Immunologic monitoring of patients with small cell anaplastic carcinoma who are treated with chemotherapy and radiotherapy

??Immunotherapy

and Immunology

IMMUNOLOGIC MONITORING OF PATIENTS WITH SMALL CELL ANAPLASTIC CARCINOMA WHO ARE TREATED WITH eHEMOTH~RAPY AND RADIOTHERAPY CHRISTIAN BRAMBILLA, M.D., FRANCOISE CARPENTIER. MICHEL. BOL.LA,

CHRISTINE GRANGE, M.D.,

M.D.,JEAN-CLAUDE

M.D. AND

BENSA,

BERNARD PARAMELLE,

M.D., M.D.

Scrvicc de Pneumologie, Centre Hospitalier RCgional et Universituire de Grenoble From January to October 1978 the diagnosis of small cell anaplastic carcinoma was made in 12 patients. Patients were treated with chemotherapy and radiotherapy and were followed for 13 months. Before treatment lymphocyte stimulation (L.S.) and blood T and B lymphocytes were within normal range. Positive skin tests were observed in patients who had a large weight loss. After treatment, the number of lymphocytes dropped, but the T/B radio did not change. T lymphocyte function was impaired (decrease of LS with phytohemagglutinine but B lymphocyte function was normal (normal LS with Pockeweed Mitogen). The skin tests became negative after radiotherapy or when patients had a loss of body weight of more than 10%. In spite of its imprecision, skin tests appear to be the best to follow immunological Status. More sophjsticated tests gave no supplementary information. Immunological status could not be related to prognosis. Small cell anaplastic Carcinoma,

Immunology.

chemotherapy,

involvement. involvement.

INTRODlJCTION

General immune competence has been reported of prognostic value in patients with bronchogenic carcinoma.’ Chemotherapy has been reported to be ineffective when it was administered to patients with a poor immunologic status.’ We attempted to monitor the immunologic response of patients with small cell anaplastic lung cnrcinoma both before and during treatment. The results of our preliminary study on a small group of patients who were treated under the same protocol may be useful for the prognosis or the modulations of treatment. Since complete im~~unological studies are expensive and time consuming. it would be advantageous to select a few reliable tests. METHODS

AND

Radiotherapy

One patients

only exhibited

lr~~niunological staging This included in vitro and in vivo studies. They were performed before treatment and every two months (generally before each chemotherapy treatment and at least 3 weeks following radiotherapy). Skin test Candidin ( 1/ 1000, I/ 10.~~00)~ Phytohemogglutinin (PHA) (1 y, IO y) Tuberculin (1, 10 units) and Dinitrochloroben~ene (DNCB) were used. Patients were considered to be skin test positive if more than 50% of the tests were positive.

MATERIALS

Lymphocyte count A total count was performed and sub populations were determined using E rosettes for T Lymphocytes, Erythrocyte Antibody Complement (EAC) rosettes and surface lmmunoglobulins for B Lymphocytes.

From January to October 1978, 12 consecutive patients (2 women and IO men) whose ages ranged from 45 to 70. were selected to participate in the study. The diagnosis of small cell carcinoma was made by bronchoscopy, mediastinoscopy and in one case by pneumonectomy. Staging included liver, bone, brain scintigraphies and bone marrow aspiration. 7 patients had intrathoracic lesions (mediastinoscopy generally proved lymph node involvement) 4 patients had lower cervical lymph node

Lymphocyte stimulation PHA (2 &g/ml and 0,4pg/ml and Pockeweed Mitogen ( IO @g/ml) were used. Lymphocyte cultures were supple-

Reprint requests mologie

C.H.R.G.,

bone marrow

to: Christian Brambilla, B.P. 217 X, 38043

Service

Grenoble

de Pneu-

France. Accepted

Cedex, 1057

for publication

9 April 1980.

1058

Radiation

Oncology

0 Biology 0 Physics

August

1980. Volume 6. Number

8

mented with patient serum and with pooled sera. We had already observed that some patients with epidermoid lung carcinoma had a normal response to PHA when lymphocytes were cultured in heterologous sera but a decreased response when their own serum was used. In some cases of epidermoid lung carcinoma, patient serum appeared to be inhibitory for lymphocyte stimulation.

Seric antibodies The presence of antinuclear, anti tissue, anti immunoglobulin, anti lymphocyte antibodies was investigated.

Treatment Treatment consisted of combination chemotherapy (adriamycin-vincristine-cyclophosphamide) and split course radiotherapy (2,000 rad in five days, three weeks of rest followed by another 2,000 rad in the next five days). Cranio spinal axis irradiation was done in all but one patient. Patients received radiotherapy between the third and fourth chemotherapeutic treatment. I

I

I

CHl

Cl43

1

I

R

I

*

April 1979

CH5

Fig. I. Total body weight: the total body weight dropped during First, Third and Fifth chemotherapy treatments (CH I, CH3. CH5) or after radiotherapy (R).

*

*

70,

A

BLOOD

LYMPHOCYTES PHA

nb/ml

50,

3000

3Q

Z&ml

*

10,

2000

100 0

1

0

,

CH3

&

m

R

Fig. 2. Blood lymphocytes: the number of blood lymphocytes dropped after a Third chemotherapy treatments (CH3) and radiotherapy (R).

Before Tmat ment

3rd chemotherapy treatment

After radiotherapy

Fig. 3. Lymphocyte stimulation with phytohemaglutinine (PHA) and pockeweed mitogen (PWM): the straight lines represent the lowest normal values.

Small cell anaplastic

carcinoma

RESULTS Survival 4 patients died between one and four months after treatment (one had bone marrow involvement, one had respiratory insufficiency, two patients had iatrogenic complications). One patient with brain metastasis was still alive after 13 months. 7 Patients had no evidence of cancer after 6 to II months.

Total body weight and general status The survey of total body weight appeared to give a very good indication of the general status of the patients (figure 1). In almost all patients, there was a large weight loss before treatment (more than 10% of the weight before symptoms of disease appeared). This weight loss must be considered when immunological tests are interpreted. Hematologic complications following high doses of chemotherapy were more frequent when there was a severe weight loss, but patients always improved both radiologically as well as clinically. Esophagitis induced by mediastinal radiotherapy increased weight loss, making the continuation of chemotherapy more difficult. We are now trying to reinstitute normal weight using intraveinous hyperalimentation. Although this procedure appears to be successful in these first patients, it is too early to make any conclusions concerning this point.

0

Lymphocytes and seric antibodies Antinuclear or anti-immunoglobulin antibodies were rarely found. The total count of lymphocytes decreased after chemotherapy and still further after radiotherapy (fig. 2) but the ratio of T and B lymphocytes did not change. However, lymphocyte stimulation exhibited an uneven impairment of T and B functions during treatment (fig. 3). Before treatment, stimulation with PHA or Pockeweed Mitogen produced normal responses in all patients. After 3 chemotherapy treatments the response was decreased but was still within accepted laboratory norms. After radiotherapy, lymphocyte stimulation was very low when two different concentrations of PHA were used while response to Pockeweed mitogen remained within the normal range. The number of lymphocytes was decreased but the T/B ratio was constant. Only T lymphocyte function was impaired, there was no abnormal production of seric antibodies by B lymphocytes. Skin tests Positive skin tests (fig. 4) appeared to be related to body weight and performance status that we presume to represent good or bad general status. After radiotherapy, all patients were skin test negative and two patients in very good condition became skin test positive within the next few months. Fig. 5 shows a good correlation between skin tests or

El cl

Positive Skin test

1059

C. BRAMBILLA et al.

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Good

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Lower cervical Bone

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Before Skin test

Treetment

3’d Chemotherapy

Fig. 4. Comparison

Radiiherapy

SthChematherapy

between skin test results and general status.

April

73

1060

Radiation Oncology 0 Biology

0 Physics

*** * --u

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