Annals of the Royal College of Surgeons of England (980) vol 62 ASPECTS OF TREATMENT* ntra-arterial chemotherapy for patients with inoperable carcinoma of the pancreas Lord Smith of Marlow KBE MS PPRCS J-C Gazet MS FRCS St George's Hospital, London Key words: PANCREATC NEOPLASMS; CARCNOMA; DRUG THERAPY Summary Percutaneous intra-arterial chemotherapy followed by intravenous maintenance therapy has been given to a highly selected group of 63 patients with inoperable carcinoma of the pancreas in most of whom the predominant symptom was pain. Relief of pain was an immediate response in 55%, with a slow recurrence of symptoms. Low toxicity was observed, with only one death attributable to the form of therapy used. it is now felt reasonable to close the series and review the final results of this form of therapy in the 63 patients who have died. Material The primary reason for selecting this group of patients was incurable disease with pain. Five patients had had a previous palliative resection and now had recurrent disease. Of the patients referred for a second opinion, 20 had a further exploration, but in only 3 was it possible to perform a palliative operation (Table ). The original primary site of the tumour was ampullary in 3 patients, in the head in 30, in ntroduction n 1973 (i) and 1974 (2) we reported our technique and preliminary results with intraarterial chemotherapy for inoperable (unresectable) carcinoma of the pancreas. This reampullary bile duct in patient. n the remain- the body and/or tail in 2, and in the periferred to a group of 65 patients treated between 968 and 973 whose primary com- of the 63 patients were found to have metaing 17 the site was not specified. Twenty-four plaint was abdominal pain. Seven to 12 years stases at operation. The tumour type was an later all but 2 patients have died. n i of the 2 adenocarcinoma in 51 patients, a cystadenocarcinoma in 2, a non-secreting islet-cell tu- still in remission the histological diagnosis was of a non-secreting islet-cell tumour of the body; mour in i, and a malignant carcinoid in i. in the other patient there is doubt about the The remaining 8 patients had no biopsy. n diagnosis as no tissue was obtained. However, 68.3% there was a T2 or locally invasive tu- TABLE Operative procedures in 63 patients now dead with carcinoma of the pancreas (1968-73) Operation Biopsy positive No biopsy Total Exploration only 22 2 24 Biliary bypass 5 3 8 Gut bypass 6 7 Biliary and gut bypass 4 2 6 Resection (Whipple) 8 o 8 Totals 55 8 63 Two alive excluded: Female, biliary bypass, no biopsy: alive 9 years Female, exploration, biopsy + (islet-cell tumour): alive O years The Editor would welcome any observations on this paper from readers *Fellows and Members interested in submitting papers for consideration with a view to publication in this series should first write to the Editor
ntra-arterial chemotherapy for patients with inoperable carcinoma of the pancreas TABLE Pancreatic tumours: TNM classification (after Rainsbury et al (5)) No N N2 N? MO M M? Po P P2 P3 P4 Si Ti 0 0 0 0 0 0 0 2 3 Ampullary T2 0 0 0 0 1 0 0 0 1 0 0 S2 3o Head and neck T 5 0 0 0 4 0 0 0 3 T2 1 4 5 9 8 9 2 0 00 i i8 T? 0 0 0 6 0 0 6 3 0 0 0 3 S3 12 BOdy T2 2 2 7 4 5 3 0 0 1 5 6 S4 i Bile duct T2 0 0 0 0 0 0 0 0 0 S6 7 Unspecified Ti 0 0 0 0 0 0 0 0 0 pancreas T2 2 3 5 2 5 4 0 0 0 0 T? o o o 5 0 1 4 5 0 0 0 0 Totals O 9 11 33 19 24 20 8 0 4 7 44 Ti, tumour resectable; T2, tumour unresectable No, no nodes found; Ni, local nodes involved; N2, distant nodes involved Mo, no metastases; Mi, metastases Po, no pathology; Pi, well differentiated; P2, moderately differentiated; P3, anaplastic; P4, not specified T2 N, N2 M Positive biopsy 43/63 = 68.3% 20/63 = 3.7% 24/63 = 38.o/% 55/63 = 87-3% mour, 31.7% had involved nodes, and 38% were noted to have distant metastases. A positive biopsy result was obtained on 85.7% Of patients (Table ). Method The method used consisted essentially in inserting, under radiographic control, an arterial catheter as for selective coeliac angiography but placing the tip preferentially into the common hepatic artery. The procedure was performed under local anaesthesia. Once the catheter had been securely placed it was connected to a constant infusion pump. ts position 209 was checked daily. Thus 63 patients were treated by percutaneous femoral intra-arterial coeliac infusion with anticancer chemotherapy. n 47 cases 5-fluorouracil (5-FU) was given in a dose of 5 mg/kg body weight/day or ig/day (whichever was the greater dose) for a period of 5 days. Each o.5 g of 5-FU was added to soo ml of physiological saline containing soo U of heparin and infused over 12 h. n i6 cases multiple drugs were given. Nine infusions included pulsed doses of g cyclophosphamide, 2 mg vincristine, and 50 mg methotrexate, 4 infusions included i g cyclophosphamide and 2 mg vincristine, and 3 included 2 mg vincristine only, added in all cases to the solution containing 5-FU. n the majority of cases prophylactic ampicillin 250 mg 6- hourly for 5 days was given at the same time. After the removal of the catheter i g of 5- FU was given intravenously weekly as maintenance therapy where possible for 3 months in the first instance. n 4 cases a second infusion was given. All patients were investigated before and after infusion. Routine investigations included liver function tests, liver and pancreatic radioactive scans, and chest X-rays. A full blood count was performed before infusion, daily during infusion, twice weekly thereafter for 2 weeks, then once weekly during intravenous therapy. Results Survival in the 63 patients varied from 4 to 1455 days from the time of infusion, with a median survival of 58 days (about 5 months) and a mean survival of 234 days (about 8 months); 21 %survived more than one year. Pain was the primary symptom in 58 out of the 67 infusions. t was graded arbitrarily and subjectively by the patients on a scale described
20 Lord Smith of Marlow and J-C Gazet TABLE Relief of pain, all cases, all drug regimens Severity of pain Time Total ntolerable Tolerable No pain Pre-infusion 46 (79.3 %) O (7.2%) 2 (3.4%) 58 (00%) One week 4 (24. %) 33 (56.9%) '' ('9%) 58 (100%) One month 13 (33-3%) 6(4%) O(25.6%) 39 (100%) Three months (34-3%) 8 (56.3%) 3 (94%) 32 (OO%) 67 infusions in 63 patients 9 excluded as no pain throughout follow-up All patients now dead. Decreasing totals reflect deaths. by Professor T R E Pilkington (unpublished observation), no pain being given a zero score and intolerable pain scores of 6-io. n 46 of these 58 infusions the severity of the pain before infus;ion was scored as above 5 (intolerable pain) and in io as tolerable (-5) (Table ). At week from the start of treatment the severity of pain was less in 32 infusions (55%), but by 1-3 months after treatment there was a tendency for it to increase or recur. This has been calculated alternatively as the percentages of patients suffering intolerable or tolerable pain in the four periods noted. At i week after infusion only 24% had intolerable pain compared with 79% before infusion, but by -3 months the relief had deteriorated and 33% had intolerable pain. n 14 infusions multiple drugs were given. Comparisons between pain relief obtained with 5-FU alone in 44 infusions and with combination therapy in 4 showed striking differences in that 5-FU alone seemed the better. How- TABLE V Survival related to primary site ever, there was such a disparity in the size of the groups, the selection of cases with pain, and the fact that combination treatment was given more frequently towards the end of the trial that no significance should at present be attached to these results. The range of survival in patients having drug combinations was from 3 to 944 days, with a median survival of 55 days and a mean survival of 224 days, similar to the figures for the whole group. t might be argued that the striking relief of pain was due to the early death of those with the severest symptoms. Patients with intolerable pain (scale 6, 7, and 9) were distributed randomly throughout the whole group of patients treated, but the severest pain (scale o) was more common in those patients surviving less than 200 days from the time of treatment. Table shows that in 8 cases no biopsy was performed. t can be assumed that there Site No. Operation (No.) and survival in days Si Ampullary (3) Bypass (i) 13 Resection (2) 56, 384 S2 Head and neck (3o) Exploration (g) Bypass (17) Resection (4) Median 37.5 Median i44 Median 217 Mean 137 Mean 258 Mean 812 Range 21-400 Range 4-1455 S3 Body and tail (2) Bypass and exploration (ii) Resection (i) Median io i 944 (Cystad) Mean 5 Range 2 1-389 S4 Bile duct (i) Bypass (i) 286 (periampullary) S6 Pancreas (7) Exploration (8) Bypass (9) (not specified) Median 135 Median 299 Mean i85 Mean 295 Range -426 Range 67-533
ntra-arterial chemotherapy for patients with inoperable carcinoma of the pancreas 2 was no doubt concerning the diagnosis. Median survival in this group was 36 days and mean survival 66 days, both below the average for the 63 patients in the series. n 30 patients in whom no secondary deposits were found but a positive biopsy was obtained both median and mean survival were well above average. This would suggest some doubt in diagnosis with a smaller yet still incurable lesion. Careful examination of the data shows that the variations in survival follow the expected pattern as seen in patients not treated with chemotherapy, depending upon the stage of the disease and its surgical treatment. This is confinned when survival is related to site of primary, tumour and type of surgery (Table V). t is extremely difficult to assess the results of therapy objectively. Liver and pancreatic scans evaluated serially have shown no definite change. Liver function tests and haemato, logical assessment have been of greater value in assessing the effect of drug toxicity on the patient than improvement in disease state. Clinically only the occasional patient has had physical signs which can be monitored. One patient with an inoperable cystadenocarcinoma and abdominal fistula had visible shrinkage of the ulcerated lesion. At laparotomy 6 weeks after therapy the tumour was resected and she survived 2 months before obvious recurrence was noted. n spite of further therapy she died 5 months later (total survival 944 days). The patient with the best response, a woman of 26 with an islet-cell tumour proved by biopsy (and excluded from this series), had a mass which disappeared after her first course of chemotherapy. Fourteen months later the mass recurred with severe pain. A second course of chemotherapy failed to relieve pain or tumour size. The pancreas was irradiated and she is still in apparent remission 9 years after the original diagnosis. Complications from intra-arterial chemotherapy have been few and only one death has been directly attributable to treatment (Table V). Discussion Carter and Comis (3) showed that the course of pancreatic cancer, whether treated or not, is usually brief and that the only effective treatment is adequate resection. n their review of 9 series in the literature of 4027 documented cases 730/3291 (22%) were inoperable. Exploration only was performed in 630/2600 (24%), 534/3699 (41%) had a palliative procedure, and in only 499/4027 (2%) was a resection performed. The operative mortality varied from o to 54% (average 29%). Nineteen of these patients survived 5 years, equivalent to 0.47% of the total. Pain, jaundice, and loss of weight are the most frequent presenting symptoms. Jaundice can be relieved by surgery and sometimes pain, too, in those cases in which it is caused by obstruction of the pancreatic duct which can be relieved by diversion of the pancreatic secretion into the stomach or small bowel. This will increase the length of survival. Pain cannot al- TABLE V Complications of intra-arterial chemotherapy in 63 patients (2 infusions) Catheter displacement 6 (Excluding deliberate readjustments) Catheter thrombosis 5 (One had to be removed and replaced) Haemorrhage nfection 4 (One abscess around femoral insertion; pancreatic slough; patient died.) Death 1* Aneurysmal dilatation Toxic symptoms (nausea and vomiting) 2 Toxic symptoms (fever, infections, marrow depression) 5 Pulmonary embolus Failure to catheterise common hepatic artery (catheter in coeliac only) 2 *Patient with infection
212 Lord Smith of Marlow and J-C Gazet ways be helped in this way and will occur at some time during the course of the illness in 8o0/o of patients. When it occurs at an early stage of the disease it persists not only as a major symptom but also as an ominous sign (4). During the period 968-73 a selected series of 2 patients with upper gastrointestinal neoplasms were treated with intraarterial chemotherapy. Short-term medium to high dosage of 5-FU intra-arterially (with or without other anticancer drugs) offered up to 457o relief of pain in the patients with pancreatic cancer. This pain relief could persist till death, though there was a tendency for symptoms to recur. n our series all patients had unresectable disease with or without metastases and 92% had pain as their main symptom. This was, then, a highly selected group of patients and it has been difficult to compare it with any other group; in few reported series is the exact length of survival or the symptomatology reported. However, it has given us a base for comparison with other forms of therapy (5), the results of which are in preparation for publication. t is as yet not possible to prejudge the results of therapy in individual patients and thus no patient has had maximum chemotherapy. But a review of the literature on intra-arterial chemotherapy (4) provides ample evidence that high-dose therapy has no great advantage over low-medium-dose treatment. Furthermore, high toxicity can produce a negation of good results. Certainly it must be accepted that with pancreatic neoplasms chemotherapy as a single agent has no curative potential. When combined with surgery it has a palliative value in relieving symptoms and prolonging life. References i Gazet J-C. ntra-arterial chemotherapy for cancer of the pancreas. n: Raven RW ed. Modern trends in oncology i. Part. Clinical progress. London: Butterworths, 973: 893. 2 Gazet J-C, Smith R. ntra-arterial chemotherapy for patients with inoperable carcinoma of the pancreas. Proc R Soc Med 19.74;67:182-3. 3 Carter SK, Comis RL. The integration of chemotherapy into a combined modality approach for cancer treatment. V. Pancreatic adenocarcinoma. Cancer Treat Rev 1975;2:193-214. 4 Braganza JM, Howat HT. Cancer of the pancreas. n: Howat HT ed. Clinics in gastroenterology, vol, part 2. The exocrine pancreas. London: WB Saunders, 1972: 2 19-38. 5 Rainsbury RM, Smith Lord, Gazet J-C. Cancer of the pancreas and extrahepatic biliary apparatus: a study of its behaviour in 50 patients. Gut i979; i9:a962.