children with advanced malignant disease.

Clinical applications of serum carcinoembryonic antigen and alpha-fetoprotein levels in children with solid tumours.

A study was carried out on serum carcinoembryonic antigen (CEA) and alpha-feto-protein (AFP) levels, both measured by radioimmunoassay, in 88 children with malignant solid tumours and in 26 children with nonmalignant disorders, who presented during the years 1973-77. Slightly or moderately raised CEA levels were found at presentation in 11 of 66 children with malignant tumours, in 2 others with recurrent tumours, and in 4 children with nonmalignant disorders. Raised CEA levels generally indicated advanced malignant disease, often affecting the liver, or other hepatic disorders, but were not associated with a specific tumour type. Except in the first months of life, significantly raised AFP levels were detected only in 11 patients with yolk sac-derived tumours, or hepatomas, and in one child with tyrosinosis who later developed a malignant hepatoma. Serial measurements of AFP accurately reflected the clinical response to treatment and in 2 patients indicated recurrence before this could be detected clinically.

Pharmacokinetic and Metabolic Studies of the Hypoxic Cell Radiosensitizer Misonidazole

1. The metabolism of the radiosensitizing 2-nitroimidazole, misonidazole, has been investigated in mice, rats, baboons, human volunteers, and in patients receiving radiotherapy for advanced malignant disease. 2. Plasma levels of unchanged drug and its desmethylated metabolite have been measured, and in humans there is good correlation of peak plasma concn. with drug dose. All drug-related material in plasma was accounted for as unchanged misonidazole or its desmethylated metabolite, both compounds being radiosensitizers in vitro. 3. Extensive faecal excretion of material not containing any nitro group occurred in mice, rats, and baboons dosed with radiolabelled drug. 4. Renal excretion is the preferred route of elimination in man, baboon and mouse. Nitroimidazole metabolites accounting for over half the urinary excretion in all species were identified. 5. The compound penetrates solid murine tumours in concentrations sufficient to achieve radiosensitization.

A COMPARISON OF DIAMORPHINE‐WITH‐COCAINE AND METHADONE

British Journal of Clinical PharmacologyVolume 4, Issue 6 p. 691-693 Free Access A COMPARISON OF DIAMORPHINE-WITH-COCAINE AND METHADONE R.G. TWYCROSS, R.G. TWYCROSS The Churchil Hospital Oxford OX3 7LJSearch for more papers by this author R.G. TWYCROSS, R.G. TWYCROSS The Churchil Hospital Oxford OX3 7LJSearch for more papers by this author First published: December 1977 https://doi.org/10.1111/j.1365-2125.1977.tb00433.xCitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Beaver, W.T., Wallenstein, S.L., Houde, R.W. & Rogers, A. (1967). A clinical comparison of the analgesic effects of methadone and morphine administered intramuscularly, and of orally and parenterally administered methadone. Clin. Pharmac. Ther., 8, 415– 426. Brunk, S.F. & Delle, M. (1974). Morphine and metabolism in man. Clin. Pharmac. Ther., 16, 51– 57. DATA SHEET COMPENDIUM. (1977). p. 966. A.B.P.I., London. Eddy, N.B., Halbach, H. & Braendon, O.J. (1957) Synthetic substances with morphine-like effect. Bull. Wld. Hlth. Org., 17, 569– 863. Goodman, L.S. & Gilman, A. (1975). The Pharmacological Basis of Therapeutics ( 5th Edition), p. 669. New York, London & Toronto: Macmillan. Lipman, A.G. (1975). Drug therapy in terminally ill patients. Am. J. hosp. Pharm., 32, 270– 276. Olsen, G.D., Wendel, H.A., Livermore, J.D., Leger, R.M., Lynn, R.K. & Gerber, N. (1977). Clinical effects and pharmacokinetics of racemic methadone and its optical isomers. Clin. Pharmac. Ther., 21, 147– 157. Rutherford, D.M. & Raymond, K. (1977). Methadone: evidence of accumulation. Br. med. J., 1, 774– 775. Seevers, M.H. (1949). Pharmacology of the newer synthetic analgesics. J. Oral Surg., 7, 30– 38. Symonds, P. (1977). Methadone in the elderly. Br. med. J., 1, 512. Troxil, E.B. (1948). Clinical evaluation of the analgesic methadone. J. Am. med. Ass., 136, 920– 923. Twycross, R.G. (1974). Diamorphine and cocaine elixir, BPC 1973. Pharm. J., 212, 153 and 159. Twycross, R.G. (1975). Relief of terminal pain. Br. med. J., 4, 212– 214. Twycross, R.G. (1976a). The measurement of pain in terminal carcinoma. J. int. med. Res., 4 (Suppl. 2), 58– 67. Twycross, R.G. (1976b). Studies on the use of diamorphine in advanced malignant disease. D.M. Thesis, Oxford. Verebely, K., Volavka, J., Mule, S. & Resnick, R. (1975). Methadone in man: Pharmacokinetic and excretion studies in acute and chronic treatment. Clin. Pharmac. Ther., 18, 180– 185. Way, E.L., Young, J.M. & Kemp, J.W. (1965). Metabolism of heroin and its pharmacological implications. Bull. Narc., 17, 25– 33. Citing Literature Volume4, Issue6December 1977Pages 691-693 ReferencesRelatedInformation

Quadruple chemotherapy for advanced malignant disease.

The results of treatment of 48 cases of advanced cancer by quadruple chemotherapy are reported. In only 4 patients was an objective remission obtained, although equivocal remissions were observed in 9 patients. This report is at variance with other recent reports. The reasons for the discrepancy are discussed, and while combination chemotherapy may prove more effective if used earlier in the natural history of malignant disease, in this series the technique does not appear to offer any greater chance of remission than chemotherapeutic agents used singly.