treatment of potentially resectable pancreatic cancer

TREATMENT OF POTENTIALLY RESECTABLE

PANCREATIC CANCER:A CLINICAL ONCOLOGIST‘S

POINT OF VIEW

Conventional treatment strategy in patients with potentially resectable

disease:

Surgery ± adjuvant (radio)chemotherapy

B. GudjonssonCritical look at resection for

pancreatic cancer(Lancet 348:1676, Dec. 1996)

“In pancreatic cancer 5-year survivors arerare, cure is exceptional, the operative mortality is significant, and the costs of theresection are excessive ......“

Problems associated with adjuvant radiochemotherapy & reported clinical trials

In about 25% of patients, adjuvant treatment can not be initiated in time

Selection bias, since only patients in good general condition will receive adjuvant treatment

No assessment of retroperitoneal margins of resection

Undefined methods of follow-up

Significant radiochemotherapy-associated adverse reactions

• GITSG 1985 No.of pts. Median survival– Surgery alone 22 11.0 mos– RT (40 Gy) + FU 21 20.0 mos

• EORTC 1999 (218 randomized, 207 analyzed of whom only 114 had pancreatic cancer)

– Surgery alone 54 12.6 mos– RT (40 Gy) + FU CI 60 17.1 mos (P = 0.099)

• ESPAC I 2000 (530 patients registered, only 285 cases randomized in the 2 x 2 factorial design)

No difference between CT, RCT, RCT+CT and observation

Postoperative Adjuvant Trials in Pancreatic Cancer

JL. Abbruzzese(ASCO 2000 Educational Booklet, pp.19-23)

“Thus, at this point in time the weight of evidence does not strongly support the use of postoperative therapy in patients with resected pancreatic cancer .......“

Rationale for preoperative (radio)chemotherapy

Poor long-term results obtained with the conventional treatment strategy. Better effectiveness of radio- and chemotherapy due to intact tumor vascularisation. Minimizing the risk of peritoneal tumor cell dissemination during surgery. Frequent non-R0-resectability in the retroperitoneum. Selection of prognostically poor cases, i.e with subclinical diffuse metastases. Better general condition of the patients – multimodal therapy is more likely to be realized/completed.

142 Patients with potentially resectable pancreatic or periampullary carcinomas

Histologically ascertained CT visible mass in the pancreatic head

Negative histology or CT non-visible tumor

5-FU 300 mg/m2/day CI x5/week+ radiotherapy 50.4 Gy for 5.5 weeks

(standard fractionation 1.8 Gy/day x5/week)or

5-FU 300 mg/m2/day CI x5/week+ hyperfractionated radiotherapy

30 Gy for 2 weeks(3 Gy/day x5/week)

Duodenopancreatectomy

R0 resected pancreatic cancer:Radiochemotherapy

(using standard fractions)

(Spitz et al. 1997)

Potential resectable carcinomas of the pancreatic head (n=142)

Preoperative radiochemotherapy91

Laparotomy67

Curative resection52

non resectable9

no adjuvant therapy6

no pancreatic cancer17

Progression24

non resectable15

Laparotomy51

Curative resection42

Pancreatic cancer25

PostoperativeRadiochemotherapy

19

Results of Treatment (Spitz et al., 1997)

Preoperative Radiochemotherapy

Postoperative Radiochemotherapy

Recurrence rate: 27/41 (66%) 11/19 (58%)Median survival: 19.2 months 22 months

Advantages of the conventional therapeutic concept (surgery » radiochemotherapy)

1.) In 9/51 patients (18%) disseminated disease was found intraoperatively

2.) In 17/51 patients (33%) periampullary adeno- carcinomas were diagnosed

3.) Adjuvant radiochemotherapy was tolerated as well as preoperative treatment

Positive aspects of preoperative Radiochemotherapy:

1.) Multimodal therapeutic concept could be realized in all patients2.) Unnecessary surgery could be avoided in 26% of the patients3.) No delay of surgery, no increase in perioperative morbidity

& mortality4.) Significantly shorter treatment duration in the hyperfractionated

arm (62 vs. 99 days)5.) Counteracts frequent non R0-resection of retroperitoneal margins6.) No locoregional tumor recurrence (0/41 versus 2/19)7.) Similar median survival despite more advanced tumor stages

(19.2 versus 22 mos)

Interim Conclusions I

• Both combined modality treatment approaches are feasible, though the preoperative use of CRT seems to be more attractive.

• 5-FU-based CRT seems to result in better locoregional tumor control, however,– it is unlikely to have a significant impact on

counteracting the development of distant metastases– can be associated with significant toxicity, requiring

hospital admissions in a considerable proportion of patients

e.g., Staley et al., MD Anderson Cancer Center

Preoperative FU 300 mg/m2/d CI x5/wk plus EBRT (50.4 Gy) Pancreaticoduodenectomy + IORT (10 Gy)

38 recurrences in 29/38 evaluable patients 8 (21%) locoregional 30 (79%) distant (liver, lung and/or bone)

Severe GI toxic effects that required hospital admissions in one third

In order to improve therapeuticIn order to improve therapeuticresults, results, more effective systemic more effective systemic

chemotherapy regimenschemotherapy regimens are required ! are required !

Rationale for the use of gemcitabinein patients with localized pancreatic cancer

• Superior treatment results in patients with meastatic disease compared to 5-FU.

• Only minor toxicities, including myelosuppression and a flu-like syndrom.

• Anticipated synergistic activity with radiation through:– direct independent antitumor activity– its radiosensitizing potential

Which treatment regimen should be used ?

• Standard dose infusional regimen (Burris et al)– 1000 mg/m2 30 min.inf. x1/wk

RR = 5% Benefit = 24% Survival = 5.6 mos

• Fixed dose rate infusional regimen (Temporo et al)– 1500 mg/m2 at a rate of 10 mg/m2/min x1/wk

RR = 17% Benefit = n.s. Survival = 6.1 mos

• Biweekly high dose regimen (Ulrich-Pur et al)– 2200 mg/m2 30 min inf. every 2 wks

RR = 21% Benefit = 44% Survival = 8.8 mos

Selected phase I/II trials investgating the use of gemcitabine as a radiosensitizing agent

• Eisbruch I: 300/m2 x1/wk 6/8 cases with severe mucositis requiring gastric feeding tube during 2nd wk of radiotherapy

• Eisbruch II: 150/m2 x1/wk 1/12 emergent tracheotomy because

of laryngeal obstruction + 6 cases with chronic late mucosal toxicity requiring pharyngeal dilations

• McGinn: 200-400/m2 x1/wk DLTs: 1 neutropenia and 3 severe GI toxicities including vomiting, dehydration & peptic ulcer

• Blackstock: 20-60/m2 x2/wk DLTs: nausea/vomiting & neutro-

thrombopenia; recommended dose: 40/m2 x2/wk

Selected phase I/II trials investgating the use of radiosensitizing gemcitabine combination regimens

• Talamonti et al., J Clin Oncol 2000 (n = 7)Gemcitabine 50-100/wk mucocutaneous, GI ulcers,

thrombopenia

5-FU 200 mg/m2 CI/wk with 3/5 episodes at XRT doses <36 Gy

• Kornek et al., Int J Radiol Biol Phys 2000 (n = 15)Gemcitabine 120-160 24h CI/wk mucositis, vomiting, neutropenia,

Mitomycin C 6 mg/m2 d1 q.4wks thrombopenia resulting in

frequent delays

Interim Conclusions II

• There are marked limitations on both radiation and gemcitabine doses when given in combination.

• Apparently, this problem can not be solved by combining small doses of gemcitabine with other conventional chemotherapeutic drugs.

• So how can we use available promising new gemcitabine combination regimens in localized disease ?

Promising Gemcitabine Combination

Regimens in Advanced Pancreatic Cancer

• Gemcitabine 1000 d1+8+15 + Epirubicin 60 d1 14/66 (21%) 43% 7.8 mos Scheithauer 99

• Gemcitabine 700-1100 d1+8+15 + 5-FU 200 CI /day 5/26 (19%) 45% 10.3 mos Hidalgo 99

• Gemcitabine 1000 d1+8+15 + Cisplatin 50 d1 + d15 8/22 (36%) n.s. 7.4 mos Philip 99

• Gemcitabine 1000 d1 + 8 + Irinotecan 100 d1 + 8 9/45 (20%) n.s. 6.0 mos Lima et al. 00

• Gemcitabine 2200 d1 + Capecitabine 2500 d1 to 7 8/28 (21%) 50% >8.5 mos Ulrich-Pur 00

Combination regimen Responses Benefit Survival Reference

Possible solution of the dilemma& ongoing Austrian pilot phase II study

• Improved systemic chemotherapy regimens

• Combined RCT with a potent radio-sensitizing agent

• Subtile restaging and surgery

Gemcitabine 2200 mg/m2 d1 Capecitabine 2500 mg/m2 d1-7 every 2 wks x 4

Combined RCT, sensitizing agent= Capecitabine 2000 mg/m2 d1-14 repeated on day 21

Evolution of multimodality neoadjuvant therapy in patients with localized pancreatic

cancer

Standard fractionation combined CRT >> surgery

Short-course hyper-fractionation CRT >> surgery (reduces GI-toxicity and treatment duration)

Improved systemic CT >> CRT >> surgery(more effective regimens with full drug doses can be given,improved preselection of patients with resectable disease)

Future Aspects

Possible improvements with the additional use of novel systemic agents such as:

– Inhibitors of angiogenesis(TNP-470, CM 101, Anti-VGEF, endostatin, SU-5416)

– Farnesyl-protein transferase inhibitors(SCH 66366, R 115777, L-778,123)

– Antisense-oligonucleotides(ISIS 5132)

– Genetherapy