Repetto L . Greater risks of chemotherapy toxicity in elderly patients with cancer. J Support Care Oncol 2003;1 Suppl 2:18-24.

J. de Naurois et al,Management of febrile neutropenia: ESMO Clinical Practice Guidelines   Ann Oncol (2010) 21 (suppl 5): v252-v256.

EORTC Cancer in the Elderly Task Force guidelines for the use of
colony-stimulating factors in elderly patients with cancer, 2003, http://www.hompedin.org/download/paper/EORTGuideline.pdf

ERajan SS, Lyman GH, Stearns SC, Carpenter WR.ffect of primary prophylactic granulocyte-colony stimulating factor use on incidence of neutropenia hospitalizations for elderly early-stage breast cancer patients receiving chemotherapy.Med Care. 2011 Jul;49(7):649-57.

Romieu G, Clemens M, Mahlberg R, Fargeot P, Constenla M, Schutte M, Easton V, Skacel T, Bacon P, Brugger W. Pegfilgrastim supports delivery of FEC-100 chemotherapy in elderly patients with high risk breast cancer: a randomized phase 2 trial. Crit Rev Oncol Hematol. 2007;64:64–72.

Balducci L, Al-Halawani H, Charu V, Tam J, Shahin S, Dreiling L, Erchler WB. Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist. 2007;12:1416–1424.

Matti Aapro et al, Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colony-stimulating factors: where are we now? Support Care Cancer. 2010 May; 18(5): 529–541.

See Lay version here

Uwagawa T, Misawa T, Iida T, Sakamoto T, Gocho T, Wakiyama S, Hirohara S, Yanaga K. Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients.J Palliat Med. 2010 Jul;13(7):815-8.

Marcus Manocha et al, ; Serotonin and GI Disorders: An Update on Clinical and Experimental Studies, Clinical and Translational Gastroenterology (2012) 3, e13

For Lay version see here

Patients with low-grade non-Hodgkin’s lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A ‘watch-and-wait’ strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.

In addition to the R-CVP regimen,  NCCN 201 on p. FOLL_B, 1 cites R-CHOP, FR(fludarabine/rituximab), radioimmunotherapy, RFNDP, bendamustine/rituximab, rituximab alone.

There is evidence to recommend platinum-based chemotherapy regimens as post-operative adjuvant therapy in the management of patients with completely resected stage II and IIIA NSCLC. Cisplatin-based treatment is preferred, although a carboplatin-based regimen can be used as an alternative if there is a contraindication to cisplatin. There is uncertainty about a benefit to patients with resected stage IB NSCLC, although adjuvant chemotherapy may still be considered in selected individuals.

A meta-analysis published in 1995 indicated that post-operative chemotherapy did not significantly reduce the risk of death in surgically resected, pathologic stage IB, II and IIIA NSCLC, although there was a trend in favour of adjuvant chemotherapy regimens that included the agent cisplatin.

Only chemotherapy regimens used in the most recent trials are evidence-based. These include the combination of cisplatin and vinorelbine as standard, as these two agents were employed in IALT, NCIC CTG BR.10 and ANITA. Cisplatin-based treatment is preferred, but in individuals with a contraindication to cisplatin, the combination of carboplatin and paclitaxel is an acceptable alternative.

References:

1. Douillard J, Rosell R, Delena M, Legroumellec A, Torres A, Carpagnano F. ANITA: phase III adjuvant vinorelbine and cisplatin versus observation in completely resected (stage I-III) non-small cell lung cancer patients: final results after 70-month median follow-up. J Clin Oncol 2005; 23 Suppl 16S: 624s.
2. Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH, for the Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000; 343: 1217-1222.
3. Logan DM, Lochrin CA, Darling G, Eady A, Newman TE, Evans WK and the Lung Cancer Disease Site Group. Adjuvant radiotherapy and chemotherapy in stage II or IIIA non-small cell lung cancer after complete resection. Cancer Prevent Control 1997; 1: 366-378.
4. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899-909.
5. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Le Chevalier T. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. Proc Am Soc Clin Oncol 2006 Part I: abstr 7008.
6. Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453-1461.
7. Strauss GM, Herndon J, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RL, Green MR. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Proc Am Soc Clin Oncol 2004; abstr 7019.
8. Strauss GM, Herndon JE, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RA, Vokes EE, Green MR. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. Proc Am Soc Clin Oncol 2006 Part I: abstr 7007.
9. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360.
10. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao M, Gandara D, Kesler K, Demmy T, Shepherd F. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597.

Chemotherapy is indicated for patients with unresectable tumor with good performance status. Standard regimens of chemotherapy for late stage cancer are not yet established, although combination chemotherapy with cisplatin (CDDP), and 5 fluorouracil ( 5FU) or its derivates may be the regimen of preference and recommendation. A number of controlled studies of two-drug combination chemotherapies, especially cisplatin-containing regimens, have shown a significant improvement in median survival and quality of life compared with best supportive care. Of these, 5-FU and cisplatin combination (FP) has been considered an active and safe regimen for a long time. More recently drugs such as paclitaxel, docetaxel, oxaliplatin and irinotecan have been added in various trials.
Many trials using combinations of three drugs have been conducted to improve treatment results further in advanced gastric cancer. One of the three-drug combination is adding docetaxel, to ‘5-FU + cisplatin’ (DCF). A randomized phase II comparison of ECF, DC, and DCF had been conducted. The DCF regimen consisted of a 21-day continuous-infusion FU schedule (similar to ECF) and a higher dose of docetaxel (85 mg/m2) compared with a shorter 5-day infusion of FU and a lower dose of docetaxel (75 mg/m2). Although comparisons are again limited by the phase II trial design, QOL analysis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 indicated improvement in QOL scores for patients receiving ECF and stable QOL scores on both of the docetaxel arms. DCF resulted in detrimental QOL effects of weight loss and decline in role functioning during therapy, which were likely a consequence of the severity of toxicity. The authors declare DCF to be the superior regimen based on a higher response rate compared with DC, although both regimens had similar overall survival. Ajani et al also opted to select DCF over DC for the V325 trial, despite comparable rates of antitumor response rate, time to progression, and overall survival for DC compared with DCF and despite greater rates of GI toxicity for DCF. It appears to be the mi\ost effective, albeit a toxic regimen.
DCF is listed by NCCN.

D.-Y. Oh, T.-Y. Kim, J. H. Kwon, J.-J. Lee, Y. Joh, D.-W. Kim, T.-Y. Kim, D. S. Heo, Y.-J. Bang, and N. K. Kim Docetaxel + 5-Fluorouracil + Cisplatin 3-day Combination Chemotherapy as a First-line Treatment in Patients with Unresectable Gastric Cancer
Jpn. J. Clin. Oncol., July 1, 2005; 35(7): 380 – 385.

NCCN, Gast-12, 2

Eric D Tetzlaff et al, Review of docetaxel in the treatment of gastric cancer Ther Clin Risk Manag. 2008 October; 4(5): 999–1007.

Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007b;25:3205–9.

Ajani JA, Phan A, Ho L, et al. Phase I/II trial of docetaxel plus oxaliplatin and 5-fluorouracil (D-FOX) in patients with untreated, advanced gastric or gastroesophageal cancer. J Clin Oncol (Meeting Abstracts) 2007;25(18_suppl):4612.

Ajani J, Bekaii-Saab T, D’Amico TA, Fuchs C, Gibson MK, Goldberg M, Hayman JA, Ilson DH, Javle M, Kelley S, Kurtz RC, Locker GY, Meropol NJ, Minsky BD, Orringer MB, Osarogiagbon RU, Posey JA, Roth J, Sasson AR, Swisher SG, Wood DE, Yen Gastric Cancer Clinical Practice Guidelines.J Natl Compr Canc Netw. 2006 Apr;4(4):350-66.

D.-Y. Oh, T.-Y. Kim, J. H. Kwon, J.-J. Lee, Y. Joh, D.-W. Kim, T.-Y. Kim, D. S. Heo, Y.-J. Bang, and N. K. Kim
Docetaxel + 5-Fluorouracil + Cisplatin 3-day Combination Chemotherapy as a First-line Treatment in Patients with Unresectable Gastric Cancer
Jpn. J. Clin. Oncol., July 1, 2005; 35(7): 380 – 385.

Most of the research on PET in testicular cancer focused on restaging, because functional assessment of residual masses after chemotherapy is of great clinical interest. Staging is less well studied. In a 2003, CMS reviewed 11 studies of FDG-PET in testicular cancer and concluded that the literature suggests a possible role for FDG PET in staging testicular cancer, but that studies had significant limitations and that further research was needed to confirm this finding. PET in general is covered for the listed indications if the results of the PET exam could potentially impact clinical management. Medicare requires the ordering physician to document in the patient medical record the indication and justification for ordering a PET study, including a statement of how the PET findings might impact clinical management. There are several difficulties with using FDG PET for distinguishing NCCN does not recommend PET for either seminomatous or non-seminomatous testicular cancer.

There are several difficulties with using FDG PET for distinguishing recurrence and residual disease from benign masses. FDG PET was not useful in detecting tumor of less than 0.5cm or teratoma of any size secondary to a low proliferation rate and glucose metabolism. Furthermore, FDG PET cannot reliably distinguish between teratoma and necrosis. Since FDG PET cannot reliably distinguish between teratoma, cancer and necrosis, regardless of a positive FDG PET, you will still resect the testicular mass (or at least perform a retroperitoneal lymph node dissection post chemotherapy if serum tumor markers are not elevated) because the standard of care is to leave no mass (or suspected recurrence) unexamined for fear of malignant transformation or “growing teratoma syndrome.” Though many studies showed FDG PET with a high specificity for detecting residual tumor, the converse, that sensitivity is low, is also true. Given this relationship, a negative FDG PET scan does not provide complete assurance that the patient does not have a mass requiring resection, especially in patients with NSGCT. To improve sensitivity of FDG PET, some authors advocate avoiding its use in patients with high probability of having residual teratoma (i.e. patients with teratomatous elements in the primary tumor). Notwithstanding the reportedly high specificity of FDG PET for detecting residual tumor, authors note that false positive results secondary to FDG PET accumulating in tissue macrophages are a common problem, especially post chemotherapy or if the patient has an infection. Additionally, false negative results are common post chemotherapy because the chemotherapy drug leads to a transient suppression of metabolic activity in germ cell tumors regardless of their final response to therapy. Though some authors conclude that they cannot recommend the routine use of FDG PET scans in the evaluation of residual postchemotherapy masses in seminoma, one potential safeguard against the false negative results is to perform PET scans at least 2 weeks or more after chemotherapy. A recent guideline rated this modality as 4 on a 4/10 scale for staging testicular cancer. However NCCN now recommends this modality, with sureillance for negative results and biopsy or surgery, if positive, for seminoma but not for non-seminoma. nccn.org, testicular, p. 6, 2009

Technology Assessment submitted to AHRQ by the Duke Center for Clinical Health Policy Research and Evidence Practice Center, David B. Matchar, MD, Shalini L. Kulasingam, PhD, Laura Havrilesky, MD, et al., December 2003.

Choyke PL, Bluth EI, Bush WH Jr, Casalino DD, Francis IR, Jafri SZ, Kawashima A, Papanicolaou N, Rosenfield AT, Sandler CM, Segal AJ, Tempany C, Resnick MI, Expert Panel on Urologic Imaging. Staging of testicular malignancy. [online publication]. Reston (VA): American College of Radiology (ACR); 2005. 6 p. [57 references]

update 3/7/2009

Gemcitabine has some dated phase II evidence in a phase II trial and the response rates were quite low. There are moore recent studies in combination with other drugs. Researchers from Italy recently conducted a small clinical trial evaluating the combination of Gemzar® , alfa interferon and Proleukin® in 16 patients with metastatic renal cell cancer. Continued therapy with alfa interferon and Proleukin® was given to patients who responded or were stabilized by treatment. One patient achieved a complete disappearance of detectable cancer (complete remission) and 3 patients (28%) achieved at least a 50% reduction in their cancer (partial remission). In addition, 7 patients had their cancer stabilized by treatment. The average time to progression of cancer was approximately 14 months and the average survival was approximately 20 months. Treatment was generally well tolerated.

These researchers concluded that although this was a small clinical trial, it appears that the addition of Gemzar® to alfa interferon and Proleukin® may augment anti-cancer activity in metastatic renal cell cancer. Future clinical trials that involve larger numbers of patients and directly compare the addition of Gemzar® to alfa interferon and Proleukin®, compared to alfa interferon and Proleukin® alone are warranted.

Lilleby W, Fossa SD. Chemotherapy in metastatic renal cell cancer.World J Urol. 2005 Feb 22;

DeMulder PH, Weissbach L, Jakse G, et al: Gemcitabine: A phase II study in patients with advanced renal cancer. Cancer Chemother Pharmacol 37:491-495, 1996

Neri B, Doni L, Gemelli M, et al. Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer. The Journal of Urology. 2002;168:956-958.

Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with metastatic disease. Paclitaxel also has significant activity.

The combination of doxorubicin plus cisplatin (AP) has produced RRs of 40% to 46%, with reported median progression-free survival (PFS) ranging from 5.2 to 7.2 months in the three most recent Gynecologic Oncology Group (GOG) randomized trials. Most recently, the GOG compared AP with doxorubicin plus paclitaxel 150 mg/m2 as a 24-hour continuous infusion with filgrastim support, and there was no statistically significant improvement in objective RR, PFS, or overall survival (OS) between the regimens. The most recent randomized study found that TAP significantly improves RR, PFS, and OS compared with AP. What this suggested is that riplet therapy is superior to doublets. I elaborate. In 2001, the GOG published the results of a dose-finding trial that combined cisplatin, doxorubicin, and a 3-hour infusion of paclitaxel (TAP) in chemotherapy-naïve patients with advanced endometrial carcinoma and other gynecologic malignancies. In that trial, doxorubicin and cisplatin were administered on day 1, and paclitaxel, on day 2 because of previous reports suggesting that the cardiotoxicity associated with the paclitaxel + doxorubicin combination was decreased when these agents were administered 16 to 24 hours apart.12 Even when low doses of the combination of TAP were used, filgrastim was required for hematopoietic support, and neurotoxicity became the dose-limiting toxicity. The recommended phase II doses were doxorubicin 45 mg/m2, cisplatin 60 mg/m2, and paclitaxel 160 mg/m2 intravenously over 3 hours, with filgrastim 5 µg/kg given on days 3 to 12. Of 20 patients treated at this dose level, two (10%) developed grade 3 peripheral neuropathy Next GOG did a phase III trial compared cisplatin plus doxorubicin to doxorubicin, cisplatin, and paclitaxel with granulocyte colony-stimulating factor (G-CSF) support. The three-drug arm produced more objective responses than the two-drug arm (57% vs 34%, P < .01). Progression-free survival was extended to 8.3 months compared with 5.3 months in the control arm (P < .01); and overall survival reached a median of 15.3 months compared with 12.3 months (P < .037). Patients who received doxorubicin plus cisplatin on this trial were not likely to receive paclitaxel as first salvage therapy, which might account for the survival advantage for the three-drug combination. As seen in previous trials, increasing efficacy with more chemotherapy also led to increasing toxicity; patients receiving the three-drug combination were more likely to suffer thrombocytopenia and grade 3 and 4 neurotoxicity. The current GOG phase III trial compares the three-drug regimen of cisplatin, doxorubicin, and paclitaxel with G-CSF support to carboplatin combined with paclitaxel. Phase II trials testing the combination of carboplatin and paclitaxel in advanced, recurrent, or metastatic endometrial cancer have shown response rates of 46% to 78%. A Cochrane review recently attempted to address the issue of whether more chemotherapy is better in the case of treating advanced, recurrent, or metastatic endometrial cancer. Eleven randomized clinical trials were identified that included a total of 2,288 patients. A meta-analysis of six trials showed improved progression-free survival with more intensive chemotherapy compared with less intense chemotherapy (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.71–0.90; P = .004) but a comparable overall survival (HR = 0.90, 95% CI = 0.80–1.03; P = .12). Grade 3 and 4 toxicity, particularly in the form of myelosuppression and gastrointestinal toxicity, was higher in patients receiving more intense chemotherapy regimens. The NCCN lists carboplatin, cisplatin and palcitaxel as options for metastatic or advanced endometrial carcinoma, as single agents or combined. For clinical use, carboplatin is interchangeable with cisplatin by general consensus because of their similarity and trial evidence in a a number of cancer sites (although not in all and not in endometrial cancer). NCCN cites a variety of regimens, including ifosfamide/paclitaxel, doxorubicin/cisplatin/paclitaxel, cisplatin/dosorubicin and the single agents: cisplatin, doxorubicin, paclitaxel and ifosfamide. Cisplatin, etoposide, adriamycin is an older regimen that was found in 1995 to be superior to a melphalan based regimen. It is not currently in any trial for endometrial cancer as per clinicaltrials.gov.

NCCN, Endometrial ENDO-B, 2019

Samarnthai N, Hall K, Yeh IT. Molecular profiling of endometrial malignancies. Obstet Gynecol Int. 2010;2010:162363.

Urick, M.E., Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer 19, 510–521 (2019)

Sarah M. Temkin, MD, Gini Fleming, MD Current Treatment of Metastatic Endometrial Cancer
Cancer Control. 2009;16(1):38-45.

Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(11):2159-2166.

Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 2007;18(3):409-420.

Wolf K, Slomovitz BM. Novel biologic therapies for the treatment of endometrial cancer. Int J Gynecol Cancer. 2005;15(2):411.

J. T. Thigpen, M. F. Brady, H. D. Homesley, J. Malfetano, B. DuBeshter, R. A. Burger, and S. Liao Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study J. Clin. Oncol., October 1, 2004; 22(19): 3902 – 3908.

G. F. Fleming, V. L. Filiaci, R. C. Bentley, T. Herzog, J. Sorosky, L. Vaccarello, and H. Gallion Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study Ann. Onc., August 1, 2004; 15(8): 1173 – 1178

Cornelison TL, Baker TR, Piver MS, Driscoll DL..Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma.: Gynecol Oncol. 1995 Nov;59(2):243-8

There is limited role for chemotherapy in second line for soft tissue sarcoma, although in first line it has some effect. Fixed-dose-rate gemcitabine and docetaxel achieved high objective response rates in three prospective phase II studies as first-line or second-line therapy for advanced uterine leyomyosarcoma. In a randomized trial, the combination of gemcitabine and docetaxel was superior to gemcitabine alone in terms of objective response, progression-free, and overall survival among patients with soft-tissue sarcoma, most of whom had received at least one prior cytotoxic regimen.Currently, NCCN recommends several combinations for metastatic soft tissue sarcoma, among them Gemzar and Taxotere (SARC-E, 1). Gemcitabine and docetaxel is an acceptable combination for metastatic leiomyosarcoma but it is not proven for adjuvant therapy. There are several studies looking at this, among them: Adjuvant Docetaxel Plus Gemcitabine in Patients With Completely Resected Leiomyosarcoma (LMS) of the Uterus, NCT00614835.

Currently, NCCN recommends several combinations for metastatic soft tissue sarcoma, among them ifosfamide and adriamycin (SARC-E, 1) but for first line and there is no specific regimen for second line therapy.

A recent review found that study has shown that more than 20% of soft tissue sarcoma patients treated with second-line chemotherapy can obtain prolonged benefit for over 6 months. In addition, confirmed responses were observed in a small proportion of patients who did not respond to first-line chemotherapy.This was not a prospective phase III trial and the conclusion needs to be confirmed and replicated.

Janice N. Cormier, MD, MPH and Raphael E. Pollock, MD, PhD, Soft Tissue Sarcomas CA Cancer J Clin 2004; 54:94-109

nccn.org, sarcomas

Hensley, Martee L Update on gemcitabine and docetaxel combination therapy for primary and metastatic sarcomas Current Opinion in Oncology: July 2010 – Volume 22 – Issue 4 – p 356–361

Anna Minchom et al, Clinical Benefit of Second-Line Palliative Chemotherapy in Advanced Soft-Tissue Sarcoma. Sarcoma Volume 2010 (2010),

Revised: 9/23/11

Two randomized clinical trials have been reported that addressed the issue of second-line treatment in patients with advanced NSCLC that progresses after they have received first-line platinum-based chemotherapy. Both trials used docetaxel because this agent had shown significant activity in this patient population in single-arm phase II trials. The eligibility requirements for both trials were also very similar, resulting in similar groups of patients being entered into each trial. Patients could have received more than one previous chemotherapy regimen, but 65 to 77% of the patients entered into these studies had received only one regimen. In the trial of Shepherd et al,65 previous treatment with a taxane was also an exclusion criteria. The majority of patients had a good PS (ECOG level 0 to 1 in 75 to 83% of patients), had stage IV NSCLC (80 to 90%), and were men (72 to 82%).

The first trial compared two doses of docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) to BSC in patients who were taxane-naïve but had previously been treated with a platinum-based regimen. The original design was a two-arm trial comparing docetaxel, 100 mg/m2, to BSC. The trial was halted when a 6% death rate was noted in 49 patients secondary to febrile neutropenia. Also, a median of only two cycles of therapy was delivered. The dose of docetaxel was subsequently reduced to 75 mg/m2. At this dose, the median number of cycles delivered was four, and no febrile neutropenic deaths occurred. In an analysis of all patients, both the median survival times (chemotherapy arm, 7.0 months; BSC arm, 4.6 months) and the 1-year survival rates (chemotherapy arm, 29%; BSC arm, 19%) were significantly better for patients receiving second-line docetaxel vs those receiving BSC (p = 0.047 [log rank test]). The median survival time and the 1-year survival rate for the patients treated with docetaxel, 75 mg/m2, were 7.5 months and 37%, respectively (p = 0.003 compared to BSC). The overall response rate was 7.1%, with 42.7% of patients having disease stabilization on treatment. Clinical benefit was shown in a QOL study68 in which all QOL parameters favored the docetaxel-treated patients. Specifically, a significant reduction in pain and fatigue scale scores among the docetaxel-treated patients and a reduction in the need for narcotics, nonmorphine analgesic agents, and radiotherapy were documented in this group of patients.

The second trial randomized 373 patients who had previously received platinum-containing chemotherapy to one of the three following arms: docetaxel, 100 mg/m2; docetaxel, 75 mg/m2; or a control regimen of either vinorelbine or ifosfamide (V/I). The overall response rates were 6.7 to 10.8% among patients in the two docetaxel arms vs 0.8% among patients in the V/I arm (p < 0.05). The time to progression and the progression-free survival at 26 weeks also significantly favored patients in the two docetaxel arms. Although the median survival time was not significantly different between the groups, the 1-year survival rate was significantly greater with docetaxel, 75 mg/m2, (32%) compared to V/I (19%; p = 0.025). The 1-year survival rate for patients receiving docetaxel at 100 mg/m2 was 21%.

Several of the other new agents have been studied in the second-line setting, including paclitaxel, gemcitabine, irinotecan, and vinorelbine. In general, these trials have included small numbers of patients with variable results. Response rates have ranged from 0 to 20% and median survival rates (when reported) of 4 to 8 months. No randomized trials including these other agents exist with the exception of vinorelbine, as noted above.

A recent review recommended that patients with a good PS who are experiencing disease progression after receiving platinum-based chemotherapy should be offered second-line chemotherapy. Level of evidence, good; benefit, moderate; grade of recommendation, B.

H. Cho, Y.-B. Song, I.-S. Choi, E.-H. Cho, J.-W. Choi, Y. M. Ahn, Y. H. Roh, S.-H. Nam, and B.-S. Kim
A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in Advanced Non-Small Cell Lung Cancer
Jpn. J. Clin. Oncol., January 1, 2006; 36(1): 50 – 54.

M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S – 243S.

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;