Karl H. Link

Treatment of Pancreatic Cancer: Challenge of the Facts

Adenocarcinoma of the pancreas is associated with the worst survival of any form of gastrointestinal malignancy. In spite of the progress in surgical treatment, resulting in increasing resection rates and a decrease in treatment-related morbidity and mortality, the true figures of cure are even today below 3%. The dissemination of pancreatic cancer behind the local tissue compartments restricts the short-term (< 3 years) and long-term outcome for patients who have undergone resection. By histological evaluation, less than 15% of the patients undergoing R0 resection have a pN0 status, more than 60% suffer from lymph angiosis carcinomatosa, and more than 50% suffer extrapancreatic nerve plexus infiltration. Hematoxylin and eosin–negative lymph nodes were found to be cancer positive when reverse transcriptase polymerase chain reaction (RT- PCR) or immunostaining was applied to the HE-negative lymph nodes. Cancer of the uncinate process has a very poor prognosis because there are no early symptoms; vessel wall involvement occurs early and frequently; a high association of liver metastasis exists as well. Surgery offers a low success rate, but it provides the only chance of cure. Ductal pancreatic cancer is diagnosed in more than 95% of the cases in an advanced stage; potentially curative resection can be performed only in about 10%–15% of these patients. Major contributions of surgery to improved treatment results are the reduction of surgical morbidity—e.g., early postoperative local and systemic complications—and a decrease of hospital mortality below 3%–5%. In most recently published prospective trials, R0 resection has been reported to result in an increase in short-term survival beyond that recorded for patients with residual tumor. However, R0 resection fails to improve long-term survival. In many published R0 series, standard tissue resection of pancreatic head cancer with the Kausch-Whipple procedure failed to include remote cancer cell–positive tissues in the operative specimen; e.g., N2-lymph nodes, nerve plexus, and perivascular extrapancreatic and retropancreatic tissues were not excised. Cancer recurrence after so-called R0 resection with curative intent is frequently the consequence of cancer left behind. Thus, long-term survival (> 5 years) is observed in a very small group of patients, contradicting the published 5-year actuarial survival rates of 20%–45% for resected patients. The assessment of clinical benefit from surgical or medical cancer treatment should therefore be based on several end points, not only on actuarial survival. Publication of actuarial survival figures must include the number of observed (actual) survivals, the definition of the subset of patients followed after resection, and the total number of patients in the study group; anything less is misleading. In reporting pancreatic cancer treatment trial results after oncological resections, more convincing primary end points to evaluate treatment efficacy are median survival (in months), actual survival at 1–5 years, and progression-free survival (in months). In series with multimodality treatment, clinical benefit response as well as quality of life measurements using the EORTC Quality of Life index C30 (QLQ-C30) are of importance in evaluating survival data. Adjuvant treatment improves survival after oncological resection; however, the short-term and long-term benefit after adjuvant chemotherapy in R0 as well as in R1-2 resected patients has not yet been underscored by data from controlled clinical trials. The survival benefit (median survival time) of adjuvant chemotherapy or radiochemotherapy has been demonstrated to be 6–10 months. Therefore, after oncological resection of pancreatic cancer each patient should be offered adjuvant treatment. A neoadjuvant treatment protocol for pancreatic cancer, however, has not been established.

Surgery of colorectal cancer: Surgical morbidity and five- and ten-year results in 2400 patients: Monoinstitutional experience

The objective of this study was to determine surgical morbidity and long-term outcome of colorectal cancer surgery for quality control reasons and as the basis for new treatment modalities. Surgically treated colorectal cancer patients (mean age 65 years) were followed prospectively in a university center (110 months mean follow-up, 1978-1999). Overall survival (OAS), radicality, extent of resection, recurrence, and morbidity were analyzed (log-rank test of survival, multivariate analysis). Altogether, 2452 colorectal cancers localized in the colon (CC, 44.6%), rectum (RC, 44.8%) or multicentric (CRC, 10.6%) were of UICC stages I (19%), II (30%), III (21%), IV (20%), or undetermined (10%). Radicality and stage but not tumor localization influenced the OAS (p <0.0001). The 5-year/10-year OASs were 50%/42% (all), 78%/66% (R0), 46%/36% (R1), 4%/0% (R2), 0% (unresected) and 86%/79% (I), 70%/58% (II), 42%/33% (III), 3%/0% (IV) or 21%/12% (undetermined), respectively (p <0.0001). Multivisceral resections (17%) resulted in morbidity and survival rates equal to those for standard resection. The overall tumor recurrence rate was 27%, mainly with both local and distant relapse (15%). Surgery-related complications occurred in 18% (all), 14% (CC), 21% (RC), or 20% (CRC). The perineal infection rate (RC) was 4%, overall anastomotic leakage 1%, and mortality rate 0.8%. A prospective, uniform follow-up used over two decades warrants quality control in colorectal cancer surgery, which was curative for half of the patients. The morbidity and mortality were low and were not increased by multivisceral resections.

Thymidylate synthase is a predictor for response and resistance in hepatic artery infusion chemotherapy

The value of intratumoral thymidylate synthase (TS) quantitation as a predictive parameter for hepatic artery infusion (HAI) chemotherapy in patients with colorectal liver metastases was investigated. Relative TS mRNA levels were determined in 29 tumor samples using a quantitative RT-PCR amplification method. The median level of expression was 3.0 x 10(-3) (no units) and varied considerably among the tumors over a range of 135-fold. Patients with low TS levels were 4.1-fold more likely to respond (P < 0.03) compared to patients with high TS levels. Our results indicate that TS quantitation is a valuable predictive marker for tumor response to HAI therapy.

Is follow-up of colorectal cancer patients worthwhile?

Between 1978 and 1989, 1,045 of 1,399 patients (580 male and 474 female) underwent curative surgery for colorectal carcinoma. Of these patients, 350 (33 percent) had recurrences, another 16 (1.5 percent) developed a metachronous colorectal cancer, and 23 (2 percent) had cancers of other organs. An isolated locoregional recurrence was found in 75/350 (21 percent). The remaining 275/350 patients (79 percent) showed systemic dissemination of the carcinoma. Reoperations with curative intent were performed on 56/350 patients (16 percent). Only 21 of the 56 resected patients (38 percent),i.e.,21/350 (6 percent), were without recurrence at the end of the follow-up period on December 31, 1990. Despite a curative reoperation, 62 percent of the patients again developed recurrent growths. There is an imbalance between the efforts invested in tumor follow-up and the benefits gained. Further follow-up programs should be investigated in a controlled, prospective fashion.

Intraarterial Adjuvant Chemotherapy after Pancreaticoduodenectomy for Pancreatic Cancer: Significant Reduction in Occurrence of Liver Metastasis

Abstract. The clinical benefit of adjuvant chemotherapy in pancreatic cancer patients is still questionable. Phase II studies using radiochemotherapy based on 5-fluorouracil (5-FU) provided evidence of an increase in median survival times. Because palliative chemotherapy by celiac artery infusion (CAI) led to an increase in survival in pancreatic cancer, we treated 24 patients with adjuvant CAI following resection of the head of the pancreas for pancreatic cancer (21 patients with Union Internationale contre le Cancer (UICC) stage III, 2 with UICC stage II, 1 with UICC stage I). Catheters were placed angiographically into the celiac artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-FU, folinic acid, and cisplatinum. This treatment was repeated five times at monthly intervals. CAI was well tolerated, and World Health Organization (WHO) grade III toxicities were observed in 8%; WHO grade IV was seen in none of the treatment cycles. Furthermore, we observed pain reduction in nearly all patients under CAI. Median survival times in patients who received CAI were 23 months for all patients, whereas in patients who did not receive adjuvant treatment the median survival was 10.5 months. With Kaplan-Meier regression analysis of the patients who were curatively resected (R0 resection) and received CAI, the overall 4-year survival was 54%, whereas in patients without CAI the 4-year survival was 9.5%. The occurrence of liver metastases in the CAI group went down to 17%. These results demonstrate that CAI is well tolerated, reduces the risk of liver metastasis, and increases the survival time of pancreatic cancer patients.

Palliative and adjuvant regional chemotherapy in pancreatic cancer

To improve the dismal prognosis of patients (pts) with pancreatic cancer we treated 32 patients with non-resectable (UICC III, 17 pts; UICC IV, 15 pts--group 1) and 20 patients with resected (UICC I, 1 pt; UICC II, 3 pts; UICC III, 16 pts--group 2) pancreatic cancer with palliative (group I) and adjuvant post-operative (group II) coeliac axis intra-arterial cyclic infusions (CAI). CAI consisted of mitoxantrone 10 mg/m2 on day 1, folinic acid 170 mg/m2 and 5-FU 600 mg/m2 during days 2-4, and cis-platinum 60 mg/m2 on day 5 for up to 11 (group I) or six (group II) cycles. In a total of 211 cycles toxicities at the level of WHO III occurred in 0-6% and of WHO IV in 0%. The median survival times, compared with institutional historical controls (treated vs controls), were 12 vs 4.8 months in UICC III (P < 0.006) and 4 vs 2.9 months in UICC IV (P < 0.05) group I pts, and 21 vs 9.3 months in group II (P < 0.0003). Hepatic disease progression appeared to be suppressed with CAI, which also appears to be effective for palliative and adjuvant treatment in non-resectable and resected pancreatic cancer.

Association of time to recurrence with thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression in stage II and III colorectal cancer.

Patients with International Union Against Cancer (UICC) stage IIb and III colon cancer and stage II and III rectal cancer may receive adjuvant chemotherapy with 5-fluorouracil (5-FU). High levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) have been associated with resistance to 5-FU in advanced colorectal cancer. The aim of this study was to investigate the association of TS and DPD mRNA levels with recurrence-free survival in patients with colorectal cancer who are receiving adjuvant 5-FU-based chemotherapy. TS and DPD mRNA quantitation was retrospectively performed in primary colorectal cancer specimens from patients receiving adjuvant 5-FU using a reverse transcription-polymerase chain reaction technique. The median TS mRNA level in patients with a recurrence (n = 142) was 0.68, and in patients without a recurrence (n = 206) the median level was 0.80 (P < 0.01). Patients with a recurrence who had a low TS level (TS ≤ 0.9; n = 102) had a median recurrence-free survival of 18 months (range 3.0 to 54 months), and those with a high TS level (TS > 0.9; n = 40) had a median recurrence-free survival of 11 months (range 1.7 to 53 months; P = 0.0024). There was no difference in the median recurrence-free survival of patients with low and high DPD mRNA levels. The TS mRNA level may be a useful marker to predict the time to recurrence in patients with colorectal cancer who are receiving adjuvant 5-FU treatment.

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5‐fluorouracil, folinic acid, and mitomycin C may prolong survival

Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5‐Fluorodeoxyuridine (5‐FUDR) has been the drug studied in most Phase II and III trials. The meta‐analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5‐FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5‐fluorouracil (5‐FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5‐FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5‐FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM.

REGIONAL CHEMOTHERAPY OF NON-RESECTABLE LIVER METASTASES FROM COLORECTAL CANCER : LITERATURE AND INSTITUTIONAL REVIEW

Abstract Background: Cure is possible by resecting colorectal isolated liver metastases. In non-resectable isolated colorectal liver metastases (CRLM), regional chemotherapy has been advocated to optimize the disease control in the liver in order to improve the results of the alternative, systemic chemotherapy. The drugs are delivered by means of hepatic artery infusion (HAI) via ports or pumps; pharmacological modifications of the hepatic arterial blood-flow-like HAI with starch microspheres or stop-flow and perfusion techniques were applied to improve HAI. Methods: We reviewed the literature and report our progress, up to May 1999, in analyzing the validity of HAI for CRLM therapy. Results: In the majority of phase-II and -III trials, the response rates to HAI were significantly higher than those from systemic chemotherapy, and local disease control could be achieved even when HAI was used second line to systemic chemotherapy. The meta-analysis of randomized trials comparing HAI with either systemic chemotherapy (five trials) or, optionally, either 5-fluorouracil (FU) or symptomatic treatment (two trials) showed a significant advantage of HAI in response (41% vs 14%, P<10–10) and median survival time (15 months vs 11 months, P<0.0009). The active anabolite of 5-FU, 5-fluordeoxyuridine (5-FUDR), the drug of choice for HAI in those trials, may cause severe hepatotoxicity. To avoid this toxicity, we developed a HAI protocol using mitoxantrone, 5-FU plus folinic acid (FA) and mitomycin C (MFFM). The response rates of HAI with 5-FU plus FA or MFFM were 45% and 66%, the interim median survival times 19.8 months and 27.4 months. 5-Year survivors were observed in all our protocols. Since no severe hepatotoxicity occurred, 9 of 74 patients were resected after response to HAI with 5-FU plus FA or MFFM, without surgical mortality and with survival times from 2+ months to 58+ months. Conclusion: The high response rates, the long survival times, the possibility of achieving 5-year-survival either by HAI alone or by resection after down staging with HAI all sum up to the evidence that HAI could be the primary choice of treatment for CRLM. Phase-III trials are conducted to compare the protocols with optimal regional versus systemic chemotherapy.

Chemosensitivity Testing and Test-Directed Chemotherapy in Human Pancreatic Cancer

Human pancreatic cancer is a devastating disease with poor prognosis. In many cases it is diagnosed at stages in which a complete resection is not possible. However, even after complete resection most tumors recur. Therefore, several chemotherapeutic strategies have been developed, so far, with little impact on the clinical outcome. Because one of the hallmarks of human pancreatic cancer is its general resistance to chemotherapeutic agents, it seems important to develop strategies to individualize chemotherapy and to render cells more sensitive to chemotherapeutic agents. In this summary we describe our methods of in vitro chemosensitivity testing using the human tumor colony-forming assay for pancreatic cancer in comparison with other solid tumors and describe how the in vitro results influence chemotherapy. Furthermore, we point out new developments of mRNA quantitation of chemoresistance target enzymes based on real-time PCR, which may help in the future to individualize chemotherapy of pancreatic cancer. Finally, we present results of studies of cyclin D1 inhibition. Suppression of cyclin D1 by cyclin D1 antisense mRNA expression was associated with growth inhibition and an increase in chemosensitivity to fluoropyrimidines and platinum compounds. Because human pancreatic cancers are relatively chemoresistant and material for chemosensitivity testing with the human tumor colony-forming assay (HTCA) is in most cases difficult to obtain, future investigations should aim at the development of methods requiring only very small samples to analyzemarkers of chemosensitivity. Our results further suggest that chemotherapy in combination with strategies to increase chemosensitivity may be a reasonable regimen for the treatment of human pancreatic cancer in the future.