Acra Radiologica Oncology 21 (1982) Ftrsc.. 6

FROM THE DIVISIONS OF RADIATION ONCOLOGY AND NEOPLASTIC DISEASES, NEW YORK MEDICAL COLLEGE, VALHALLA, NEW YORK 10595, USA.

CHEMOTHERAPY AND CYCLIC RADIATION THERAPY IN LOCALLY ADVANCED NON-SMALL CELL LUNG CARCINOMA

A. ABITBOL, M. J. STRAUS, D. BILLET, P. SULLIVAN J. AMBINDER and R. MORAN

The treatment results of locally advanced non- small cell carcinoma remain unsatisfactory. For those patients not amenable to curative resection, the likelihood of persistent local control following radical radiation therapy is often less than 58 per cent and chances of extended survival are approxi- mately 6 per cent at 5 years (WHITE & BOLES 1981). While recognized as a disease with a high propensity for dissemination, a significant proportion of pa- tients (30-60 %) failing following initial irradiation relapse regionally and approximately 1/2 to 3/4 of these patients succumb to local disease (WHITE & BOLES). A number of prognostic variables have been identified which impact on survival: these in- clude performance status, weight loss, presence of supraclavicular and mediastinal adenopathy , pain, malignant pleural effusion and histopathologic type. Little emphasis has been placed on correlating local response following irradiation with survival. How- ever, recent reports suggest that local response may impact on survival (EMANI et coll. 1979, PEREZ et coll. 1980, PETROVICH et coll. 1981). Newer ap- proaches designed to enhance the local effective- ness of irradiation are currently being investigated and include hypoxic cell sensitizers, high LET irra- diation and combined modality therapy.

Recently, 5-fluorouracil has been increasingly used as a continuous infusion in combination with irradiation (BYFIELD et coll. 1980, 1981, SEAGREN et coll. 1981). This use of fluorouracil has the advan- tage of delivery of higher drug doses and a de-

creased incidence of myelo-suppression as opposed to pulse 5-fluorouracil (SIEFERT et coll. 1975). More- over, several laboratory experiments have demon- strated synergism between irradiation and fluorou- racil, which may be a radiation sensitizer (BAG- SHAW 1961, VIETTI et COll. 1971).

In this treatment cyclic irradiation was combined with continuously infused fluorouracil for 4 days followed by a pulse of methotrexate and 24 hours later by platinum continuous infusion. This is based on the presumption that a human cell cycle time is 4 days and that a constant serum concentration of fluorouracil may be required to achieve radiation sensitization (BYFIELD et coll. 1977). Moreover, methotrexate, an S phase specific drug, is used to take advantage of a possible progression delay in early S phase induced by fluorouracil. The average duration of S phase in human solid tumors is close to one day. Furthermore, it has been demonstrated in vivo that the predominant cytotoxic effect of platinum first occurs in G2 phase (MORAN & STRAUS 1981). Therefore, following methotrexate, the administration of platinum was delayed one day,

Materials and Methods

Nine patients (6 males and 3 females) were treated between April 1979 and August 1981 and the data were evaluated as of December 31, 1981. The me-

Accepted for publication 13 May 1982.

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408 A. ABITBOL, M. J . STKAUS, D. BILLET, P. SULLIVAN, J . AMBlNDEK AND K. MOKAN

dian age was 61.5 years (range 48-69). A smoking history was present in all 9 patients. Four patients had moderate to severe chronic obstructive pulmo- nary disease. Four patients were in performance status 1 , 4 status 2, and one status 3. The type of tumor was squamous cell carcinoma (41, adenocar- cinoma (4) and undifferentiated large cell ( I ) . Five patients were previously treated, 2 with surgery and irradiation (50 Gy, 46 Gy, respectively), 2 with irra- diation only (60 and 50 Gy), and one with chemo- therapy. Initial interval from the time of diagnosis to the time of treatment in these 5 patients was a median of 8 months with a range of.6.5 to 69 months. All 5 patients had locally recurrent disease with one having disseminated disease and 4 having endobronchial disease with atelectasis of one lobe in 2, atelectasis on one lung in one, and bronchial stump recurrence in one, while one patient had an apical tumor with brachial plexus involvement.

All patients underwent an initial staging or restag- ing which included complete blood count, sequen- tial multiple analyser (SMA), chest radiography, liv- er and bone scintigraphy, and in most cases CT of the chest and brain. Fiberoptic bronchoscopy was routinely performed in all patients at the time of initial therapy and afforded the opportunity to fol- low the disease in 5 patients (4 squamous and 1 undifferentiated) by means of repeat bronchoscopy after treatment. The patients were staged according to the AJCCS (1978). Four previously untreated patients had stage 111 and 5 previously treated pa- tients were restaged as stage 111. Six patients had T3 disease, 2 had T2 disease and one Tx.

Chemotherapy schedule. All patients were begun on therapy if their serum creatinine was less than 2.0 mg/lOO ml, WBC more than 4000/mm3, and platelet count more than 100000/mm3. The treat- ment delivered was 5-fluorouracil 800 mg/m2/24 hours for 4 days. Each 24 hour dose was diluted in 1000 ml 1/2 normal saline. Immediately after the fluorouracil, methotrexate, 30 mg intravenously, was administered. Twenty-four hours later platinum 35 mg/m2/24 hours was infused for a duration of 2 days. Each 24 hour dose was diluted in 2000 ml 112 normal saline.

The patients were scheduled to be treated every other week for a total of 3 courses in previously irradiated patients and 5 courses in previously un- treated patients. If at the time of retreatment, the WBC was 2500 to 3000 or platelets 75000 to 100000, the fluorouracil dose was decreased 20 per

cent. At lower counts, the treatment was usually delayed one week and resumed at full doses if WBC was 2000 to 2499 and platelets 50000 to 74999. Mucositis was common although it usually cleared before resumption of treatment. If mucositis was severe, the dose of fluorouracil was reduced 20 per cent in the next course.

Radiation therapy was commenced on day 2 of each cycle approximately 24 hours after initiation of fluorouracil infusion. Treatment was given with a 6oCo unit at a dose of 10 Gy per week ( 4 ~ 2 . 5 Gy) for a maximum of 50 Gy. In 4 patients previously irradiated to the mediastinum, oscillating lateral arcs were generally used to minimize the dose to the spinal cord and a maximum dose of 30 Gy was delivered. No attempt was made to encompass the entire mediastinum in these patients and the treated volume included the tumor with reasonable mar- gins. In previously untreated patients, the initial 30 Gy were delivered through anterior and posterior parallel opposed fields encompasing the lesion and mediastinum while the subsequent 20 Gy were de- livered using a 3 field isocentric technique with field reductions at 40 Gy. Correction for lung transmis- sion was made during this 2nd phase of treatment. All fields were irradiated daily. Radiation therapy was always given concomitantly with chemothera- py. If chemotherapy was delayed, irradiation was likewise delayed.

Patients were evaluated for response in the irradi- ated field only. Sites of disease evaluated for re- sponse included the primary or recurrent tumor in 8 patients and regional lymph nodes in 2 patients in- cluding one patient with undetected primary tumor. A complete response in the chest is defined as a complete clinical and endoscopic remission of dis- ease and required a repeat bronchoscopy with biop- sy for confirmation in those patients with positive pretreatment bronchoscopy . A partial response is defined as a 50 per cent decrease in the area of measurable disease as confirmed on repeat exami- nation including chest radiography, CT, broncho- scopy or lymph node measurement. A minimum response duration of one month is required for pa- tients with partial response. The survival data are computed from the day when the therapy was initi- ated.

Results

The results are indicated in the Table. The overall response rate was 67 per cent with one complete

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CHEMOTHERAPY A N D CYCLIC RADIATION THERAPY IN LUNG CARCINOMA 409

Table

Clinical results in 9 cases with non-smull cell lung carcinoma

Restaging Histopathology Previous No. of Response Duration of Survival Status TNM stage treatment cycles response (months)

(months)

T3NOMO

T3NOMO T3NOMO T3NOMO

T3NOMO T2N2M I

(brain) T2NOM2

hep., lymph.)

Undifferentiated

Squamous Adenocarcinoma Squamous

large

Squamous Adenocarcinoma

Adenocarcinoma

None 2

60 Gy 3 50 Gy 3 Pneumonectomy 3

None 5 None 1

+46 Gy

Chemotherapy I + 18 Gy/ 2 weeks

TxNIMl Adenocarcinoma None 5 (lymph.) Squarnous Lobectomy+ 3

T3NOMO 50 Gy

response of 7.5+ months duration and 5 partial re- sponses (56%) for 3, 4+ , 4, 4.5 and 7 months. The median survival time for the responders was 11.0 months and the average survival time was 9.25 months for responders versus 3.0 months for non- responders. The difference in mean survival time is statistically significant, p (lt132.43)<0.05.

The median time to response was 45.5 days (mean 49.8 days, range 15-100 days, SD 34.5 days). No adverse effect between previous therapy and re- sponse rate was noted. Three of 5 previously treated patients responded while 3 of 4 previously untreated patients responded. Out of 4 patients previously irradiated to the mediastinum, 2 achieved responses (1 complete and 1 partial) in spite of the limited radiation dose delivered (30 Gy in all patients). The patient with complete response had extensive dis- ease occluding 40 per cent of the right main stem bronchus and extending across the midline to entire- ly occlude the left main stem bronchus. The endo- bronchial disease was completely eradicated, which was maintained at 14 months but then a left extra- pleural metastasis developed.

The response rate was no< absolutely related to dose, but because of the small number of cases a more definite conclusion cannot be made. With rela- tively modest doses (G30 Gy), 4 of 7 patients re- sponded including one complete response while 2 of 2 patients receiving 50 Gy responded.

Partial 3 9 Dead

Partial 4.5 13 Dead None 0 4.5 Alive None 0 4 Alive

Partial 4.0+ 4.5 Alive None 0 0.5 Dead, pneumonia

Partial 4 4.5 Dead, pneumonia; (WBC 18 OOO)

microscopic disease in chest

Partial 7 10.5 Dead, pneumonia Complete 7.5 14 Alive with

extrapleural metas.

The response rate was not related to the perfor- mance status. Two of 4 ambulatory patients (status I ) responded while 4 of 5 non-ambulatory patients (status 2 and 3) responded.

No correlation between response rate and tumor type was found since 3 of 4 patients with squamous cell carcinoma responded while 3 of 5 with adeno- carcinoma or undifferentiated carcinoma respond- ed. The difference in mean survival time between both groups was not statistically significant: squa- mous carcinoma 8.8 months, adenocarcinoma and undifferentiated 5.8 months, p=(Jtl=0.967)<0.2. Out of 3 patients with disseminated disease, one achieved partial response in an unirradiated distant lymph node while 2 other patients were not evalua- ble for chemotherapy response since both were irra- diated to the distant site (cervical node, brain metas- tasis).

No pulmonary, cardiac or skin toxicity was en- countered in any patient. In one patient transient increase in serum creatinine occurred from a base- line of I .6 mg/l00 ml to 2.2 mg/100 ml which subse- quently stabilized at 1.9 mg/100 ml. Nausea was universal in all patients but was generally mild ex- cept in one patient who had severe nausea but was nonetheless able to tolerate 3 cycles. Oral mucositis occurred in 4 patients (mild in 2, moderate in 2). Hematologic toxicity was moderate and consisted of both leukopenia and thrombocytopenia. Two pre-

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410 A. ABITBOL. M. J . STRAUS. D. BILLET, P. SULLIVAN, J. AMBINDER AND R . MORAN

viously irradiated patients had a WBC below 2 . 0 ~ 103/mm3 (1.6, 1.8) and none developed septic complications. In one patient on Decadron for meta- static brain disease the WBC dropped from 35 000 to 18 000 and fatal pneumonitis developed. The pneu- monia cannot be ascribed to a septic episode sec- ondary to leukopenia. One patient had a platelet count of 45x 103/mm3 without a bleeding episode, 5 patients had platelet counts below 75x 103/mm3 (45, 54, 54, 56, 64).

Discussion

This analysis was performed in order to assess local response and control, toxicity and survival. Current results with irradiation in inoperable non- small cell lung carcinoma stage I11 are disappoint- ing. In assessing treatment related factors, the most important determinant of local response is the total dose with the best results achieved with doses of 50 and 60 Gy (PEREZ et coll.). In patients with T3, NO2 disease 12 to 15 per cent complete response and 35 to 48 per cent partial response will be achieved for an overall response rate of 51 per cent (PEREZ et coll.).

Moreover, it has now been demonstrated that local response impacts on patient survival with me- dian survivals of 75, 45, 36 and 29 weeks for com- plete response, partial response, stable or progres- sion, respectively (PEREZ et coll.). The results of systemic chemotherapy are generally inferior to those of irradiation with overall response rates 13 to 37 per cent; the median survival is between 13 and 34 weeks in patients with both local and disseminat- ed disease (STRAW 1976, 1979, CREECH et coll. 1981).

The rational of combining systemic chemotherapy and irradiation is based on the premise that different modalities with non-overlapping toxicity may be ad- vantageously integrated to enhance local response and to treat occult distant sites of involvement. By combining two relatively non-myelosuppressive drugs, 5-fluorouracil and platinum with irradiation, an acceptable hematologic toxicity was achieved. Moreover, no additional untoward toxicity was noted.

The 67 per cent response rate achieved with this regimen appears to be better than that achieved with radical irradiation. Four of 9 patients had been pre- viously irradiated, thus the present radiation doses were limited. Hence, it is the contention that this

encouraging response rate can be partially ascribed to the cytotoxic effect of 5-fluorouracil, methotrex- ate and paltinum. Whether continuous infusion of 5- fluorouracil offers potential radiation sensitization to tumor cells is speculative. BY FIELD^^ coll. (1981) using fluorouracil infusion and split course irradia- tion achieved 10/28 complete response. The present series is small and the radiation doses limited, hence the data are not readily comparable to those of BYFIELD et coll. Nonetheless, these results are en- couraging and the utility of this regimen as the initial therapy of stage I11 disease should be further inves- tigated.

SUMMARY Nine patients with non-small cell lung carcinoma (4

squamous, 4 adenocarcinoma, 1 large cell) were treated with a combination of radiation therapy and cyclic chemo- therapy with 5-fluorouracil, methotrexate and platinum. Four previously untreated patients had stage 111, 2 having distant metastases, 5 previously treated patients were re- staged as stage I11 with distant metastasis in one. Moder- ate hematologic toxicity was noted. Objective responses occurred in 67 per cent, regardless of previous treatment or performance status. Responders survived for a median of 1 1 months with one complete response patient surviv- ing at 14 months while 5 partial response patients survived for a median of 10 months. This regimen is feasible and its utility as the initial treatment of locally advanced disease should be further investigated.

ACKNOWLEDGEMENT

Searcy in the preparation of this manuscript. The authors acknowledge the contribution of Ms Elza

Request for reprints: Dr A. Abitbol, Department of Radiation Therapy, The Hospital of the Albert Einstein College of Medicine, 1825 Eastchester Road, Bronx, New York 10461, USA.

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